PSY12 • Psychiatric Special Offer

Table of Contents

PSY12 • Psychiatric Special Offer

How to Receive Credit

NetCE 4 Hour Course #96472 • Obsessive-Compulsive Disorder

96472 • Obsessive-Compulsive Disorder

1. INTRODUCTION

2. EPIDEMIOLOGY

3. NATURAL HISTORY

4. DIAGNOSTIC CRITERIA

5. PATHOPHYSIOLOGY

6. DIFFERENTIAL DIAGNOSIS

7. COMORBIDITIES

8. TREATMENT

9. CONCLUSION

10. RESOURCES

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 15 Hour Course #96362 • Postpartum Depression

96362 • Postpartum Depression

1. INTRODUCTION

2. CATEGORIES OF POSTPARTUM MOOD DISORDERS

3. HISTORICAL PERSPECTIVE

4. CULTURAL PERSPECTIVE

5. RISK FACTORS

6. ETIOLOGY

7. TYPES AND SEVERITY OF POSTPARTUM DISORDERS

8. ASSESSMENT FOR POSTPARTUM DEPRESSION

9. COMPLICATIONS OF POSTPARTUM DEPRESSION

10. IMPACT ON SOCIOEMOTIONAL AND COGNITIVE DEVELOPMENT

11. STRATEGIES FOR RECOVERY

12. TREATMENT STRATEGIES

13. PREVENTIVE STRATEGIES

14. CONCLUSION

15. GLOSSARY

16. RESOURCES

17. APPENDIX

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 10 Hour Course #96962 • Opioid Use Disorder

96962 • Opioid Use Disorder

1. INTRODUCTION

2. DEFINITIONS

3. BACKGROUND

4. EPIDEMIOLOGY OF OPIOID USE DISORDER

5. CLASSIFICATION

6. OPIOID SYNTHESIS

7. PHARMACOLOGY

8. CLINICAL EFFECTS

9. SPECIFIC OPIOID DRUGS

10. NATURAL HISTORY OF OPIOID DEPENDENCE

11. PATHOPHYSIOLOGY

12. EFFECTS OF OPIOID USE DISORDER

13. OPIOID OVERDOSE

14. OPIOID WITHDRAWAL

15. LIABILITY OF ABUSE/DEPENDENCE OF LEGITIMATELY PRESCRIBED OPIOID DRUGS

16. MANAGEMENT OF OPIOID USE DISORDER

17. MANAGEMENT OF COMORBID PSYCHOPATHOLOGY

18. OPIOID USE DURING PREGNANCY

19. PROGNOSIS OF TREATMENT FOR OPIOID USE DISORDER

20. CONCLUSION

21. GLOSSARY

Works Cited

Evidence-Based Practice Recommendations Citations

PSY12 • Psychiatric Special Offer

John J. Whyte, MD, MPH

Anele Runyion, RN, MS

www.netce.com

Copyright © 2026 NetCE, All rights reserved.

PSY12 • Psychiatric Special Offer

Expiration Date: 03/20/2020

How to Receive Credit

To complete this Special Offer for continuing education credit please go to http://www.netce.com/specials in your browser.

For assistance with receiving continuing education credit, please contact us at help@netce.com.

96472 • Obsessive-Compulsive Disorder

John J. Whyte, MD, MPH

www.netce.com

Copyright © 2018 NetCE, All rights reserved.

Obsessive-compulsive disorder (OCD) is a debilitating psychiatric illness affecting approximately 2.5% of the population. Characterized by recurrent thoughts or worries (obsessions) and a strong desire to perform certain actions or activities (compulsions), OCD has a significant effect on day-to-day functioning and on quality of life. Unfortunately, OCD often goes unrecognized. Patients may hesitate to disclose their symptoms, and healthcare professionals unfamiliar with this disorder may confuse its manifestations with other psychiatric illnesses. Common comorbidities can further cloud the diagnosis. This course will discuss the epidemiology, diagnostic criteria, pathophysiology, and differential diagnosis of OCD. Then, it will review the first-line treatments, recommended duration of therapy, and options for patients who do not respond to initial therapy. Finally, it will address roles of inpatient treatment and experimental options.

Table of Contents

96472 • Obsessive-Compulsive Disorder

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. EPIDEMIOLOGY

SOCIOECONOMIC IMPACT

3. NATURAL HISTORY

4. DIAGNOSTIC CRITERIA

COMMON THEMES

INSIGHT

SUICIDE RISK

CHALLENGES TO DIAGNOSIS

OVERCOMING CHALLENGES TO DIAGNOSIS

5. PATHOPHYSIOLOGY

6. DIFFERENTIAL DIAGNOSIS

7. COMORBIDITIES

8. TREATMENT

TREATMENT GOALS

PHARMACOLOGIC THERAPY

PSYCHOLOGIC THERAPY

ADDITIONAL TREATMENT OPTIONS

9. CONCLUSION

10. RESOURCES

Works Cited

Evidence-Based Practice Recommendations Citations

96472 • Obsessive-Compulsive Disorder

Education Category. Psychiatric / Mental Health

Release Date. 05/01/2018

Expiration Date. 04/30/2021

Course Overview

Obsessive-compulsive disorder (OCD) is a debilitating psychiatric illness affecting approximately 2.5% of the population. Characterized by recurrent thoughts or worries (obsessions) and a strong desire to perform certain actions or activities (compulsions), OCD has a significant effect on day-to-day functioning and on quality of life. Unfortunately, OCD often goes unrecognized. Patients may hesitate to disclose their symptoms, and healthcare professionals unfamiliar with this disorder may confuse its manifestations with other psychiatric illnesses. Common comorbidities can further cloud the diagnosis. This course will discuss the epidemiology, diagnostic criteria, pathophysiology, and differential diagnosis of OCD. Then, it will review the first-line treatments, recommended duration of therapy, and options for patients who do not respond to initial therapy. Finally, it will address roles of inpatient treatment and experimental options.

Audience

This course is designed for healthcare professionals working with adults or adolescent patients who exhibit symptoms of obsessive-compulsive disorder.

Course Objective

The purpose of this course is to provide healthcare professionals with a basic understanding of obsessive-compulsive disorder (OCD), its clinical manifestations, and basic treatment approaches in order to facilitate optimum patient care and outcomes.

Learning Objectives

Upon completion of this course, you should be able to:

1. Review the epidemiology of obsessive-compulsive disorder (OCD).

2. Outline the diagnostic criteria and pathophysiology of OCD and possible barriers to diagnosis.

3. Describe the differential diagnosis and common comorbidities associated with OCD.

4. Discuss the use of pharmacotherapy in the management of OCD, including selection of treatment, duration, and how to address partial response or non-response.

5. Describe the use of cognitive-behavioral therapy in OCD treatment, with a focus on exposure and response prevention.

6. Identify appropriate interventions for treatment refractory OCD and experimental therapies.

Faculty

John J. Whyte, MD, MPH, is currently the Chief Medical Officer at WebMD. In this role, he leads efforts to develop and expand strategic partnerships that create meaningful change around important and timely public health issues. Previously, Dr. Whyte was the Director of Professional Affairs and Stakeholder Engagement at the FDA’s Center for Drug Evaluation and Research and the Chief Medical Expert and Vice President, Health and Medical Education at Discovery Channel, part of the media conglomerate Discovery Communications.
Prior to this, Dr. Whyte was in the Immediate Office of the Director at the Agency for Healthcare Research Quality. He served as Medical Advisor/Director of the Council on Private Sector Initiatives to Improve the Safety, Security, and Quality of Healthcare. Prior to this assignment, Dr. Whyte was the Acting Director, Division of Medical Items and Devices in the Coverage and Analysis Group in the Centers for Medicare & Medicaid Services (CMS). CMS is the federal agency responsible for administering the Medicare and Medicaid programs. In his role at CMS, Dr.Whyte made recommendations as to whether or not the Medicare program should pay for certain procedures, equipment, or services. His division was responsible for durable medical equipment, orthotics/prosthetics, drugs/biologics/therapeutics, medical items, laboratory tests, and non-implantable devices. As Division Director as well as Medical Officer/Senior Advisor, Dr. Whyte was responsible for more national coverage decisions than any other CMS staff.
Dr. Whyte is a board-certified internist. He completed an internal medicine residency at Duke University Medical Center as well as earned a Master’s of Public Health (MPH) in Health Policy and Management at Harvard University School of Public Health. Prior to arriving in Washington, Dr. Whyte was a health services research fellow at Stanford and attending physician in the Department of Medicine. He has written extensively in the medical and lay press on health policy issues.

Faculty Disclosure

Contributing faculty, John J. Whyte, MD, MPH, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Jane C. Norman, RN, MSN, CNE, PhD

Alice Yick Flanagan, PhD, MSW

James Trent, PhD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

1. INTRODUCTION

Obsessive-compulsive disorder (OCD) is a debilitating psychiatric illness affecting up to 2.5% of the population [1]. More than half (50.6%) of these cases are classified as "severe" [2]. Characterized by recurrent thoughts or worries (obsessions) and a strong desire to perform certain actions or activities (compulsions), OCD has a significant effect on day-to-day functioning and on quality of life.

Unfortunately, OCD often goes unrecognized [3]. Patients may hesitate to disclose their symptoms, and healthcare professionals unfamiliar with this disorder may confuse its manifestations with other psychiatric illnesses. Common comorbidities can further cloud the diagnosis.

This course will cover the epidemiology, diagnostic criteria, pathophysiology, and differential diagnosis of OCD. It will go on to discuss the first-line treatments, recommended duration of therapy, and options for patients who do not respond to initial therapy. Finally, it will address the role of inpatient treatment and experimental options.

2. EPIDEMIOLOGY

The exact prevalence of OCD is unknown. The National Comorbidity Survey Replication (NCS-R), a nationally representative household survey designed to assess the prevalence, severity, and comorbidity of various psychiatric disorders in the United States, found that OCD affects roughly 2.2 million American adults, or about 1% of adults in any given year [2,4]. The NCS-R researchers used criteria from the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) to make the diagnosis, based on responses to a version of the World Health Organization's Composite International Diagnostic Interview (CIDI). The Epidemiologic Catchment Area Study, conducted in the 1980s, found an OCD lifetime prevalence of 1.94% to 3.29% across five study sites [5]. This study employed lay interviewers to administer the National Institute of Mental Health Diagnostic Interview Schedule (DIS). However, the reliability of the DIS-based diagnosis is open to question; at re-interview 12 months later, only 19.2% of patients who met OCD criteria on initial interview admitted to ever having had OCD-criteria symptoms.

OCD affects men and women about equally, and the prevalence appears to be similar across races and ethnicities. The NCS-R found a median age of onset of 19 years, with about one-fifth of cases starting before 10 years of age [4]. Other studies suggest a mean age of onset between 22 and 35 years, with one-third beginning before 15 years of age [6]. Younger age at onset appears to be associated with more severe symptoms and higher rates of specific comorbidities, including attention deficit hyperactivity disorder, tic disorders, and other anxiety disorders. These patients may be less responsive to first-line pharmacologic treatment as adults [6].

SOCIOECONOMIC IMPACT

OCD can have significant effects on functioning, including work and personal relationships. It can adversely affect marriage, sexual functioning, family life, religious expression, leisure activities, and friendships [7]. Patients may avoid social situations due to embarrassment or anxiety. Carrying out compulsions may consume too much time to allow attending social events or may interfere with punctuality and efficiency at work. Several studies have shown a link between severity of OCD and decreased quality of life [8,9,10].

In 2001, the World Health Organization rated OCD among the top 20 causes of disability for people 15 to 44 years of age worldwide [11]. Studies of the costs of mental disorders are limited; however, in the mid-1990s it was estimated that lifetime indirect costs of OCD due to lost wages were $40 billion [10]. A 2008 estimate on the economic cost of OCD in the United States showed $10.6 billion in annual direct and indirect costs among those with a formal diagnosis who were in treatment [12]. This study noted that OCD had the lowest cost of all mental disorders, mainly due to the comparatively greater functionality of affected individuals and low frequency of the disorder.

3. NATURAL HISTORY

OCD tends to have a waxing and waning course. Most studies have followed patients for only a few months to years, making it difficult to draw conclusions about long-term outcomes.

Much of what is known about the course of OCD comes from a Swedish study that tracked more than 100 patients for a mean of 47 years, beginning in the mid-1950s [13]. Participants had been hospitalized for OCD between 1947 and 1953 and were examined for the study between 1954 and 1956, then again between 1989 and 1993. By the end of four decades, 83% had improved, with 20% recovering completely and 28% having minimal symptoms. Improvement was gradual in 65% and fast in only 9%; the rest had a course of improvement that was difficult to qualify. Among patients who had no symptoms at the first study examination, 37% had symptoms at the second. Conversely, among patients who did have symptoms at the first examination, only 58% had symptoms at the second.

4. DIAGNOSTIC CRITERIA

The first step in correctly diagnosing and treating OCD is understanding its definition. Although previously considered an anxiety disorder, OCD is classified as an obsessive-compulsive disorder in the fifth edition of the DSM (DSM-5) along with other related conditions, including body dysmorphic disorder, hoarding disorder, trichotillomania, and excoriation disorder. Essentially, OCD involves obsessions and/or compulsions that cause distress or interfere with functioning. The obsessions are usually associated with anxiety, and compulsions often serve to ameliorate that anxiety. People with the disorder are usually aware, at least at some point in time, that their obsessions or compulsions are not reasonable.

The DSM-5 definition of OCD is based on four criteria [14]. The first criterion is the presence of either obsessions or compulsions. Obsessions are defined by [14]:

- Recurrent and persistent thoughts, urges, or images that are experienced, at some time during the disturbance, as intrusive and unwanted and cause marked anxiety or distress in most individuals.

- The person attempts to ignore or suppress such thoughts, urges, or images, or to neutralize them with some other thought or action.

Compulsions are defined by:

- Repetitive behaviors (e.g., handwashing, ordering, checking) or mental acts (e.g., praying, counting, repeating words silently) that the individual feels driven to perform in response to an obsession or according to rules that must be applied rigidly.

- The behaviors or mental acts are aimed at preventing or reducing anxiety or distress or preventing some dreaded event or situations; however, these behaviors or mental acts are not connected in a realistic way with what they are designed to neutralize or prevent or are clearly excessive. Note: Young children may not be able to articulate the aims of these behaviors or mental acts.

Secondly, diagnosis of OCD is dependent upon disruption of day-to-day life. The obsessions or compulsions are time consuming (take more than one hour per day) or significantly interfere with the person's normal routine, occupational (or academic) functioning, usual social activities or relationships, or other important areas of functioning.

The third diagnostic criterion is that the disturbance is not due to the direct physiologic effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition.

Disease-specific manifestations are the fourth criterion. In order for OCD to be diagnosed in patients with another Axis 1 disorder, the content of the obsessions or compulsions may not be restricted to the other disorder (e.g., preoccupation with food in the presence of an eating disorder; hair pulling in the presence of trichotillomania; concern with appearance in the presence of body dysmorphic disorder; preoccupation with having a serious illness in the presence of hypochondriasis; preoccupation with sexual urges or fantasies in the presence of a paraphilia; or guilty ruminations in the presence of major depressive disorder).

The diagnosis of OCD may specify insight. At some point during the course of the disorder, the person may recognize that the obsessions or compulsions are excessive or unreasonable; this would be diagnosed as OCD with good or fair insight. If, for most of the time during the current episode, the person does not recognize that the obsessions and compulsions are excessive or unreasonable, the diagnosis is OCD with poor insight. If an individual is completely convinced that obsessions and compulsions are true or necessary, OCD with absent insight/delusional beliefs would be diagnosed.

COMMON THEMES

The DSM-5 diagnostic criteria do not specify the content of obsessions or any specific form of compulsion. However, several themes are common in OCD. These include being contaminated or spreading contamination, contracting a disease, causing harm to others, making an important mistake, committing a religious or moral sin, the possibility of committing homosexual or pedophilic acts, and being thought homosexual [6]. Common compulsions include cleaning or washing hands, checking to be sure a task was done, counting, arranging objects, confessing to sins or errors, making lists, and hoarding. Compulsions may be physical or mental, such as repeating a silent prayer.

Patients may have multiple, concomitant symptoms fitting more than one theme, and different symptoms may appear at different times. In addition, the possibility of OCD should not be dismissed merely because a patient's thoughts or behaviors do not fit these themes. Many patients will have obsessions involving other topics and compulsions with different manifestations.

INSIGHT

Most patients with OCD will have some insight into the fact that their obsessions or compulsions are not logical or reasonable. However, as noted, there is a subpopulation of patients for whom insight is absent. Lack of insight may be a manifestation of a particular bout with OCD symptoms, for example if the patient's level of anxiety overrules what, at another time, he or she might recognize as common sense. Occasionally, patients will report that they have never interpreted the fears or compulsions as less than reasonable. The actual number of patients who lack insight is unknown. In a DSM-IV field trial involving 431 patients at seven outpatient sites, 8% of participants had no insight at the time of interview and 5% had never had insight [15]. Among the 250 subjects whose obsessions involved some feared consequence, only 13% felt certain that the consequence would not occur. Twenty-six percent were mostly certain that it would occur, and 4% were certain that it would occur. Poorer insight has been linked to poorer outcomes [14].

SUICIDE RISK

Evidence Based Practice Recommendation

According to the American Psychiatric Association (APA), clinicians should understand that individuals with OCD are not immune to co-occurring disorders that may increase the likelihood of suicidal or aggressive behavior. When such co-occurring conditions are present, it is important to arrange treatments that will enhance the safety of the patient and others.

https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/ocd.pdf

Last Accessed: April 5, 2018

Strength of Recommendation: I (Recommended with substantial clinical confidence)

The risk of suicide appears to be elevated in patients with OCD compared to the population as a whole [6]. OCD symptoms and comorbid depression may be contributing factors. The precise risk of suicide is not known; in the NCS-R, the odds ratio for suicidal ideation in patients with OCD, compared to the general population, was 6.9 [16]. In the intake sample for the Brown Longitudinal Obsessive Compulsive Study, an ongoing, non-random, prospective study of the course of OCD, 52% of patients had a history of suicidal ideation and 15% had at least one suicide attempt [3]. In general, patients with OCD should be carefully evaluated for suicidal ideation and any history of suicide attempts [6].

CHALLENGES TO DIAGNOSIS

While the criteria for OCD are straightforward, research has demonstrated that the diagnosis is often missed. Among the population in the Brown Longitudinal Obsessive Compulsive Study intake, subjects first received treatment an average of more than 17 years after having their first obsessive-compulsive symptoms and 11 years after meeting the diagnostic criteria [3].

Challenges to diagnosis include patients' own reluctance to discuss symptoms. They may be embarrassed to admit to their obsessions or ashamed of the extent to which they pursue compulsions, and they may be unaware that treatment is available. The wide differential diagnosis and the fact that comorbidities are common may also serve to obscure the diagnosis.

Symptoms resembling those of OCD can appear in the absence of disease [6]. Up to 80% of healthy people have intrusive or unwanted thoughts, and about 50% may have ritualized behaviors. The same themes common in OCD can appear in these thoughts and behaviors. However, the thoughts and behaviors do not cause marked distress and do not interfere greatly with functioning.

OVERCOMING CHALLENGES TO DIAGNOSIS

Asking more than once about possible or suspected symptoms, perhaps at different visits, and making these questions part of routine history taking can help patients overcome embarrassment. Recalling that OCD can have widely varied themes, not merely the popularly recognized handwashing or counting, will help prevent missed diagnoses.

Most patients will have both obsessions and compulsions, but a small percentage will have only one or the other. In the DSM-IV field trial, about 2% of participants had mostly obsessions and 2% mostly compulsions [6]. Patients may be more troubled by obsessions, more concerned about compulsions, or equally disturbed by both.

When OCD is suspected, a thorough patient interview can both confirm the diagnosis and provide a baseline for evaluating treatment. The interview should include [6]:

- Current symptoms, including content of obsessions and manifestations of compulsions

- Effect of symptoms on functioning and quality of life

- Evaluation of safety of the patient and others

- Past psychiatric history, including any treatment

- Presence of other psychiatric symptoms

- General medical history and review of systems

- Family history, with attention to OCD and other psychiatric disorders

A physical exam is also important, both as an element of general medical care and to help establish that symptoms are not caused by an underlying neurologic problem. There are no distinctive physical signs of OCD, but an exam may reveal clues. Some patients will have chapped hands from handwashing or evidence of common comorbidities, such as skin picking or trichotillomania. However, most can be expected to have a normal physical exam.

The physical exam should include [6]:

- A mental status exam, with particular attention to thought process and content, illusions or hallucinations, suicide or homicide risk, insight, and judgment

- A neurologic exam, which may identify tics related to OCD

Screening tools are available to help evaluate the impact of OCD. One of the best-known is the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). The Y-BOCS includes two components: a symptom checklist and a severity scale. The Y-BOCS is widely used in research studies of OCD treatment, with reductions in severity used as markers of treatment success. The symptom checklist includes obsessions and both physical and mental compulsions. The severity scale is based on time spent on obsessions and compulsions, resistance to these symptoms, interference from symptoms, related distress, and level of control. Increasing numbers of points are assigned for increasing levels of impact. The scale is scored as follows:

- Mild: 8–15 points

- Moderate: 16–23 points

- Severe: 24–31 points

- Extreme: 32–40 points

Other measurement tools are also available. The Obsessive-Compulsive Inventory-Revised is a brief, self-rated scale asking about specific symptoms and degrees of distress related to them [17]. A simple visual analog scale, with symptoms rated from "none" to "incapacitating," may also be used.

Language Barriers

As a result of the evolving racial and immigration demographics in the United States, interaction with patients for whom English is not a native language is inevitable. Because patient history is such a vital aspect of the assessment of OCD, it is each practitioner's responsibility to ensure that information and instructions are explained in such a way that allows for patient understanding. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required.

In this multicultural landscape, interpreters are a valuable resource to help bridge the communication and cultural gap between clients/patients and practitioners. Interpreters are more than passive agents who translate and transmit information back and forth from party to party. When they are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers, who ultimately enhance the clinical encounter. In any case in which information regarding diagnostic procedures, treatment options, and medication/treatment measures are being provided, the use of an interpreter should be considered.

5. PATHOPHYSIOLOGY

The pathophysiology of OCD is not fully understood. A genetic component is apparent, with higher incidence in first-degree relatives of affected patients. In a meta-analysis of five family studies involving adult probands, researchers found a four-fold increase of OCD incidence among first-degree relatives [18,71]. Twin studies consistently show higher concordance of OCD in monozygotic than in dizygotic twins [19]. Concordance ranges from 47% to 50% for dizygotic to 80% to 87% for monozygotic twins [6].

Evidence Based Practice Recommendation

Patients with OCD who are parents of young children may want advice regarding the genetic risk of OCD. The APA recommends that clinicians explain to such patients that the available data indicate an increased but modest risk of OCD in the children of affected individuals; patients wanting more information may be referred to a genetic counselor.

https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/ocd.pdf

Last Accessed: April 5, 2018

Strength of Recommendation: I (Recommended with substantial clinical confidence)

While the possibility of a specific genetic etiology has been considered, none has been identified with certainty, and research is limited. A 2017 study analyzing more than 600 genes thought to be associated with OCD among humans, dogs, and mice elicited the identification of four specific genes prominent in several of those with OCD [71]. These findings are consistent and provide evidence of the current common genetic theories of OCD [71].

One theory is that a defect in neural pathways, likely including orbitofrontal-striatal circuits, may be involved, but specific pathology has not been consistently shown [20,21]. The theory posits that hard-wired primal behaviors (e.g., checking, cleaning) are exacerbated due to a hyperstimulated thalamus [22]. Imaging studies of OCD brains have found increased metabolic activity in the caudate nucleus, cingulate gyrus, and orbital frontal cortex.

One study also showed defects in neural pathways, with a hyperactivation in the connections between the structures in the cortico-striato-thalamo-cortical (CSTC) circuit, which is primarily responsible for regulating complex behaviors [71,72]. In addition, the cell-adhesion gene CTTNBP2 was one of the commonly identified genes in those with OCD, supporting the potential that neural pathways play a significant role in OCD behaviors [71]. Another 2017 study showed results similar to previous studies, with inflammation occurring in the neurocircuitry in more than 30% of participants, especially in the orbitofrontal cortex and CSTC [75].

Another hypothesis regarding the underlying cause of OCD involves serotonin. Research regarding a role for serotonin was spurred by studies of the effectiveness of antidepressants, such as clomipramine and desipramine, for OCD in non-depressed patients [20,23]. Clomipramine, which acts primarily as a serotonin reuptake inhibitor (SRI), has proved to be more effective than desipramine, which is thought to act primarily by inhibiting norepinephrine reuptake [24]. The ability of selective serotonin reuptake inhibitors (SSRIs) to reduce OCD symptoms further supports a role for serotonin abnormalities in the pathogenesis of OCD, a theory supported by the 2017 study in which a gene that includes a serotonin receptor, HTR2A, was found to be among the most commonly associated in those with OCD [71]. A specific mechanism, however, has not been elucidated, and studies involving measures of serotonergic function have been inconsistent.

An important challenge to the serotonin hypothesis is that SSRIs fail to bring significant improvement for a substantial number of patients with OCD. Other neurotransmitters, including dopamine and glutamate, are also being investigated for their influence in OCD. The 2017 study supports this, showing that two of the four genes found to have a possible association with OCD, NRXN1 and REEP3, are involved in a process that may cause OCD behaviors by creating an imbalance of excitatory glutamate and inhibitory GABAergic neuron differentiation [71].Some researchers have raised the question of whether OCD may be an immune-related disorder [25]. Exploration of this possibility began with the observation of an association between Sydenham chorea and OCD. Obsessive-compulsive symptoms have been observed in children following streptococcal infection, a condition termed pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS). However, much more research is needed to establish whether there is a significant autoimmune contribution to OCD [24].

6. DIFFERENTIAL DIAGNOSIS

The differential diagnosis of OCD is broad and includes other anxiety disorders, such as generalized anxiety disorder and post-traumatic stress disorder, as well as schizophrenia, delusional disorder, depression, Tourette syndrome, and obsessive-compulsive personality disorder (OCPD).

OCPD is characterized by preoccupation with order, perfection, and control, but not by the presence of obsessions or compulsions [15]. It is often compared to a "perfectionist" personality. Unlike OCD, symptoms must appear by early adulthood for the diagnosis to be made; however, OCD and OCPD may occur in the same person. The frequency of both diagnoses occurring together is not known, but studies suggest that it is not uncommon [26]. Estimates from OCD study populations indicate a concomitant rate between 23% and 32%, although these samples were not designed to be representative of all patients with OCD [26,73]. For comparison, the prevalence of OCPD has been observed to be about 0.9% to 2% in community samples [26,73]. There is also some evidence that OCPD is more common in people with OCD than in patients with other psychiatric disorders.

Post-traumatic stress disorder is characterized by onset in the wake of an extreme traumatic stressor. Symptoms include avoidance of stimuli associated with the trauma and persistent thoughts about the event, which may seem to resemble behaviors and obsessions seen in OCD [14]. However, the obsessions and compulsions of OCD are not related to a specific, preceding traumatic event.

Generalized anxiety disorder involves excessive anxiety and worry about feared events. Unlike OCD, the diagnostic criteria also include the presence of additional symptoms, including restlessness, a tendency to be easily fatigued, difficulty concentrating, irritability, muscle tension, and sleep disturbance [14]. Further, the anxiety in generalized anxiety disorder tends to focus on more realistic forthcoming problems and concerns.

Delusional disorder features the presence of one or more nonbizarre delusions. The content of the delusions may resemble that of an obsession in OCD; for example, a delusion that one has contracted an infection may resemble anxiety about contamination in OCD. Classically, a patient with OCD would have insight into his or her illness while a patient with delusional disorder would not; however, when insight is lacking, OCD may closely resemble delusional disorder. OCD with delusional beliefs may also superficially resemble schizophrenia. However, the additional symptoms of schizophrenia will generally be lacking.

Depression may be accompanied by intrusive, unpleasant thoughts, as in OCD, but these thoughts do not generally lead to compulsions. Depression may occur in conjunction with OCD, but OCD itself is not characterized by depressed mood and anhedonia. However, these conditions frequently co-occur, and careful evaluation is necessary [27].

Tourette syndrome is characterized by tics, which first manifest during childhood in the majority of patients. Tics in Tourette syndrome tend to be preceded by a physical sense of "needing" to do the movement, but not by anxiety about a specific outcome or the desire to avert a feared event. However, the tics may be quite complex and may even resemble compulsions, leading to diagnostic confusion in some cases.

7. COMORBIDITIES

Most studies of comorbidities in OCD are based on case series or convenience samples, making it difficult to estimate the prevalence of comorbid conditions among patients with OCD overall. Available evidence does suggest that certain psychiatric illnesses are more common among people with OCD than among the general population. In one interview-based study of 334 patients with OCD, only 8% of participants had no psychiatric comorbidity [28]. In the Brown Longitudinal Obsessive Compulsive Study intake, 91% of subjects had at least one other Axis 1 disorder [3].

Depression is a particularly common comorbidity. A chart review of 120 patients with OCD in the Netherlands found depression in one-third, and a separate structured psychiatric interview found similar results (31%) for major depression [29,74]. The Epidemiologic Catchment Area Study in the United States found 67% of individuals identified as having OCD had at least one episode of major depression [27]. In addition, OCD has been shown to comorbidly occur with social phobia (11%), simple phobia (including body dysmorphic disorder) (7%), and panic disorder (6%). Associations have also been observed between OCD and other conditions, including bipolar disorder, eating disorder, generalized anxiety disorder, alcohol dependence/substance abuse, and Tourette syndrome [6,30]. Richter and colleagues looked at patients with OCD, social anxiety disorder, or panic disorder and found that trichotillomania, skin picking, body dysmorphic disorder, and tics were more strongly associated with OCD than with the other two anxiety disorders [31].

In addition to considering other psychiatric diagnoses in the setting of OCD, clinicians should be alert for OCD symptoms in patients who have already been diagnosed with a different psychiatric illness. For example, eating disorders are often accompanied by anxiety disorders, including OCD. One survey showed the comorbid rate of eating disorder and OCD to be roughly 8% [74]. OCD is also common in patients with Tourette syndrome. One large international registry found that 27% of people with Tourette syndrome also had OCD, and other studies have found percentages ranging from 28% to 62% [6,32,33,34]. A separate study showed that of patients with OCD, approximately 5% will have comorbid Tourette syndrome [74].

8. TREATMENT

In the 2008 Practice Guideline for the Treatment of Patients with Obsessive-Compulsive Disorder, the American Psychiatric Association (APA) recommends two options for first-line therapy, either alone or in combination: SRIs and cognitive-behavioral therapy (CBT) [6].

Five SRIs are approved by the U.S. Food and Drug Administration (FDA) for OCD treatment, including four SSRIs and one serotonin-specific tricyclic antidepressant (TCA):

- Fluoxetine

- Fluvoxamine

- Paroxetine

- Sertraline

- Clomipramine

Two other SSRIs also appear to be effective, although they do not have an indication for OCD:

- Citalopram (approved for depression)

- Escitalopram (approved for depression and generalized anxiety disorder in the United States; approved for OCD in Europe)

All of the SSRIs are recommended as options for first-line therapy by the APA. Pharmacologic therapy is also recommended for those patients whose symptoms may be exacerbated by CBT or when access to a mental healthcare professional is unavailable and severe symptoms are present [76]. Specific aspects of these medications, including efficacy and side effects, will be discussed further in this course.

The form of CBT most commonly studied in OCD involves exposure and response prevention. Exposure and response prevention consists of talk therapy and specific exercises designed to reduce anxiety and dampen the need to perform compulsions. Unless otherwise specified, "CBT" will be used in this course to refer to forms of therapy that incorporate exposure and response prevention.

CBT should be initiated and monitored by a professional trained in this specific mode of treatment. The exercises often can and should be done by the patient at home, which requires a strong level of commitment. Patients who experience too much anxiety to do the exercises or are not willing to accept this form of participatory treatment may be better candidates for pharmacotherapy, at least as the first step.

Overall considerations for selecting pharmacotherapy or CBT include:

- Patient choice

- Failure of prior attempt with the other option

- Willingness to take medication

- Willingness to do the work of CBT

Another form of CBT commonly used is Internet-based self- or professional-guided therapy. This form of treatment may be beneficial for those in rural areas or whose behaviors make them resistant to seek traditional face-to-face treatment [76].

Whether SRIs, CBT, or their combination are more effective has not been widely studied. One meta-analysis suggested SRIs and CBT are equally effective, but the authors concluded that there was not enough evidence to draw a firm conclusion [35]. There also appears to be a benefit to combining SRI and CBT in some patients, although possibly not all. In addition, there is some limited evidence that CBT, alone or in combination with medication, may lead to lower symptom severity after treatment is discontinued [36,37]. The APA recommends combining treatments for patients who do not respond adequately to monotherapy, who wish to limit the duration of SRI use, who have comorbidities that will benefit from SRIs, or who have severe OCD [6].

In 2008, Simpson and colleagues conducted a randomized controlled trial to examine the effects of augmenting SRIs with exposure and ritual prevention [36]. Participants were 108 adult outpatients with OCD. All had been taking an SRI at a therapeutic dose for at least 12 weeks prior to entry but still had a Y-BOCS total score of 16 or greater. The patients were provided with 17 biweekly sessions of CBT, either an OCD-specific program of exposure and ritual prevention or a control setting of stress management training, while still continuing the SRI. After eight weeks, patients receiving the exposure and response prevention sessions were more likely to have at least a 25% decrease in severity on the Y-BOCS scale. They were also more likely to have achieved a Y-BOCS score of 12 or less.

In 2011, the Pediatric OCD Treatment Study II (POTS II) compared SRI therapy combined with 14 one-hour CBT sessions over 12 weeks to both medication alone and medication plus CBT instructions given at in-person medication management visits [38]. Each of the three study groups consisted of 42 patients, and the measure for success was 30% improvement in initial Y-BOCS score over the 12-week study period. The success rate of combination SRI and CBT (68.8%) was twice as high as either SRI plus instruction (34%) or medication alone (30%) [38].

TREATMENT GOALS

Evidence Based Practice Recommendation

Because the patient's beliefs about the nature of the illness and its treatments will influence adherence, the APA asserts that providing patient and family education may enhance adherence to treatment.

https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/ocd.pdf

Last Accessed: April 5, 2018

Strength of Recommendation: II (Recommended with moderate clinical confidence)

Unfortunately, OCD is a difficult disease to fully cure. Some patients will achieve full remission, but many will retain at least some obsessive or compulsive symptoms. In most cases, the goal is to allow the patient to return to normal or near-normal functioning, including the ability to work and to have healthy and satisfying social relationships. Elements of this process include decreasing the frequency and severity of symptoms and helping the patient to cope with residual disease. Discussing with patients the possibility that medication or CBT may not make OCD disappear entirely can help avoid disappointment and frustration.

Improvement in OCD often occurs slowly, requiring months-long medication trials and/or many weeks or months of CBT. Patients may also need extra time to consider their treatment options, especially if their symptoms include "doubting," as they may doubt their ability to make the right decision.

PHARMACOLOGIC THERAPY

When pharmacologic therapy is selected as first-line treatment, the APA recommends beginning with an SSRI instead of clomipramine, due to the better safety profile of the SSRIs [6]. Choice of SSRI should be individualized and should include consideration of [6]:

- Drug-specific side effects

- Drug-drug interactions

- Comorbidities

- Past response

Some have suggested that the response of first-degree relatives to a specific medication may indicate an increased chance for response. Additional research is necessary before a recommendation may be made.

Studies suggest that approximately 40% to 60% of patients will have a clinically useful response to SRIs, with about a 20% to 40% decrease in symptoms [39,76]. Data on long-term improvement is limited. In a 3-year prospective follow-up study, Catapano and colleagues studied outcomes in 79 Italian patients with OCD treated with SSRIs [40]. Some patients also received augmented therapy with low doses of neuroleptics. They found a 65% probability of achieving at least partial remission and a 38% probability of achieving full remission. However, the rate of relapse was 60%. Worse outcomes were predicted by greater severity of illness, longer duration, and comorbid schizotypal personality disorder. In a systematic review of 17 studies involving 3,097 participants, researchers examined the efficacy and adverse effects of SSRIs versus placebo for the treatment of OCD [41]. They found that SSRIs were more effective than placebo in achieving clinical response at six and 13 weeks post-treatment. The pooled relative risk was similar between individual SSRI drugs. Nausea, headache, and insomnia were the most commonly reported adverse effects in each of the studies. The long-term efficacy and tolerability of SSRIs for OCD has yet to be established [41].

Clomipramine

Clomipramine is a TCA with multiple actions, including significant activity as a serotonin reuptake inhibitor. It was the first medication approved in the United States for treatment of OCD [42]. Some studies have suggested that clomipramine is more effective than the SSRIs, but others have found equal effectiveness or more improvement with an SSRI [42,77]. Due to serious adverse effects, a high daily dose of clomipramine is not advised unless SSRI monotherapy is not adequate to control OCD behaviors [77]. In addition, clomipramine may be used as combination therapy with an SSRI to receive the benefits of the TCA without the problematic side effects of higher doses of the drug [77]. Concurrent use of clomipramine and fluoxetine is not advised, as fluoxetine inhibits the metabolism of clomipramine in the liver, creating high serum levels of clomipramine [77].

Clomipramine does have a higher potential for adverse effects than the SSRIs, particularly if used in combination with an SSRI [43]. Anticholinergic side effects are common, and overdose can lead to cardiac arrhythmias, seizures, hypotension, and death [44]. Risks of arrhythmogenic effects, cardiotoxicity, and seizure are concerns at doses greater than the maximum dose of 250 mg/day, and electrocardiograph monitoring is recommended for continued high dosages [77].

SSRIs

The use of each SSRI in OCD is supported by placebo-controlled trials. Although available evidence suggests that efficacy is similar across this class of drugs, no trials have compared all the SSRIs under controlled conditions [42]. Thus, their actual relative efficacy is unknown. Further, different trials have used different definitions for response, making comparisons difficult.

Paroxetine

A multinational, double-blind, 12-week trial conducted by Zohar and colleagues compared flexible-dose paroxetine, 20–60 mg daily, to placebo [45]. Response was defined as a 25% decrease in the Y-BOCS score. Response rates were 55% for paroxetine and 35% for placebo.

Hollander and colleagues compared paroxetine 20 mg, 40 mg, or 60 mg per day to placebo in a 12-week, double-blind trial [46]. Response was considered to be a decrease of 25% in the Y-BOCS score or a decrease in Clinical Global Impression-Severity (CGI-S) score of two points or more. Response rates were 25% for the 40-mg dose, 29% for the 60-mg dose, and 13% for placebo. Improvement with the 20-mg dose was not statistically significant compared to placebo.

Another trial supports effectiveness in a Japanese population. In a 12-week, double-blind trial, Kamijima and colleagues compared flexible-dose paroxetine, starting at 20 mg and titrating to as high as 50 mg per day, to placebo [47]. Response rates were significantly higher for paroxetine.

Fluvoxamine

The largest study of fluvoxamine was conducted by Hollander and colleagues [48]. This double-blind, 12-week trial involved 253 subjects and identified two response levels: a 35% or 25% reduction in the Y-BOCS score. Response at both levels was significantly higher for the treatment group compared to the placebo group. Remission rates were also significantly higher: 44% versus 31% for a Y-BOCS score of 16 or less, and 18% versus 8% for a Y-BOCS score of 8 or less.

Two pivotal trials for fluvoxamine in OCD found that after 10 weeks of treatment, Y-BOCS scores decreased significantly more in the fluvoxamine group compared to the placebo group. Among patients who received one or more post-baseline ratings, the mean Y-BOCS score decreased by 21% in patients who received fluvoxamine and 7% in patients who received placebo [6].

Sertraline

A placebo-controlled trial of flexibly dosed sertraline for OCD was published by Kronig and colleagues in 1999 [49]. The trial involved 167 patients, with treatment for 12 weeks and doses ranging from 50–200 mg. The treatment group had significantly greater improvement on Y-BOCS scores, and significantly more sertraline patients showed a therapeutic response according to Clinical Global Impression-Improvement (CGI-I) scores (41% versus 23%).

An earlier trial, published by Greist and colleagues in 1995, compared different doses of sertraline in 325 patients [50]. Patients were randomized to 50 mg, 100 mg, or 200 mg per day for 12 weeks, and were assessed using the Y-BOCS, the National Institute of Mental Health Global Obsessive Compulsive Scale (NIMH-GOCS), CGI-S and CGI-I, and the Maudsley Obsessive Compulsive Inventory. Overall, patients using sertraline did better than those prescribed placebo on all measures. The 50-mg and 200-mg groups also did better than placebo on all of the investigator-related scales, although the 100-mg group was better only on the NIMH-GOCS.

Fluoxetine

The largest trials of fluoxetine for OCD were published in the mid-1990s. Montgomery and colleagues followed 214 patients over eight weeks of treatment with daily fluoxetine doses of 20 mg, 40 mg, or 60 mg, or placebo [51]. At the 40-mg and 60-mg doses, the response rates, defined as a decrease in the Y-BOCS total score of at least 25% and a CGI-I rating of "much improved" or "very much improved," were significantly higher with fluoxetine than with placebo. Response rate was 47% at the 60-mg dose, 48% at the 40-mg dose, and 26% with placebo.

Tollefson and colleagues studied 355 patients over 13 weeks, again comparing fluoxetine doses of 20 mg, 40 mg, 60 mg, or placebo [52]. At all doses, there was significant improvement on Y-BOCS scores compared to placebo.

Citalopram

Citalopram is the most serotonin-selective of the SSRIs. Although it does not have an FDA-approved indication for OCD, it is included as an equivalent option to the other SSRIs in the APA guideline [6].

Montgomery and colleagues tested different doses of citalopram against placebo in 401 patients with OCD over 12 weeks, with "improvement" considered to be a 25% reduction in baseline Y-BOCS scores [53]. The percentage of patients who reached this endpoint was significantly higher in the treatment groups: 65% of subjects at 60 mg per day, 52% at 40 mg per day, and 57% for 20 mg per day, compared to 37% of subjects receiving placebo. The differences between the individual doses of citalopram were not statistically significant.

In 2011, the FDA issued a warning advising patients and prescribers that citalopram should no longer be used at a dosage greater than 40 mg due to risk of potentially fatal abnormal heart rhythms, including torsades de pointes and should not be used in patients with factors predisposing them to either of those conditions [54]. Additionally, doses of 60 mg per day have not been found to have reasonable benefit over doses of 40 mg per day [54,78]. In 2012, a revised warning was issued to clarify that citalopram is "not recommended" rather than "contraindicated" in those with congenital long QT interval syndrome, should not be used at doses greater than 20 mg per day in patients older than 60 years of age, and should be discontinued in patients with a QTc measurement greater than 500 ms [78].

Escitalopram

Escitalopram, an enantiomer of citalopram, is also not FDA approved for OCD. Like citalopram, it is included with the other SSRIs as an option in the APA recommendations [6].

A 24-week, double-blind, randomized trial, conducted by Stein and colleagues, showed a benefit of escitalopram over placebo in OCD [55]. Escitalopram at both 10 mg and 20 mg per day was superior to placebo on multiple measures, including remission at 12 weeks, defined as a Y-BOCS score of 10 or less. At 24 weeks, remission was significantly greater than placebo for escitalopram 10 mg per day, although only numerically greater than placebo for the 20-mg dose.

SRIs in OCD

Although clomipramine and the SSRIs are also used to treat depression, their use in OCD has somewhat different parameters. Patients with OCD may require higher doses, and the onset of action may be slower. In depression, improvement may be expected as early as one week after initiating treatment. The APA guideline for the treatment of major depressive disorder recommends re-evaluating treatment if at least moderate improvement has not occurred after six to eight weeks [6]. In OCD, a full trial of SRI therapy takes 8 to 12 weeks, including 4 to 6 weeks on the highest tolerable dose [77].

Starting at a low dose of an SRI helps to avoid side effects, including nausea, diarrhea, drowsiness, and headache. Many pills can be split, and some SRIs are available in liquid formulations that allow for even more flexible titration schedules. Usual doses of SRIs in OCD are provided in the APA guideline and updated manufacturer labeling (Table 1).

Table 1: ADULT DOSING OF SSRIs FOR THE TREATMENT OF OCDa

SSRI

Starting and Incremental Dose

Usual Target Dose

Usual Maximum Dose

Occasionally Prescribed Maximum Dose

Citalopram

20 mg

40 mgb

40 mgb

40 mgb

Escitalopram

10 mg

10–20 mg

40 mg

60 mg

Fluoxetine

20 mg

40–60 mg

80 mg

120 mg

Fluvoxamine

50 mg

100–300 mg

300 mg

450 mg

Paroxetine

20 mg

20–60 mg

60 mg

100 mg

Sertraline

50 mg

200 mg

200 mg

400 mg

aDosages are for immediate-release formula, not controlled-release.

bMaximum dose: 40 mg

Source: [6,56]

Side Effects

Many patients will tolerate SSRIs well, but for some, side effects can be significant. Some side effects, including nausea, agitation, and sleep disturbances, commonly occur when the medication is first started and disappear over the first few weeks to months. Explaining this to patients can help to encourage them to continue the medication, with the understanding that other options are available should the side effects fail to subside.

In some cases, lowering the dose, changing the timing of doses, or changing to a different SRI will help to alleviate side effects; in others, adding an additional medication may be helpful [6]. Some side effects are particularly likely with certain SSRIs. For example, paroxetine is the most anticholinergic and appears to be more likely to cause weight gain than other SSRIs. Insomnia may be addressed by taking the SSRI in the morning instead of the evening or by the addition of a sleep-promoting agent. Modafinil may help with fatigue. Excessive diaphoresis may be improved by the addition of a low-dose anticholinergic.

Sexual symptoms, including decreased libido and difficulty with orgasm, may be difficult to overcome, but there are options that will work for some patients. In some cases, sexual symptoms will decrease over time. Some patients may be willing to wait until OCD symptoms have improved and weaning from the SSRI is appropriate. Some may benefit from a "drug holiday" up to once per week, stopping the SSRI for one day before a sexual encounter. In general, stopping an SSRI abruptly is not recommended due to the possibility of withdrawal effects, but with most of the SSRIs, missing one dose is not expected to affect outcomes adversely. The short half-life of paroxetine makes it a poor choice for this technique, and the half-life of fluoxetine may be too long for the one-day "holiday" to be useful.

SSRIs and clomipramine carry a warning from the FDA regarding a possible increased risk of suicidality in children, adolescents, and young adults [56]. Patients should be closely monitored for suicidality throughout therapy, particularly when beginning treatment or altering the dose.

Partial Response and Non-Response

As noted, the APA recommends a trial of at least 8 to 12 weeks with a given SRI, including at least four to six weeks at the highest tolerable dose [6]. For patients who fail to achieve a reduction in symptoms by the end of this time or who have only minimal response, there are several APA-recommended options [6]. One strategy is to offer a trial of a different SSRI. It may take multiple trials to find the right match for a given patient. Additional options include switching to clomipramine, switching to the serotonin-norepinephrine reuptake inhibitor venlafaxine, or adding a second-generation antipsychotic. Switching to mirtazapine is also offered as a strategy, although supporting evidence is limited. Switching to venlafaxine may be less effective than switching to a different SRI.

Some patients will be partial responders to SSRIs, with symptoms improving but still having a significant impact on functioning. For these patients, the APA recommends continuing the pharmacotherapy but augmenting it with either a second-generation antipsychotic or CBT. Antipsychotics alone have not proven useful in OCD. However, there is some evidence to support their use to augment SRI therapy, with response rates of about 40% to 55% [6]. Unfortunately, the details of best use, including dose, duration, and subsets of patients who may benefit most, have not yet been established.

Duration of Treatment

The best duration for pharmacotherapy in OCD has not been determined. A minimum of one to two years has been recommended before withdrawal should be considered [6,57]. The decision to continue or to stop medication should be individualized and discussed with each patient.

As noted, neither SSRIs nor clomipramine should be stopped abruptly. Instead, these medications should be tapered slowly, decreasing by 10% to 25% every one to two months [6]. Sudden discontinuation can lead to a drug discontinuation syndrome, with symptoms that may include nausea and vomiting, headache, dizziness, insomnia, and agitation or lethargy. Patients may also experience paresthesias or myoclonic jerks.

PSYCHOLOGIC THERAPY

Of all potential psychologic therapies for OCD, CBT is supported by the best evidence. Most studies have used some form of exposure and response prevention as the mode of therapy, with variations in frequency, intensity, and guidance. These studies have generally been small, with at most a few dozen patients. One larger, multisite trial compared exposure and response prevention to clomipramine, placebo, or a combination of the two treatments [58]. This study involved intensive, daily exposure and response prevention for four weeks, followed by maintenance sessions for another eight weeks. Overall, 71% of the 122 randomized patients completed treatment. Response rates at week 12, measured as improvement on the Y-BOCS, CGI-S, and NIMH-GOCS, were all significantly better for exposure and response prevention than for clomipramine. Exposure and response prevention plus clomipramine was not significantly better than exposure and response prevention alone. Based on the CGI-I measure, an "excellent" response was seen more often in the exposure and response prevention group and in the combination group than in the clomipramine-alone group.

Another large trial, involving 218 patients, compared two different techniques for exposure and response prevention to a control group [59]. One group received weekly instruction by therapists on performing exposure and response prevention techniques at home. The second group used a workbook and a computer program. The controls received relaxation training. In an intent-to-treat analysis, both the therapist-guided and computer-guided exposure and response prevention sessions were significantly superior to the control therapy, and the therapist-guided therapy was significantly more effective than the computer sessions.

In 2007, a Cochrane review compared psychologic treatment for OCD with "treatment as usual" [60]. Eight relevant studies, all randomized trials, were identified, and in each one, patients on a waiting list were used as the controls. In all but one of the studies, some patients also received pharmacologic treatment. Study treatment duration ranged from six to 20 weeks. Patients receiving any type of CBT were found to have significantly fewer symptoms following treatment, with overall effect being influenced by baseline severity. The authors recommended further study to identify the best forms of CBT, predictors of response, and cost-effectiveness.

Not all patients will be able to complete a course of CBT. For some, the commitment level is too high. For others, the anxiety induced by facing or thinking about the feared objects or events is simply too strong. An estimated 22% to 30% of patients can be expected to drop out or refuse to comply with exposure and response prevention therapy [61]. For these patients, Internet-based self- or professional-guided therapy may be a beneficial alternative [76].

Some patients who are willing and able to attempt CBT will be stymied by insurance constraints. For these patients, and with appropriate guidance, self-help in the form of workbooks and exercises to be done at home is an option. However, as experienced in the POTS II trial, CBT instruction-only response rates are likely much lower than that of weekly CBT sessions [38].

Techniques for CBT

Exposure and response prevention consists of a specific series of techniques. It may be offered as individual therapy or in a group setting. The APA recommends at least weekly sessions [6].

Exposure and response prevention is based on the idea that obsessions and compulsions serve to reinforce one another [62,63]. The obsessions are associated with great anxiety; because compulsions serve to reduce that anxiety, the performance of these behaviors is reinforced with each cycle. At the same time, the use of ritualized behaviors to combat anxiety prevents the development of other methods of coping with the anxious feelings. Thus, repeated exposure to a feared stimulus while avoiding the use of ritualized behavioral responses should, over time, lead to a dampening of the anxiety response and a lessening of the need to perform compulsions. Exercises generally start with exposure to a situation that causes a moderate level of anxiety and progress to exposures that are more intensely feared. Patients are encouraged to think about the feared consequences of not performing their rituals. At the same time, they are asked to abstain from these ritualistic behaviors and encouraged to develop alternative ways of tolerating and overcoming anxiety. When exposure and response prevention is successful, patients gradually become accustomed to the idea that feared outcomes are unlikely to happen even though rituals are not performed.

Recommended Duration of CBT

There is no strong evidence to support a given duration of CBT. However, the consensus, according to the APA guideline, is for an initial course of 13 to 20 weeks of weekly CBT or three weeks of daily sessions [6]. If treatment is successful, it may be tapered to monthly sessions for another three to six months. Some patients will benefit from occasional booster sessions as well. The APA recommends ongoing maintenance, although details are not specified [6]. The exact probability of relapse following CBT is unclear.

Patients who have not achieved benefit after an initial course of CBT should be re-evaluated. Lack of compliance with treatment may be a barrier to success, and reasons for noncompliance should be explored and, if possible, addressed. Some patients may require a longer duration of therapy. For partial responders, the APA recommends a trial of an SSRI to accompany CBT [6]. Other options include increasing the intensity of treatment or adding cognitive therapy to exposure and response prevention, although the effectiveness of these choices has not been established.

ADDITIONAL TREATMENT OPTIONS

Some patients will fail to respond to both standard pharmacologic options and to outpatient CBT. Others will achieve a partial response but remain unable to return to a satisfactory level of functioning. A subset of patients will be so disabled by symptoms that they are unable to participate in standard outpatient treatment. These patients should generally be referred to specialty psychiatric care, preferably to a physician with expertise in OCD.

One option for patients with severe OCD is inpatient therapy. Highly structured, intensive outpatient treatment may also be beneficial. Treatment-refractory patients may benefit from the use of other medications added to standard pharmacotherapy or from monotherapy with drugs other than SRIs. Limited evidence suggests that patients who are not helped by oral SRIs may benefit from oral morphine, IV clomipramine, IV citalopram, combinations of antidepressants, or other therapies; however, more research is needed to determine efficacy and identify appropriate use [24,64,65].

Several other experimental treatments have been investigated. Cingulotomy, anterior capsulotomy, subcaudate tractotomy, limbic leucotomy, and deep brain stimulation may have benefit for select patients with severe OCD who do not respond to less invasive treatment [22,66]. However, best practice for these procedures has not been established, and the risk of serious adverse effects, including seizures, apathy, and executive dysfunction, must be weighed carefully against the potential benefit. There is conflicting evidence for transcranial magnetic stimulation (TMS), with some trials showing improvement while others show no effect. A 2003 Cochrane review concluded that there was too little evidence to draw conclusions about the usefulness of this treatment [67]. More recent analyses confirm that additional research, using large controlled trials, is needed to determine the usefulness of TMS for the treatment of OCD [68,69,70].

9. CONCLUSION

OCD is a potentially debilitating illness that affects work, interpersonal relationships, and overall quality of life. In spite of straightforward criteria, evidence shows that the diagnosis is frequently missed. Varied presentations, comorbidities, and patients' own hesitation to discuss symptoms can cloud the diagnosis. Physicians must be familiar with the diagnostic criteria and with the variations in presentation in order to identify patients with OCD.

First-line therapies for OCD will relieve symptoms in some patients and provide partial improvement in others; however, some patients will prove to have illness that is refractory to established treatments. Changing or augmenting therapy, as according to recommendations in the APA guideline, can be helpful when initial therapy provides only partial improvement or no improvement at all. Patients with severe or treatment-refractory OCD should generally be referred to specialty care.

Although treating OCD can be challenging, recognition and appropriate care of this disorder can help a great many patients, reducing or even eliminating disability and improving their overall quality of life.

10. RESOURCES

American Psychiatric Association

https://www.psychiatry.org

Medical specialty society concerned with ensuring humane care and effective treatment for all persons with mental disorders.

American Psychological Association

http://www.apa.org

An association of professional psychologists actively involved in basic psychologic research, applied research, and the treatment of psychologic and mental disorders.

Anxiety and Depression Association of America

https://adaa.org

National nonprofit organization including clinicians, researchers, and consumers concerned with informing the public, healthcare professionals, and media about anxiety disorders.

Association for Behavioral and Cognitive Therapies

http://www.abct.org

An interdisciplinary organization for the scientific study of problems that may be treated by behavioral and/or cognitive therapies.

Behavioral Health Treatment Services Locator

https://findtreatment.samhsa.gov

A service of the Substance Abuse and Mental Health Services Administration, part of the U.S. Department of Health and Human Services, that provides a listing of local mental health services throughout the United States and its territories.

National Institute of Mental Health

https://www.nimh.nih.gov

A division of the National Institutes of Health, a component of the U.S. Department of Health and Human Services, with the goal of improving the understanding and treatment of mental illnesses through basic and clinical research.

International OCD Foundation

https://iocdf.org

International not-for-profit organization offering education and support to people with OCD and supporting medical research and education about OCD and related disorders.

Works Cited

1. Pittenger C, Bloch MH. Pharmacological treatment of obsessive-compulsive disorder. Psychiatr Clin North Am. 2014;37(3):375-391.

2. National Institute of Mental Health. Obsessive Compulsive Disorder. Available at https://www.nimh.nih.gov/health/statistics/obsessive-compulsive-disorder-ocd.shtml. Last accessed March 27, 2018.

3. Pinto A, Mancebo MC, Eisen JL, Pagano ME, Rasmussen SA. The Brown Longitudinal Obsessive Compulsive Study: clinical features and symptoms of the sample at intake. J Clin Psychiatry. 2006;67(5):703-711.

4. Kessler RC, Chiu WT, Demler O, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication (NCS-R). Arch Gen Psychiatry. 2005;62(6):617-627.

5. Nelson E, Rice J. Stability of diagnosis of obsessive-compulsive disorder in the Epidemiologic Catchment Area Study. Am J Psychiatry. 1997;154(6):826-831.

6. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Obsessive-Compulsive Disorder. Arlington, VA: American Psychiatric Association; 2007.

7. Norberg MM, Calamari JE, Cohen RJ, Riemann BC. Quality of life in obsessive-compulsive disorder: an evaluation of impairment and a preliminary analysis of the ameliorating effects of treatment. Depress Anxiety. 2008;25(3):248-259.

8. Eisen JL, Mancebo MA, Pinto A, et al. Impact of obsessive-compulsive disorder on quality of life. Compr Psychiatry. 2006;47(4):270-275.

9. Huppert JD, Simpson HB, Nissenson KJ, Liebowitz SR, Foa EB. Quality of life and functional impairment in obsessive-compulsive disorder: a comparison of patients with and without comorbidity, patients in remission, and healthy controls. Depress Anxiety. 2009;26(1):39-45.

10. Hollander E, Kwon JH, Stein DJ, et al. Obsessive-compulsive and spectrum disorders: overview and quality of life issues. J Clin Psychiatry. 1996;57(Suppl 8):3-6.

11. World Health Organization. The World Health Report 2001—Mental Health: New Understanding, New Hope. Available at http://www.who.int/whr/2001/en/. Last accessed March 27, 2018.

12. Eaton WW, Martins SS, Nestadt G, Bienvenu OJ, Clarke D, Alexandre P. The burden of mental disorders. Epidemiol Rev. 2008;30:1-14.

13. Skoog G, Skoog I. A 40-year follow-up of patients with obsessive-compulsive disorder. Arch Gen Psychiatry. 1999;56(2):121-132.

14. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Washington, DC: American Psychiatric Publishing, Inc.; 2013.

15. Foa EB, Kozak MJ, Goodman WK, Hollander E, Jenike MA, Rasmussen SA. DSM-IV field trial: obsessive-compulsive disorder.Am J Psychiatry. 1995;152(1):90-96.

16. Borges G, Angst J, Nock MK, et al. Risk factors for twelve-month suicide attempts in the National Comorbidity Survey Replication (NCS-R). Psychol Med. 2006;36(12):1747-1757.

17. Foa EB, Huppert JD, Leiberg S, et al. The Obsessive-Compulsive Inventory: development and validation of a short version. Psychol Assess. 2002;14(4):485-496.

18. Hettema JM, Neale MC, Kendler KS. A review and meta-analysis of the genetic epidemiology of anxiety disorders. Am J Psychiatry. 2001;158(10):1568-1578.

19. Kim SJ, Kim CH. The genetic studies of obsessive-compulsive disorder and its future directions. Yonsei Med J. 2006;47(4):443-454.

20. Stein DJ, Lochner C. Obsessive-compulsive spectrum disorders: a multidimensional approach. Psychiatr Clin North Am. 2006;29(2):343-351.

21. Menzies L, Chamberlain SR, Laird AR, Thelen SM, Sahakian BJ, Bullmore ET. Integrating evidence from neuroimaging and neuropsychological studies of obsessive-compulsive disorder: the orbitofrontal-striatal model revisited. Neurosci Behav Rev. 2008;32(3):525-549.

22. Stanford Medicine. Understanding Obsessive-Compulsive and Related Disorders. Available at http://ocd.stanford.edu/about/understanding.html. Last accessed March 27, 2018.

23. Gentile S. Efficacy of antidepressant medications in children and adolescents with obsessive-compulsive disorder: a systematic appraisal. J Clin Psychopharmacol. 2011;31(5):625-632.

24. Stein DJ. Obsessive compulsive disorder. Lancet. 2002;360(9330):397-405.

25. Kurlan R, Johnson D, Kaplan EL; Tourette Syndrome Study Group. Streptococcal infection and exacerbations of childhood tics and obsessive-compulsive symptoms: a prospective blinded cohort study. Pediatrics. 2008;121(6):1188-1197.

26. Coles ME, Pinto A, Mancebo MC, Rasmussen SA, Eisen JL. OCD with comorbid OCPD: a subtype of OCD? J Psychiatr Res. 2008;42(4):289-296.

27. Dunner DL. Management of anxiety disorders: the added challenge of comorbidity. Depress Anxiety. 2001;1392):57-71.

28. LaSalle VH, Cromer KR, Nelson KN, Kazuba D, Justement L, Murphy DL. Diagnostic interview assessed neuropsychiatric disorder comorbidity in 334 individuals with obsessive compulsive disorder. Depress Anxiety. 2004;19(3):163-173.

29. Overbeek T, Schruers K, Vermetten E, Griez E. Comorbidity of obsessive-compulsive disorder and depression: prevalence, symptom severity, and treatment effect. J Clin Psychiatry. 2002;63(12):1106-1112.

30. Ivarsson T, Melin K, Wallin L. Categorical and dimensional aspects of co-morbidity in obsessive-compulsive disorder (OCD).Eur Child Adolesc Psychiatry. 2008;17(1):20-31.

31. Richter MA, Summerfeldt LJ, Antony MM, Swinson RP. Obsessive-compulsive spectrum conditions in obsessive-compulsive disorder and other anxiety disorders. Depress Anxiety. 2003;18(3):118-127.

32. Freeman RD, Fast DK, Burd L, Kerbeshian J, Robertson MM, Sandor P. An international perspective on Tourette syndrome: selected findings from 3,500 individuals in 22 countries. Dev Med Child Neurol. 2000;42(7):436-447.

33. Ferrão YA, Miguel E, Stein DJ. Tourette's syndrome, trichotillomania, and obsessive-compulsive disorder: how closely are they related? Psychiatry Res. 2009;170(1):32-42.

34. Lombroso PJ, Scahill L. Tourette syndrome and obsessive-compulsive disorder. Brain Dev. 2008;30(4):231-237.

35. Kobak KA, Greist JH, Jefferson JW, Katzelnick DJ, Henk HJ. Behavioral versus pharmacological treatments of obsessive compulsive disorder: a meta-analysis. Psychopharmacology. 1998;136(3):206-216.

36. Simpson HB, Foa EB, Liebowitz MR, et al. A randomized, controlled trial of cognitive-behavioral therapy for augmenting pharmacotherapy in obsessive-compulsive disorder. Am J Psychiatry. 2008;165(5):621-630.

37. Freyer T, Klöppel S, Tüscher O, et al. Frontostriatal activation in patients with obsessive-compulsive disorder before and after cognitive behavioral therapy. Psychol Med. 2011;41(1):207-216.

38. Franklin ME, Sapyta J, Freeman JB, et al. Cognitive behavior therapy augmentation of pharmacotherapy in pediatric obsessive-compulsive disorder: the Pediatric OCD Treatment Study II (POTS II) randomized controlled trial. JAMA. 2011;306(11):1224-1232.

39. Greist J, Jefferson JW, Kobak KA, Katzelnick DJ, Serlin RC. Efficacy and tolerability of serotonin transport inhibitors in obsessive-compulsive disorder: a meta-analysis. Arch Gen Psychiatry. 1995;52(1):53-60.

40. Catapano F, Perris F, Masella M, Rossano F, Cigliano M, Magliano L, Maj M. Obsessive-compulsive disorder: a 3-year prospective follow-up study of patients treated with serotonin reuptake inhibitors OCD follow-up study. J Psychiatr Res. 2006;40(6):502-510.

41. Soomro GM, Altman D, Rajagopal S, Oakley-Browne M. Selective serotonin re-uptake inhibitors (SSRIs) versus placebo for obsessive compulsive disorder (OCD). Cochrane Database Syst Rev. 2008;(1):CD001765.

42. Math SB, Janardhan Reddy YC. Issues in the pharmacological treatment of obsessive-compulsive disorder. Int J Clin Pract. 2007;61(7):1188-1197.

43. Andrade C. Augmenting selective serotonin reuptake inhibitors with clomipramine in obsessive-compulsive disorder: benefits and risks. J Clin Psychiatry. 2013;74(12):e1128-e1133.

44. U.S. Food and Drug Administration. Anafranil (Clomipramine Hydrochloride) Capsules USP: Labeling Information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019906s039lbl.pdf. Last accessed March 27, 2018.

45. Zohar J, Judge R, OCD Paroxetine Study Investigators. Paroxetine versus clomipramine in the treatment of obsessive-compulsive disorder. Br J Psychiatry. 1996;169(4):468-474.

46. Hollander E, Allen A, Steiner M, et al. Acute and long-term treatment and prevention of relapse of obsessive-compulsive disorder with paroxetine. J Clin Psychiatry. 2003;64(9):1113-1121.

47. Kamijima K, Murasaki M, Asai M, et al. Paroxetine in the treatment of obsessive-compulsive disorder: randomized, double-blind, placebo-controlled study in Japanese patients. Psychiatry Clin Neurosci. 2004;58(4):427-433.

48. Hollander E, Koran LM, Goodman WK, et al. A double-blind, placebo-controlled study of the efficacy and safety of controlled-release fluvoxamine in patients with obsessive-compulsive disorder. J Clin Psychiatry. 2003;64(6):640-647.

49. Kronig MH, Apter J, Asnis G, et al. Placebo-controlled, multicenter study of sertraline treatment for obsessive-compulsive disorder. J Clin Psychopharmacol. 1999;19(2):172-176.

50. Greist JH, Jefferson JW, Kobak KA, et al. A 1-year double-blind placebo-controlled fixed dose study of sertraline in the treatment of obsessive-compulsive disorder. Int Clin Psychopharmacol. 1995;10(2):57-65.

51. Montgomery SA, McIntyre A, Osterheider M, et al. A double-blind, placebo-controlled study of fluoxetine in patients with DSM-III-R obsessive-compulsive disorder. Eur Neuropsychopharmacol. 1993;3(2):143-152.

52. Tollefson GD, Rampey AH, Potvin JH, et al. A multicenter investigation of fixed-dose fluoxetine in the treatment of obsessive-compulsive disorder. Arch Gen Psychiatry. 1994;51(7):559-567.

53. Montgomery SA, Kasper S, Stein DJ, Hedegarrd KB, Lemming OM. Citalopram 20 mg, 40 mg, and 60 mg are all effective and well tolerated compared with placebo in obsessive-compulsive disorder. Int Clin Psychopharmacol. 2001;16(2):75-86.

54. US Food and Drug Administration. FDA Drug Safety Communication: Abnormal Heart Rhythms Associated With High Doses of Celexa (Citalopram Hydrobromide). Available at https://www.fda.gov/Drugs/DrugSafety/ucm269086.htm. Last accessed March 27, 2018.

55. Stein DJ, Andersen EW, Tonnoir B, Fineberg N. Escitalopram in obsessive-compulsive disorder: a randomized, placebo-controlled, paroxetine-referenced, fixed-dose, 24-week study. Curr Med Res Opin. 2007;23(4):701-711.

56. LexiComp Online. Available at http://online.lexi.com. Last accessed March 27, 2018.

57. Greist JH, Bandelow B, Hollander E, et al. WCA recommendations for the long-term treatment of obsessive-compulsive disorder in adults. CNS Spectr. 2003;8(S1):7-16.

58. Foa EB, Liebowitz MR, Kozak MJ, et al. Randomized, placebo-controlled trial of exposure and ritual prevention, clomipramine, and their combination in the treatment of obsessive-compulsive disorder. Am J Psychiatry. 2005;162(1):151-161.

59. Greist JH, Marks IM, Baer L, et al. Behavior therapy for obsessive-compulsive disorder guided by a computer or by a clinician compared with relaxation as a control. J Clin Psychiatry. 2002;63(2):138-145.

60. Gava I, Barbui C, Aguglia E, et al. Psychological treatments versus treatment as usual for obsessive compulsive disorder (OCD). Cochrane Database Syst Rev. 2007;(2):CD005333.

61. Foster PS, Eisler RM. An integrative approach to the treatment of obsessive-compulsive disorder. Compr Psychiatry. 2001;42(1): 24-31.

62. Conlan L, Heyman I. Helping patients to overcome obsessive compulsive disorder. Practitioner. 2007;251(1700):57, 59, 61.

63. Bolton D, Perrin S. Evaluation of exposure with response-prevention for obsessive compulsive disorder in childhood and adolescence. J Behav Ther Exp Psychiatry. 2008;39(1):11-22.

64. Koran LM, Aboujaoude E, Bullock KD, Franz B, Gamel N, Elliott M. Double-blind treatment with oral morphine in treatment-resistant obsessive-compulsive disorder. J Clin Psychiatry. 2005;66(3):353-359.

65. Pallanti S, Quercioli L, Koran LM. Citalopram intravenous infusion in resistant obsessive-compulsive disorder: an open trial. J Clin Psychiatry. 2002;63(9):796-801.

66. Lipsman N, Neimat JS, Lozano AM. Deep brain stimulation for treatment-refractory obsessive-compulsive disorder: the search for a valid target. Neurosurgery. 2007;61(1):1-11.

67. Martin JLR, Barbanoj MJ, Pérez V, Sacristán M. Transcranial magnetic stimulation for the treatment of obsessive-compulsive disorder. Cochrane Database Syst Rev. 2003;(3):CD003387.

68. Blom RM, Figee M, Vulink N, Denys D. Update on repetitive transcranial magnetic stimulation in obsessive-compulsive disorder: different targets. Curr Psychiatry Rep. 2011;13(4):289-294.

69. Jaafari N, Rachid F, Rotge JY, et al. Safety and efficacy of repetitive transcranial magnetic stimulation in the treatment of obsessive-compulsive disorder: a review. World J Biol Psychiatry. 2012;13(3):164-177.

70. Berlim MT, Neufeld NH, Van den Eynde F. Repetitive transcranial magnetic stimulation (rTMS) for obsessive-compulsive disorder (OCD): an exploratory meta-analysis of randomized and sham-controlled trials. J Psychiatr Res. 2013;47(8):999-1006.

71. Noh HJ, Tang R, Flannick J, et al. Integrating evolutionary and regulatory information with a multispecies approach implicates genes and pathways in obsessive-compulsive disorder. Nature Communications. 2017;8(774):1-13.

72. Li B, Mody M. Cortico-striato-thalamo-cortical circuitry, working memory, and obsessive-compulsive disorder. Frontiers in Psychiatry. 2016;7:78.

73. Fineberg NA, Reghunandanan S, Kolli S, et al. Obsessive-compulsive (anankastic) personality disorder: toward the ICD-11 classification. Rev Bras Psiquiatr. 2014;36(1):40-50.

74. Stanford Medicine. About OCD. Available at http://ocd.stanford.edu/about. Last accessed March 27, 2018.

75. Attwells S, Setiawan E, Wilson AA, et al. Inflammation in the neurocircuitry of obsessive-compulsive disorder. JAMA Psychiatry. 2017;74(8):833-840.

76. Brakoulias V. Managing obsessive compulsive disorder. Australian Prescriber. 2015;38(4):121-123.

77. Pittenger C, Bloch MH. Pharmacological treatment of obsessive-compulsive disorder. Psychiatr Clin North Am. 2014;37(3):375-391.

78. U.S. Food and Drug Administration. FDA Drug Safety Communication: Revised Recommendation for Celexa (Citalopram Hydrobromide) Related to the Potential Risk of Abnormal Heart Rhythms with High Doses. Available at https://www.fda.gov/Drugs/DrugSafety/ucm297391.htm. Last accessed March 27, 2018.

Evidence-Based Practice Recommendations Citations

1. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Obsessive-Compulsive Disorder. Arlington, VA: American Psychiatric Association; 2007. Available at https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/ocd.pdf. Last accessed April 5, 2018.

96362 • Postpartum Depression

Anele Runyion, RN, MS

www.netce.com

Copyright © 2017 NetCE, All rights reserved.

Postpartum depression is a devastating illness that begins in or extends into the postpartum period. This serious health problem affects 10% to 15% of childbearing women worldwide irrespective of culture. Postpartum depression is often undetected by healthcare providers, which should be of great concern as its consequences have serious implications for the welfare of the mother and her family and the psychological development of the child. Considered to be the result of a combination of biochemical, hormonal, genetic, environmental, and psychosocial factors, the complications of this form of depression can have profound negative impact on the mother's ability to bond with the infant and to sufficiently provide routine care for the infant. A more rare form of postnatal disorder is postpartum psychosis, which, if not treated immediately when it is detected, can have deadly consequences for both mother and infant. Early detection and a sound clinical assessment by knowledgeable healthcare professionals are essential to treat the mother's depression and to prevent complications that can endanger the mother-infant relationship and the child's normal development.

Table of Contents

96362 • Postpartum Depression

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. CATEGORIES OF POSTPARTUM MOOD DISORDERS

3. HISTORICAL PERSPECTIVE

4. CULTURAL PERSPECTIVE

5. RISK FACTORS

RISK FACTORS EVIDENT PRIOR TO PREGNANCY

RISK FACTORS EVIDENT DURING PREGNANCY

RISK FACTORS EVIDENT AFTER BIRTH

6. ETIOLOGY

BIOCHEMICALS INVOLVED IN POSTPARTUM DEPRESSION

FAMILY HISTORY

STRESSFUL LIFE EVENTS

PSYCHOSOCIAL FACTORS

7. TYPES AND SEVERITY OF POSTPARTUM DISORDERS

POSTPARTUM BLUES

POSTPARTUM DEPRESSION

POSTPARTUM PSYCHOSIS

INFANTICIDE

8. ASSESSMENT FOR POSTPARTUM DEPRESSION

CLINICAL ASSESSMENT

EDINBURGH POSTNATAL DEPRESSION SCALE

POSTPARTUM DEPRESSION SCREENING SCALE

9. COMPLICATIONS OF POSTPARTUM DEPRESSION

PROBLEMS IN THE MOTHER-INFANT RELATIONSHIP

10. IMPACT ON SOCIOEMOTIONAL AND COGNITIVE DEVELOPMENT

POTENTIAL LONG-TERM EFFECTS ON CHILDREN

CONFLICTS IN THE MARITAL RELATIONSHIP

SUICIDE

HOMICIDE

11. STRATEGIES FOR RECOVERY

SPONTANEOUS RECOVERY

SELF-CARE

EDUCATION

12. TREATMENT STRATEGIES

PHYSIOLOGIC

PHARMACOTHERAPY

PSYCHOSOCIAL INTERVENTIONS

13. PREVENTIVE STRATEGIES

SCREENING

POSTPARTUM DEBRIEFING

COMPANIONSHIP IN THE DELIVERY ROOM

BRIEF PSYCHOTHERAPY

CONTINUITY OF CARE

PREVENTIVE HORMONE TREATMENT

14. CONCLUSION

15. GLOSSARY

16. RESOURCES

17. APPENDIX

MISCONCEPTIONS AND MYTHS REGARDING PPD: PATIENT EDUCATION

Works Cited

Evidence-Based Practice Recommendations Citations

96362 • Postpartum Depression

Education Category. Psychiatric / Mental Health

Release Date. 04/01/2017

Expiration Date. 03/31/2020

Course Overview

Postpartum depression is a devastating illness that begins in or extends into the postpartum period. This serious health problem affects 10% to 15% of childbearing women worldwide irrespective of culture. Postpartum depression is often undetected by healthcare providers, which should be of great concern as its consequences have serious implications for the welfare of the mother and her family and the psychological development of the child. Considered to be the result of a combination of biochemical, hormonal, genetic, environmental, and psychosocial factors, the complications of this form of depression can have profound negative impact on the mother's ability to bond with the infant and to sufficiently provide routine care for the infant. A more rare form of postnatal disorder is postpartum psychosis, which, if not treated immediately when it is detected, can have deadly consequences for both mother and infant. Early detection and a sound clinical assessment by knowledgeable healthcare professionals are essential to treat the mother's depression and to prevent complications that can endanger the mother-infant relationship and the child's normal development.

Audience

This course is designed for all healthcare professionals who work directly with pregnant women, new mothers, and infants. The target audience is primarily those in the obstetric/gynecologic, neonatal, and psychiatric fields, but all healthcare professionals who provide services to women will benefit from this course.

Course Objective

The purpose of this course is to allow healthcare providers to detect postpartum depression using screening tools and a clinical assessment to intervene early and prevent the devastating consequences of the disorder.

Learning Objectives

Upon completion of this course, you should be able to:

1. Discuss the prevalence of postpartum depression (PPD), including historical and transcultural perspectives.

2. Identify risk factors for PPD evident prior to pregnancy, during pregnancy, and after birth.

3. Review the effects of biochemistry, such as serotonin, estrogen and progesterone, cortisol, and thyroid, on the development of PPD.

4. Describe the role of family history, stressful life events, and psychosocial factors in the etiology of depression.

5. List the emotional, physical, and cognitive symptoms of postpartum blues.

6. Discuss emotional, physical, cognitive, and behavioral symptoms of PPD.

7. Identify severe forms of postpartum disorders, focusing on postpartum psychosis and cases of infanticide.

8. Review the clinical assessment of PPD, including the Edinburgh Postnatal Depression Scale (EPDS) and the Postpartum Depression Screening Scale (PDSS).

9. List the effects of PPD on maternal bonding, mother-infant attachment, and a child's socioemotional and cognitive development.

10. Describe the potential long-term effects of PPD on children.

11. List maternal and familial complications of PPD, including marital conflict, suicide, and homicide.

12. Discuss self-care strategies for recovery, such as nourishment, sleep, rest and relaxation, exercise, and socializing.

13. Review the role of education in the diagnosis of and recovery from PPD.

14. Discuss the physiologic treatment of PPD with postpartum hormone treatments.

15. Specify pharmacologic treatment strategies, noting benefits, adverse reactions, and risks.

16. Discuss psychosocial interventions used in the treatment of PPD.

17. List strategies for preventing PPD, including screening, postpartum debriefing, companionship in the delivery room, psychotherapy, midwife continuity of care, and progesterone preventive treatment.

Faculty

Anele Runyion, RN, MS, received her diploma in nursing from Berea College School of Nursing in Berea, Kentucky. She subsequently received a Baccalaureate and Master’s degree in psychiatric nursing from the University of California, San Francisco. She has extensive experience in psychiatric nursing, including adolescent and adult psychiatry.
For 20 years she was psychiatric nurse consultant and coordinator of psychiatric nursing consultation at San Francisco General Hospital. She was Assistant Clinical Professor in Mental Health, Community and Administrative Nursing at the University of California, San Francisco. She created and co-chaired a National Psychiatric Consultation/Liaison Conference in 1987, which provided continuing education in nursing. This conference meets annually and has subsequently become an international conference.
She created a brief curriculum and practicum in consultation/liaison nursing for graduate nursing students at UCSF that is currently being practiced. As a psychiatric nurse consultant, she assisted non-psychiatric nurses in the hospital to assimilate and integrate psychological principles into their practice. During this time, she developed a protocol for management of acute post-traumatic stress response. This protocol was adopted by the hospital as a standard care plan for nursing management of patients with acute post-traumatic stress response in the non-psychiatric areas of the hospital.
Ms. Runyion has published and spoken nationally. She was listed in Who’s Who in American Nursing in 1991-92 and 1996-97. Currently, she is a self-employed consultant and writer.

Faculty Disclosure

Contributing faculty, Anele Runyion, RN, MS, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

Jane C. Norman, RN, MSN, CNE, PhD

Alice Yick Flanagan, PhD, MSW

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

1. INTRODUCTION

The World Health Organization (WHO) has designated the first 28 days after birth as the neonatal period. Although it has never been officially designated, the postpartum period is considered to start about an hour after the delivery of the placenta and is complete six weeks after birth. After six weeks, the mother's physical status will largely return to the nonpregnant state in most instances [1].

The nature of the association between childbirth and mental disturbance is of great interest. It is during this critical postpartum period that the mother and her infant are the most vulnerable to both physical and emotional problems. During this time, there must be increased concern for women who are the most vulnerable to postpartum depression (PPD).

The etiology of PPD is complex and not readily understood by many healthcare professionals. Neurophysiologic changes, underlying postpartum changes, the stress of childbirth, and predisposing factors, such as genetics, the environment, and psychologic stressors, combine to produce PPD in some women. Furthermore, there are distinguishing characteristics in brain chemistry that involve a theory of cyclical hormonal patterns and mood disorders in women. Psychosocial factors such as past history of mood disorder; family history of depression; stressful relationships with spouse, family, and friends; and lack of sufficient social support also play a role in the development of PPD.

2. CATEGORIES OF POSTPARTUM MOOD DISORDERS

Postpartum mood disorders are generally divided into three categories: postpartum blues, or "baby blues," PPD, and postpartum psychosis. These conditions do not exist on a continuum; each category is a distinct postpartum state [2].

Postpartum blues, a mild and transient depression in the immediate postpartum period, occur in up to 85% of new mothers [3]. The condition is characterized by mild dysphoria, with symptoms such as tearfulness, fatigue, sleep disturbances, and physical exhaustion, that lasts a few days following delivery. The majority of women experiencing postpartum blues recover spontaneously within three to five days [2,3,4].

PPD occurs in approximately 10% to 15% of new mothers [2,3,5]. According to multiple studies, PPD occurs at the same rate in new mothers around the world [6]. There is little evidence to suggest that any country or class of persons is not at risk for PPD. Symptoms usually occur shortly after childbirth but may occur as late as one year after delivery. PPD is a serious, long-lasting type of depression in women that can have harmful consequences for the mother and child if undetected and untreated [3].

The symptoms of PPD are similar to the symptoms of any major depressive disorder. However, due to the unique issues regarding the mother-infant relationship, the adaptation to parenthood following the delivery of a baby, and the impact of the mother's depression on the infant, PPD should be considered in its own right as a unique mood disorder suffered by postpartum women [7].

The third type of postpartum mental disturbance, postpartum psychosis, occurs in 1 to 2 of every 1,000 new mothers [8,9]. If undetected and untreated, postpartum psychosis presents a danger to both the life of the mother and her infant. Infanticide is rare but does occur in 1 of 250,000 women with postpartum psychosis [10]. An estimated 5% of patients with postpartum psychosis will attempt infanticide or suicide [9].

Screening for postpartum mood disorders as early as possible following childbirth is essential for early detection and treatment. Treatment strategies include a combined approach to address both the physiologic and psychologic factors that precipitate PPD. If the condition is detected and treated early, there is a greater likelihood of complete symptom relief in a shorter time span than if detection and treatment is delayed. Screening early for PPD in all new mothers, with referral of affected women to appropriate healthcare professionals, should become the standard of care for all childbearing women.

3. HISTORICAL PERSPECTIVE

Documentation of PPD can be traced to the writings of Hippocrates in the fourth century B.C.E. Hippocrates described melancholia as a state of "aversion to food, despondency, sleeplessness, irritability, and restlessness" [6]. Galen (131–201 C.E.) described melancholia as "fear and depression, discontent with life, and hatred of all people" [6]. Greco-Roman medicine recognized melancholia in the form of fear, suspicion, aggression, and suicidal thoughts. In 1436, the life story of a young mother was published and described how she felt "insane" and despaired of her life and survival after the birth of her first child [11].

In the 19th century, two French physicians became interested in PPD. In 1838, Dr. J.E.D. Esquirol documented 90 women with emotional problems and divided their illnesses into three types: illnesses that occurred during pregnancy, those that occurred immediately after childbirth, and those that occurred six weeks or more after birth. Many of these women had suffered in silence for fear of being stigmatized, misunderstood, or removed from their families [2].

In 1858, Dr. Louis Victor Marcé similarly observed 300 French women using the three categories established by Dr. Esquirol. He concluded that the types of emotional illnesses occurring in the postpartum time frame had unique characteristics of their own. He was convinced that there was an element in the body's physical mechanism causing postpartum illness, although he could not identify it. Marcé's conclusions have become important cornerstones of modern thinking on PPD and the endocrine system [2].

The symptoms of puerperal septicemia in women following birth confused the issue of PPD until the more widespread use of hand washing, antiseptic techniques, penicillin, and other antibiotics in the early 1900s. The removal of the toxicity of septicemia from the hazards of childbirth seemingly uncovered the problems of PPD [10]. In 1926 in the United States, two researchers declared that depression after childbirth was no different than any other depression in women. The term "postpartum" was not used in any textbooks describing depression in women at that time [11]. The "blues" that had long been recognized by midwives were brought to the attention of psychiatrists by Dr. Bruce Pitt in England. In 1964, Pitt interviewed 100 women at the Royal London Hospital between day 7 and 10 after birth. He discovered that 50% of these women had felt tearful or depressed since giving birth. For six of these women, the depression lasted a month or longer [10].

In 1971, Dr. Katherine Dalton, a British obstetrician, published the results of a survey conducted among 500 women from birth to six months postpartum. She concluded that 7% of the women developed PPD severe enough to require medical treatment, although none required hospitalization. With the publication of these findings in the British Journal of Psychiatry, psychiatrists and psychologists began to appreciate that depression experienced by new mothers extended beyond the postpartum blues [10].

The Marcé Society, an international medical society founded in 1980, has held conferences throughout the world to further the study of PPD. In 1987, the British Journal of Psychiatry published an article that established the standard of care for screening for PPD [12]. The Edinburgh Postnatal Depression Scale (EPDS) was introduced and has subsequently become the standard screening tool for PPD [10,12].

In the United States in the 1980s, women began to be recognized as having distress and inability to care for their infants after birth. Counseling was provided to assist these women to resolve their stresses and conflicts. In 1986, Dr. James Hamilton presented the idea that postpartum disorders were biologically driven. Mainstream medicine and psychiatry did not address these problems at the time, resulting in inadequate recognition and treatment [13].

In the last decade, greater emphasis has been placed on the role of a woman's brain chemistry in the development of depression in the postpartum period. The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), published by the American Psychiatric Association, does not recognize PPD as a distinct entity. Instead, patients must meet the criteria for a major depressive episode and the criteria for the peripartum-onset specifier (onset during pregnancy or in the four weeks following delivery) [14,15]. Limiting the onset of symptoms of depression to within four weeks postpartum has been considered too restrictive by some researchers and clinicians [2]. Postpartum Support International has argued that the timeframe should be extended to six months postpartum. Debate continues regarding how PPD fits into the larger classification of depressive disorders [16,17].

There are many mother and baby admission units in psychiatric hospitals in England, Wales, Canada, Australia, and New Zealand [18,19]. In the United States, Sichel and Driscoll established a mother-baby admissions unit in a Boston Psychiatric Hospital during the 1990s. A mother-baby day hospital has also been established at Brown University Medical School in Rhode Island [20]. In 2011, the first inpatient perinatal psychiatric unit for new mothers with severe PPD in the United States opened at the University of North Carolina at Chapel Hill hospital [21]. Several states have passed legislation either mandating screening for PPD or mandating education of PPD for all pregnant women [22,23,24,25]. In 2015, federal legislators introduced a bill titled "Bringing Postpartum Depression Out of the Shadows Act of 2015 [H.R. 3235]." The legislation would authorize the Department of Health and Human Services to make grants to states for screening and treatment for maternal depression [26]. This bill was not passed by the Senate.

4. CULTURAL PERSPECTIVE

Although PPD occurs worldwide, cultural differences can influence the perception of depression in women. Culture influences the expression and interpretation of symptoms, the definition of stressors, the nature of the social support system, and the relationship between healthcare provider and patient. Culture also dictates whether certain expressions of symptoms are socially acceptable. An individual's view of illness and health is also culturally bound. Displays of emotion may be encouraged in some cultures and discouraged in others [27].

Anthropologic studies show that cultural perceptions shape attitudes toward illness. Many cultures may not recognize depression as a disorder due to cultural differences or religious interpretations of emotional expressions. In some cultures, such as Nepalese, it would be considered inappropriate for a woman to seek treatment for sadness. In India, depression is viewed as a spiritual experience, described as the "suffering of the spirit" [28]. Muslims in some Arab countries also perceive depressive symptoms as a religious experience, connoting a deep understanding of the tragic nature of the human condition. Cultures that place a high value on social harmony, including many cultures in Africa and Asia, may encourage and support the suppression of internal conflict in women. Women living in these cultures would likely be reluctant to discuss emotional issues with their healthcare providers.

The explicit or implicit gender roles present in various cultures also affect expressions of PPD. Many women live in subordinate roles to their husbands and/or family in a patriarchal culture that disallows independent expression of self. Feelings may be suppressed in these cultures to safeguard women from cultural exclusion or punishment [28].

In Western societies, the hospital stay has generally been shortened to very few days following birth, after which the new mother is left virtually on her own. However, some cultures have rituals and myths surrounding childbirth that acknowledge the special attention required for postpartum women during their recuperation period. For example, a seven- to eight-day period is observed in some parts of the Philippines, during which time the new mother is given a special diet, heat treatment, and herbal medications, and she is expected to rest at home. The Ibido people of Nigeria create a "fattening room" for new mothers, where they are cared for by older women and are expected to only eat, sleep, and care for their infants. Other cultures have similar special rituals that accord distinct recognition to the new mother [2]. Whether the incidence of PPD is lower in these cultures is yet to be determined.

Dr. Laurence Kruckman, an anthropologist who has studied various cultural rituals, asserts that North American women may experience postpartum emotional disorders because [2]:

- The postpartum period is not structured as a distinct event that has particular needs.

- There is little social recognition of a woman's transition to the role of mother.

- Mothers receive minimal assistance after childbirth, including information about caring for themselves and their children.

Given these differences in cultural perception of sadness and depression and of childbirth, it is interesting to note that studies conducted in Canada, Puerto Rico, France, West Germany, Italy, Lebanon, Korea, New Zealand, and Taiwan show incidences of PPD comparable to those reported in the United States and the United Kingdom [13]. PPD has also been reported in women in Uganda, Sumatra, and Guatemala [10]. In addition, a study of 2,423 white, African American, Hispanic, and Asian/Pacific Islander women who had recently given birth in Massachusetts found that being foreign-born was associated with postpartum anhedonia in each group except Hispanics [29]. However, this may be linked more to the unique stressors of living as an immigrant or away from family.

In order to provide optimum care, healthcare professionals should understand how depression is viewed in the culture of the women who seek treatment. The cultural views of motherhood and the rituals and myths of childbirth should be taken into consideration when treating any woman during and after her pregnancy.

5. RISK FACTORS

RISK FACTORS EVIDENT PRIOR TO PREGNANCY

Evidence Based Practice Recommendation

According to the U.S. Preventive Services Task Force, risk factors for depression during pregnancy and postpartum include poor self-esteem, child-care stress, prenatal anxiety, life stress, decreased social support, single/unpartnered relationship status, history of depression, difficult infant temperament, previous postpartum depression, lower socioeconomic status, and unintended pregnancy.

https://jamanetwork.com/journals/jama/fullarticle/2484345

Last Accessed: March 21, 2019

Level of Evidence: Expert Opinion/Consensus Statement

PPD affects women of all ages, economic statuses and racial/ethnic backgrounds. Any woman who is pregnant or has given birth can develop PPD. Whether the birth is a first child or one of multiple births has not been shown to affect the incidence of PPD. However, women with a history of depressive episodes have a greater risk for developing PPD than women with no prior history of depression. The risk of PPD is highest in women younger than 25 years of age with a prior history of mood instability. Among these women, it is estimated that 30% to 40% will have a postpartum episode of depression [30]. There are additional risk factors evident prior to pregnancy that may increase the chances of developing PPD, including [5,30,31,32,225]:

- Past history of depression or other mental health problems

- Family history of mood instability

- Difficulties in relationships with the father of the baby or family, especially the woman's own mother

- Insufficient social support or peer support group

- Onset of depression immediately prior to conception

- Social or financial stressors, such as money or housing problems

- Mood disturbances, such as premenstrual syndrome (PMS)

- Infertility treatment

- History of abuse

- High school or lower levels of education

RISK FACTORS EVIDENT DURING PREGNANCY

Depression may occur during pregnancy and, if not treated, continue and worsen after childbirth. The number of women who develop depression during pregnancy is difficult to determine. In many cases, depression during pregnancy is not recognized or treated because normal pregnancy can cause similar symptoms, including fatigue, sleep disturbances, stronger emotional reactions, and changes in body weight. However, it is important that depression during pregnancy be diagnosed and managed, as it may be harmful to both the mother and the infant if not treated [19].

Treating depression during pregnancy is a challenge because the vast majority of antidepressants cross the placenta and can have negative effects on fetal development. Psychiatrists, family practice physicians, and obstetricians may find themselves in a dilemma when diagnosing and treating depression in pregnant women. As previously noted, the onset of depression may not become evident until symptoms become severe due to the similarity of depressive symptoms and neurovegetative signs during pregnancy [33]. Although diagnosis and treatment pose a serious challenge, early recognition, diagnosis, and treatment are warranted [33]. Indication of certain risk factors that may contribute to depression during pregnancy can be helpful in a prenatal assessment. Risk factors for an onset of depression during pregnancy include [5,33,225]:

- History of depression or substance abuse

- Family history of mental illness

- Lack of support from family and friends

- Anxiety about the fetus

- Problems with a previous pregnancy or birth

- Marital or financial problems

- Young maternal age

- Single mother

- Stressful life event, such as moving to a new area or death of family member

- Excessive fatigue

- Feelings of worthlessness

- Divorce

RISK FACTORS EVIDENT AFTER BIRTH

Risk factors for PPD following the birth of a baby are similar to those present prior to conception and during pregnancy. Any combination of the following factors should be considered concerning, as it indicates a potential to develop PPD [5,32,34,225]:

- Persisting postpartum anhedonia without sufficient social support

- Feeling detached from the infant, not wanting to hold the baby, having negative thoughts about the baby

- Persistent sleep disturbances

- A fussy infant who has problems feeding or has colic

- Signs of developing depression, such as anxiety or feeling overwhelmed

- Birth complications or a difficult labor

- A birth that did not live up to expectations

- Having an infant with special needs

- Excessive fatigue

- Feeling overwhelmed with responsibilities of new parenthood and experiencing persistent self-doubt about mothering ability

- Stress from changes in home and work routines, coupled with unrealistic expectations of motherhood

- Feelings of loss: loss of identity or self- image, loss of control, loss of body image, or feeling less attractive

- Previous episode of PPD

- An episode of anxiety or depression during pregnancy

- Prior experience of postpartum blues after delivery

- History of mood changes related to normal menstrual cycle

- Any major changes resulting in undue stress during pregnancy, such as a death in the family, unresolved conflict with her spouse, divorce, or moving from one location to another

6. ETIOLOGY

The integration of biochemistry, hormonal functions, genetic history, stressful life events, and psychosocial factors allows the potential for an occurrence of PPD. Any episode of depression in women is affected by the considerable impact of female biology on the emotional lives of women. The full consequences of female reproductive events and their effect on brain chemistry should be considered in any assessment of depression in women [13].

It is acknowledged that brain chemistry has a major role in producing depression. In some ways, a woman's brain functions differently than a man's brain, which in turn affects the experiences and manifestations of depression [13]. Sex differences in depressive episodes begin to appear as early as adolescence, a time of major changes in the neuroendocrine reproductive cycle with the onset of menses. This indicates the significant impact that brain chemistry has in the development of mood disorders in women [35].

The areas of the brain affected by female reproductive hormones (i.e., estrogen and progesterone) are the same as those known to regulate mood stability and behavior. Therefore, it may be concluded that different hormonal circumstances can alter mood and anxiety in a woman [13]. There are several events associated with a woman's reproductive cycle that provoke mood instability in predisposed individuals, including the use of oral contraceptives, phases of the menstrual cycle, pregnancy and the postpartum period, and menopause. The vulnerability of women for mood instability bears some relationship to the fluctuation of ovarian steroids during specific phases of the reproductive cycle [36,37].

The areas of the brain associated with anxiety and mood disorders are the limbic brain and the cortex. The paralimbic cortex is the first layer of the cortex that surrounds the limbic brain. The cingulate gyrus is a part of the limbic brain that is believed to be involved in the fight/flight response, mood regulation, and the maternal bonding process. It works collaboratively with other structures of the limbic brain. The instinct for mothering, nurturing, and the emotional responses of the mother toward her infant emanate from the cingulate gyrus area of the brain. This area has evolved to allow for the development of bonding behavior between mother and infant, thus assuring the attachment process [13].

In addition to the cingulate gyrus, the limbic brain is composed of the amygdala, hippocampus, hypothalamus, and thalamus. In concert with the cortex, these areas of the brain recall, correlate, store, and impart emotion to all experiences. The amygdala is an almond-shaped structure that responds to perceived threats to determine whether to fight, flee, or freeze. It is believed that this segment of the brain modulates the production of the neurotransmitters serotonin and norepinephrine. Researchers have discovered that the amygdala is overactive in depressed persons. This finding correlates with the clinical assessment of the simultaneous occurrence of stress with depression [13].

The hippocampus is involved in the creation of memories and in the modulation of stress responses and emotions. The hypothalamus, which is connected to the pituitary gland, orchestrates the menstrual cycle, thyroid function, physiologic stress responses, body temperatures, the sleep-wake cycle, appetite, growth, and lactation. Secretions from the hypothalamus stimulate the release of hormones from the pituitary gland. The feeling of fear, which is an emotion that colors perception, emanates from this area of the brain. Unresolved fear can lead to an incapacitating anxiety, which may also be present in depressed persons [13].

Every significant event in life is accompanied by emotions. These events are thus emotional experiences that are "recorded" in the brain. The "emotional brain" is thought to consist of the prefrontal cortex, which is the area located directly above the eyes, and the frontal cortex. The prefrontal cortex is significantly involved with developing judgment [13]. Sichel and Driscoll refer to the connections between the limbic brain, the paralimbic brain, and the prefrontal cortex as the "prefrontal limbic complex" [13]. This complex has a large role in processing emotions, regulating mood, and storing memories. The memories of powerful life experiences, both stressful and pleasurable, are stored in this area of the brain.

Intellect and good judgment are functions of the prefrontal cortex that override the instinctual urges of the limbic brain; the cortex acts as a buffer to inhibit impulses originating from the limbic brain. If it is too overwhelmed by hormonal fluctuations, the prefrontal cortex may no longer be able to inhibit angry and/or aggressive impulses. Aggressive behavior breaks through when chemical dysregulation within the mood pathways overcomes the buffering effects of the prefrontal cortex. The chemistry of the mood pathway must be stabilized and the disruption in the limbic brain soothed to allow the prefrontal cortex to function properly. If the chemical equilibrium between the paralimbic areas and the cortex is disrupted, then mood regulation can be destabilized [13].

Neurotransmitters are the chemical messengers that allow the nerve cells within the brain to communicate with each other. They help determine the mood pathways in the brain and serve as a chemical messenger system that travels through and innervates the prefrontal limbic complex [13].

Although there are numerous neurotransmitters, those that primarily affect anxiety and mood are dopamine, serotonin, norepinephrine, gamma-amino butyric acid (GABA), and glutamate. Together, these neurotransmitters regulate thinking, emotions, and behavior. Dopamine is involved in learning, memory, and emotional arousal. Norepinephrine is a hormone similar to adrenaline that is released during stress. A lack of norepinephrine may be associated with depression [38]. An excess of norepinephrine can produce agitation or irritability, which also frequently accompanies depression. GABA regulates how fast messages are sent along the nerve cells and helps to maintain a steady rhythm. Excessive stimulation of nerve cells produces a sense of anxiety [34].

These neurotransmitters are operative in both sexes. However, reproductive hormones that act in the same areas of the brain play a part in producing the unique characteristics of depression in women [19]. It is thought that the dramatic rise in reproductive hormones during pregnancy and the equally dramatic fall in these hormones following childbirth neurochemically affect those areas of the brain associated with mood stability. During pregnancy, the elevated levels of estrogen and progesterone have the effect of elevating mood. After delivery, the precipitous drop in the levels of these hormones creates a lowering of mood in some women [13].

The fact that these hormones are measured as nearly absent immediately following delivery of the baby and the placenta is a significant factor in producing depression in women whose brain chemistry may have already been destabilized by earlier events. These hormones are not produced again until approximately six weeks after delivery, when the next menstruation begins [10].

BIOCHEMICALS INVOLVED IN POSTPARTUM DEPRESSION

Serotonin

Serotonin is a neurotransmitter known to be involved in mood and anxiety disorders. It is one of the major classes of chemical messengers known as monoamines and is associated with the induction of emotional calmness and the perception and regulation of pain, restful sleep, sexual behavior, and appetite control. A person's general level of well-being depends largely on his or her levels of serotonin [19].

Serotonin imbalance is thought to be one of the causes of depression, and it may be a source of PPD. Inadequate amounts of serotonin may lead to sleep disturbance, agitation, worry, lethargy, and hopelessness, all of which are symptoms of depression [39,40]. Multiple studies have linked low-expressing serotonin transporter (5-HTT) genotypes and PPD, and this is an interesting area of research for future treatment options [41].

Serotonin levels in the brain are regulated by reabsorption into the nerve cell, breakdown within the synapse, availability of storage, timing of release, number of receptors, and the amount of tryptophan in the daily diet. Changes occurring in any of these areas can alter the serotonin pathway and/or availability and lead to anxiety or depression. Serotonin is formed from tryptophan, a basic protein building block stored in nerve cells. Adequate levels of tryptophan are essential to ensure the availability of serotonin. Alternatively, a depressive state can be induced by a depletion of tryptophan [13].

As noted, there are numerous estrogen and progesterone receptors in the same area of the brain where serotonin acts. Research has indicated that reproductive hormone levels seem to influence the availability of tryptophan [42]. The serotonin pathway is heavily influenced by hormonal fluctuations occurring normally during the menstrual cycle and during other major reproductive events, including the postpartum period. The integrity of this serotonin pathway may be jeopardized after childbirth due to the precipitous drop in estrogen and progesterone [13].

Estrogen and Progesterone

Women have a greater lifetime risk than men for depression, with two times the incidence of depressive episodes or recurrent depression [43,44]. Because higher risk is correlated with gender, it is highly likely that reproductive hormones in women play a role in mood instability [43,44].

Stabilization of brain chemistry is necessary in order for all systems to function normally. Any disturbances in any one area of the prefrontal-limbic complex affects all other areas. A woman's reproductive cycle and the resultant shifts in hormone levels within the brain can produce a disruption. If a woman's brain chemistry has been altered by previous stressful life events, hormonal shifts can be the catalyst that destabilizes the system and disrupts the capacity to stabilize mood. The impact of normal hormonal fluctuations caused either by the menstrual cycle or reproduction on an already destabilized brain chemistry may induce depression [13].

Estrogen

Estrogen and progesterone can induce changes in all of the neurochemical pathways involved in mood disturbances. This may be a vital aspect of mental health for women, but it remains largely unstudied [13,44,45]. Estrogen and progesterone influence serotonin levels as well as the function of the other neurotransmitters [42].

Estrogen receptors are present in many areas of the brain; however, they are found significantly clustered in the limbic area. Estrogen appears to help maintain the orderly firing rates of serotonin, dopamine, acetylcholine, and norepinephrine from nerve cells, which are involved with promoting positive moods, memory, thinking, perception, motivation, appetite, sex drive, anxiety, and stress responses. Estrogen can affect the action of these chemicals by altering the number of receptors on the nerve cells, slowing the breakdown of neurotransmitters, and enhancing sensitivity. Estrogen also enhances glutamate activity; glutamate is another neurotransmitter that encourages mood stability [13].

Sichel and Driscoll believe that estrogen may act within the brain as a natural antidepressant and mood stabilizer [13]. When estrogen levels drop, as they do after childbirth, this effect would presumably be reversed. Fluctuations of estrogen levels at any point during a woman's reproductive cycle can disrupt the delicate balance of neurotransmitters and affect a woman's mood stability. Thus, under normal circumstances, estrogen could be regarded as protecting women against depression [46,47].

Mood changes, however, do not occur in all women during their menstrual cycle or during the postpartum period [48]. Therefore, it seems that some women have a natural resilience to withstand the impact of hormonal changes. In a study to explore possible early biomarkers of PPD, researchers found that serum estradiol and estriol levels were similar among patients with and without PPD, indicating that a difference in sensitivity of the pathway, at the receptor level or the targets themselves, may be responsible for onset of PPD [49]. In fact, the women in the study who developed PPD were found to be more likely to have an estrogen-sensitive gene expression pattern, indicating that genetic testing of at-risk women may be useful in guiding treatment decisions in the future. Other researchers have proposed that a subgroup of women who constitute a "hormone-sensitive" PPD phenotype may be particularly sensitive to the effects of perinatal changes in hormone levels. Study of this subgroup independent of other PPD phenotypes may identify the underlying pathophysiology and help in the development of novel treatment targets [50].

Progesterone

Progesterone is produced during the second phase of the menstrual cycle and functions to dismantle the nerve connections established by estrogen, decreasing the number of available estrogen receptors [13]. Like estrogen, progesterone is also available in large quantities during pregnancy and drops significantly after childbirth.

Estrogen, progesterone, and endorphins work in concert to influence the brain's chemical pathways. The hypothalamus is responsible for controlling reproductive hormones (i.e., follicle-stimulating hormone [FSH], luteinizing hormone [LH], estrogen, and progesterone), mood, weight, and the circadian day/night rhythm. When an event changes the production or availability of any one of these, there can be an upset of the delicate balance of all the components. During the abrupt decline in estrogen and progesterone, for example, following labor and delivery, there may be a subsequent instability of mood, sleep, and weight (gain or loss) [10].

Conversely, as soon as conception occurs, levels of estrogen and progesterone begin to rise. When the placenta takes over the production of estrogen and progesterone from the ovaries, the level of progesterone rises to 50 times higher than the normal peak of progesterone during the menstrual cycle, and the level of estrogen rises to 130 times higher than the normal peak [10,19]. The amount of hormones produced by the adrenals also increases during pregnancy; therefore, twice as many corticosteroids are produced. During pregnancy all of these hormones are controlled by the hypothalamus, the placenta, and the fetal adrenals [10].

As noted, after childbirth and delivery of the placenta, there is a precipitous drop in the levels of estrogen and progesterone. A small amount of estrogen is present, but progesterone is almost completely absent. As a result of these falling levels, available serotonin also decreases. There is an approximate six-week period postpartum during which estrogen and progesterone production is absent; this persists until a new menstrual cycle begins. It is during this critical period, between birth and six weeks postpartum, that a new mother is considered to be the most susceptible to emotional disturbance [10].

Studies conducted by Dalton and colleagues in the United Kingdom indicated a correlation between symptoms in women who were feeling postpartum blues and a drop in blood levels of progesterone [10]. Levels of progesterone were measured over a five-day period. As progesterone levels decreased, women in the study reported increased feelings of sadness [10].

Another study administered high doses of estradiol and progesterone to women, then withdrew it abruptly. Researchers found that 62% of women in the study with a history of PPD had an onset of mood disorder. Interestingly, none of the women without a history of PPD demonstrated symptoms of a mood disorder [30].

Cortisol

Traumatic events provoke a stress response and the release of cortisol, along with other stress hormones. While necessary for survival, this protective stress hormone can exhaust or overwhelm an individual if its level remains too high. When the stress response continues unabated, the nerve cells can continue to maintain the response after the precipitating event has ended, causing emotional distress [13].

In pregnant women, placental hormones stimulate the production of cortisol, the level of which remains high until the placenta is delivered. There is conflicting evidence regarding the role of cortisol levels in PPD [51,52,53,54]. Discrepancies in the studies of cortisol and PPD may result from the lack of control for variables that influence cortisol levels, such as stressful life events. However, it is possible that the sustained high levels, and subsequent drop, of cortisol may have an effect on mood stability in the postpartum period. Some have suggested that women for whom cortisol levels remain higher after delivery of the placenta may have a greater risk of developing PPD [52].

Thyroid Hormones

The role of the thyroid gland is to produce thyroid hormones, including levothyroxine (T4) and L-triiodothyronine (T3). These hormones influence the body's metabolism as well as the function of many organs. T3 is the more biologically active hormone, and it is thought to be the hormone that functions at the cellular level. When the thyroid is underactive, nonfunctioning, or has been surgically removed, hypothyroidism, or insufficient production of thyroid hormone, will develop. Thyroid hormones affect the body's metabolism in multiple areas, including the regulation of vitamins, proteins, carbohydrates, electrolytes, water, and the immune system. They can also alter the actions of other hormones and drugs.

Evidence Based Practice Recommendation

According to the American Thyroid Association, there is insufficient evidence to conclude whether an association exists between postpartum depression and postpartum thyroiditis. However, as it is a potentially reversible cause of depression, women with postpartum depression should be screened for thyroid dysfunction and appropriately treated.

https://www.liebertpub.com/doi/full/10.1089/thy.2016.0457

Last Accessed: March 21, 2019

Level of Evidence: Low quality

Approximately 5% to 7% of postpartum women have abnormal thyroid levels [55,56]. Thyroid dysfunction is associated with depressed mood, and in one study, having a thyroid-stimulating hormone (TSH) level greater than 4.0 mU/L at delivery was associated with increased risk for depressive symptoms at six months postpartum [42,57,58,59]. Thyroid dysfunction has not been consistently identified in PPD; however, there may be a subgroup for whom it does play a role.

If thyroid levels remain abnormal, it can alter the effectiveness of the treatment for depression [13]. Therefore, laboratory tests of thyroid function, particularly in women with signs or symptoms of thyroid dysfunction, should be included in the evaluation for PPD. Screening for thyroid dysfunction in the postpartum period may help identify women at risk for PPD; however, consensus guidelines do not advocate screening of all women [42,60,61].

FAMILY HISTORY

Some families appear to be more prone to depressive illness than others [13]. Therefore, a woman's genetic makeup may be a risk factor for PPD. A detailed family history specifically documenting incidences of depression or mental illness is useful in any PPD assessment.

With this in mind, certain traits are possible indicators of disturbances in brain chemistry and mood instability in some individuals [30]. Some important traits that may become evident when taking a patient's history include:

- Family history of suicide or a preoccupation with suicidal thoughts

- Family history of depression

- Family history of addiction to alcohol or drugs

- Poor judgment as indicated by inappropriate or impulsive financial, sexual, or violent behavior

- Aggression

- Grandiose expressions and behaviors

- Family history of bipolar disorder

- Unstable or chaotic lifestyles

- Lack of empathy for others

- Enmeshed or estranged family system

- Family history of bouts of rage or physical abuse

- Extremely rigid parents (disciplinarians)

- Compulsive behavior

The presence of any of these traits in a woman's family may be indicative of a family history of alterations in brain chemistry and mood instability, which may have been inherited by the patient [2,13,30].

As noted, some women seem to display a resilience to chemical dysregulation, and these women do not have mood destabilization at critical junctures in the hormonal reproductive cycle. Much research is being conducted in this area of inquiry to determine the role genetics play in protecting from and/or inducing PPD [13]. As discussed, genetic differences in estrogen signaling, cortisol levels, and serotonin expression have all been linked to higher risks of PPD [41,49,52].

STRESSFUL LIFE EVENTS

Childhood traumatic events and powerful emotional responses to those events are unconsciously encoded in the paralimbic cortex area of the brain. A woman who has endured traumatic events early in life can become psychologically and biochemically overloaded. These biochemical changes then predispose her for a depressive episode in response to various reproductive events later in life, including pregnancy and childbirth. Over time, it becomes increasingly difficult to maintain physiologic and psychologic balance. When a woman's history is examined closely, certain stressful life events preceding PPD may be present. These stressful events, many of which may have occurred early in life, sensitize the brain and may affect its biochemistry and subsequent behavior. Evidence of prior mood disturbance is often present in a depressed woman's history [13].

The brain's mood pathways can presumably be restored to normal following one depressive event without any further episodes, assuming that the depression is treated aggressively and appropriately. However, research has shown that 70% of those who become depressed will have another depressive episode [13,62].

PSYCHOSOCIAL FACTORS

Part of a woman's preparation for motherhood involves her expectation and anticipation of the event and her ideals regarding labor, delivery, the child, and how she will feel. These ideals are often based on the image of the "perfect" mother or "perfect" child. A significant discrepancy may exist between what is expected and the actual delivery and birth of the baby. Confusion, unhappiness, and guilt may be the result. Even the happiest of new mothers feel some disappointments, and high concern over mistakes and perfectionism are risk factors for PPD [63,64].

It is observed that women with PPD do not experience the initial stages of motherhood as they had fantasized; consequently, their disappointments are more intense and severe. Women with postpartum blues or depression may seem unable to deal with disappointments with equanimity. When a woman is already biochemically predisposed to depression, unfulfilled expectations, unanticipated losses, and/or lack of social support create the potential for PPD to develop. For a woman with PPD, disappointments will be felt more intensely and with a greater degree of emotional sensitivity and self-criticism [63].

There are many expectations attached to having a baby. For a woman without a positive relationship with her mother, there may be a desire to demonstrate that she can be a better parent to her child, or she may have the fantasy that having a baby will bring her emotionally closer to her mother. If a woman feels that her own mother was a poor role model, she may have conflicting emotions about becoming a mother herself. This can lead to self-criticism and intensify feelings of being a "bad mother," which often accompany depressive symptoms of PPD [13].

In some cases, the child may have been conceived with the idea that it would improve a relationship with the father or bring greater harmony to a marriage [63]. Pregnancy conceived to resolve a troubled marriage may actually worsen an already difficult relationship as a result of the additional adjustments a pregnancy demands. Due to the hormonal changes caused by pregnancy, women may be particularly sensitive. Disharmony in a marriage can trigger depression in a pregnant woman, making her more vulnerable to PPD [19].

Desertion of a partner or husband during or after pregnancy produces enormous stress on a new mother. The lack of support that a father/partner affords to the new baby may create a crisis and negatively impact the woman's ability to care for her child. Mixed emotions of anger, guilt, and insecurity can be critical stressors if a woman's partner is absent or unsupportive. Marital conflict is a common finding among depressed pregnant women and women with PPD [65,66].

In some families, especially in some cultures, enormous value is placed on male heirs; therefore, there may be a considerable amount of pressure to have a male child. In these cases, having a female child can be a huge disappointment, and the woman may feel that she is a failure [63].

The psychologic impact of infertility may also play a role in the development of depression in some women. Impaired fertility affects approximately 12.3% of women of childbearing age in the United States [67]. Studies of women receiving fertility treatments have shown that these women generally had less satisfaction with life, higher levels of anxiety, and tested higher on the depression scores than women who were fertile [19]. Infertility had an impact on sexuality and self-esteem, and women being treated for infertility were likely to blame themselves and to avoid contact with friends [68]. Women receiving, or who have received, fertility treatments require compassion, understanding, and support. Treatments can take considerable time and require a woman to deal with the emotional and mental consequences of hope and loss. Fertility medications themselves, which generally act on the pituitary gland, may disrupt mood stability [19].

The expectations of motherhood carry an immense emotional weight. Fantasies about the kind of mother a woman will be establish presumptions of having to behave, respond, and feel a certain way. When a woman's reactions do not correspond to these idealized fantasies, there may be resulting feelings of failure and self-defeating disappointment [63,69]. Most women have coping mechanisms that allow them to deal with the conflicting emotions of disappointment and joy, or love and resentment, and are able to enjoy being mothers. Women with PPD have great difficulty dealing with these ambivalent, conflicting feelings and, as a result, are unable to maintain emotional balance [63].

7. TYPES AND SEVERITY OF POSTPARTUM DISORDERS

POSTPARTUM BLUES

Postpartum blues, also referred to as "baby blues," is the most common type of postpartum mood disturbance, occurring in approximately 70% to 85% of all new mothers [3,70]. Its onset is usually shortly after birth, and it generally resolves within 10 days [2,3]. A study by Iles et al. indicated a characteristic pattern of mood changes that peaked on day 5 after delivery and declined by day 10, perhaps best described as a period of emotional upheaval following birth [71]. Incessant crying and tearfulness are the most common emotional expressions of postpartum blues [2,3].

Miller and Rukstalis prefer the term "postpartum reactivity" to describe the mood fluctuations that occur with postpartum blues, as they believe the term "blues" is often confused with depression [72]. However, the term "baby blues" has been popularized in modern culture and is often used to describe the phenomenon that occurs shortly after birth. It is important to distinguish the postpartum blues from PPD both to avoid confusion and to aid in treatment.

Postpartum blues are characterized by heightened responsiveness to stimuli, wide mood swings, tearfulness, and irritability. The exhaustion and fatigue experienced by women following birth significantly alters sleep patterns, further inducing mood alterations and irritability secondary to sleep deprivation [73]. The cause of the postpartum blues is considered to be primarily physiologic in nature [72].

The incidence of postpartum blues varies in different cultures; however, it has been demonstrated in every culture in which it has been studied [72,74,75,76,77]. Psychosocial variables that affect postpartum blues tend to influence how women express their emotions, but not whether the blues occur [72]. Therefore, research into the most accurate assessment tool for postpartum blues and depression across cultures is ongoing [3,39].

As discussed, incessant crying and tearfulness are the most common emotional expressions of the postpartum blues. The tearfulness is not necessarily linked to sadness, but occurs in response to numerous environmental triggers, such as insufficient milk production, too much or too little attention from nurses, or a sarcastic remark [10]. Essentially, an emotional oversensitivity exists. All of the emotions associated with childbirth are normal and healthy so long as they are not excessive and resolve within one to two weeks [10]. The signs and symptoms of postpartum blues include [10,13,72]:

Emotional Symptoms

- Crying easily

- Mood swings

- Feelings of sadness for no reason

- Irritability towards the baby and/or the father of the baby

- Anxiety

- Excessive worrying

- Emotional sensitivity

Physical Symptoms

- Fatigue

- Apathy

- Exhaustion

- Inability to sleep

Cognitive Symptoms

- Poor concentration

- Confusion

- Slowness to learn new skills (e.g., bathing and feeding the new baby)

- Mental fatigue

Healthcare professionals in contact with a mother who is experiencing postpartum blues should listen to her without judgment and explain that what she is experiencing is not uncommon, she is not to blame, and the symptoms should soon resolve, allowing her to return to her normal state. Women are treated by one set of healthcare professionals during prenatal visits and an entirely new set after childbirth. This can produce its own set of problems. The attitude of nurses and other healthcare professionals towards mothers who are experiencing postpartum blues can help or hinder the mothers' recovery [10].

The postpartum period is a challenging time for any mother, but may be particularly difficult for first-time mothers who may feel insecure and apprehensive about their new maternal responsibilities. Attending to the demands of a new infant who requires total care while also recovering from fatigue and sleeplessness can be overwhelming. In some countries, home visits are key in providing emotional support and practical advice to new mothers as a matter of routine. For example, in the United Kingdom, it is common for nurses to make home visits to provide support and advice to new mothers. In the United States, however, this is less common, with minimal support often available for mothers during this unique and stressful time. In most instances, a mother is discharged from the hospital to her home situation and is left to navigate the postpartum period and care for herself and her new baby on her own [2].

An estimated 10% to 25% of women experiencing the transient state of postpartum blues will subsequently become seriously depressed [2,3,78]. The development of a more serious depression involves psychologic and psychosocial factors that are not prevalent in the development of the postpartum blues. An early warning sign for more serious depression is feeling overwhelmed combined with suicidal ideation; this should not be ignored. Feeling overwhelmed is normal after childbirth, but feeling suicidal is not. Being overwhelmed and/or distressed for longer than two weeks should be a warning signal that the patient requires an evaluation for depression.

POSTPARTUM DEPRESSION

With an annual live birth rate of nearly 4 million in the United States each year, an estimated 600,000 women experience PPD in the United States [79,80]. Women who miscarry or whose children are stillborn are also susceptible to PPD. When this group is included in the figures, an estimated 900,000 women suffer from PPD each year [80]. Several studies have shown that PPD occurs with greater frequency in the first 3 months following childbirth than in the 6 or 12 months following [81]. Although exact percentages vary, it has been reported that between 40% to 90% of PPD cases occur within three months after childbirth. Nonetheless, women should be carefully assessed throughout the first year after childbirth, as PPD can occur up to one year postpartum [31,66].

In some cases, the first symptoms of PPD occur within hours or days after birth and increase in severity over the following weeks. When this is the case, mothers often do not understand what is happening; they do not understand why they are not happy about the new baby in the way that they are expected to be [10].

It has been posited that PPD diagnoses should be exclusive to the postpartum period [10]. If a woman has been depressed prior to giving birth, depression in the postpartum period may be diagnosed as recurrent depression. PPD has been formally defined as, "the first occurrence of psychiatric symptoms severe enough to require medical help, occurring after childbirth and before the return of menstruation" [10].

Women for whom PPD is their first incidence of depression tend to experience a shorter duration of symptoms, be significantly less likely to experience recurrent depression outside the postpartum period, and be more likely to experience subsequent PPD [66]. Whether PPD is determined to be the first episode of depression may depend upon the clinician's history-gathering skills. Many women who are diagnosed with PPD as a first episode of depression may realize, upon careful examination, that they have experienced depressive symptoms in the past, although the symptoms may never have been diagnosed as depression [13,82].

Whether it is the first or a recurrent depressive episode, PPD is a serious, debilitating depression that affects the mother in profound ways. PPD is classified as a major depressive disorder [13]. It is characterized as a downward spiral in total functioning, involving mood changes and changes in bodily functions, including appetite, concentration, sleep-wake cycles, and energy levels [13,82].

Similar to postpartum blues, the symptoms of PPD can be classified as emotional, physical, cognitive, or behavioral. Ultimately, the mind and body are both affected by biochemical dysregulation of the brain.

Emotional Symptoms

The emotional symptoms of PPD may include [2,3,5,10,13,82]:

- Pervasive sense of sadness and melancholy

- Loss of interest and enjoyment in life

- Loss of interest in all or most of usual activities

- Irritability and emotional outbursts

- Unpredictable tearfulness and crying spells

- Hopelessness and helplessness

- Suicidal thoughts

- Feeling overwhelmed

- A sense of emotional numbness or of feeling trapped

- A strong sense of failure, inadequacy, and guilt

- Fear of being alone

- Feelings of shame

Physical Symptoms

The physical manifestations of PPD are diverse and include [2,3,5,13,82]:

- Sleep disturbances (i.e., sleeping either too little or too much)

- Increased or decreased appetite

- Weight gain or significant weight loss

- Decreased energy, lethargy, and fatigue

- Restlessness and agitation

- Loss of libido and disinterest in sexual activity

- Headaches

- Chest pains and palpitations

- Hyperventilation

Cognitive Symptoms

When PPD affects cognitive abilities, it may present as [2,3,10,82]:

- Thoughts of worthlessness

- Recurrent thoughts of death or suicide

- Difficulty concentrating

- Memory problems

- Difficulty thinking clearly and making decisions

- Pervasive anxiety with excessive fear and worry

- Excessive concern about the welfare of the child

- Negative self-talk

- Thoughts of harming the baby

Behavioral Symptoms

Finally, the behavioral symptoms of PPD are [2,3,10,82]:

- Withdrawal from her infant, spouse, family, and friends

- Physical neglect of herself and/or her infant

- Physical and mental exhaustion

- Inability to cope with daily routine

- Lack of concern for herself or her infant

- Neglect of personal environment

Symptoms may vary among women and over time in any one woman. Not every woman will have all of these symptoms. There are some general ways these symptoms might be expressed, giving the clinician clues to look for in women who might be predisposed to PPD.

Due to the shame experienced by some women with PPD and the subsequent secrecy with which they may hide their symptoms, it may not be obvious to a clinician how this illness impacts mothers and their children, spouses, and families. Women with PPD who ask for help often find that their problems are minimized or trivialized. It is crucial to understand how much women suffer from this disorder and acknowledge that their symptoms are not trivial. A description of the most common symptoms of PPD may therefore be helpful in diagnosing and managing the disorder.

Pervasive Sense of Sadness and Melancholy

Some women may feel sad most of the time; others have days in which their moods seem more normal and they feel good. However, the good moods do not last more than one or two days, after which the sadness falls upon them again.

Loss of Interest and Enjoyment in Life and Usual Activities

Women who are depressed suffer from lethargy, fatigue, and apathy. Family and friends may find it difficult to accept that activities that once brought the individual pleasure no longer interest her. It may be too difficult for women with PPD to generate sufficient energy to even engage in certain activities.

Irritability and Emotional Outbursts

Irritability is one of the main mood changes most women experience with PPD. This type of irritability is characterized by emotional swings from anger to distress. Frequently, attacks of irritability end with uncontrollable sobbing. Mothers find that this irritability is out of their control, which adds to the distress [3,10]. If the irritability continues, it can make dealing with the tasks of caring for an infant very difficult and can damage other relationships. Irritability may be expressed either verbally or through physical violence. Mothers may describe themselves as intolerant, impatient, jittery, short-tempered, spiteful, or quarrelsome. Irritability varies in its intensity among women with PPD and may develop in the weeks to months after childbirth.

Unpredictable Tearfulness and Crying Spells

Another of the most common symptoms of PPD is tearfulness and uncontrollable sobbing, with or without discernible external stimuli. These symptoms are also common among women who experience the postpartum blues; however, if these symptoms continue beyond two weeks after birth, they should be considered as part of the onset of PPD.

Sleep Disturbances

All new mothers experience a change in sleep patterns. Due to the baby's presence and the need for feedings during the night, most new mothers suffer from some degree of sleep deprivation. There is a different quality to sleep problems in women with PPD. These women have difficulty getting to sleep, have disturbed sleep, and/or wake early and are unable to go back to sleep. Insomnia is a common complaint. Even when they do sleep, it is never enough; the sleep is not refreshing. Five hours of solid sleep is often recommended; however, women with PPD are rarely able to sleep for that length of time. It is usual for new mothers to have their sleep interrupted by a crying baby, but women with PPD report that they cannot go to sleep even when the baby is settled and goes to sleep. They may lie awake worrying. Although rare, some women with PPD report sleeping too much [2,82].

Feeling Overwhelmed and Unable to Cope

Most mothers realize that they have new responsibilities and demands with the arrival of a child. Some new mothers feel overwhelmed by the constant demands of caring for infants, fulfilling the role of mother and wife/partner, and maintaining other relationships. They may also feel pressure to run the household smoothly, especially if caring for additional children. Bothered by fatigue and lack of sleep, it is difficult not to feel overwhelmed at times. However, mothers experiencing PPD can feel overwhelmed by the smallest tasks, including breastfeeding and changing diapers. A strong feeling of helplessness and a lack of confidence in her ability to cope undermines any self-confidence she may have enjoyed prior to her depression.

Hopelessness and Helplessness

For some women with PPD, there is a loss of hope in life. Women may wish they were dead and have thoughts of suicide. Although thoughts of harming oneself are prevalent among women suffering from PPD, these drastic thoughts often are not that they actually want to die, but that they want the situation to change and feel hopeless about being able to change it. In some instances, thoughts of suicide may become too strong to resist, and some women with PPD do commit suicide. Any thoughts of suicide should be taken seriously and warrant immediate intervention [2,69].

A Sense of Failure and Inadequacy

An inability to cope with everyday functions may lead to a negative self-concept and negative self-talk. The negative perception of self can be so convincing that an individual believes she is incompetent as a woman, wife, and mother. Such feelings are difficult to eliminate for women who are depressed [69].

Thoughts of Worthlessness or Guilt

One of the most prominent features that a woman with PPD experiences is that somehow she is not worthy of having a child; she may feel that because of the depressive symptoms, she is a bad mother. These thoughts may cause an individual to detach herself, in an effort to hide perceived inadequacies from others. Women who believe that they are "bad mothers" also have significant feelings of guilt. There is an accompanying loss of self-confidence in other areas of life that is difficult to shake. These women may have excessive guilt about any minor wrongs committed in the past [2,69].

Difficulty Concentrating, Thinking Clearly, and Making Decisions

The loss of concentration associated with PPD may cause women to forget things that ordinarily come easily, such as turning off the stove or putting things away. Everyday tasks may become so difficult that they seem monumental. In order to cover up the confusion, women may avoid certain activities. Women who were previously leaders or extroverts or who enjoyed a high level of confidence prior to childbirth may be distressed by a loss of confidence. Loss of confidence is often accompanied by a desire to withdraw from one's surroundings, become detached, and avoid socializing or making contact with other people [10,69].

Pervasive Anxiety with Excessive Fear and Worry

Anxiety is a common symptom that accompanies depression. Symptoms of anxiety may be felt emotionally, cognitively, and/or physically. Anxiety permeates everything a woman with PPD experiences, bringing with it a feeling of dread that does not resolve with any amount of reassurance. Anxiety can be incapacitating, affecting the ability to think, concentrate, or make sound decisions [34,69].

Thoughts of Harming the Baby

Any thoughts of harming the baby should be taken seriously, and immediate help should be given. Unfortunately, suicide and homicide can be consequences of PPD. Although a mother may not wish to harm her baby, these thoughts may have an alarming obsessive quality that could eventually override her ability to make rational judgments to control her behavior [2,69].

POSTPARTUM PSYCHOSIS

Postpartum psychosis is an extreme condition that can occur during the postpartum period. The term "psychosis" is defined as a mental state characterized by being out of touch with reality [2]. Postpartum psychosis affects approximately 1 or 2 in 1,000 first-time mothers [3,15]. For women who experience psychosis after the birth of their first child, the risk increases by 50% for subsequent deliveries [15]. The major risk factors for postpartum psychosis are a personal history of PPD or psychosis, a family history of depression, or the presence of bipolar disorder [3,15,43,69]. One study found that nearly 10% of women hospitalized for psychiatric conditions before delivery went on to develop postpartum psychosis after their first child was born [83]. When it does occur, psychosis in a new mother constitutes a psychiatric emergency, requiring immediate treatment and, in many cases, psychiatric hospitalization.

Women are seven times more likely to be hospitalized for a psychotic episode during the first month after delivery than at any other time before or after childbirth [69]. For women with a history of postpartum psychosis, the risk of psychiatric hospitalization after childbirth is increased [8]. One-half of all psychotic mothers are admitted to a psychiatric hospital within 14 days of delivery [13]. In one study, 90% of women with postpartum psychosis had an onset of symptoms within four weeks of delivery [83]. In most women, symptoms develop within the first two weeks postpartum [3].

Several studies have indicated that the incidence of postpartum psychosis worldwide has been essentially unchanged over the last century and a half [8,84,85]. The fact that the rate has remained constant suggests that modern scientific medical care and the mother's physical health are not factors in the development of the condition. Although the prevalence has remained unchanged, maternal morbidity and mortality have been greatly reduced [8].

Psychosis may take different forms depending upon a woman's history of prior psychiatric illness. Psychotic disorders in the postpartum period are typically characterized by an abrupt onset, severe symptoms, and dramatic, difficult, and disruptive features [3]. As noted, symptoms of psychosis usually occur in the first few days to weeks after childbirth. However, in some cases psychosis occurs immediately following delivery [3,8].

Postpartum psychosis may not be obvious unless the mother is questioned about her emotions and mental status. She may be successful at hiding her psychotic thinking until it manifests in her behavior. Psychosis may also be delayed until after the mother stops breastfeeding, which produces a secondary hormonal shift and may trigger depressive or psychotic symptoms in predisposed women. Fortunately, postpartum psychosis is rare [3]. Nonetheless, it is the most dangerous and tragic postpartum disorder and should not be overlooked [2].

Postpartum psychosis is characterized by hallucinations, delusions, confusion, extreme agitation, inability to carry on a coherent conversation, and inability to sleep or eat [3,69]. Moods may swing from euphoria to homicidal or suicidal ideation in a short period of time without warning. The risk of suicide or infanticide requires immediate attention. Safeguards should be established to protect the mother from harming herself or her baby until psychiatric intervention becomes available [13]. Irrationality is the hallmark of postpartum psychosis, and a mother's behavior may be peculiar or described as bizarre. She may engage in frenzied activities, as though in response to stimuli not apparent to anyone other than herself [10].

Psychotic women may become paranoid or suspicious of other people's intentions or behavior. Women may imagine that people are ridiculing or talking about them. In extreme cases, individuals may refuse food or prevent their infants from feeding appropriately [2,69]. Psychotic mothers feel alienated from what is going on around them, and to the observer, they may appear obviously disturbed.

Mood alterations may suggest a postpartum manic-depressive psychosis or bipolar disorder. Women with this illness have extreme polarity of moods, from bliss to deep depression [69]. The manic state is marked by physical hyperactivity, a rapid rate of speech, disconnected thought patterns, and grandiose ideas. There may also be periods of anger or aggression, with verbal or physical manifestations. Delusions may center on perceived special powers, fame, or capability to carry out enormous exploits. The infant may also be incorporated into the delusions, creating a risk of harm. The depressive phase is profound in its depth of despair. Bipolar psychosis is dramatic and usually (although not always) occurs in postpartum women who have a history of bipolar disorder prior to pregnancy [2,69].

Psychosis may also result in auditory or visual hallucinations [69]. Visual hallucinations present distorted or unreal images of the people around her, the environment, or her baby, and they can be very disturbing and frightening. Auditory hallucinations include hearing voices that appear to come from sources that are not present. These hallucinations become dangerous when they issue commands to commit certain acts that would ordinarily be against her will; these are called command hallucinations. If these commands coerce a woman to hurt her baby and are too compelling for her to resist, they may lead to infanticide [2,69].

Women with postpartum psychosis may also feel pressured to get rid of the baby or to give the baby away because they are convinced something is terribly wrong with it or with themselves. Women may completely reject their babies and refuse to have anything to do with them as a result of delusions that the baby is defective. Some express the belief that death would be an improvement for the child. Reassurances ordinarily do not work in cases of postpartum psychosis; no amount of evidence to the contrary will change the attitude towards the baby. In these circumstances, a mother should never be left alone with the child. Furthermore, the baby should not be forced upon her, as she could harm the child in her delusional state [10]. As the mother's psychosis is treated and her delusions abate, assisting her in bonding with her infant, under direct supervision, becomes possible.

Another symptom of psychosis is confusion or disorientation [69]. Confusion is defined by a lack of awareness of identity, surroundings, or time. Disorientation, on the other hand, is characterized by forgetfulness from one moment to the next. If confusion and disorientation are present, organic brain conditions should be ruled out. An acute organic brain condition is a medical emergency and should be diagnosed and treated immediately. Generally, when the condition is corrected, the symptoms will resolve [2]. As with the onset of any psychotic or delirious symptoms, toxic, metabolic, and neurologic causes should be ruled out. Toxic delirium and psychosis may present with similar symptomatology [8,86].

If, for some reason, a psychotic mother must be cared for at home, it is essential that both the mother and her baby remain under constant observation by family or friends who have been educated about postpartum psychosis and know when and whom to call in case of an emergency. A psychotic mother's actions are totally irrational, and irreversible damage can be done if she is left alone [2]. Possible other sources of supervision include home health providers or social workers.

Relatives and friends should be warned of the possibility of psychosis returning even if a mother is treated in a psychiatric hospital and released. There is a danger of psychosis returning at the resumption of menstruation, even if the mother is undergoing continuous psychiatric outpatient treatment. Twenty-four hour surveillance is necessary at this vulnerable time [3,10].

INFANTICIDE

It is estimated that 1 in every 250,000 women with postpartum psychosis commits infanticide [10]. Any time a new mother is psychotic, the risk of infanticide should be considered. There is always a possibility that the mother will incorporate the baby into her delusional thinking, and this will increase the risk of infanticide [2,3]. When healthcare professionals are unaware of the symptoms of psychosis and how dangerous the condition is for the mother and her baby, tragedy can occur. Psychotic mothers retain little ability to appreciate what they are doing; some may kill their infants unwittingly in a state of confusion, when out of touch with reality [13].

In general, healthcare professionals should be alert for early signs of psychosis, such as agitation, hyperactivity, or restlessness following delivery [69]. Suspicious, paranoid ideations might manifest as a certainty that there is something seriously wrong with the baby or that nurses are hurting or trying to poison the baby. These symptoms are usually indicators that the mother is in the early phases of a psychosis; they should be reported immediately to facilitate a psychiatric consultation [10].

It is also important to note that cases of child abuse and infanticide are not limited to mothers who are psychotic. A study of mothers of children younger than 3 years of age found that 41% of depressed mothers had thoughts of harming their child [87]. However, postpartum psychosis is a significant risk factor for both ideation of child harm and completed infanticide.

Legal Issues

In the United Kingdom, it was lawyers, not medical professionals, who first appreciated that a mother who killed her baby was temporarily mentally disturbed. The crime of infanticide was introduced into law in England and Wales in 1922, and later amended in the Infanticide Act of 1938 [87,88]. This law states that a mother who kills her own child can be charged with a lesser offence of infanticide, not murder. Murder, if proved, must be punished by a prison sentence. This only covers the killing of an infant younger than 12 months of age and does not extend to other individuals [10].

Given the rigidity with which the legal system in the United States views mental illness, infanticide becomes legally challenging. By the time a case of infanticide reaches trial, the mother's mental status has usually improved and is no longer psychotic. An aggressive prosecutor can make it appear as though the psychosis was fabricated to cover up the crime. In many cases, there are inadequate records to support the mother's claim that she did not know what she was doing and that she killed her child, "in a fit of insanity, which has since passed" [8].

The public understandably finds infanticide repugnant and incomprehensible. Without proper instruction from the judge at trial and without a specific law to guide jurisprudence in cases of infanticide, it is difficult for a jury to acquit a mother when an infant has been killed. However, given the media focus on cases of infanticide, some guilty verdicts have been overturned in the Court of Appeals. There may be a tendency toward leniency developing in the United States; however, mothers in the United States who commit infanticide may face the death penalty [89]. In a case study of 24 infanticide cases in the United States in which postpartum psychosis was the defense, 33% of defendants were found not guilty by reason of insanity, 17% were given probation, and 42% were incarcerated, with 8% sentenced to life in prison [87]. The laws in the United States that govern insanity pleas and infanticide remain inconsistent, differing from state to state [88,89,90]. The lack of formal DSM-5 diagnostic criteria for postpartum psychiatric disorders contributes to disparate treatment under the law [89,91]. Judges, without precedents to follow, generally attempt to give broad latitude to infanticide defendants [8].

Broad latitude shown to infanticide defendants by the justice system is a step in the right direction, but it does not fully address the realities of postpartum psychosis. Sichel and Driscoll have stipulated that, "there is a difference between a person who kills with malice and one who kills under the influence of postpartum psychosis" [13]. There are women who do harm their children with malice; however, the criminal justice system, when properly supplied with accurate information regarding postpartum psychosis, should conceivably be able to enact laws that protect women who kill their infants while under the influence of postpartum psychosis [13,89].

Spectrum of Infanticidal Thoughts and Actions

Infanticidal fears, or women who think about or are frightened about harming their baby and manage to resist, have not been studied carefully. There are few statistics on the frequency of these fears in women with PPD or postpartum psychosis. Mothers may not readily confess to such fears if they are aware that they may be incarcerated or that their children may be removed from their care [10].

Dalton studied PPD and, in her research, saw an unusual number of women charged with infanticide or who, under the influence of postpartum psychosis, have very nearly killed their children. She noted three varieties of infanticide: those occurring shortly after birth while the mother is acutely psychotic; those occurring with the return of menstruation; and those occurring during "domestic feuds." According to Dalton, many of these incidents "do not appear in the press or in law reports and remain hidden from the public" [10].

8. ASSESSMENT FOR POSTPARTUM DEPRESSION

CLINICAL ASSESSMENT

Data from the Centers for Disease Control and Prevention (CDC) Pregnancy Risk Assessment Monitoring System (PRAMS) and the U.S. Preventive Services Task Force (USPSTF) indicate that 10% to 15% of new mothers suffer from PPD, and up to 85% experience postpartum blues [92,93,94,95]. The CDC has therefore recommended that healthcare providers address the issue of PPD during prenatal visits, preferably during the third trimester [92]. Other sources, including the USPSTF, recommend assessing for depression throughout the prenatal period [94,96]. The USPSTF has stated that screening pregnant and postpartum women for depression may reduce depressive symptoms in women and that screening instruments can identify pregnant and postpartum women who need further evaluation and who may need treatment [94]. The screening should be implemented with adequate systems in place to ensure accurate diagnosis, effective treatment, and appropriate follow-up [94,97].

Consultation with patients about their risk for psychiatric illness during the postpartum period also should be discussed [92,96]. Clinicians should understand that knowing about a pregnant woman's mental and emotional state is as important as knowing about her neurophysiologic status. This initial assessment should include a psychosocial history that is sufficiently comprehensive to determine a woman's vulnerability to developing PPD [96]. Early detection and treatment of depression during pregnancy can prevent a more serious downward spiral into PPD following delivery [94]. Early treatment has also been shown to decrease the duration of PPD [73].

Both the USPSTF and the American College of Obstetricians and Gynecologists recommend that assessment for depression using a standardized, validated tool occur at least once during the perinatal period [94,97]. Women with current depression or anxiety, a history of perinatal mood disorders, or risk factors for perinatal mood disorders should receive close monitoring, evaluation, and assessment [97]. Women most likely to suffer from PPD often describe pregnancy as "one of the worst times of my life" or a "very hard time" [98]. In order to avoid a delay in learning about a woman's problems caring for the baby or herself, a plan for early detection of women at risk for PPD should be in place [94,97].

Specific areas should be addressed in the initial clinical assessment [13,96]. This includes asking a woman about any prior history of depression or hormonal mood changes, such as premenstrual irritability. Patients should also be asked if they have ever been treated for depression or if any family members have been depressed, suicidal, or hospitalized for a psychiatric illness [94,96].

Many women are reluctant to reveal a personal history of mental disorder; therefore, education regarding the occurrence of postpartum blues and PPD should accompany the discussion about personal history. Educational materials should be available and distributed in clinics or women's health centers. Questions asked by clinicians will make more sense to a woman if she understands that PPD is a complication of childbirth and that she is undergoing an evaluation for her sensitivity to this condition. Reassuring patients that most women go through pregnancy and childbirth with minimal problems can help to put them at ease.

Although women may initially be reluctant to reveal personal information regarding their mental/emotional state or psychosocial history, many women who have had PPD relate how they wish that someone had told them about the illness before it happened to them. This is important because knowing what is causing their altered moods and behavior helps to give women a sense of control [11,99,100].

The lack of openness, public awareness, and education about PPD contributes to its secrecy. Ignorance of this disorder causes women to not seek treatment, which in turn can allow the depression to worsen and potentially endanger both the mother and her baby. Educational materials made available to pregnant women are an excellent way to begin an assessment of a woman's risk for developing PPD.

When an assessment indicates that a prenatal woman is at risk for developing PPD, she should be referred to a mental health clinician for further evaluation. A collaborative relationship between the woman's healthcare provider and the mental health clinician should be maintained throughout the woman's pregnancy and postpartum period [94]. Establishing specific boundaries at the outset makes for better, more effective treatment for the mother [73]. Kennedy et al. recommend an interdisciplinary model of care that includes practitioners from the mental health, women's health, medicine, pediatrics, nursing, nutrition, and social work fields [73]. A team approach will most likely serve the mother's and her family's needs. It is essential that an accurate diagnosis of depression is made by a qualified professional. If clinicians cannot detect high risk on their own, they should refer the patient to a specialist. As stated, the USPSTF recommends that the assessment be implemented with adequate systems in place to ensure accurate diagnosis, effective treatment, and appropriate follow-up [94,97].

Various states have enacted PPD legislation that mandates that information regarding PPD be made available to women and their families. For example, New Jersey specifically requires that physicians, nurse midwives, and other licensed health care professionals providing postnatal care to women screen new mothers for PPD symptoms prior to discharge from the birthing facility and at the first few postnatal check-up visits [23]. Hospitals and other healthcare facilities must provide departing fathers/partners and/or other family members with written information about PPD as needed, including its symptoms, methods of coping with the illness, and treatment resources to overcome the spillover effects of the illness and improve their ability to be supportive of the new mother. Illinois requires professionals to screen new mothers before discharge, to invite PPD screening at prenatal visits and at each well-baby checkup until the infant's first birthday, and to provide information to fathers and families [24]. Other states (e.g., Minnesota) require that materials regarding PPD be made available to new mothers, fathers, and their families, but do not specifically mandate screening [101]. Healthcare professionals should be familiar with state law in their jurisdiction.

Healthcare professionals who have 24-hour contact with women after delivery should be equipped to recognize women who are struggling with depressive symptoms beyond postpartum blues. These women should be referred for psychiatric consultation and follow-up before being discharged from the hospital. These women should also be given an emergency number to call if suicidal or infanticidal ideation emerges. To assist the healthcare professional in detecting which women are at highest risk, several screening tools have been developed; two examples of validated instruments are the Edinburgh Postnatal Depression Scale (EPDS) and the Postpartum Depression Screening Scale (PDSS).

EDINBURGH POSTNATAL DEPRESSION SCALE

The EPDS has been developed to assist primary care professionals to detect mothers suffering from PPD. The EPDS was created at health centers in Livingston and Edinburgh and consists of ten short statements. The mother chooses one of the four possible responses to indicate how she has been feeling during the past week. The responses are then given a score between 0 and 3. Most mothers complete the scale without difficulty in less than five minutes [12].

A validation study showed that mothers who scored above 13 were likely to be suffering from a depressive illness of varying severity. Nevertheless, the EPDS score should not override clinical judgment. A careful clinical assessment should be carried out to confirm the diagnosis. The scale indicates how the mother has felt during the previous week, and in doubtful cases, it may be usefully repeated after two weeks. The scale will not detect mothers with anxiety neuroses, phobias, or personality disorders. Users should be instructed to [12]:

- Underline the response that comes closest to how they have been feeling in the previous seven days.

- Complete all ten items.

- Avoid discussing answers with others.

- Complete the scale by herself. However, if a patient has limited English proficiency or difficulty reading, she may require assistance.

The EPDS may be used to screen women at six to eight weeks postpartum. The pediatric health clinic or postpartum check-up may provide suitable opportunities for its completion.

The EPDS is limited to certain depressive symptoms and does not evaluate a woman's exhaustion, irrational irritability, or thoughts of harming her baby. These symptoms should be examined during a clinical assessment by asking specific questions relevant to these areas. Nonetheless, the EPDS is the most widely used screening tool available to detect PPD [10]. Given prenatally, the EPDS has been shown to effectively identify women at risk for PPD [102]. The EPDS may be accessed online at http://www.fresno.ucsf.edu/pediatrics/downloads/edinburghscale.pdf.

POSTPARTUM DEPRESSION SCREENING SCALE

Beck and Gable developed the PDSS, a 35-item self-report instrument, in an effort to improve early detection of PPD [103]. The screening scale is composed of seven dimensions, each of which consists of specific questions relevant to the dimension being measured (Table 1).

Table 1: POSTPARTUM DEPRESSION SCREENING SCALE (PDSS)

Dimensions

Sample Statement

Sleeping/eating disturbances

Tossed and turned for a long time trying to fall asleep

Anxiety/insecurity

Felt really overwhelmed

Emotional lability

Cried a lot for no real reason

Cognitive impairment

Thought I was going crazy

Loss of self

Felt like I was not normal

Guilt/shame

Felt like a failure as a mother

Contemplating harming oneself

Just wanted to leave this world

Source: [103]

Women are asked to indicate their degree of disagreement or agreement with each item on a scale of 1 (strongly disagree) to 5 (strongly agree). The validity of this scale to detect PPD has been tested and validated to be effective for screening women after delivery [103,104,105]. Additionally, a woman's response to items in the self-harm dimension can be used to gauge her level of suicidal thinking.

The test yields an overall severity score falling into three ranges:

- Normal adjustment

- Significant symptoms of PPD

- Positive screen for major PPD

The PDSS is available in short and long versions, with a manual for use in clinical settings.

9. COMPLICATIONS OF POSTPARTUM DEPRESSION

PROBLEMS IN THE MOTHER-INFANT RELATIONSHIP

Evidence Based Practice Recommendation

Where there is evidence of impairment in the mother-infant relationship as a result of maternal depression, the Scottish Intercollegiate Guidelines Network recommends additional interventions specifically directed at that relationship be offered.

https://www.sign.ac.uk/assets/sign127_update.pdf

Last Accessed: March 21, 2019

Level of Evidence: C (Well-conducted case control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal, directly applicable to the target population and demonstrating overall consistency of results)

The occurrence of PPD raises concerns about the quality of the mother-infant relationship and the potential impact of a mother's depression on the infant. One important aspect of the mother-infant relationship is a mother's adjustment to her baby and her understanding of her infant's needs and communications. When a mother's depression interferes with her sensitivity to her baby, their interactions can have a negative effect on the child [106,107].

Bonding

The benefits of bonding are well known. Most hospitals have incorporated a ritual of mother-infant bonding that occurs shortly after delivery, whereby the infant is placed in the mother's arms. It is often referred to as the moment of "falling in love," when the mother looks into the eyes of the infant and the infant looks back. Whether born of myth or scientific reasoning, bonding is considered an important element in initiating the mother-infant attachment. The ritual is important, but not essential. If, for some reason, this initial bonding is missed, as in the case of a caesarean section, it is obtainable the moment the mother sees her baby for the first time [108].

Bonding, in actuality, is a process of closeness, comfort, and familiarity that develops over time [19]. When the process of bonding with an infant is disrupted, it can have long-term consequences for the future relationship between mother and child. The delay in developing attachment may be unusually prolonged and delayed with a clinically depressed mother. This attachment difficulty may take different forms. The mother may not be nurturing to the infant, or she may have limited interaction with the infant. In some cases, the depressed mother may reject her baby emotionally and refuse to have anything to do with the infant. The mother may have an adverse sentiment towards the baby and handle the baby with irritability. Depressed mothers may also be outwardly angry or resentful toward the infant. Some mothers are so consumed with fears of harming their child that they avoid even touching him or her. All of these emotions and attitudes toward the child affect the process of attachment [2,109].

Klier and Muzik describe the role of perinatal psychiatry in maternal-infant bonding issues [110]. They classify the disorders of mother-infant bonding into three groups [110]:

- Delay, ambivalence, or loss in maternal response: Ambivalence or delay in bonding may be due to a mother's disappointment about her feelings toward the infant. She may have no feelings, feel estranged from the infant, or feel the infant is not hers.

- Rejection (threatened or established): Rejection of the infant is expressed through strong negative feelings. The mother may dislike or hate the infant and express regret over the infant's birth. There is a notable absence of affectionate behavior, such as kissing, hugging, cooing, and cuddling. Essentially, she wants to keep the infant away from her. A mother may feel trapped by motherhood, and the infant is the source of the entrapment. She may wish the infant would be stolen, given away, or killed.

- Pathologic anger: Pathologic anger toward the infant may be a mild form, which causes the mother distress but is controllable. Alternatively, it may be more severe, leading the mother to scream or yell at the infant or have an impulse to harm or kill the baby.

A study of approximately 100 subjects found that mother-infant bonding disorders were present in 29% of those diagnosed with PPD [111].

Bonding difficulties should be assessed immediately to determine if intervention is necessary. Women may be reluctant to admit these problems, but they also may be grateful to receive help from someone who understands their distress [110].

Mother-Infant Attachment

Researchers of infant behavior have come to acknowledge that the establishment of social relationships is a primary process of development. When a child successfully accomplishes communication with others, normal development occurs. A child who does not engage the world successfully will not develop normally, regardless of the source of the failure. Success or failure depends upon three critical processes [112]:

- The integrity and capacity of the infant's physiologic systems and central nervous system to organize and control physiologic states and behavior

- The integrity of the infant's communicative system to express the infant's intention for action to the caretaker and the extent to which the infant succeeds

- The caretaker's capacity to read the infant's communications appropriately and willingness to take appropriate action

These processes make up what is called "mutual regulation," which is the capacity of both the mother (or other caregiver) and infant to express their intentions, appreciate the intentions of the other, and allow each other to achieve their goals [112].

The literature on maternal-child interactions supports the concept of caretaker behavior as an external regulator of the infant's states. Maternal body warmth modulates infants' physiologic systems [108,112]. The quality of a caretaker's efforts affects the function, structure, and neurochemical architecture of the infant brain. Both mother and infant appreciate and adjust their behavior in relation to their partner's behavior and the state of the interaction. This system of meaning is established long before the child can engage in words, and the effects have lifetime consequences [112].

Both mother and infant develop the skill to sense when the interaction fulfills the infant's needs or when the mother's intervention met her intention. Adjustments are made as they develop sensitivity to each other's responses. This is how the mother-child relationship develops and sets the course for the development of future relationships for the infant. The development of an effective sense of self and a reliable relationship with caregivers is crucial for the establishment of stable and secure relationships in the future [112,113].

Studies have shown that when the mother is depressed, a break in the mutual regulatory system occurs [114]. Depressed mothers disrupt the interaction in two distinct ways: intrusiveness and withdrawal. It has been reported that intrusive mothers with PPD engaged in rough handling, spoke in an angry tone of voice, and interfered with their infants' activities. Withdrawn mothers, by contrast, were disengaged, unresponsive, and affectively flat and did little to support their infants' activities.

Both disruptions have a deleterious effect on the infant's development [112]. The infants of intrusive mothers eventually adopt an angry and protective style of coping, which is used defensively in anticipation of the mother's behavior. Infants of withdrawn mothers attempt to regulate their own emotional states. They may fail at social connectedness due to the mother's lack of response. Eventually, the infant will attempt to regulate their affective states, resulting in passivity and withdrawal [115]. Infants of either intrusive or withdrawn mothers develop a negative affective core characterized by anger and sadness, a representation of the mother as unresponsive and untrustworthy, and a representation of themselves as ineffective and helpless. This does not lead to successful normal development unless some intervention changes the mother's interaction style [112,115,116].

10. IMPACT ON SOCIOEMOTIONAL AND COGNITIVE DEVELOPMENT

Research on infants' early social development demonstrates a remarkable sensitivity to the quality of their interpersonal environment from the first days of life [95,106,117]. Findings from a study conducted at the Winnicott Research Unit in London suggest that exposure to maternal depression in the early postpartum months may have an enduring influence on child psychologic adjustment. Researchers report that, "depression has been found to be associated with insensitive and negative maternal interactions with the infant in the early postpartum months, particularly if the depression persists" [118].

Parents are crucial figures to an infant, acting as the primary partners in teaching their children, through their interactions, how to modulate their emotional states. These lessons help children learn to cope with failure, anger, and frustration, as well as how to channel these emotions into productive activities. A faulty foundation can result in a failure to cope as the child enters a larger social arena.

A mother's unresponsiveness or inappropriate parenting during infancy may prevent the child from achieving the developmental goals of social interaction and object exploration. If an infant learns that a parent is unavailable and unreliable, it interferes with the infant's development of a sense of mastery and control over events; the infant develops a sense of helplessness and hopelessness [112]. Infants eventually become aware of their mothers' anger, sadness, or hostility and begin to react to their parents' state of mind. Infants also must cope with their own sadness, anger, and apprehensiveness. Tronick and Weinberg speculate that infants become hypervigilant of their mothers' emotional state in order to protect themselves [112]. They must also protect themselves from their mother's responses by disallowing a high level of emotional arousal. Therefore, they become emotionally constricted. One study has indicated that, at the end of the first year, infants of depressed mothers express less intense emotional reactions to stressful situations and are less emotionally responsive than infants of nondepressed mothers. These early patterns can lead to the development of pathologic methods of coping [112,115].

Typically, mothers learn to read their infants' intentions and to understand how they can respond to fulfill their infants' needs. A mother eventually knows that when the infant cries it is because he or she is hungry, cold, or needs a diaper change. This is learned through interaction with the infant. These interactions take place over time and are part of a child's process of establishing social relatability.

A depressed mother may misread an infant's intentions and react angrily rather than supportively. This confuses the infant and may ultimately cause the infant to stop attempting to interact socially for fear of rejection. The pattern that is established does not promote a healthy or successful strategy for reaching out to others. In order to facilitate healthy interactions, it is essential for a mother to comprehend her infant's state of consciousness and for the infant to comprehend the mother's state of consciousness [112].

Studies have attempted to research cognitive functioning in infants of mothers with PPD at 18 months and 5 years of age. Results of these studies suggest that the quality of the mother's communication was influenced both by her mental state and the level of adversity that she experienced [119]. Further research supported this study, indicating that PPD may have lasting adverse effects on a child's cognitive development [120]. A review of studies showed that PPD reduced children's cognitive performance by impairing maternal mental and behavioral care [117]. A study of 1,053 mothers of infants 6 to 18 months of age found that 46.7% (491 mothers) suffered mild to extremely severe depression. The results indicated a correlation between mothers' depression levels and developmental delay in infants and a significant correlation between mothers' depression and development delays in gross-motor and problem-solving skills [121].

The way in which a mother engages with her infant in the postpartum months comes to influence the general nature of infant cognitive performance. One study considered a concept, originally proposed by Winnicott in 1956, that a depressed mother's interactions with her infant could be "good enough" to sustain a relationship without serious negative outcomes [119]. In instances in which there are no additional adverse circumstances at home for the mother, she may be able to provide "good enough" mothering in spite of her depression. Campbell and Cohn confirm that a consistent variable affecting a positive outcome in the early postpartum mother-infant relationship is a depressed mother's ability to provide a "good enough" environment for her infant [7].

In a separate study, latent depressive cognitions were investigated in 94 children of depressed and nondepressed mothers in a situation of mild stress [122]. Results indicated that children who had been exposed to maternal depression either in the previous 12 months or at any other time during their lifetime were more likely than children whose mothers were not depressed to express thoughts of hopelessness, pessimism, and low self-worth.

Kurstjens and Wolke found that long-term effects may be present when a mother's depression is chronic [123]. In the postpartum period, chronic depression in mothers may make infants more vulnerable to negative outcomes; short-lived depressions may have fewer consequences for the quality of the mother-infant relationship and for infant development. It is thought that short-lived PPD with an onset in the first few weeks postpartum and resolution by four to five months should have less of an impact on the quality of the attachment than depressions lasting six months or longer [123]. A longitudinal study of 296 mother-child dyads found that maternal depression at 30 to 90 days postpartum and at 12 months was significantly associated with the language development of infants at 12 months of age, with the impact correlated with the duration of the mother's depression [95].

However, some studies have shown that women experiencing depression in the early postpartum period may continue to have difficulties in their relationship with their infants, despite remission of their symptoms [7]. Factors influencing a more positive outcome for the mother-infant relationship include satisfaction with spousal support and help with childcare and involvement in early treatment for PPD [7,73,124,125].

It is important to identify factors that might buffer the mother-infant relationship in order to secure a more positive outcome. Studies suggest that chronically depressed mothers who remain at home full-time without support may have more difficulty relating to their babies than mothers who work outside the home at least part-time [7]. Mothers who benefit from considerable support and help from others may be considered low risk. The father of the child and other family members may provide childcare and sufficient support to help circumvent potential problems, or alternate caregivers may help buffer the infant from stressful interactions with a depressed mother. The father's presence, level of functioning, and willingness to participate in childcare alters the consequences of PPD for children [7,124].

POTENTIAL LONG-TERM EFFECTS ON CHILDREN

A study has been completed assessing the long-term effects on the children of mothers who were depressed three months postpartum [126]. In a community sample from two general practices in London, 149 women were given psychiatric interviews at three months after childbirth, and 89% of their children were assessed at 11 years of age. The children of women who were depressed at three months postpartum suffered attention deficit problems, difficulty with mathematics, and were more likely than other children to have special educational needs. The cognitive deficits present at 11 years of age may be a result of the quality of the infant's social environment in the first three months of life. Problems were noted in the children whether or not the mothers' depression continued beyond three months. Boys were more severely affected than girls. These effects on cognitive development were not altered by the parent's intelligence quotient (IQ) or socioeconomic status, or by the mother's later mental health problems. In this study, PPD was a risk factor for children's subsequent cognitive and behavioral problems. These findings demonstrate a long-term legacy of PPD that continues to affect children's intellectual development into adolescence [126]. Subsequent studies have reported similar findings [127,128,129].

Protective factors make a difference in long-term outcomes. Breastfeeding offers an emotional interaction between mother and infant that fosters regulation of attention and learning. Mothers' levels of distress and self-preoccupation are seemingly reduced during the act of breastfeeding, while focusing on the infants' satisfaction [126]. Furthermore, not all depressed mothers are insensitive towards their infants.

CONFLICTS IN THE MARITAL RELATIONSHIP

PPD puts a strain on marital relationships. According to Dalton and Horton, PPD is a significant medical cause of marital and relationship breakdown [10]. This is especially true when a woman's depression is untreated and/or chronic. Marital conflict and dissatisfaction are generally common in the first year after childbirth; PPD intensifies stress on the relationship during this period. Support from the baby's father or a partner is critical to a woman's recovery from PPD and may act as a buffer to the mother-infant interaction. Most partners do offer support to women coping with PPD. However, as the effects of depression multiply, they may become impatient or frustrated by the extra burden. In some cases, husbands or partners may be unsupportive or become verbally abusive, intentionally or unintentionally. Even when a husband or partner is supportive, the woman may feel, due to her depression and feelings of being overwhelmed, that it is not enough [63]. Lack of communication and misunderstandings of feelings, behavior, and attitudes are common occurrences. Each partner perceives the other as being uninterested in his or her activities. Given that women with PPD are often preoccupied and withdrawn, these problems may not be resolved and miscommunication can grow. Women may feel ashamed to ask for help, which can create a strain in the relationship [63].

Three areas have been identified as the most affected: the need for practical support, emotional needs, and sexuality. These are complex issues that should be dealt with, and most couples struggle to resolve conflicts in these areas. Assistance from health or mental health professionals may be needed and has shown to be helpful to women with PPD and their husbands or partners [63].

SUICIDE

Statistics show that psychiatric disorders, and specifically suicide, account for 20% to 30% of all maternal deaths [130]. A review of deaths from 2006 to 2008 identified psychiatric illness as the leading cause of maternal deaths in the United Kingdom [131]. In the United States, suicide is considered the greatest cause of maternal mortality in the year following childbirth [132].

Approximately 5% of women with postpartum psychosis commit suicide. Therefore, suicide prevention in a woman with PPD or psychosis should be a high priority [133,134,135]. Although there are no specific statistics for suicide rates among women with PPD, a 2013 study of service women in the United States found that suicidality (i.e., completed suicides, suicide attempts, and suicide ideation including thoughts of self-harm) was 42 times more prevalent in first-time mothers with PPD than in those without [136]. The risk of suicide in people with a major depressive disorder is about 25 times that of the general population. Most suicides in depressed persons are among those who do not receive treatment [137].

For women with PPD, suicide is an ever-present possibility [10,136]. Many women with PPD have reported continual fears of suicide or suicidal thoughts. These women may act on suicidal thoughts out of hopelessness and a sense of desperation. Family members and those close to mothers with PPD should be instructed to keep the danger of suicide in the forefront of their minds at all times. A failed suicide attempt may be followed by a successful suicide if it is not taken seriously and appropriate treatment undertaken.

Eight out of ten suicidal persons give some sign of their intentions [138]. Persons who talk about suicide, threaten to commit suicide, or call suicide crisis centers are 30 times more likely to attempt suicide than those that do not [138]. Although not all suicidal individuals indicate their plans, nearly three-fourths of all persons who commit suicide have visited a physician in the four months before their deaths [138]. It is therefore advisable that mental status and signs of suicidal ideation be assessed at every contact with postpartum women [139].

Recognizing warning signs of suicidality is essential to suicide prevention. Warning signals may include [138,140]:

- Feelings of despair and hopelessness. The more these feelings are described as unbearable, the more likely it is that the idea of suicide will enter the person's mind.

- Organization of surroundings or affairs. When a woman is making preparations for her absence or giving away prized possessions, it is possible she is seriously considering suicide.

- Establishment of a specific suicide plan. If a person has a specific method in mind, she is more likely to follow through on suicidal thoughts.

- Alcohol or drug abuse. Substance abuse in a depressed person has the effect of enhancing impulsive behavior and clouding judgment.

- Improved feeling of well-being. Paradoxically, a person with depression is more likely to attempt suicide just when she is on the way to recovery.

HOMICIDE

As noted, approximately 5% of women with postpartum psychosis commit infanticide [133]. Therefore, postpartum psychosis poses an immediate danger to the infant, who may require protection from the mother. Mother-infant interactions require supervision until the mother is successfully treated for her psychosis. There are no statistics available to indicate how many mothers with PPD (but not psychosis) commit infanticide. Although a psychotic mother may be a threat to her infant if she goes untreated, there is no evidence to date to suggest that these mothers are a danger to other people [133].

If a mother with PPD or postpartum psychosis tells any family member or healthcare professional that she is having thoughts of harming her baby, she should be taken seriously and immediate help should be forthcoming. If she is not already being treated for depression or psychosis, she should be referred immediately for psychiatric consultation and treatment. A mother who expresses concern that thoughts of harming her baby are becoming strong and she is afraid she might act on them should be supervised when she is with her baby. Alternatively, she may require hospitalization. A mother with PPD or postpartum psychosis who indicates that she has thought about harming or wants to harm her baby should never be dismissed.

11. STRATEGIES FOR RECOVERY

SPONTANEOUS RECOVERY

Postpartum blues produce symptoms of increased emotionality and sensitivity in new mothers. These symptoms are transitory and usually resolve within 5 to 10 days without the necessity of formal treatment. However, there is no clear evidence that women recover spontaneously from PPD [141]. Mothers who are breastfeeding may appear to have recovered from depression when, in fact, they have not. Some women may breastfeed their children for months to years, during which time they may be protected from depression by the production of prolactin. Depression may appear in these women after they stop breastfeeding [19]. Other studies of PPD and breastfeeding practices suggest that a mother's breastfeeding self-efficacy can both put her at risk for PPD and can predict a change in symptoms of currently experienced PPD [142,143]. This should all be taken into account when assessing women for recovery and symptom resolution, and it should also reinforce the need for early screening for PPD [143]. It has been suggested that there may be a possibility for spontaneous recovery in depressed women with milder symptoms and a shorter duration [144]. Unfortunately, withholding treatment while waiting for a spontaneous recovery may put women at risk for a more chronic or severe depressive episode [145,146].

SELF-CARE

For women with PPD, the reduction of stress is essential to protecting against further anxiety and to help the brain restore its own potential for self-regulation. In addition to the professional treatment a woman receives for her depression, she may choose to engage in certain activities to reduce stress and to promote a calmer, more relaxed state of mind [13,147].

Caring for a new baby is demanding, and mothers who are depressed can easily feel overwhelmed. To take care of the baby adequately, she must also take care of herself. Eating healthily, getting enough rest and relaxation, doing gentle exercises, and socializing are all part of maintaining and promoting health.

Diet

New mothers should consume two to three portions daily of protein-rich foods, such as fish, cheese, eggs, nuts, or meat. Four to five portions of fruit and vegetables should also be part of the diet [10]. Dalton and Horton recommend that starchy foods every three hours be added to the regular diet for a woman with PPD [10]. This may allow women with PPD to maintain sufficiently high blood sugar levels required to effectively utilize available progesterone. A carbohydrate-rich food should be eaten within one hour of waking and one hour before bedtime. Foods high in carbohydrates include flour, rice, potatoes, oats, and corn. Starchy foods added to a healthy diet of fruits, vegetables, and protein are not necessarily fattening; this may be stressed to new mothers.

Tryptophan is a vital amino acid that must be consumed, as the body does not produce it. Tryptophan can be obtained through plant or animal proteins, such as peanuts, brown rice, soybeans, fish, turkey, and beef. In the brain, tryptophan is converted into serotonin, which facilitates a calming effect [19]. Ensuring that sufficient quantities of iron, folic acid, and vitamin A are being obtained is also an important aspect of the postpartum diet [1].

Research has indicated that omega fatty acids may have a protective effect against PPD. In a Norwegian study of omega-3 fatty acid levels (generally from seafood consumption) in women throughout and after pregnancy, a low omega-3 index in late pregnancy was associated with higher depression score three months postpartum [148]. A 2012 meta-analysis supported this finding, noting that poor omega-3 intake is common among women of childbearing age [41].

Rest and Relaxation

Sleep is necessary to restore a woman's mood and brain chemistry following pregnancy, labor, and delivery. The brain requires a minimum of five hours of uninterrupted sleep per day to restore itself to normal functioning [13].

If possible, a spouse or other caregiving partner can alternate nights getting up to take care of the baby, allowing the mother to sleep at least five hours at a time. Knowing in advance that arrangements for nighttime feedings and attention to the baby can be made, mothers may ask for help without feelings of guilt or inadequacy [5]. Because women with PPD often complain of insomnia, a safe sedative may be prescribed to allow patients to obtain enough sleep.

As women with PPD may be overstressed and overly focused on perceived inadequacies, only those things that are of high priority, such as taking care of herself and the baby, should be attempted. Ideally, she should obtain assistance with household chores, such as cooking, cleaning, and shopping, at least for the first few weeks to allow more time for her to rest. Extended family can be useful if they are available and willing to help [5]. Family members or friends should also be allowed to help with childcare and other activities of daily living. This will free the mother's time for therapy sessions, support groups, and unpressured time with the baby [5].

Exercise

Exercise is important to a sense of well-being, as it enhances production of endorphins in the brain. Exercise can also help to promote a sense of calm, relaxation, and better sleep. For women with PPD, exercises should be gentle, not strenuous, and may include walking, swimming, physical therapy, and massage [149,150].

Socializing

Although it may be difficult to do, a woman should be encouraged to discuss her feelings with her partner/husband, close family members, and intimate friends. Hiding feelings due to shame and embarrassment contributes to isolation and loneliness. Therefore, although it may be difficult, it will ultimately help a depressed woman to have companionship. Isolation can lead to a sense of detachment from others, which may make depressive symptoms worsen. The depressed woman should avoid spending all of her time alone. Whenever possible, she should be encouraged to get dressed and leave the house.

It is also important for a woman with PPD to spend time alone with her partner/husband when the baby is quiet or asleep. These times together can be productive for both parents and allow them to be together without the usual stress of caring for a new baby [5].

EDUCATION

Evidence Based Practice Recommendation

According to the American Psychiatric Association, education about the symptoms and treatment of major depressive disorder should be provided to postpartum mothers in language that is readily understandable to the patient.

https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf

Last Accessed: March 21, 2019

Strength of Recommendation: I (Recommended with substantial clinical confidence)

Knowledge about PPD can be very helpful to new mothers who suffer symptoms of depression. Women have reported that not understanding their symptoms greatly added to their distress [11,100]. Given the effects of PPD on new mothers, it is vital to send a new mother home with proper education about one of the most common complications of delivery and its effects on her and her baby. In addition to having patient education materials on PPD readily available, it is equally important for healthcare professionals to educate women about parenting skills. Taking the time to discuss the care of a new baby can make a big difference in helping new mothers feel competent and confident.

Fathers also need education regarding PPD and potentially coping with a depressed mother. In cases when PPD has been diagnosed, a father's education might consist of suggestions regarding his supporting role in assisting his wife/partner through her recovery. The following suggestions may be helpful [10,63,149]:

- Listen without giving logical advice or trying to fix the problem.

- Offer hope that she will recover.

- Take care of the baby as much as possible.

- Ensure that the mother gets at least five continuous hours of sleep during the night whenever possible.

- Make regular, unsolicited offers of assistance.

- Hire household help, if possible.

Fathers should not feel helpless or useless if they have been advised about how to offer emotional and practical support to mothers with PPD [63]. A father often finds that he has unexpected physical and emotional adjustments after having a baby. He may experience his own form of exhaustion as a result of changes in household schedule, interrupted sleep, increased financial responsibilities, and concern for the mother's emotional and physical needs. A father should be encouraged to participate as much as possible in educational activities with his wife or partner and to also seek professional help should he begin to feel overwhelmed with the additional burdens of new fatherhood and PPD [149].

There is some evidence that men may experience a form of PPD following the birth of their child [151,152]. The strongest predictor of paternal PPD in one study was the presence of maternal depression, with symptoms tending to arise after those of the mother [152]. Therefore, fathers should also be assessed for signs and symptoms of depression in the postpartum period, particularly when their partner is depressed. Educating both parents can assist them to work together for mutual benefit and for the benefit of the baby, and may alleviate possible marital discord.

12. TREATMENT STRATEGIES

PHYSIOLOGIC

Hormone Therapy

A reduction in hormones after delivery is thought to be a major factor in the etiology of PPD in predisposed women. Therefore, the use of hormonal treatment as prophylaxis or a treatment component seems plausible. Since 1970, several studies were carried out investigating the efficacy of either estrogen or progesterone in the management of PPD. There are several problem areas in these studies, both in regards to methodologic issues and in the use of different hormones in the studies [153]. More structured research is necessary in order to ascertain efficacy.

Estrogen

The value of estrogen in the treatment of PPD is supported by studies conducted between 1970 and 2002. However, methodologic shortcomings make the studies unreliable. The use of estrogen in the postpartum period, particularly the use of synthetic estrogen, may have significant side effects [153]. In addition, more recent evidence indicates the impact of reproductive hormones may be mediated by differences in sensitivity to estrogen among postpartum women [49].

Measurements of hormonal levels proved to be one methodologic flaw. Levels of hormones measured from plasma sampling determine the total amounts of progesterone and estrogen rather than the free fraction, which is unbound to plasma proteins and freely permeates into the central nervous system. It is this biologically active fraction that modulates the synthesis of proteins, neurotransmitters, and receptors in the central nervous system. Thus, serum levels of hormones may render inaccurate results [153]. Dalton and Horton stipulate that the only accurate method of measuring free estrogen and progesterone levels is via saliva testing [10].

In 1996, Gregoire et al. conducted a double-blind, placebo-controlled study of estrogen skin patches in the treatment of PPD [154]. The women who participated in the study had either severe or chronic depressive symptoms that began 3 months postpartum and persisted up to 18 months. The women were assessed monthly using the EPDS. Although the study concluded that estrogen was better than placebo in relieving both dysphoric mood and biologic symptoms of depression, many of the women who received estrogen took antidepressants simultaneously [154]. The use of estrogen combined with antidepressants requires further consideration.

Other studies have been conducted evaluating estrogen as a treatment for PPD; however, many of these studies were also complicated by the co-administration of antidepressants, which leads to inconclusive evidence of the benefits of estrogen alone to treat PPD. Whether estrogen is of value in the treatment of PPD is yet to be determined [153,155,156].

Evidence Based Practice Recommendation

According to the Scottish Intercollegiate Guidelines Network, the use of estrogen therapy in the routine management of patients with postpartum depression is not recommended.

https://www.sign.ac.uk/assets/sign127_update.pdf

Last Accessed: March 21, 2019

Level of Evidence: B (High-quality systematic reviews of case control or cohort studies, directly applicable to the target population, and demonstrating overall consistency of results)

There are concerns regarding the risks associated with the use of synthetic estrogens in the postpartum period, including the increased risk for the development of deep vein thrombosis, cardiovascular complications, endometrial hyperplasia, problems with breastfeeding, and increased depression. The safest dosage and route of administration should be clarified before it can be recommended [153]. There are no reported studies on the use of natural estrogen in the treatment of PPD [155].

Estrogen may be taken orally, vaginally, transdermally, or through a device inserted into the uterus. Natural estrogens are available through the use of skin patches, transdermal creams, or vaginal creams [13]. Natural transdermal estrogen creams, such as bio-identical 17-beta estradiol and vaginal creams, are available only from compounding pharmacies.

Progesterone

It has been suggested that only naturally occurring progesterone has mood-elevating properties [10]. Thus, studies using synthetic progestogens as prophylaxis or treatment for PPD are not comparable to studies using natural progesterone.

Critics of Dalton's use of progesterone both as prophylaxis and treatment for PPD cite methodologic problems and the fact that the dosages are not standardized. Other criticisms include the fact that patients who participated in the studies were volunteers and there was not an adequately constructed control group against which to test the treatments [153]. Although criticisms of Dalton's progesterone treatments persist, no further studies have been conducted on the use of natural progesterone for the treatment of PPD [155].

One problem with the use of progesterone is that it cannot be given successfully by mouth or as a skin patch, but must be administered by injection or vaginal or rectal suppository. According to Dalton and Horton, 400-mg suppositories administered twice daily are the minimum effective dose [10]. However, empirical data has not found progesterone to be effective in the treatment of PPD and it may intensify depressive symptoms in some patients [157].

As with estrogen, the largest concentration of progesterone receptors is in the limbic area of the brain, which is considered to be the center of emotion. The amount of progesterone present in the blood is not as important in regards to PPD treatment as the amount of progesterone that reaches the nuclei and is then metabolized [10].

Progesterone receptors will not transport molecules of progesterone in the presence of adrenalin, because during times of stress the receptors transport corticosteroids rather than progesterone into the nuclei. If there is low blood sugar, the progesterone receptors transport glucocorticoids back into the cells in preference to progesterone. This helps to explain why oral progesterone is not effective. Oral progesterone must pass through the liver, which contains many progesterone receptors that metabolize the progesterone before it reaches the brain. Also, progesterone does not pass easily through the skin into the blood stream and is therefore not suitable for administration by cream or patch. There are no routine laboratory tests to determine the number or function of progesterone receptors [10].

Progesterone therapy may be given with any other medications, including antidepressants. It is considered safe for women who are breastfeeding. Progesterone should be halted for a 14-day period every month beginning with menstruation. As noted, the minimum effective dose for management of depressive symptoms is 400 mg suppositories twice daily or, alternatively, one 50 mg injection daily. These doses can be titrated upward to a maximum of six 400 mg suppositories daily or one 100 mg injection daily. Blood sugar should be monitored and kept stable [10].

Given the controversy over treatment of PPD with estrogen or progesterone, consensus has not been reached on the use of hormonal treatments for PPD. This area of inquiry deserves further study.

PHARMACOTHERAPY

Healthcare professionals should engage in a dialogue with patients with PPD to determine the treatment or medication that works best and to attempt to establish an informed decision. There is no way to know in advance which medication will be the most effective in treating PPD for an individual. If a woman has taken an ineffective medication for depression in the past, then it is wise to avoid it. If a medication has been effective in the past, it should be considered the drug of choice [2]. The main classifications of antidepressants used to treat depression are selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and atypical antidepressants.

Selective Serotonin Reuptake Inhibitors

SSRIs affect the action of the neurotransmitter serotonin. When serotonin is released in the synapse between neurons, it is reabsorbed by the brain cells, through the process of reuptake. Depression is assumed to be connected with decreased availability of serotonin and other neurotransmitters; therefore, interference with the reuptake of serotonin allows more to be available to boost communication in the brain. SSRIs inhibit only the reuptake of serotonin. Because SSRIs affect only one neurotransmitter, they presumably have less uncomfortable side effects than the more traditional antidepressants [158,159]. The more acceptable side effect profile of SSRIs makes them the drugs of choice for many depressive disorders [159,160].

Some of the most commonly used SSRIs are fluoxetine, paroxetine, sertraline, fluvoxamine, escitalopram, and citalopram [159,161]. Of these drugs, fluoxetine, paroxetine, and sertraline are prescribed most often [159,162]. Fluvoxamine, which is approved to treat obsessive-compulsive disorder, is sometimes used off-label to treat depression [161].

Benefits

The major benefit of SSRIs is their effectiveness in reducing symptoms of depression more quickly than the tricyclic antidepressants. These medications are also less likely than other antidepressants to have adverse interactions with other medications. However, some do exist [161].

SSRIs are especially useful if given in the early stages of depression, when symptoms are mild-to-moderate and are particularly effective in patients with obsessive-compulsive symptoms (particularly fluvoxamine) [161]. However, they are also effective for severe depressive disorders. Administration of an SSRI should result in elevated mood, lessened depressive symptoms, and an increase in self-confidence. Women should also experience less fatigue and a renewed ability to care for themselves and their babies. As depression improves, medication may be gradually decreased and eventually discontinued altogether [158,160].

Treatment with antidepressants as early as possible in the course of the illness may shorten and lessen the symptoms of PPD, affecting change within several weeks rather than months. Antidepressant treatment also reduces parenting stress. Improvement in the mother-infant interaction then has the benefit of reducing the negative impact of PPD on child development [127,133]. It should be noted that the effects of the SSRIs may not be seen for many days or weeks after instituting treatment.

Possible Adverse Reactions

The side effects of SSRIs are generally considered to be milder than traditional antidepressants, although there are still several side effects. They may initially increase anxiety or panic symptoms, and so should be avoided in patients whose depression includes these features. Those sensitive to SSRIs may have more severe reactions. Side effects may include [163,164]:

- Loss of appetite, weight loss

- Increased appetite, weight gain

- Nausea

- Allergic reactions, rash

- Dry mouth

- Headache

- Nervousness

- Restlessness

- Manic or hypomanic behavior

- Agitation

- Irritability/Anxiety

- Tremors

- Dizziness

- Increased sweating

- Insomnia

- Convulsions (rarely)

- Sexual dysfunction

- Drowsiness

Side effects that do occur usually subside after two weeks, when the body adjusts to the medications [161,165]. Adverse drug interactions have been noted with [163,164]:

- All other antidepressants

- Antihistamines

- Diabetes medications

- Antihypertensives

- Psychotropic drugs

- Caffeine

- Alcohol

- Cough suppressants

- Theophylline

- Tobacco

- Warfarin

These substances should be avoided while taking an SSRI for depression [164].

There are also certain medical conditions that warrant caution when considering the use of SSRIs, including [163,164]:

- Epilepsy

- Individuals receiving electroconvulsive therapy

- A personal or family history of bipolar disorder

- Heart disease

- Liver or kidney disease (Severe kidney or liver disease can result in higher than normal levels of the SSRIs.)

- Bleeding disorders

- Manic-depressive disorder

- Pregnancy or breastfeeding

Patients should be cautioned not to abruptly stop taking SSRIs, as withdrawal symptoms may occur [165,166].

Risks

The U.S. Food and Drug Administration (FDA) has alerted healthcare professionals and the public regarding a potentially life-threatening condition called serotonin syndrome. Serotonin syndrome, or serotonin toxicity, results from an excess of serotonergic activity in the central nervous system. It is seen only rarely in postpartum women, usually when multiple antidepressants, such as TCAs, MAOIs, St. John's wort, or opioids are combined. Serotonin syndrome is a medical emergency that requires immediate treatment. Symptoms and signs of this syndrome include [167,168]:

- Restlessness

- Tachycardia

- Diarrhea

- Nausea

- Vomiting

- Overactive reflexes

- Loss of coordination

- Hallucinations

- Hyperthermia

- Hypertension

- Coma

A risk of violent behavior has been associated with the use of SSRIs in a small number of people. In adverse drug event monitoring in the United Kingdom, violent events were reported in 56 of 13,741 (0.41%) patients taking paroxetine and 60 of 12,692 (0.47%) patients taking fluoxetine [169]. At the time of the study, researchers concluded that instances of serious violence among individuals using antidepressants were likely to be very rare [169]. However, Swedish researchers examined data from more than 850,000 individuals and found that SSRI use was linked to a 43% increased risk for violent crime among people 15 to 24 years of age. There was no significant association among older individuals [170].

An increased risk of suicidal thinking and behavior has been observed in young adults 18 to 24 years of age who are taking antidepressants, generally during the first one to two months of treatment. In 2004, the FDA issued a black box warning about the increased risk of suicidality for all antidepressants. The warning has been updated and states that, "antidepressants increased the risk [compared to placebo] of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with major depressive disorder and other psychiatric disorders. Anyone considering the use of [any antidepressant] in a child or adolescent must balance this risk with the clinical need" [171; 172]. The warning statements also emphasize that depression and certain other psychiatric disorders are themselves the most important causes of suicide [172].

Patients of all ages, including adolescent mothers with PPD, should be monitored carefully for clinical worsening, unusual changes in behavior, or suicidal risk both if treated with antidepressants or if no pharmacologic treatment is offered. Families and caregivers should be advised of the need for close observation and communication with the prescriber [172]. Fluoxetine is approved for use in children and adolescents for the treatment of major depressive disorder. Fluoxetine, sertraline, and fluvoxamine are approved for use in children and adolescents for the treatment of obsessive-compulsive disorder [163]. The remaining antidepressants are not FDA-approved for use in children [163,172,173]. The issue of treatment of depression in the pediatric population is hotly debated and requires additional research [174,175].

The FDA has recommended that healthcare providers consider the following points when treating patients with antidepressants [172]:

- All patients being treated with antidepressant medications, particularly those being treated for depression, should be watched closely for worsening of depression and for increased suicidal ideation or behavior.

- Close observation may be especially important when antidepressant medications are started for the first time or when doses have been changed.

- Patients whose symptoms worsen while being treated with antidepressants, including an increase in suicidal ideation or behavior, should be evaluated immediately.

- Consideration should be given to changing the therapeutic regimen, including discontinuing the medication, in patients whose depression is consistently worse or who are experiencing symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the person's presenting symptoms.

Patients taking antidepressants should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (i.e., psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day-to-day basis, as changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication [171,172].

Women who are planning to breastfeed should be made aware that antidepressant medications are secreted in breast milk, and breastfeeding while taking antidepressants exposes infants to potential effects of these drugs. The concentration of antidepressants in breast milk represents relatively low doses; however, the significance of infant exposure remains unknown. Toxic symptoms appearing in an infant should be reported immediately [133].

The AAP recommends exclusive breastfeeding for six months, with continuation for one additional year as mutually desired by the mother and child. If breastfeeding is helping a mother bond with her infant (rather than contributing to symptoms), it should be incorporated into PPD treatment. Alternatively, if breastfeeding is contributing to a woman's distress, she should not feel guilty for choosing to seek alternative forms of feeding.

Studies have shown that SSRIs peak in the breast milk seven to nine hours after maternal dosing. The highest concentrations are found in the hindmilk [163,176]. The best time to nurse is one hour before taking the SSRIs. If a mother must breastfeed during the peak concentration, she may nurse for a brief period and discard the hindmilk, which will help to reduce the amount of medication the baby receives [177].

A few studies of breastfeeding children have found low infant serum levels of sertraline [178,179]. Another study indicated the relative safety of nortriptyline, paroxetine, and sertraline [180]. Although sertraline may appear to be the safest SSRI for breastfeeding mothers, the long-term neurobehavioral development of exposed infants has not been investigated [163,176]. A review of evidence about the safety of each SSRI during pregnancy found evidence suggesting a teratogenic potential of the whole SSRI class. The teratogenic effects are mainly in the heart region, often described as septal defects [181].

Evidence Based Practice Recommendation

The Scottish Intercollegiate Guidelines Network recommends avoiding doxepin for treatment of depression in women who are breastfeeding. If initiating selective serotonin reuptake inhibitor treatment in breastfeeding women, then fluoxetine, citalopram, and escitalopram should be avoided, if possible.

https://www.sign.ac.uk/assets/sign127_update.pdf

Last Accessed: March 21, 2019

Level of Evidence: D (Non-analytic studies or expert opinion)

Fluoxetine produces the highest proportion of infant levels (22%), elevated more than 10% above the average maternal level, and fluoxetine has a longer half-life than either sertraline or paroxetine [166]. Two case reports of nursing infants whose mothers were taking fluoxetine related instances of increased irritability, colic, increased crying, decreased sleep, increased vomiting, and watery stools [176]. The long-term neurobehavioral development of infants exposed to fluoxetine has not been investigated. It is a drug "of concern" and should be used with caution in nursing mothers [163].

In the past, the AAP has maintained a list of drugs for which the effect on nursing infants is unknown but may be of concern [182]. However, in 2010 the AAP retired this guideline [183]. The AAP now states that only a small proportion of medications are contraindicated in breastfeeding mothers or associated with adverse effects on their infants [184]. Prescribers are advised to follow labelled warnings and consult online tools, such as LactMed (http://toxnet.nlm.nih.gov), for up-to-date information on medication use during breastfeeding [184,185].

Serotonin-Norepinephrine Reuptake Inhibitors

SNRIs act by inhibiting the reuptake of the neurotransmitters serotonin and norepinephrine. This results in an increase in the extracellular concentrations of serotonin and norepinephrine and therefore an increase in neurotransmission [186,187]. Most SNRIs, including venlafaxine, desvenlafaxine, levomilnacipran, and duloxetine, are several-fold more selective for serotonin over norepinephrine.

Benefits

SNRIs are a newer class of antidepressants, with use in the United States beginning in the 2000s. As such, there is not a large body of evidence comparing SNRIs to other available antidepressants. Venlafaxine is especially beneficial in treating anxiety in depressed patients. At lower doses (75 mg/day), venlafaxine acts much like an SSRI; SSRI-like side effects such as gastrointestinal upset often improve at higher doses (150–300 mg/day) [187]. However, discontinuation syndrome has been reported to be markedly worse for venlafaxine when compared to other SNRIs. The SNRIs also have an important role as second-line agents in patients who have not responded to SSRIs

Adverse Reactions

Safety, tolerability, and side effect profiles of SNRIs are similar to SSRIs, with the exception that the SNRIs have been associated (rarely) with sustained elevated blood pressure. SNRIs can be used as first-line agents, particularly in patients with significant fatigue or pain syndromes associated with the episode of depression [186,187]. Typical side effects include [163]:

- Headache

- Fatigue

- Dizziness

- Insomnia

- Anxiety

- Nausea

- Xerostomia

- Sexual dysfunction

- Weakness

- Diaphoresis

The manufacturer of venlafaxine specifically does not recommend breastfeeding during therapy [163].

Tricyclic Antidepressants (TCAs)

TCAs act by increasing levels of both serotonin and norepinephrine in the brain. In this way, TCAs differ from SSRIs in that they affect two neurotransmitters rather than just serotonin, and they have a different side effect profile. As with SSRIs, there is no way of knowing which antidepressant will be most beneficial to each individual woman [159].

The most common TCAs are clomipramine, amitriptyline, nortriptyline, desipramine, trimipramine, and imipramine. Treatment with TCAs should be at the lowest possible therapeutic dose to minimize possible side effects. To be most effective, antidepressant treatment should be combined with counseling or psychotherapy in most instances [188].

Benefits

The main benefit of TCAs is their long history of effectiveness in treating depression. TCAs were first utilized in the late 1950s and have amassed a record of treatment success [188]. Therefore, TCAs remain a viable option. Women for whom PPD is a recurrent depression may have a prior history of success with one of the TCAs, which makes the choice easier [160].

Some benefits of TCA use are the same as those described for SSRIs, including the reduction of symptoms and the potential positive effects of the mother's rapid recovery. Relief from symptoms can help a mother function despite continuing depressive symptoms and difficulty coping with problems. The degree of response, from a slight relief of symptoms to complete relief, depends on a variety of factors related to the individual woman and the severity of the depression being treated [159]. A potential benefit of nortriptyline for breastfeeding women is that it usually produces undetectable infant levels [180]. There are no food restrictions with any of the TCAs, with the exception of caffeine and alcohol.

Adverse Reactions

TCAs tend to have more adverse side effects than SSRIs. Although side effects associated with TCAs vary with the individual and the specific antidepressant taken, in some cases, the side effects may make the drug unusable for some women. Some typical side effects are [163,189]:

- Drowsiness

- Anxiety

- Restlessness

- Dry mouth

- Constipation

- Blurred vision

- Urinary retention

- Cognitive and memory difficulties

- Weight gain

- Increased sweating

- Dizziness

- Decrease in sexual ability and desire

- Muscle twitches

- Fatigue and weakness

- Nausea

- Increased heart rate

- Arrhythmias (very rare)

These side effects usually resolve within two weeks and can be reduced by lowering the dosage or switching to another TCA. If the adverse effects are unbearable or if they do not resolve, use of the medication is discontinued. When discontinuing an antidepressant, doses should be gradually tapered to avoid withdrawal symptoms [159].

Risks

There are a variety of factors that contraindicate the use of TCAs. TCAs should not be prescribed to anyone with a history of heart disease, as they may cause cardiovascular problems. There have also been cases of TCAs triggering manic episodes in patients with a personal or family history of bipolar disorder [190,191]. It is also important not to prescribe TCAs with any of the following medications or other items, as there are risks of dangerous interactions [189]:

- Bicarbonate of soda

- Oral contraceptives

- Some sleeping medications

- Some anticoagulants

- Aspirin

- Other antidepressants

- Diabetes medications

- Antiarrhythmic medications

- Mood stabilizers and anticonvulsants

- Pain medications and anesthetics

- Blood pressure medications

- Stimulants

- Weight loss drugs

- Diuretics

- Thyroid supplements

- Tobacco

- Antihistamines

- Alcohol

- Antibiotics

- Sedatives and tranquilizers

- Estrogen

- Disulfiram

- Antipsychotic drugs

- Antifungal agents

- Ephedrine

Heart arrhythmias have been reported in adolescents taking desipramine; therefore, extreme caution is advised about the use of desipramine with adolescent mothers [159,189]. The drug is not FDA approved for use in pediatric patients [163]. Due to the possibility of serious cardiac complications, TCAs can be lethal if misused at high doses [163]. Because suicidality is a risk in PPD, the danger of overdosing should be considered in prescribing TCAs [188].

As approximately 50% of all new mothers choose to breastfeed, treatment with antidepressants should be of concern [133]. As mentioned, while essentially all antidepressant medications transfer to breast milk, different medications are excreted at different levels. The treatment goal should be to minimize the amount of antidepressant the baby receives while maximizing the mother's emotional health. For healthy, full-term babies, the known benefits of breast milk could outweigh the potential hazards of most antidepressant medications [177]. The TCA doxepin should be avoided due to a case report of infant respiratory distress. Data on citalopram, fluvoxamine, bupropion, and venlafaxine are more limited, and their use cannot be recommended during breastfeeding. One study evaluating the potential consequences of TCA exposure through breast milk followed exposed children through preschool age and found that exposed children were developmentally similar to non-exposed children [186].

Monoamine Oxidase Inhibitors (MAOIs)

There are a small number of people for whom MAOIs are the best treatment [159]. Monoamine oxidase, an enzyme found in the brain, destroys neurotransmitters such as serotonin and norepinephrine. MAOIs act by inhibiting the activity of monoamine oxidase, blocking the breakdown of the neurotransmitters and making more serotonin and norepinephrine available to the neurons [192,193]. The traditional MAOIs are phenelzine, tranylcypromine, selegiline, and isocarboxazid [192,193].

Benefits

MAOIs work more quickly than TCAs and provide relief from symptoms shortly after beginning treatment. MAOIs are generally prescribed for people who do not initially respond to TCAs or SSRIs and for cases of atypical depression. Due to their stimulating effect, MAOIs may be preferable in the treatment of chronic low-level depression [159,163].

Adverse Reactions

The side effects of the common MAOIs are generally minimal. When adverse effects do occur, they include dizziness, rapid heartbeat, loss of sexual interest, and food interactions [163,192]. MAOIs can react with certain foods, alcohol, and some medications to produce a severe reaction. Reactions, which may not appear until several hours following ingestion of the medication, may include a severe rise in blood pressure, headache, nausea, vomiting, rapid heartbeat, confusion, seizures, stroke, psychotic symptoms, or coma [192].

Foods that contain a high level of tyramine can interact with MAOIs [163]. These foods mostly consist of aged cheeses; smoked, dried, or fermented meat; fish; air-dried sausages; soy products; red wine; beer and ale; fava beans; ripe figs; Brewer's yeast or yeast extracts; pickled or salted herring; beef or chicken liver; overripe bananas or avocados; sauerkraut; soups made from beef bouillon or Asian soup stocks, such as miso soup; white wine; gin; vodka; sour cream; yogurt; saccharine; and chocolate. Any of these foods can cause problems if ingested in large amounts [194].

Drug interactions are similar to those described for TCAs and may occur with [163,195]:

- Other antidepressants

- Asthma medications

- Cold, cough, allergy, sinus, and decongestant medications

- Diabetes medications

- Antihypertensives

- Mood stabilizers

- Painkillers and anesthetics

- Sedatives and tranquilizers

- Stimulants and street drugs

- Weight loss and appetite-suppression medications

MAOIs should also never be combined with SSRIs due to the risk of serotonin syndrome [159,163]. Serotonin syndrome, or serotonin toxicity, results from an excess of serotogenic activity in the central nervous system. The symptoms include tachycardia, diaphoresis, hypertension, hyperthermia, clonus, and disseminated intravascular coagulation. It is seen only rarely in postpartum women, usually when multiple antidepressants, such as SSRIs, SNRIs, TCAs, MAOIs, and St. John's wort, are combined [159,163].

Brexanolone

In 2019, the FDA approved the first drug specifically for the treatment of PPD [226]. Chemically, brexanolone is identical to endogenous allopregnanolone, a hormone that decreases after childbirth. It modulates GABA-A receptors, which become dysregulated in the postpartum period [163]. It is administered as a continuous IV infusion over a total of 60 hours [226].

At the time of its approval, available only through a restricted program called the Zulresso REMS Program that requires the drug be administered by a healthcare provider in a certified healthcare facility. Patients must be enrolled in the program prior to administration of the drug [226].

Benefits

Studies indicate that infusion of brexanolone results in a significant and clinically meaningful reduction in HAM-D total score in women with severe PPD, compared with placebo [227]. The drug appears to have a rapid onset of action and durable treatment response, adding a novel option for women with severe or refractory disease [227,228].

Risks

Brexanolone includes a black-box warning regarding the risk of serious harm due to the sudden loss of consciousness and for potential risk to children. As such, patients must be monitored for excessive sedation and sudden loss of consciousness and have continuous pulse oximetry monitoring [226]. While receiving the infusion, patients must be accompanied during interactions with their child(ren). Patients should be counseled on the risks and instructed that they must be monitored for these effects at a healthcare facility for the entire 60 hours of infusion. Patients should not drive, operate machinery, or do other dangerous activities until feelings of sleepiness from the treatment have completely dissipated [226].

PSYCHOSOCIAL INTERVENTIONS

Individual Therapy

Often, individual therapy and antidepressant medications are combined in a treatment regimen. However, some women with PPD will respond well to psychotherapy alone [63]. The decision of whether to use a medication is based on a complex combination of factors that include the severity of symptoms, the individual's preferences, the response to other treatments or changes in support, and the risk of side effects. In many cases, support and education alone are not effective treatments for PPD, and medication must be added. The presence of certain symptoms, such as loss of concentration, severe insomnia, confusion, extreme indecisiveness, and severe feelings of guilt, indicate that psychotherapy alone will not be a sufficient treatment option. It is important to remember that in severe cases of PPD, medications may contribute to a quicker, fuller, and longer-lasting recovery [63,196].

Success has been reported with the use of interpersonal psychotherapy [66,196]. However, it is unclear whether individual psychotherapy is effective prophylaxis to prevent recurrence of PPD in the five years after the initial onset of depression. Individual psychodynamic psychotherapy and cognitive behavioral therapy have also been effective in the treatment of PPD [196,197,198]. All women with PPD should be offered psychosocial treatment, and this is of particular urgency for women with severe symptoms or psychosis. Some women, however, may refuse treatment.

Group Therapy

As is well known, group therapy is an established form of professional treatment involving several individuals with similar issues meeting together at a specified time. The group is usually led by a singular therapist, but may include more than one group leader. Group therapy sessions may be limited to a specific number of meetings or may be ongoing. Meetings may be structured, with a set agenda or format for each group, or nondirective, with no specific topic except those issues that the participants decide to discuss. To obtain the best results, group therapy should be combined with individual psychotherapy rather than undertaken as a singular therapeutic regimen, especially for those depressed mothers who require individualized care.

The advantages of group therapy are that it is cost effective, reduces isolation, and offers support and empathy from others with similar problems. The disadvantages are that there is no one-on-one interaction between the therapist and each individual, and the group is not specifically tailored to meet each individual's particular needs [34]. Additionally, some mothers' childcare responsibilities may interfere with their ability to attend and participate in group therapy sessions [199]. A feasibility study on the effects of telecare therapy (i.e., a combination of cognitive-behavioral therapy, relaxation techniques, and problem-solving strategies) indicated that this may be an effective treatment option for women with PPD who are unable to attend group therapy sessions or support groups [200].

Support Groups

Social groups and self-help groups specifically established for women with PPD may be very helpful. These groups are not intended to provide therapeutic outcomes, but are created to provide support, empathetic listening, understanding, and information, all of which are important for depressed mothers. Women who wrote about their experiences with PPD specified that these groups gave them valuable practical guidance on day-to-day issues [11,99].

Self-help groups for PPD are usually led by a woman who has personal experience with PPD. This woman shares her knowledge and experience as guidance for other women, helping them deal with PPD. Resources for treatment of PPD and practical advice are usually part of such groups. They are also beneficial experiences for those women who feel alone and isolated [63].

According to one study, social support groups did not positively affect depressive symptoms per se, but did have a positive effect on the mother-infant interaction [66]. Support groups and self-help groups are no substitute for formal treatment. Like group therapy, they are best used as an adjunct to traditional therapy and medical intervention.

Overall, both psychosocial (e.g., peer support, nondirective counseling) and psychologic (e.g., cognitive behavioral therapy, interpersonal psychotherapy) interventions have been found to be effective in reducing symptoms of PPD and, more recently, to be effective in preventing PPD [201]. Overall, these interventions significantly reduce the number of women who develop PPD. However, the long-term benefits are unknown and larger trials are needed to determine the specific benefits of each type of intervention [201,202].

Psychiatric Hospitalization

Mothers suffering from severe mental illness in the postpartum period will inevitably require psychiatric hospitalization as part of their treatment. Unless the mother and infant are admitted together to a specialty unit, there may be little or no contact between them for several days or weeks. Separation of the mother and infant may have negative consequences [203]. However, the consequences (e.g., delayed bonding, cessation of breastfeeding) are secondary to the patient's and child's safety.

The physical separation of mother and infant protects the infant from the potential risks of interaction with a severely ill mother. However, separating mother and infant may have adverse effects on their subsequent relationship and the infant's socioemotional development. Although there are concerns about admitting infants with their mothers to psychiatric hospitals, there is no evidence of major disadvantages, and the advantages afforded to the mother and infant seem to be great [203].

Other concerns about the effects of separation include stunting of parenting skills and lack of infant attachment. These concerns have led mental health units in some countries to develop ways to provide psychiatric care for mentally ill mothers without separating them from their children [204].

Studies have shown that mothers separated from their infants during hospitalization have a longer duration of illness and experience greater difficulty bonding with their infants than mothers jointly admitted to a mother-baby unit. Most of the mothers admitted to a mother-baby unit showed a positive clinical outcome and were discharged home to care for their infant without further supervision. Mothers in a supportive social relationship had the best chance for a positive outcome [205].

Mother-baby units have been difficult to maintain in the United States. Although they offer significant advantages to mothers and families, data to support cost effectiveness are not available, which is a barrier to implementation [206]. As an example, the Women and Infant's Hospital, associated with Brown Medical School in Rhode Island, has operated since 1999. Services are provided in a mother-baby day hospital. The hospital admits both pregnant women with psychiatric problems and postpartum psychiatric patients for therapy [20].

13. PREVENTIVE STRATEGIES

Prevention of PPD is of utmost interest to researchers and clinicians, and it is clear that preventing severe depression would have clear benefits for mothers and children. Two barriers to effective and efficient postpartum care in the United States have been identified: the lack of parity between insurance coverage for mental and physical illnesses decreases access to care, and the current model of postpartum care fails to incorporate screening and follow-up. In developing a prevention model in the United States, these concerns should be taken into account. The types of prevention strategies employed should be determined by the risk factors with which a woman presents. Early detection and treatment are keys to a full recovery [207]. Healthcare professionals involved in childbirth education are in an excellent position to offer pregnant women anticipatory information about postpartum complications, including PPD [124].

SCREENING

Evidence Based Practice Recommendation

The Scottish Intercollegiate Guidelines Network recommends inquiry about depressive symptoms should be made, at minimum, on booking in and postpartum at four to six weeks and three to four months.

https://www.sign.ac.uk/assets/sign127_update.pdf

Last Accessed: March 21, 2019

Level of Evidence: D (Non-analytic studies or expert opinion)

An effort to place greater emphasis on identifying any previous psychiatric illness in pregnant women and their families, combined with the continuous observation of the psychologic well-being of women during pregnancy, will enable potential sufferers of PPD to receive treatment at the earliest possible stage. In addition to screening for PPD during pregnancy, screening at six weeks, three months, and six months postpartum should become routine. It remains the primary responsibility of physicians treating women of childbearing age to ensure that all healthcare professionals involved in prenatal care have a full knowledge of the devastating effects of PPD and actively work to detect women at risk as early as possible [10]. As noted, the EPDS is the most accepted and widely used screening tool available today and takes only a few minutes to administer. Having a standardized mechanism of screening available for all pregnant women should become the standard of care. Without a formal assessment, most depressive symptoms will remain undetected by primary care health professionals [201].

POSTPARTUM DEBRIEFING

For all women who have given birth, prevention planning should consist of an unstructured debriefing in the postpartum ward by a nurse, midwife, or someone functioning in a similar capacity. Studies show that providing women the opportunity to talk about their feelings following delivery allows them to integrate and make sense of their birth experiences. One study of postpartum debriefing, which is regularly utilized in many British and Australian hospitals, showed that unstructured debriefing resulted in a significant decrease in the likelihood of depressive symptoms [207]. These results indicate that even a short meeting with a nurse or similar professional involving listening, support, counseling, and explanations may be sufficient to prevent PPD in some first-time mothers. Evidence in support of formal, structured debriefings is inconclusive [208,209,210].

COMPANIONSHIP IN THE DELIVERY ROOM

It is believed that negative perceptions of labor and delivery, particularly a lengthy or difficult labor, may be a precursor to developing PPD. It is also posited that not having a supportive companion during labor and delivery might place women at risk for PPD. This would suggest that preventive work can be carried out in the delivery room [207,211,212,213].

One study examining companionship during labor and delivery designed an intervention involving a community volunteer to provide support during labor and delivery. The companion was instructed to use touch and verbal communication to comfort, reassure, and praise the woman. The study found that depression scores were significantly lower for women with a companion during labor and delivery compared to those women who did not have a companion [207]. A 2013 meta-analysis did not find evidence that companionship during delivery improved maternal mental health in the postpartum period, but the authors concluded that there was no harm with the use of support during childbirth and it could be considered due to the positive effects on the labor experience and newborn responsiveness [214]. They also state that "continuous support from a person who is present solely to provide support, is not a member of the woman's social network, is experienced in providing labor support, and has at least a modest amount of training, appears to be most beneficial" [214].

BRIEF PSYCHOTHERAPY

Interpersonal psychotherapy and cognitive behavioral therapy have been useful in preventing depression among at-risk persons. Consequently, there is interest in determining whether brief psychotherapy could be used to prevent PPD among predisposed women. In one study conducted among women who were considered at high risk for developing PPD, the effectiveness of group psychotherapy was tested [215]. Risk factors were identified as previous episodes of depression, mild-to-moderate levels of depressive symptoms, poor social support, and a life stressor within the past six months. The therapy consisted of four weekly, one-hour group sessions based on an interpersonal psychotherapy model. Each group was comprised of four to six women. The study found that improvement in depression scores was significantly greater among women in the intervention group compared to women receiving no therapy. Women receiving brief psychotherapy were significantly less likely to develop PPD. Authors of another study followed 34 women with perinatal depression through a nine-week cognitive behavioral therapy group program. On completion of the program, 80% of the women showed a clinically significant improvement in depressive symptoms as well as meaningful gains in social support, mother-infant bonding, and quality of partner relationship [216]. These findings suggest that brief group psychotherapy may be an effective prevention strategy for women who are at risk for PPD. However, more research is necessary to determine the usefulness of this treatment [216,217].

A single, brief cognitive behavioral therapy session taking place prior to being discharged from the hospital has also been shown to be effective in preventing PPD in at-risk women. In this study, women were considered to be at-risk if they were experiencing elevated depressive symptoms shortly after birth. The therapy given was a one-hour, individual session consisting of education, support, empathetic listening, and a cognitive-behavioral approach to dealing with ideas of perfectionistic standards. The researchers concluded that a single, brief intervention provided to high-risk women focusing on education, support, and modification of maladaptive thoughts can help to reduce the incidence of PPD [207]. While long-term effectiveness remains unclear, psychosocial and psychologic interventions (i.e., professionally based postpartum home visits, telephone-based peer support, interpersonal psychotherapy) have been found to significantly reduce the number of women who develop PPD [201].

The Mother-Infant Dyad

Most interventions to prevent PPD focus on just the mother rather than on the mother-infant dyad. One study examined the effectiveness of practical resources for effective postpartum parenting, a new PPD prevention protocol that aims to treat women at risk for PPD by promoting maternally mediated behavioral changes in their infants, while also including mother-focused skills [218]. Fifty-four women were included in this randomized control trial. Results indicate that this novel, brief intervention was well tolerated and effective in reducing maternal symptoms of anxiety and depression, particularly at six weeks postpartum [218].

Another study tested perinatal dyadic psychotherapy (PDP), a dual-focused mother-infant intervention designed to prevent or decrease maternal PPD and improve aspects of the mother-infant relationship that are related to the child's development [219]. Forty-two first-time mothers with depressive symptoms (recruited from hospital postpartum units) and their 6-week-old infants were enrolled and randomized to receive either the PDP intervention or usual care plus depression monitoring by telephone. The PDP intervention consisted of eight home-based, nurse-delivered mother-infant sessions consisting of supportive, relationship-based, mother-infant psychotherapy and a developmentally based infant-oriented component focused on promoting positive mother-infant interactions. Measures of maternal depression, anxiety, self-esteem, parenting stress, and mother-infant interaction were collected at baseline, post-intervention, and three-month follow-up. Depression and anxiety symptoms and diagnoses decreased significantly and maternal self-esteem increased significantly across the study time frame, with no differences between the two groups. There also were no significant differences between the groups on parenting stress or mother-infant interaction. No participants developed onset of PPD during the study. The authors concluded that although this novel intervention holds potential for treating depression in the context of the mother-infant relationship, usual care plus depression monitoring showed equal benefit [219]. Further research is needed.

A novel maternal-infant dyadic group therapy intervention was the focus of an open-label pilot study that targeted mothers with mood or anxiety disorders and their infants 6 to 12 months of age [220]. Three 12-week groups were conducted using evidence-based maternal and mother-infant dyadic strategies to enhance mood, insight, parenting, and mentalizing capacity. Outcome measures included recruitment and retention rates, reasons for nonparticipation, and missed sessions. Enhanced insight, parenting capacity, affect regulation, and positive interaction with the infant were supported with self-report surveys and interviews [220].

CONTINUITY OF CARE

Prevention studies involving care by midwives or other healthcare professionals suggest that the incidence of PPD in the general population may be reduced by providing personalized care to women in the hospital and at home after childbirth [201]. Continuity of care is ensured if the same professional provides personalized care during home visits. Ideally, the same nurse or midwife would provide care throughout the antepartum and postpartum periods, tailoring the care to the individual woman's needs rather than to a standardized care plan. A program focused on continuity of care, individualization, and emotional support has the potential to prevent or minimize the effects of PPD and could be implemented for many pregnant women [201,207,221,222]. Home visits should become the standard of care of at-risk women [201].

Because women are more likely to be engaged with health care during pregnancy, those involved in their care have a unique opportunity. By emphasizing prevention, addressing disparities, and focusing on integrating behavioral healthcare into primary care settings, those involved in the care of women can dramatically and positively impact women's health [223].

PREVENTIVE HORMONE TREATMENT

The use of hormones in the prevention of recurrence of PPD was first reported in 1964 [10]. There is some conflicting evidence regarding the efficacy of progesterone and estrogen, and the use of synthetic progestins is associated with increased risk of developing PPD [155,224].

If utilized, it is advised that, upon completion of labor, the patient is given 100 mg of progesterone by injection daily for seven days, followed by a 400 mg suppository twice daily until the return of menstruation. The dosage of suppositories may be increased if the mother experiences a return of mild early symptoms. Each woman should also be equipped with information about the symptoms of PPD [10]. At the end of two months, if menstruation has not begun and no symptoms appear, the number of suppositories may be reduced and then discontinued. If menstruation has begun and symptoms appear, progesterone should be given from day 14 of the cycle until the next menstruation. Natural progesterone should only be given in the prescribed method of administration. Studies have been conducted on progesterone preventive treatment in 1985, 1989, 1994, and 1995 [10]. In these studies, the prevention of symptom recurrence was 90% to 92% successful.

A comprehensive meta-analysis published in 2000 and updated in 2008 concluded that synthetic progestogens should be used with caution in the postpartum period and that the role of natural progesterone in the prevention and treatment of PPD requires further evaluation. Estrogen therapy was found to be of modest value for treatment of severe PPD, while its role in the prevention of recurrent PPD requires further research [46,47,155].

14. CONCLUSION

PPD is a major complication of childbirth. Given the potential negative consequences for the mother, baby, and entire family, early detection and treatment are essential. Studies have shown that PPD not only responds well to treatment, but is preventable [207]. However, there remains a knowledge gap about PPD and its effects on women and children. This knowledge gap exists in most facets of society, including the healthcare sector. PPD remains a misunderstood illness that is often improperly diagnosed and treated.

All healthcare professionals who treat pregnant women should assess their patients for the early warning signs and risks of PPD and undertake the appropriate courses of action [124]. Devastating cases of suicide and infanticide can be prevented, and the potential harm to families through isolation and neglect can be minimized.

In addition to educating themselves, healthcare providers should educate all pregnant women about the symptoms of PPD and the resources available to treat it. Screening for PPD and education about PPD should become the standard for postpartum care.

15. GLOSSARY

Adrenal glands: A pair of small glands above each kidney responsible for producing numerous hormones, including adrenaline; also referred to as adrenals

Acetylcholine: A neurotransmitter released and hydrolyzed in certain synaptic transmissions of the nervous system and in the initiation of muscle contraction

Adrenaline: A neurotransmitter produced by the adrenal gland released in response to fear, heightened emotion, or other physiologic stresses

Amygdala: A group of neuronal nuclei in the dorsomedial temporal lobe that subserve informational learning in conjunction with the hippocampus

Brain stem: The portion of the brain, composed of the medulla oblongata, the pons, and the midbrain, that governs a variety of vegetative functions and contains sensory and motor fibers of passage

Cerebral cortex: The outermost region of the cerebrum, consisting of several dense layers of neural cell bodies and including numerous conscious centers; also referred to as gray matter

Circadian rhythm: A biologic rhythm about one day in length

Cortex: The outer layer of an organ, such as the brain

Corticosteroids: Hormones produced by the cortex of the adrenal glands

Cortisol: A steroid hormone produced and released by the adrenal gland that helps to regulate blood sugar, blood pressure, and bone growth as well as other functions

Dysphoria: A lowering of mood, characterized by malaise, unrest, or anxiety

Endocrine gland: An organ that releases hormones into the blood to act on distant cells

Endometrium: The inner lining of the uterus

Estrogen receptor: A protein on some cells to which an estrogen molecule can attach

Etiology: The causative agent of a disorder or disease

Follicle: A cyst or sac in which each egg in the ovary develops

Follicle-stimulating hormone (FSH): A hormone produced by the pituitary, acting on the ovary to ripen the follicles and produce estrogen

Gonadotrophin releasing hormone (GnRH): A hormone from the hypothalamus that stimulates the ovaries in women

Hippocampus: The area of the brain involved in learning and memory

Hormone receptors: Compounds that transport hormone molecules into the nucleus of cells

Human chorionic gonadotropin (hCG): The placental hormone of pregnancy

Hypothyroidism: An underactive thyroid function caused by abnormally low levels of circulating thyroid hormone; symptoms include physical and mental sluggishness, weight gain, hair loss, and infertility

Hypothalamus: A portion in the brain that produces hormones that initiate the reproductive cycle as well as other functions

Limbic system: A group of structures in the brain operating below the level of consciousness important in regulating such behavior as eating, drinking, aggression, sexual activity, and expressions of emotion; the emotional brain

Luteinizing hormone (LH): The hormone secreted by the pituitary that triggers ovulation and the production of progesterone

Menarche: The first menstruation at puberty

Menstrual clock: A specialized portion of the hypothalamus responsible for the cyclical timing of menstruation

Neurotransmitters: Chemical signals that communicate among neurons, resulting in electrical impulse activity, altered gene expression, growth, and survival

Oxytocin: A hormone produced by the pituitary gland that causes uterine contractions

Pituitary gland: A pea-sized gland located between and behind the eyes in the base of the brain that secretes hormones to control many other glands in the body, including ovaries, thyroid, and adrenal glands; it is controlled by the hypothalamus

Postpartum: The period following childbirth, generally considered to be six weeks

Progesterone: A hormone produced by the ovaries for the preparation of the lining of the uterus and the production of numerous corticosteroids

Steroids: A family of lipid molecules including cholesterol and the naturally-occurring hormones estrogen, progesterone, and testosterone

Synapse: The junction between nerve cells

Thyroid gland: A gland located in the neck in front and on each side of the trachea that secretes thyroxin and other hormones responsible for numerous metabolic and essential processes

16. RESOURCES

American College of Nurse-Midwives

http://www.midwife.org

National Institute of Mental Health

https://www.nimh.nih.gov

Postpartum Education for Parents

http://www.sbpep.org

Postpartum Support International

http://www.postpartum.net

U.S. Department of Health and Human Services Office on Women's Health

https://www.womenshealth.gov

17. APPENDIX

MISCONCEPTIONS AND MYTHS REGARDING PPD: PATIENT EDUCATION

Myth: Women who have PPD are weak and lacking in character. They probably bring it on themselves.

Fact: There are numerous factors that cause PPD. Women who have PPD are no weaker than any other women nor do they bring it on themselves.

Myth: Depressionis just an excuse to get out of difficult circumstances.

Fact: Depression is not an excuse nor is it sought deliberately by any person. It happens to them. The sufferer should not be blamed for her depression.

Myth: PPD is just a temporary sadness or something a woman can just "snap out of" and "pull herself together."

Fact: PPD is not simply sadness or something a woman can just "snap out of." PPD can impair a woman's social and physical functioning to the point of disability and even suicide.

Myth: There is nothing a medical professional can do about depression. It is untreatable.

Fact: Depression is caused by an interaction of biologic and environmental influences. It is a treatable condition.

Myth: Once depressed, it is a lifetime problem. The person never recovers.

Fact: Depression can recur and seem to be a lifetime problem for some people. However, depression is a treatable illness, and the depressed person can recover and live a normal, healthy life.

Myth: Women with PPD are demonstrating that they are self-centered and manipulative.

Fact: Women with PPD are suffering an emotional disorder. Their symptoms are real, not manipulative.

Myth: Depression does not require medical treatment. One can cure depression by will power, buying a new dress, throwing a party, drinking champagne, or taking a vacation.

Fact: Depression requires medical treatment. Will power alone cannot cure depression, as it involves experiencing a lack of pleasure in things of everyday life such as shopping, partying, and vacations. Drinking alcoholic beverages can worsen depression.

Myth: Medications used for treating depression are habit forming.

Fact: Medications used for treating depression are not habit forming. As depression goes into remission, drugs can be tapered off and stopped.

Myth: When a depressed mother expresses suicidal ideation, she has no intention of acting on them. She is probably just trying to get special attention.

Fact: Suicide is always a risk with a mother who is depressed. Any expressed suicidal ideas should be taken seriously.

Myth: People who do commit suicide just do it, they do not talk about it.

Fact: People who commit suicide have generally given clues to their friends and family of their intentions. These clues are often not understood or not taken seriously.

Myth: If a person is suspected of having suicidal thoughts, one should not talk about it as it will make it worse.

Fact: An empathetic, tactful discussion about suicidal thoughts with a person who is depressed often alleviates the risk of suicide and assists the person to obtain appropriate medical care.

Myth: Only women from lower socioeconomic levels suffer from PPD.

Fact: Low socioeconomic status can be a factor for PPD; however, it affects women across all socioeconomic levels.

Works Cited

1. World Health Organization Department of Reproductive Health and Research. Postpartum Care of the Mother and Newborn: A Practical Guide. Available at http://apps.who.int/iris/bitstream/10665/66439/1/WHO_RHT_MSM_98.3.pdf. Last accessed February 14, 2017.

2. Misri S. Shouldn't I Be Happy? Emotional Problems of Pregnant and Postpartum Women. New York, NY: The Free Press; 1995.

3. Joy S, Isaacs C. Postpartum Depression. Available at http://reference.medscape.com/article/271662-overview. Last accessed February 14, 2017.

4. March of Dimes Foundation. Baby Blues After Pregnancy. Available at http://www.marchofdimes.org/pregnancy/baby-blues-after-pregnancy.aspx. Last accessed February 14, 2017.

5. Office of Women's Health. Depression During and After Pregnancy Fact Sheet. Available at https://www.womenshealth.gov/publications/our-publications/fact-sheet/depression-pregnancy.html. Last accessed February 14, 2017.

6. Khandelwal S, Chowdhury AKMN, Regmi SK, Mendis N, Kittirattan. Conquering Depression. New Delhi: World Health Organization Regional Office for South-East Asia; 2001.

7. Campbell SB, Cohn JF. The timing and chronicity of postpartum depression: implications for infant development. In: Murray L, Cooper PJ (eds). Postpartum Depression and Child Development. New York, NY: The Guilford Press; 1997: 165-197.

8. Attia E, Downey J, Oberman M. Postpartum psychoses. In: Miller LJ (ed). Postpartum Mood Disorders. Washington, DC: American Psychiatric Press, Inc.; 1999: 99-117.

9. Postpartum Support International. Postpartum Psychosis. Available at http://www.postpartum.net/learn-more/postpartum-psychosis. Last accessed February 14, 2017.

10. Dalton K, Horton WM. Depression After Childbirth: How to Recognize, Treat, and Prevent Postnatal Depression. 4th ed. New York, NY: Oxford University Press; 2001.

11. Resnick SK. Sleepless Days: One Woman's Journey Through Postpartum Depression. New York, NY: St. Martin's Press; 2000.

12. Cox JL, Holden JM, Sagovsky R. Detection of postnatal depression: development of the 10-item Edinburgh Postnatal Depression Scale. Br J Psychiatry. 1987;150:782-786.

13. Sichel D, Driscoll JW. Women's Moods: What Every Woman Must Know About Hormones, the Brain, and Emotional Health. New York, NY: William Morrow and Company; 1999.

14. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Publishing; 2013.

15. Monzon C, Lanza T, Pearlstein T. Postpartum Psychosis: Updates and Clinical Issues. Available at http://www.psychiatrictimes.com/special-reports/postpartum-psychosis-updates-and-clinical-issues. Last accessed February 14, 2017.

16. Class QA, Verhulst J, Heiman JR. Exploring the heterogeneity in clinical presentation and functional impairment of postpartum depression. J Reprod Infant Psychol. 2013;31(2):183-194.

17. Bernstein IH, Rush AJ, Yonkers K, et al. Symptom features of postpartum depression: are they distinct? Depress Anxiety. 2008;25(1):20-26.

18. Glangeaud-Freudenthal NMC, Barnett BEW. Mother-baby inpatient psychiatric care in different countries: data collection and issues. Introduction. Arch Womens Ment Health. 2004;7(1):49-51.

19. Misri SK. Pregnancy Blues: What Every Woman Needs to Know About Depression During Pregnancy. New York, NY: Bantam Dell; 2005.

20. Howard M, Battle CL, Pearlstein T, Rosene-Montella K. A psychiatric mother-baby day hospital for pregnant and postpartum women. Arch Womens Ment Health. 2006;9(4):213-218.

21. University of North Carolina at Chapel Hill. Perinatal Psychiatry Inpatient Unit. Available at http://www.med.unc.edu/psych/wmd/patient_care/perinatal-inpatient. Last accessed February 14, 2017.

22. U.S. Congress. Mom's Opportunity to Access Health, Education, Research, and Support for Postpartum Depression Act, S 1375, 110th Cong, (2007).

23. New Jersey Legislature. Section 2 of P.L.2000, c.167 (C.26:2-176). Available at http://www.njleg.state.nj.us/2006/bills/pl06/12_.htm. Last accessed February 14, 2017.

24. Illinois General Assembly. Public Act 095-0469. Available at http://www.ilga.gov/legislation/publicacts/fulltext.asp?Name=095-0469. Last accessed February 14, 2017.

25. Storrs C. Do Laws on Postpartum Depression Screening Help Women? Available at https://www.seleni.org/advice-support/article/do-laws-on-postpartum-depression-screening-help-women. Last accessed February 14, 2017.

26. Postpartum Support International. Legislation. Available at http://www.postpartum.net/professionals/legislation. Last accessed February 14, 2017.

27. Wile J, Arechiga M. Sociocultural aspects of postpartum depression. In: Miller LJ (ed). Postpartum Mood Disorders. Washington, DC: American Psychiatric Press, Inc.; 1999: 83-98.

28. Stahura B. Tangled up in blue: living with depression. Soroptimist Am. 2003;12-17.

29. Liu CH, Tronick E. Prevalence and predictors of maternal postpartum depressed mood and anhedonia by race and ethnicity. Epidemiol Psychiatr Sci. 2014;23(2):201-209.

30. Huysman AM. The Postpartum Effect: Deadly Depression in Mothers. New York, NY: Seven Stories Press; 2003.

31. PubMed Health. Postnatal Depression (Postpartum Depression). Available at https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0024789. Last accessed February 14, 2017.

32. Liu CH, Tronick E. Rates and predictors of postpartum depression by race and ethnicity: results from the 2004 to 2007 New York City PRAMS survey (Pregnancy Risk Assessment Monitoring System). Matern Child Health J. 2013;17(9):1599-1610.

33. Marcus SM. Depression during pregnancy: rates, risks and consequences—Motherisk Update, 2008. Can J Clin Pharmacol. 2009;16(1):e15-e22.

34. Sebastian L. Overcoming Postpartum Depression and Anxiety. Omaha, NE: Addicus Books, Inc.; 2009.

35. Young E, Korszun A. Sex, trauma, stress hormones and depression. Mol Psychiatry. 2010;15(1):23-28.

36. Parry BL. Postpartum depression in relation to other reproductive cycle mood changes. In: Miller LJ (ed). Postpartum Mood Disorders. Washington, DC: American Psychiatric Press, Inc.; 1999: 21-46.

37. Payne JL, Palmer JT, Joffe H. A reproductive subtype of depression: conceptualizing models and moving toward etiology. Harv Rev Psychiatry. 2009;17(2):72-86.

38. Robinson DS. The role of dopamine and norepinephrine in depression. Primary Psychiatry. 2007;14(5):21-23.

39. Gorman LL, O'Hara MW, Figueiredo B, et al. Adaptation of the structured clinical interview for DSM-IV disorders for assessing depression in women during pregnancy and post-partum across countries and cultures. Br J Psychiatry. 2004;184(46):S17-S23.

40. Hasler G. Pathophysiology of depression: do we have any solid evidence of interest to clinicians? World Psychiatry. 2010;9(3):155-161.

41. Shapiro GD, Fraser WD, Séguin JR. Emerging risk factors for postpartum depression: serotonin transporter genotype and omega-3 fatty acid status. Can J Psychiatry. 2012;57(11):704-712.

42. Hendrick V, Altshuler LL. Biological determinants of postpartum depression. In: Miller LJ (ed). Postpartum Mood Disorders. Washington, DC: American Psychiatric Press, Inc.; 1999: 65-82.

43. Parry L, Haynes P. Mood disorders and the reproductive cycle. J Gend Specif Med. 2000;3(5):53-58.

44. Steiner M, Dunn E, Born L. Hormones and mood: from menarche to menopause and beyond. J Affect Disord. 2003;74(1):67-83.

45. Soares CN, Poitras JR, Prouty J. Effect of reproductive hormones and selective estrogen receptor modulators on mood during menopause. Drugs Aging. 2003;20(2):85-100.

46. Li W, Li QJ, An SC. Preventive effect of estrogen on depression-like behavior induced by chronic restraint stress. Neurosci Bull. 2010;26(2):140-146.

47. Insel T. Spotlight on Postpartum Depression. Available at https://www.nimh.nih.gov/about/directors/thomas-insel/blog/2010/spotlight-on-postpartum-depression.shtml. Last accessed February 14, 2017.

48. Wise DD, Felker A, Stahl SM. Tailoring treatment of depression for women across the reproductive lifecycle: the importance of pregnancy, vasomotor symptoms, and other estrogen-related events in psychopharmacology. CNS Spectr. 2008;13(8):647-662.

49. Mehta D, Newport DJ, Frishman G, et al. Early predictive biomarkers for postpartum depression point to a role for estrogen receptor signaling. Psychol Med. 2014;44(11):2309-2322.

50. Schiller CE, Meltzer-Brody S, Rubinow DR. The role of reproductive hormones in postpartum depression. CNS Spectr. 2015;20(1):48-59.

51. Jolley SN, Elmore S, Barnard KE, Carr DB. Dysregulation of the hypothalamic-pituitary-adrenal axis in postpartum depression.Biol Res Nurs. 2007;8(3):210-222.

52. Glynn LM, Davis EP, Sandman CA. New insights into the role of perinatal HPA-axis dysregulation in postpartum depression. Neuropeptides. 2013;47(6):363-370.

53. Meinlschmidt G, Martin C, Neumann ID, Heinrichs M. Maternal cortisol in late pregnancy and hypothalamic-pituitary-adrenal reactivity to psychosocial stress postpartum in women. Stress. 2010;13(2):162-171.

54. O'Hara MW, McCabe JE. Postpartum depression: current status and future directions. Annu Rev Clin Psychol. 2013;9:379-407.

55. Sylvén SM, Elenis E, Michelakos T, et al. Thyroid function tests at delivery and risk for postpartum depressive symptoms. Psychoneuroendocrinology. 2013;38(7):1007-1013.

56. Alexander EK, Pearce EN, Brent GA, et al. 2017 guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid. 2017;27(3):315-389.

57. Albacar G, Sans T, Martin-Santos R, et al. Thyroid function 48h after delivery as a marker for subsequent postpartum depression. Psychoneuroendocrinol. 2010;35(5):738-742.

58. Negro R, Schwartz A, Gismondi R, Tinelli A, Mangieri T, Stagnaro-Green A. Universal screening versus case finding for detection and treatment of thyroid hormonal dysfunction during pregnancy. J Clin Endocrinol Metab. 2010;95(4):1699-1707.

59. Sylvéna SM, Elenisa E, Michelakos T, et al. Thyroid function tests at delivery and risk for postpartum depressive symptoms. Psychoneuroendocrinology. 2013;38(7):1007-1013.

60. Wier FA, Farley CL. Clinical controversies in screening women for thyroid disorders during pregnancy. J Midwifery Womens Health. 2006;51(3):152-158.

61. De Groot L, Abalovich M, Alexander EK, et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline. JCEM. 2012;97(8):2543-2565.

62. Stricker G, Widiger TA, Weiner IB. Handbook of Psychology, Clinical Psychology. Vol. 8. Hoboken, NJ: Wiley; 2003.

63. Kleiman KR, Raskin VD. This Isn't What I Expected: Overcoming Postpartum Depression. 2nd ed. Boston, MA. DaCapo; 2013.

64. Gelabert E, Subirà S, García-Esteve L, et al. Perfectionism dimensions in major postpartum depression. J Affect Disord. 2012;136 (1-2):17-25.

65. Cummings EM, Cheung RY, Koss K, Davies PT. Parental depressive symptoms and adolescent adjustment: a prospective test of an explanatory model for the role of marital conflict. J Abnorm Child Psychol. 2014;42(7):1153-1166.

66. O'Hara MW. The nature of postpartum depressive disorders. In: Murray L, Cooper PJ (eds). Postpartum Depression and Child Development. New York, NY: The Guilford Press; 1997: 3-34.

67. Centers for Disease Control and Prevention. Infertility. Available at https://www.cdc.gov/nchs/fastats/infertility.htm. Last accessed February 14, 2017.

68. McDonald EE. A Global Perspective on Infertility: An Under Recognized Public Health Issue. The University of North Carolina Center for International Studies: Chapel Hill, NC; 2004.

69. Spinelli MG. Postpartum psychosis: detection of risk and management. Am J Psychiatry. 2009;166:405-408.

70. U.S. National Library of Medicine. Postpartum Depression. Available at https://medlineplus.gov/ency/article/007215.htm. Last accessed February 14, 2017.

71. Iles S, Gath D, Kennerly H. Maternity blues, II: a comparison between post-operative women and post-natal women. Br J Psychiatry. 1989;155:363-366.

72. Miller LJ, Rukstalis M. Beyond the "blues:" hypotheses about postpartum reactivity. In: Miller LJ (ed). Postpartum Mood Disorders. Washington, DC: American Psychiatric Press, Inc.; 1999: 3-20.

73. Kennedy HP, Beck CT, Driscoll JW. A light in the fog: caring for women with postpartum depression. J Midwifery Womens Health. 2002;47(5):318-330.

74. Adewuya AO. The maternity blues in Western Nigerian women: prevalence and risk factors. Am J Obstet Gynecol. 2005;193(4):1522-1525.

75. Taniguchi H, Baruffi G. Childbirth overseas: the experience of Japanese women in Hawaii. Nurs Health Sci. 2007;9(2):90-95.

76. Klainin P, Arthur DG. Postpartum depression in Asian cultures: a literature review. Int J Nurs Stud. 2009;46(10):1355-1373.

77. Goldbort J. Transcultural analysis of postpartum depression. MCN AM J Matern Child Nurs. 2006;31(2):121-126.

78. Thurgood S, Avery DM, Williamson L. Postpartum depression (PPD). Am J Clin Med. 2009;6(2):17-22.

79. National Center for Health Statistics. Births and Natality. Available at https://www.cdc.gov/nchs/fastats/births.htm. Last accessed February 14, 2017.

80. Postpartum Progress. The Statistics. Available at http://postpartumprogress.org/the-facts-about-postpartum-depression. Last accessed February 14, 2017.

81. The American College of Obstetricians and Gynecologists (ACOG). ACOG Committee Opinion No. 343: psychosocial risk factors: perinatal screening and intervention. Obstet Gynecol. 2006;108(2):469-477.

82. American Psychological Association. What is Postpartum Depression and Anxiety? Available at http://www.apa.org/pi/women/resources/reports/postpartum-depression.aspx. Last accessed February 14, 2017.

83. Harlow BL, Vitonis AF, Sparen P, Cnattingius S, Joffe H, Hultman CM. Incidence of hospitalization for postpartum psychotic and bipolar episodes in women with and without prior prepregnancy or prenatal psychiatric hospitalizations. Arch Gen Psychiatry. 2007;64(1):42-48.

84. Almond P. Postnatal depression: a global public health perspective. Perspect Public Health. 2009;129(5):221-227.

85. Tschinkel S, Harris M, Le Noury J, Healy D. Postpartum psychosis: two cohorts compared, 1875–1924 and 1994–2005. Psychol Med. 2007;37(4):529-536.

86. Alagiakrishnan K. Delirium. Available at http://emedicine.medscape.com/article/288890-overview. Last accessed February 14, 2017.

87. Hatters Friedman S, Sorrentino R. Commentary: postpartum psychosis, infanticide, and insanity—implications for forensic psychiatry. J Am Acad Psychiatry Law. 2012;40(3):326-332.

88. Spinelli MG. Infanticide: Psychosocial and Legal Perspectives on Mothers Who Kill. Arlington, VA: American Psychiatric Publishing, Inc.; 2002.

89. Spinelli MG. Maternal infanticide associated with mental illness: prevention and the promise of saved lives. Am J Psychiatry. 2004;161(9):1548-1557.

90. BBC News. Analysis: U.S. Law and Infanticide. Available at http://news.bbc.co.uk/2/hi/americas/1401667.stm. Last accessed February 14, 2017.

91. Friedman SH, Hrouda DR, Holden CE, Noffsinger SG, Resnick PJ. Child murder committed by severely mentally ill mothers: an examination of mothers found not guilty by reason of insanity. J Forensic Sci. 2005;50(6):1466-1471.

92. Kinniburgh B, Morrow B, Lipscomb L, PRAMS Working Group. PRAMS and Postpartum Depression. Atlanta, GA: Centers for Disease Control and Prevention; 2004.

93. Epperson CN. Postpartum major depression: detection and treatment. Am Fam Physician. 1999;59(8):2247-2254, 2259-2260.

94. O'Connor E, Rossom RC, Henninger M, et al. Primary care screening for and treatment of depression in pregnant and postpartum women: evidence report and systematic review for the U.S. Preventive Services Task Force. JAMA. 2016;315(4):388-406.

95. Quevedo LA, Silva RA, Godoy R, et al. The impact of maternal post-partum depression on the language development of children at 12 months. Child Care Health Dev. 2012;38(3):420-424.

96. National Collaborating Centre for Women's and Children's Health. Antenatal Care: Routine Care for the Healthy Pregnant Woman. London: National Institute for Health and Clinical Excellence; 2008.

97. American College of Obstetricians and Gynecologists. ACOG Committee Opinion No. 630: Screening for Perinatal Depression. Washington, DC: American College of Obstetricians and Gynecologists; 2016.

98. Gross KH, Wells CS, Radigan-Garcia A, Dietz PM. Correlates of self-reports of being very depressed in the months after delivery: results from the Pregnancy Risk Assessment Monitoring System. Matern Child Health J. 2002;6(4):247-253.

99. Lasalandra SM. A Daughter's Touch: A Journey of a Mother Trying to Come to Terms with Postpartum Depression. Quattro M Publishing; 2004.

100. Shields B. Down Came The Rain: My Journey Through Postpartum Depression. New York, NY: Hyperion; 2005.

101. The Office of the Revisor of Statutes, State of Minnesota. 2016 Minnesota Statutes: 145.906 Postpartum Depression Education and Information. Available at https://www.revisor.mn.gov/statutes/?id=145.906. Last accessed February 14, 2017.

102. Bennett SS, Indman P. Beyond the Blues: A Guide to Understanding and Treating Prenatal and Postpartum Depression. San Jose, CA: Moodswings Press; 2006.

103. Beck CT, Gable RK. Postpartum depression screening scale: development and psychometric testing. Nurs Res. 2000;49(5):272-282.

104. Boyd RC, Le HN, Somberg R. Review of screening instruments for postpartum depression. Arch Womens Ment Health. 2005;8:141-153.

105. Zubaran C. Schumacher M, Roxo MR, Foresti K. Screening tools for postpartum depression: validity and cultural dimensions.Afr J Psychiatry (Johannesbg). 2010;13(5):357-365.

106. Murray L, Cooper PJ. The role of infant and maternal factors in postpartum depression, mother-infant interactions, and infant outcome. In: Murray L, Cooper PJ (eds). Postpartum Depression and Child Development. New York, NY: The Guilford Press; 1997: 111-135.

107. Beck CT. Postpartum depression: it isn't just the blues. Am J Nurs. 2006;106(5):40-50.

108. Phillips R. The sacred hour: uninterrupted skin-to-skin contact immediately after birth. Newborn Infant Nurs Rev. 2013;13(2): 67-72.

109. Klier CM. Mother-infant bonding disorders in patients with postnatal depression: the Postpartum Bonding Questionnaire in clinical practice. Arch Womens Ment Health. 2006;9(5):289-291.

110. Klier CM, Muzik M. Mother-infant bonding disorders and use of Parental Bonding Questionnaire in clinical practice. World Psychiatry. 2004;3(2):102-103.

111. Brockington IF, Oats J, George S, et al. A screening questionnaire for mother-infant bonding disorders. Arch Womens Ment Health. 2001;3(4):133-140.

112. Tronick EZ, Weinberg MK. Depressed mothers and infants: failure to form dyadic states of consciousness. In: Murray L, Cooper PJ (eds). Postpartum Depression and Child Development. New York, NY: The Guilford Press; 1997: 54-84.

113. Feldman R, Granat A, Pariente C, Kanety H, Kuint J, Gilboa-Schechtman E. Maternal depression and anxiety across the postpartum year and infant social engagement, fear regulation, and stress reactivity. J Am Acad Child Adolesc Psychiatry. 2009;48(9):919-927.

114. Manian N, Bornstein MH. Dynamics of emotion regulation in infants of clinically depressed and nondepressed mothers. J Child Psychol Psychiatry. 2009;50(11):1410-1418.

115. Tronick E, Reck C. Infants of depressed mothers. Harv Rev Psychiatry. 2009;17(2):147-156.

116. Forman DR, O'Hara MW, Stuart S, Gorman LL, Larsen KE, Coy KC. Effective treatment for postpartum depression is not sufficient to improve the developing mother-child relationship. Dev Psychopathol. 2007;19(2):585-602.

117. Mirhosseini H, Moosavipoor SA, Nazari MA, et al. Cognitive behavioral development in children following maternal postpartum depression: a review article. Electron Physician. 2015;7(8):1673-1679.

118. Murray L, Sinclair D, Cooper P, Ducournan P, Turner P, Stein A. The socioemotional development of 5-year-old children of postnatally depressed mothers. J Child Psychol Psychiatry. 1999;40(8):1259-1271.

119. Murray L, Hipwell A, Hooper R, Stein A, Cooper P. The cognitive development of 5-year-old children of postnatally depressed mothers. J Child Psychol Psychiatry. 1996;37(8):927-935.

120. Grace SL, Evindar A, Stewart DE. The effect of postpartum depression on child cognitive development and behavior: a review and critical analysis of the literature. Arch Womens Ment Health. 2003;6(4):263-274.

121. Vameghi R, Akbari S, Saijadi H, Sajedi F, Alavimajd H. Correlation between mothers' depression and developmental delay in infants aged 6-18 months. Glob J Health Sci. 2015;8(5):11-18.

122. Murray L, Woolgar M, Cooper PJ, Hipwell A. Cognitive vulnerability to depression in 5-year-old children of depressed mothers.J Child Psychol Psychiatry. 2001;42(7):891-899.

123. Kurstjens S, Wolke D. Effects of maternal depression on cognitive development of children over the first 7 years of life. J Child Psychol Psychiatry. 2001;42(5):623-636.

124. Zauderer C. Postpartum depression: how childbirth educators can help break the silence. J Perinat Educ. 2009;18(2):23-31.

125. Day EH. Applying the Listening to Mothers II results in Lamaze class. J Perinat Educ. 2007;16(4):52-54.

126. Hay DF, Pawlby S, Sharp D, Asten P, Mills A, Kumar R. Intellectual problems shown by 11-year-old children whose mothers had postnatal depression. J Child Psychol Psychiatry. 2001;42(7):871-889.

127. Brand SR, Brennan PA. Impact of antenatal and postpartum maternal illness: how are the children? Clin Obstet Gynecol. 2009;52(3):441-455.

128. Hay DF, Pawlby S, Waters CS, Sharp D. Antepartum and postpartum exposure to maternal depression: different effects on different adolescent outcomes. J Child Psychol Psychiatry. 2008;49(10):1079-1088.

129. Betts KS, Williams GM, Najman JM, Alati R. Maternal depressive, anxious, and stress symptoms during pregnancy predict internalizing problems in adolescence. Depress Anxiety. 2014;31(1):9-18.

130. Oates M. Perinatal psychiatric disorders: a leading cause of maternal morbidity and mortality. Br Med Bull. 2003;67(1):219-229.

131. Centre for Maternal and Child Enquiries. Saving mothers' lives: reviewing maternal deaths to make motherhood safer: 2006–The Eighth Report on Confidential Enquiries into Maternal Deaths in the United Kingdom. BJOG. 2011;118(Suppl 1):1-203.

132. Bhugra D. Suicide and gender: cultural factors. Harv Health Policy Rev. 2006;7(2):166-180.

133. Newport DJ, Hostetter A, Arnold A, Stowe ZN. The treatment of postpartum depression: minimizing infant exposures. J Clin Psychiatry. 2002;63(Suppl 7):31-44.

134. Comtois KA, Schiff MA, Grossman DC. Psychiatric risk factors associated with postpartum suicide attempt in Washington State, 1992–2001. Am J Obstet Gynecol. 2008;199(2):120.e1-e5.

135. Miller ML, Kroska EB, Grekin R. Immediate postpartum mood assessment and postpartum depressive symptoms. J Affect Disord. 2017;207:69-75.

136. Do T, Hu Z, Otto J, Rohrbeck P. Depression and suicidality during the postpartum period after first time deliveries, active component service women and dependent spouses, U.S. Armed Forces, 2007–2012. MSMR. 2013;20(9):2-7.

137. American Association for Suicidology. Facts and Statistics. Available at http://www.suicidology.org/resources/facts-statistics. Last accessed February 14, 2017.

138. Mental Health America. Suicide. Available at http://www.mentalhealthamerica.net/suicide. Last accessed February 14, 2017.

139. Kim JJ, La Porte LM, Saleh MP, et al. Suicide risk among perinatal women who report thoughts of self-harm on depression screens. Obstet Gynecol. 2015;125(4):885-893.

140. Depression and Bipolar Support Alliance. Suicide Prevention. Available at http://www.dbsalliance.org/site/PageServer?pagename=urgent_crisis_suicide_prevention. Last accessed February 14, 2017.

141. Sexton MB, Flynn HA, Lancaster C, et al. Predictors of recovery from prenatal depressive symptoms from pregnancy through postpartum. J Womens Health (Larchmt). 2012;21(1):43-49.

142. Haga SM, Ulleberg P, Slinning K, Kraft P, Steen TB, Staff A. A longitudinal study of postpartum depressive symptoms: multilevel growth curve analyses of emotion regulation strategies, breastfeeding self-efficacy, and social support. Arch Womens Ment Health. 2012;15(3):175-184.

143. Wouk K, Stuebe AM, Meltzer-Brody S. Postpartum mental health and breastfeeding practices: an analysis using the 2010–2011 Pregnancy Risk Assessment Monitoring System. Matern Child Health J. 2017;21(3):636-647.

144. Howell EA, Mora PA, DiBonaventura MD, Leventhal H. Modifiable factors associated with changes in postpartum depressive symptoms. Arch Womens Ment Health. 2009;12(2):113-120.

145. Friedman SH, Resnick PJ. Postpartum depression: an update. Womens Health (Lond Engl). 2009;5(3):287-295.

146. Mian AI. Depression in pregnancy and the postpartum period: balancing adverse effects of untreated illness with treatment risks.J Psychiatr Pract. 2005;11(6):389-396.

147. eMedicineHealth. Postpartum Depression. Available at http://www.emedicinehealth.com/postpartum_depression-health/article_em.htm. Last accessed February 14, 2017.

148. Markhus MW, Skotheim S, Graff IE, et al. Low omega-3 index in pregnancy is a possible biological risk factor for postpartum depression. PLoS ONE. 2013;8(7):e67617.

149. Postpartum Education for Parents. Available at http://www.sbpep.org. Last accessed February 14, 2017.

150. Daley AJ, MacArthur C, Winter H. The role of exercise in treating postpartum depression: a review of the literature. J Midwifery Womens Health. 2007;52(1):56-62.

151. Musser AK, Ahmed AH, Foli KJ, Coddington JA. Paternal postpartum depression: what health care providers should know.J Pediatr Health Care. 2013;27(6):479-485.

152. Don BP, Mickelson KD. Paternal postpartum depression: The role of maternal postpartum depression, spousal support, and relationship satisfaction. Couple Family Psychol. 2012;1(4):323-334.

153. Karuppaswamy J, Vlies R. The benefit of oestrogens and progestogens in postnatal depression. J Obstet Gynaecol. 2003;23(4):341-346.

154. Gregoire AJ, Kumar R, Everitt B, Henderson AF, Studd JW. Transdermal oestrogen for treatment of severe postnatal depression. Lancet. 1996;347(9006):930-933.

155. Dennis CL, Ross LE, Herxheimer A. Oestrogens and progestins for preventing and treating postpartum depression. Cochrane Database Syst Rev. 2008;(4):CD001690.

156. Wisner KL, Sit DKY, Moses-Kolko EL, et al. Transdermal estradiol treatment for postpartum depression: a pilot randomized trial.J Clin Psychopharmacol. 2015;35(4):389-395.

157. Pearlstein T. Perinatal depression: treatment options and dilemmas. J Psychiatry Neurosci. 2008;33(4):302-318.

158. WebMD. Understanding Postpartum Depression: Diagnosis and Treatment. Available at http://www.webmd.com/depression/postpartum-depression/understanding-postpartum-depression-treatment. Last accessed February 14, 2017.

159. National Institute of Mental Health. Mental Health Medications. Available at https://www.nimh.nih.gov/health/topics/mental-health-medications/index.shtml. Last accessed February 14, 2017.

160. Gjerdingen D. The effectiveness of various postpartum depression treatments and the impact of antidepressant drugs on nursing infants. J Am Board Fam Pract. 2003;16:372-382.

161. Mayo Clinic. Depression (Major Depressive Disorder): Selective Serotonin Reuptake Inhibitors (SSRIs). Available at http://www.mayoclinic.org/diseases-conditions/depression/in-depth/ssris/art-20044825. Last accessed February 14, 2017.

162. U.S. Food and Drug Administration. Depression: FDA-Approved Medications May Help. Available at https://www.fda.gov/forconsumers/consumerupdates/ucm095980.htm. Last accessed February 14, 2017.

163. Lexi-Comp Online. Available at http://online.lexi.com. Last accessed February 14, 2017.

164. Holisticonline. Drug Interaction Guide for SSRI Antidepressants. Available at http://www.holisticonline.com/Remedies/Depression/dep_interactions_SSRI.htm. Last accessed February 14, 2017.

165. Medinfo. SSRIs. Available at http://www.medinfo.co.uk/drugs/ssris.html. Last accessed February 14, 2017.

166. Healthy Place. SSRI Antidepressants: About SSRIs, Side-Effects, Withdrawal. Available at http://www.healthyplace.com/depression/antidepressants/ssri-antidepressants-about-ssris-side-effects-withdrawal. Last accessed February 14, 2017.

167. U.S. Food and Drug Administration. Public Health Advisory: Combined Use of 5-Hydroxytryptamine Receptor Agonists (Triptans), Selective Serotonin Reuptake Inhibitors (SSRIs) or Selective Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs) May Result in Life-Threatening Serotonin Syndrome. Available at https://www.fda.gov/Drugs/DrugSafety/ucm124349.htm. Last accessed February 14, 2017.

168. MedlinePlus. Serotonin Syndrome. Available at https://medlineplus.gov/ency/article/007272.htm. Last accessed February 14, 2017.

169. Healy D, Herxheimer A, Menkes DB. Antidepressants and violence: problems at the interface of medicine and law. PLoS Med. 2006;3(9):e372.

170. Molero Y, Lichtenstein P, Zetterqvist J, Gumpert CH, Fazel C. Selective serotonin reuptake inhibitors and violent crime: a cohort study. PLoS Med. 2015;12(9):e1001875.

171. U.S. Food and Drug Administration. Medication Guide: Class Suicidality Labeling Language for Antidepressants: Suicidality in Children and Adolescents. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/20031s045,20936s020lbl.pdf. Last accessed February 14, 2017.

172. U.S. Food and Drug Administration. Antidepressant Use in Children, Adolescents, and Adults. Available at https://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm096273.htm. Last accessed February 14, 2017.

173. U.S. Food and Drug Administration. FDA Launches a Multi-Pronged Strategy to Strengthen Safeguards for Children Treated with Antidepressant Medications. Available at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2004/ucm108363.htm. Last accessed February 14, 2017.

174. Gibbons RD, Brown CH, Hur K, et al. Early evidence on the effects of regulators' suicidality warnings on SSRI prescriptions and suicide in children and adolescents. Am J Psychiatry. 2007;164(9):1356-1363.

175. Hetrick SE, McKenzie JE, Cox GR, Simmons MB, Merry SN. Newer generation antidepressants for depressive disorders in children and adolescents. Cochrane Database Syst Rev. 2012;11:CD004851.

176. Misri S, Burgmann A, Kostaras D. Are SSRIs safe for pregnant and breastfeeding women? Can Fam Physician. 2000;46:626-633.

177. Greene A. Antidepressants and Nursing. Available at https://www.drgreene.com/qa-articles/antidepressants-nursing. Last accessed February 14, 2017.

178. Hantsoo L, Ward-O'Brien D, Czarkowski KA, Gueorguieva R, Price LH, Epperson CN. A randomized, placebo-controlled, double-blind trial of sertraline for postpartum depression. Psychopharmacology (Berl). 2014;231(5):939-948.

179. Pearlstein T. Use of psychotropic medication during pregnancy and the postpartum period. Womens Health (Lond Engl). 2013;9(6):605-615.

180. Weissman AM, Levy BT, Hartz AJ, et al. Pooled analysis of antidepressant levels in lactating mothers, breast milk, and nursing infants. Am J Psychiatry. 2004;161(6):1066-1078.

181. Tuccori M, Montagnani S, Testi A, et al. Use of selective serotonin reuptake inhibitors during pregnancy and risk of major and cardiovascular malformations: an update. Postgrad Med. 2010;122(4):49-65.

182. American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics. 2001;108(3):776-789.

183. American Academy of Pediatrics. AAP publications reaffirmed and retired. Pediatrics. 2010;126(2):404.

184. Sachs HC, Committee on Drugs. The transfer of drugs and therapeutics into human breast milk: an update on selected topics. Pediatrics. 2013;132:e796-e809.

185. Oystein Berle J. Spigset O. Antidepressant use during breastfeeding. Curr Womens Health Rev. 2011;7(1):28-34.

186. Institute for Clinical Systems Improvement. Major Depression in Adults in Primary Care Guideline: Executive Summary. Available at https://www.icsi.org/_asset/lfhfzf/DeprES.pdf. Last accessed February 14, 2017.

187. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd ed. Washington, DC: American Psychiatric Publishing, Inc.; 2010.

188. Holisticonline. Tricyclic Antidepressants. Available at http://www.holisticonline.com/Remedies/Depression/dep_antidepressants-tricyclic.htm. Last accessed February 14, 2017.

189. Holisticonline. Drug Interactions for Tricyclic Antidepressants (TCAs). Available at http://www.holisticonline.com/Remedies/Depression/dep_interactions-TCA.htm. Last accessed February 14, 2017.

190. Viktorin A, Lichtenstein P, Thase ME, et al. The risk of switch to mania in patients with bipolar disorder during treatment with an antidepressant alone and in combination with a mood stabilizer. Am J Psychiatry. 2014;171(10):1067-1073.

191. Lepping P, Menkes DB. Abuse of dosulepin to induce mania. Addiction. 2007;102(7):1166-1167.

192. Holisticonline. The Monoamine Oxidase Inhibitors (MAOI). Available at http://www.holisticonline.com/Remedies/Depression/dep_antidepressant-MAOI.htm. Last accessed February 14, 2017.

193. Mayo Clinic. Depression (Major Depressive Disorder): Monoamine Oxidase Inhibitors (MAOIs). Available at http://www.mayoclinic.org/diseases-conditions/depression/in-depth/maois/art-20043992. Last accessed February 14, 2017.

194. Holisticonline. Foods and Beverages to Avoid if You Are Taking MAOI. Available at http://www.holisticonline.com/Remedies/Depression/dep_MAOI-foods-to-avoid.htm. Last accessed February 14, 2017.

195. Holisticonline. Drug Interaction Guide for MAOI Antidepressants. Available at http://www.holisticonline.com/Remedies/Depression/dep_interactions_MAOI.htm. Last accessed February 14, 2017.

196. Horowitz JA, Goodman JH. Identifying and treating postpartum depression. J Obstet Gynecol Neonatal Nurs. 2005;34(2):264-273.

197. Miniati M, Callari A, Calugi S, et al. Interpersonal psychotherapy for postpartum depression: a systematic review. Arch Womens Ment Health. 2014;17(4):257-268.

198. Flores DL, Hendrick VC. Etiology and treatment of postpartum depression. Curr Psychiatry Rep. 2002;4(6):461-466.

199. Ugarriza DN. Group therapy and its barriers for women suffering from postpartum depression. Arch Psychiatr Nurs. 2004;18(2): 39-48.

200. Ugarriza DN, Schmidt L. Telecare for women with postpartum depression. J Psychosoc Nurs Ment Health Serv. 2006;44(1):37-45.

201. Dennis CL, Dowswell T. Psychosocial and psychological interventions for preventing postpartum depression. Cochrane Database Sys Rev. 2013;2:CD001134.

202. Dennis CL, Hodnett ED. Psychosocial and psychological interventions for treating postpartum depression. Cochrane Database Syst Rev. 2007;(4):CD006116.

203. Hipwell WE, Kumar RC. The impact of postpartum affective psychosis on the child. In: Murray L, Cooper PJ (eds). Postpartum Depression and Child Development. New York, NY: The Guilford Press; 1997: 265-293.

204. Cazas O, Glangeaud-Freudenthal NMC. The history of mother-baby units (MBUs) in France and Belgium and of the French version of the Marcé checklist. Arch Womens Ment Health. 2004;7(1):53-58.

205. Salmon MP, Abel K, Webb R, Warburton AL, Appleby L. A national audit of joint mother and baby admissions to UK psychiatric hospitals: an overview of findings. Arch Womens Ment Health. 2004;7(1):65-70.

206. Glangeaud-Freudenthal NM, Howard LM, Sutter-Dallay AL. Treatment: mother-infant inpatient units. Best Pract Res Clin Obstet Gynaecol. 2014;28(1):147-157.

207. Ogrodniczuk JS, Piper WE. Preventing postnatal depression: a review of research findings. Harv Rev Psychiatry. 2003;11(6):291-307.

208. Rowan C, Bick D, Bastos MH. Postnatal debriefing interventions to prevent maternal mental health problems after birth: exploring the gap between the evidence and UK policy and practice. Worldviews Evid Based Nurs. 2007;4(2):97-105.

209. Gamble JA, Creedy DK, Webster J, Moyle W. A review of the literature on debriefing or non-directive counseling to prevent postpartum emotional distress. Midwifery. 2002;18(1):72-79.

210. Gamble J, Creedy D. Content and processes of postpartum counseling after a distressing birth experience: a review. Birth. 2004;31(3):213-218.

211. DONA International. Available at https://www.dona.org. Last accessed February 14, 2017.

212. Sapkota S, Kobayashi T, Takase M. Impact on perceived postnatal support, maternal anxiety and symptoms of depression in new mothers in Nepal when their husbands provide continuous support during labour. Midwifery. 2013;29(11):1264-1271.

213. Rosen P. Supporting women in labor: analysis of different types of caregivers. J Midwifery Womens Health. 2004;49(1):24-31.

214. Hodnett ED, Gates S, Hofmeyr GJ, Sakala C. Continuous support for women during childbirth. Cochrane Database Sys Rev. 2013;(5):CD003766.

215. Zlotnick C, Johnson SL, Miller IW, Pearlstein T, Howard M. Postpartum depression in women receiving public assistance: pilot study of an interpersonal-therapy-oriented group intervention. Am J Psychiatry. 2001;158:638-640.

216. Van Lieshout RJ, Yang L, Haber E, Ferro MA. Evaluating the effectiveness of a brief group cognitive behavioural therapy intervention for perinatal depression. Arch Womens Ment Health. 2017;20(1):225-228.

217. Leung SS, LeeAM, Wong DF, et al. A brief group intervention using a cognitive-behavioural approach to reduce postnatal depressive symptoms: a randomised controlled trial. Hong Kong Med. 2016;22(Suppl 2):S4-S8.

218. Werner EA, Gustafsson HC, Lee S, et al. PREPP: postpartum depression prevention through the mother-infant dyad. Arch Womens Ment Health. 2016;19(2):229-242.

219. Goodman JH, Prager J, Goldstein R, Freeman M. Perinatal dyadic psychotherapy for postpartum depression: a randomized controlled pilot trial. Arch Womens Ment Health. 2015;18(3):493-506.

220. de Camps MD, Phillipp D, Israel A, Vigod S. Maternal-infant mental health: postpartum group intervention. Arch Womens Ment Health. 2016;19(2):243-251.

221. MacArthur C, Winter HR, Bick DE, et al. Effects of redesigned community postnatal care on womens' health 4 month after birth: a cluster randomized controlled trial. Lancet. 2002;359(9304):378-385.

222. MacArthur C, Winter HR, Bick DE, et al. Redesigning postnatal care: a randomized controlled trial of protocol-based midwifery- led care focused on individual women's physical and psychological health needs. Health Technol Assess. 2003;7(37):1-98.

223. Thomas M, Hutchison M, Castro G, et al. Meeting women where they are: integration of care as the foundation of treatment for at-risk pregnant and postpartum women. Matern Child Health J. 2017;21(3):452-457.

224. Karuppaswamy J, Vlies R. The benefit of oestrogens and progestogens in postnatal depression. J Obstet Gynaecol. 2003;23(4):341-346.

225. Ko JY, Rockhill KM, Tong VT, Morrow B, Farr BL. Trends in postpartum depressive symptoms—27 states, 2004, 2008, and 2012. MMWR. 2017;66(6);153-158.

226. U.S. Food and Drug Administration. FDA Approves First Treatment for Post-Partum Depression. Available at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm633919.htm. Last accessed March 21, 2019.

227. Kanes S, Colquhoun H, Gunduz-Bruce H, et al. Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial. Lancet. 2017;390(10093):480-489.

228. Meltzer-Brody S, Colquhoun H, Riesenberg R, et al. Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet. 2018;392(10152):1058-1070.

Evidence-Based Practice Recommendations Citations

1. U.S. Preventive Services Task Force. Screening for depression in adults: U.S. Preventive Services Task Force recommendation statement. JAMA. 2016;315(4):380-387. Available at https://jamanetwork.com/journals/jama/fullarticle/2484345. Last accessed March 21, 2019.

2. Alexander EK, Pearce EN, Brent GA, et al. 2017 guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid. 2017;27(3):315-389. Available at https://www.liebertpub.com/doi/full/10.1089/thy.2016.0457. Last accessed March 21, 2019.

3. Scottish Intercollegiate Guidelines Network. Management of Perinatal Mood Disorders: A National Clinical Guideline. Edinburgh: Scottish Intercollegiate Guidelines Network; 2012. Available at https://www.sign.ac.uk/assets/sign127_update.pdf. Last accessed March 21, 2019.

4. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd ed. Arlington, VA: American Psychiatric Association; 2010. Available at https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf. Last accessed March 21, 2019.

96962 • Opioid Use Disorder

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2018 NetCE, All rights reserved.

Morphine and heroin were first synthesized and used medicinally in the nineteenth century, and recreational and illicit use followed. Historically, heroin dependence has been difficult to treat successfully, with poor outcome being attributed to patient characteristics, environmental factors, and the powerful reinforcing effects of the drug. Agonist-replacement therapy was introduced 40 years ago and represented a breakthrough in the management of heroin addiction. Advances in treatment have included newer pharmacotherapies, psychosocial therapy, and the growth and accessibility of 12-step programs such as Narcotics Anonymous. This course will provide the most pertinent, up-to-date information regarding the characteristics of the opioid-addicted patient; the mechanism of opioid action and the neurobiology of opioid addiction; the epidemiology, diagnosis and risk factors of opioid abuse and dependence; and pharmacologic, psychosocial, 12-step/self-help, and alternative therapies that are effective in treating opioid use disorders. Additionally, the demographics, characteristics, comorbidity and treatment of prescription opioid abuse and dependence (i.e., OxyContin and Vicodin) will be addressed. The actual liability of abuse and dependence of legitimately prescribed prescription opioids will be conveyed.

Table of Contents

96962 • Opioid Use Disorder

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. DEFINITIONS

3. BACKGROUND

4. EPIDEMIOLOGY OF OPIOID USE DISORDER

DEMOGRAPHICS OF ILLICIT OPIOID USERS

GEOGRAPHIC PATTERNS OF MISUSE

RISK FACTORS FOR OPIOID USE DISORDER

EPIDEMIOLOGY OF OVERDOSE

5. CLASSIFICATION

6. OPIOID SYNTHESIS

7. PHARMACOLOGY

ENDOGENOUS OPIOID PEPTIDES

OPIOID RECEPTORS

ABSORPTION, DISTRIBUTION, METABOLISM, AND ELIMINATION

8. CLINICAL EFFECTS

ANALGESIA

EFFECT ON MOOD AND REWARD

NEUROENDOCRINE SYSTEM

RESPIRATION

GASTROINTESTINAL TRACT

CARDIOVASCULAR SYSTEM

OTHER EFFECTS

9. SPECIFIC OPIOID DRUGS

FULL AGONISTS

MIXED AGONISTS/ANTAGONISTS

OPIOID ANTAGONISTS

10. NATURAL HISTORY OF OPIOID DEPENDENCE

INITIATION

CONTINUATION

DETOXIFICATION AND WITHDRAWAL

RELAPSE FOLLOWING SUSTAINED ABSENCE

11. PATHOPHYSIOLOGY

OPIOID TOLERANCE

OPIOID DEPENDENCE

12. EFFECTS OF OPIOID USE DISORDER

INFECTIOUS DISEASE

ENDOCRINE/METABOLIC EFFECTS

NEUROCOGNITIVE EFFECTS

13. OPIOID OVERDOSE

RISK FACTORS

SYMPTOMS

14. OPIOID WITHDRAWAL

ACUTE OPIOID WITHDRAWAL

PROTRACTED WITHDRAWAL

PERSISTENT NEUROADAPTATION AND RELAPSE VULNERABILITY

15. LIABILITY OF ABUSE/DEPENDENCE OF LEGITIMATELY PRESCRIBED OPIOID DRUGS

DEVELOPMENT OF DEPENDENCE

16. MANAGEMENT OF OPIOID USE DISORDER

CRISIS INTERVENTION

HARM REDUCTION

DETOXIFICATION AND WITHDRAWAL

AGONIST REPLACEMENT OR ABSTINENCE THERAPY

ACUPUNCTURE

INTERVENTIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

17. MANAGEMENT OF COMORBID PSYCHOPATHOLOGY

ASSESSMENT

TREATMENT APPROACH

TREATING POLYSUBSTANCE ABUSE/DEPENDENCE

18. OPIOID USE DURING PREGNANCY

HEROIN

METHADONE

BUPRENORPHINE

OXYCODONE

NALTREXONE

19. PROGNOSIS OF TREATMENT FOR OPIOID USE DISORDER

20. CONCLUSION

21. GLOSSARY

Works Cited

Evidence-Based Practice Recommendations Citations

96962 • Opioid Use Disorder

Education Category. Psychiatric / Mental Health

Release Date. 04/01/2018

Expiration Date. 03/31/2021

Course Overview

Morphine and heroin were first synthesized and used medicinally in the nineteenth century, and recreational and illicit use followed. Historically, heroin dependence has been difficult to treat successfully, with poor outcome being attributed to patient characteristics, environmental factors, and the powerful reinforcing effects of the drug. Agonist-replacement therapy was introduced 40 years ago and represented a breakthrough in the management of heroin addiction. Advances in treatment have included newer pharmacotherapies, psychosocial therapy, and the growth and accessibility of 12-step programs such as Narcotics Anonymous. This course will provide the most pertinent, up-to-date information regarding the characteristics of the opioid-addicted patient; the mechanism of opioid action and the neurobiology of opioid addiction; the epidemiology, diagnosis and risk factors of opioid abuse and dependence; and pharmacologic, psychosocial, 12-step/self-help, and alternative therapies that are effective in treating opioid use disorders. Additionally, the demographics, characteristics, comorbidity and treatment of prescription opioid abuse and dependence (i.e., OxyContin and Vicodin) will be addressed. The actual liability of abuse and dependence of legitimately prescribed prescription opioids will be conveyed.

Audience

This course is designed for medical and mental healthcare providers, including physicians, nurses, psychologists, dentists, and social workers, who may be involved in identifying or treating opioid dependence.

Course Objective

The purpose of this course is to assist healthcare professionals in identifying, treating, and providing appropriate referrals to patients with opioid use disorders. Fear of creating new opioid addicts has influenced prescribing practices for decades, and this course will convey the actual risk of patient addiction to these pain-relieving drugs when used legitimately.

Learning Objectives

Upon completion of this course, you should be able to:

1. Define key terms associated with opioid abuse and dependence.

2. Outline the background and epidemiology of opioid use and abuse, including risk factors for misuse and dependence.

3. Describe the pharmacology and clinical effects of opioids.

4. Discuss characteristics of specific opioid drugs and opioid antagonists.

5. Review the natural history, pathophysiology, and effects of opioid abuse and dependence.

6. Identify signs and symptoms of opioid overdose and withdrawal.

7. List the issues associated with the abuse of or dependence on legitimately prescribed opioids.

8. Discuss the role of crisis intervention and harm reduction in the management of opioid abuse and dependence.

9. Identify methods of managing the detoxification and withdrawal associated with cessation of opioid abuse or dependence.

10. Discuss therapies used to maintain extended abstinence from opioids, including agonist replacement and abstinence therapies.

11. Identify common psychologic comorbidities present in opioid-dependent patients and implications for treatment.

12. Outline the effects of opioid use on fetuses and neonates and appropriate interventions for opioid-dependent pregnant women.

13. Identify factors associated with favorable/ unfavorable treatment outcome.

Faculty

Mark Rose, BS, MA, LP, is a licensed psychologist in the State of Minnesota with a private consulting practice and a medical research analyst with a biomedical communications firm. Earlier healthcare technology assessment work led to medical device and pharmaceutical sector experience in new product development involving cancer ablative devices and pain therapeutics. Along with substantial experience in addiction research, Mr. Rose has contributed to the authorship of numerous papers on CNS, oncology, and other medical disorders. He is the lead author of papers published in peer-reviewed addiction, psychiatry, and pain medicine journals and has written books on prescription opioids and alcoholism published by the Hazelden Foundation. He also serves as an Expert Advisor and Expert Witness to law firms that represent disability claimants or criminal defendants on cases related to chronic pain, psychiatric/substance use disorders, and acute pharmacologic/toxicologic effects. Mr. Rose is on the Board of Directors of the Minneapolis-based International Institute of Anti-Aging Medicine and is a member of several professional organizations.

Faculty Disclosure

Contributing faculty, Mark Rose, BS, MA, LP, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Jane C. Norman, RN, MSN, CNE, PhD

Alice Yick Flanagan, PhD, MSW

James Trent, PhD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

1. INTRODUCTION

The purpose of this course is to provide the reader with a current, evidence-based overview of opioid use disorder and its treatment. Topics covered in this review include the history and demographics of illicit and prescription opioid abuse; risk factors, background characteristics, and comorbid conditions of opioid abusers; the pharmacology of opioid drugs; the biologic and behavioral characteristics of opioid dependence; and management of opioid dependence, including treatment of overdose, detoxification and withdrawal, agonist replacement therapy, and drug-free approaches. Additional areas of the course will be devoted to the abuse liability of prescription opioids and the impact of opioids on the fetus.

2. DEFINITIONS

A confusing aspect of the body of research on opioid abuse and dependence is the inconsistent use of important terminology that describes the nature and severity of involvement with therapeutic and illicit opioids. Misuse and misunderstanding of these concepts and their correct definitions has resulted in misinformation and represents an impediment to proper patient care. The following definitions have been proposed in an effort to encourage more correct usage of this terminology [1,2,3,4,5,6]:

- Misuse, nonmedical use: Patients' use of an opioid that departs from intended prescribing, including use for an unintended purpose, exceeding the prescribed amount, or taking the drug more frequently or for longer than prescribed.

- Abuse: Definition varies widely depending on the context, but generally means a maladaptive pattern of use with the primary intent of achieving euphoria or getting high. The Drug Enforcement Administration (DEA) defines abuse as the use of a schedule II through V drug in a manner or amount inconsistent with the medical or social pattern of a culture. The American Psychiatric Association defines abuse as "a maladaptive pattern of substance use, leading to clinically significant impairment or distress as manifested by one or more behaviorally based criteria."

- Addiction: Defined by the American Society of Addiction Medicine (ASAM) as "a primary chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing the development and manifestations." It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Addiction is also referred to as psychologic dependence.

- Dependence: This term has replaced the term "addiction" in some contexts. Opioid dependence refers to both psychologic dependence (or addiction) and physical dependence. Physical dependence consists of neurobiologic adaptation (development of tolerance) from chronic exposure.

The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) defines opioid use disorder as a problematic pattern of opioid use, leading to clinically significant impairment or distress. Opioid use disorder may be diagnosed if a patient exhibits two or more of the following [2,7]:

- Opioids taken in larger amounts or over a longer period than was intended

- A persistent desire or unsuccessful efforts to cut down or control use

- A great deal of time is spent in activities necessary to obtain, use, or recover from use

- Craving, or a strong desire or urge to use

- Recurrent opioid use resulting in failure to fulfill major role obligations at work, school, or home

- Continued use despite having persistent or recurrent social or interpersonal problems caused by or exacerbated by use

- Important social, occupational, or recreational activities are given up or reduced because of use

- Recurrent use in situations in which it is physically hazardous

- Continued use despite knowledge of having a persistent or recurrent physical or psychologic problem that is likely to have been caused by or exacerbated by use

- Tolerance

- A need for markedly increased amounts to achieve intoxication or desired effect

- A markedly diminished effect with continued use of the same amount

- Withdrawal

Note: The criteria for tolerance and withdrawal are not considered to be met for those taking opioids solely under appropriate medical supervision.

In summary, the term dependence is used to describe two separate phenomena. Pharmacologically, drug dependence is characterized by the presence of tolerance and a withdrawal syndrome. Psychiatrically, drug dependence is characterized by compulsive use, inability to reduce use, preoccupation, drug-seeking behaviors, and a heightened vulnerability to relapse after abstinence [8].

Pseudoaddiction describes drug-seeking behaviors iatrogenically produced in pain patients by inadequate pain treatment. This is manifested as preoccupation with and pursuit of opioid medication driven by a desire for pain relief, not the drug's mood-altering effects. Pseudoaddiction develops in three phases. Initially, the patient receives an inadequate level of analgesia, which leads to the patient's escalation of analgesic demands and behavioral changes. This may be exaggerated to convince others of the pain severity and need for more medication, which results in a crisis of mistrust between the patient and the healthcare team. Pseudoaddiction is preventable when the patient's report of pain is accepted as valid [1,3,4,5].

3. BACKGROUND

The first reference to opium is found in the 3rd century BCE. The use of opium was well-understood by Arab physicians, and Arab traders introduced the drug to Asia, where it was utilized primarily for the control of dysentery [9].

The isolation of morphine from opium was achieved in 1806 and was named for Morpheus, the Greek god of dreams [9]. The discovery of other alkaloids in opium followed: codeine in 1832 and papaverine in 1848. By the mid-nineteenth century, pure alkaloids were used in medical practice in place of crude opium preparations [9].

In addition to the highly beneficial therapeutic effects, the toxic side effects and addictive potential of opioids have been known for centuries. These undesired effects have prompted a search for a potent synthetic opioid analgesic free of addictive potential and other complications. However, all synthetic opioids introduced into medical use share the same liabilities of the classical opioids. The search for new opioid therapeutics has resulted in the synthesis of opioid antagonists and compounds with mixed agonist-antagonist properties, such as buprenorphine, which has expanded therapeutic options and provided the basis of expanded knowledge of opioid mechanisms [9].

Nonmedical use of prescription opioids was reported in literature as early as 1880. A report in 1928 documented that injection of opioids contributed to the development of nonmedical use and misuses of prescription opioids. Before 1930, the prevalence of nonmedical opioid injecting in the United States was low. But by the mid-1940s, more than one-half the admissions to the National Institute of Mental Health's Lexington Hospital were for the misuse of prescription opioids [10].

4. EPIDEMIOLOGY OF OPIOID USE DISORDER

As of 2015, the estimated worldwide prevalence of past-year opioid use was 35 million people [11]. In 2015, an estimated 12 million people in the United States had misused prescription opioids in the past year and 6.5 million had done so in the past month [11]. With only 4.5% of the world's population, the United States annually consumes more than 80% of all opioid supplies, including [12]:

- 99% of all hydrocodone

- 78% of all oxycodone

- 57% of all methadone

- 51% of all hydromorphone

- 43% of all meperidine

- 31.5% of all fentanyl

Substantial regional differences in abuse patterns exist. In the majority of Europe, Africa, and Asia, heroin is the most prevalent illegally consumed opioid. In the Americas and Oceania (Australia and New Zealand), illegally diverted or misused prescription opioids (e.g., codeine, hydrocodone, morphine, hydromorphone, oxycodone, meperidine) are the primary opioids of abuse. However, some African and Asian nations have reported a surge in prescription opioid abuse in the last decade, and there is growing evidence of the nonmedical use of opioids, specifically tramadol, in some countries in the Near and Middle East [11,13]. Traditional opium-cultivating countries and their neighbors contain the majority of raw opium users. Although comprising less than 5% of the world population, Americans consume roughly 80% of the global opioid supply [14,15].

The Drug Abuse Warning Network (DAWN) was established in 1972 by the DEA to track and publish data collected from participating states on emergency department (ED) visits resulting from substance misuse or abuse, adverse reactions, drug-related suicide attempts, and substance abuse treatment [16]. By its final year in 2011, DAWN had collected data from metropolitan areas in 37 states, with complete coverage in 13 states. Although their total figures did not capture all 50 states, the population rates were representative and able to be extrapolated to the United States as a whole [16].

Data from the DAWN network indicates that opioid abuse is a growing problem in the United States. In 2011, the overall admission rate for misuse or abuse of opioid analgesics (excluding adverse reactions) was 134.8 per 100,000, an increase of 153% compared with 2004. In the 13 states involved in the DAWN network, the top four opioid analgesics involved in drug-related ED visits for 2011 were various formulations of oxycodone (175,229), hydrocodone (97,183), methadone (75,693), and morphine (38,416). Between 2004 and 2011, ED admissions increased 74% for methadone, 220% for oxycodone, 96% for hydrocodone, and 144% for morphine. Heroin-related emergency department episodes increased from 213,118 in 2009 to 258,482 in 2011 [17]. There was no meaningful change in ED admission rates involving opioid analgesics between 2009 and 2011 [16]. However, from July 2016 to September 2017, across 52 jurisdictions in 45 states, there were more than 140,000 suspected opioid-involved overdose ED visits, a nearly 30% increase during the period. The increases were observed across both sexes (30% in men and 24% in women) and all age groups, with the greatest increase (36%) occurring in those 35 to 54 years of age [18].

Although prescription opioid abuse decreased by approximately 12% between 2010 and 2011, heroin use increased. There were 119,000 total users in 2003, but 281,000 by 2011 and 669,000 by 2012 [19]. In addition, first-time past-year use increased significantly between 2006 (90,000) and 2012 (156,000), with the greatest increases among young adults 18 to 25 years of age [19]. In 2016, an estimated 11.8 million people in the United States 12 years of age or older reported past-year use of heroin and 3.6 million reported past-month use [20]. According to the National Survey on Drug Use and Health, there were 171,000 new heroin users older than 12 years of age in 2016 [20]. Most new users are male and older than 18 years of age. In 2016, an estimated 636,000 persons received treatment for heroin abuse [20]. It is important to note that this survey underestimates heroin use, possibly to a substantial extent, as obtaining accurate statistics on illicit drug use is difficult [20].

According to the Monitoring the Future survey, NIDA's nationwide annual survey of drug use among the nation's 8th-, 10th-, and 12th-graders, heroin use either declined or remained relatively stable from 2014 to 2017 [21]. Lifetime heroin use (at least one use in an individual's lifetime) measured 0.7% among 8th-graders, 0.4% among 10th-graders, and .0.7% among 12th-graders; past-month use measured 0.2% among 8th-graders, 0.1% among 10th-graders, and 0.3% among 12th-graders. The survey also monitors the use of diverted opioids and shows past year oxycodone use rates at .08%, 2.20%, and 2.0%, respectively [21].

Nonmedical use of prescription opioids has caused increasing concern among law enforcement officials and regulatory, pain relief advocacy, and drug abuse organizations [22]. Between 1992 and 2003, the U.S. population increased 14%, while persons abusing opioid analgesics increased 94% and first-time nonmedical opioid analgesic users 12 to 17 years of age increased 542% [12]. The prevalence of lifetime nonmedical oxycodone use increased from 8.9% in 2003 to 10.1% in 2004 [23]. Although 2003 was the last year data was reported for total oxycodone-containing product use, based on other data it is likely that its illicit use has increased. For example, OxyContin (an extended-release formulation of oxycodone) misuse alone doubled in the last half of the 2000s. Lifetime nonmedical users of pain relievers grew from 31.8 million (13.2%) in 2004 to 34.8 million (13.7%) in 2010. During 2015 in the United States, an estimated 12.4 million (4.7%) individuals misused prescription pain relievers; 2.1 million (0.8%) initiated misuse of prescription pain relievers; and 2 million (0.8%) had a substance use disorder involving prescription pain relievers [24]. ED visits involving nonmedical use of narcotic pain relievers increased 117%, from 168,379 visits in 2005 to 366,181 visits in 2011 [25].

Among high school seniors, 2% used hydrocodone/acetaminophen (Vicodin) nonmedically in 2017, while rates were 0.7% and 1.5% among 8th- and 10th-graders, respectively [21]. More than 137 million prescriptions were written for hydrocodone-containing products in 2013, making it the most prescribed drug in the United States [26]. At least 24 million Americans have ever used a hydrocodone product illicitly. In 2014, the DEA reclassified hydrocodone-containing products from Schedule III to Schedule II of the Controlled Substances Act. Following the rescheduling, prescriptions dropped from 120 million in 2014 to 93.5 million in 2015 [27,28].

Some studies estimate that as many as 20% of individuals in the United States have used a prescription opioid for nonmedical purposes at least once during their lifetime [29,30]. In 2015, 2.9 million young adults had used an opioid medication for nonmedical purposes in the past year. This number dropped to 2.5 million in 2016 [20]. The greatest misuse was among individuals 18 to 25 years of age, and the incidence was higher in women than men of all age groups, except among those 12 to 17 years of age where the rates were similar [20]. Among persons 12 years of age or older, treatment admissions for prescribed opioid abuse have more than doubled in the last decade. In 2015, 491,000 people received past-year substance use treatment for prescription opioids. . This number decreased slightly to 453,000 in 2016 [20].

The number of new nonmedical users of the four major classes of prescription-type drugs (pain relievers, tranquilizers, stimulants, and sedatives) increased between 1991 and 2010; the largest increase occurred with pain relievers. In 1990 there were 628,000 initiates compared with 5.1 million in 2016 [20]. As of 2016, it is conservatively estimated that 1.7 million individuals are dependent on prescription pain medication for nonmedical use [20]. The number of primary treatment admissions for pain medication abuse/dependence was 718,000 in 2016 [20].

Between 2002 and 2016, lifetime nonmedical use of pain relievers increased among persons 12 years of age and older, from 29.6 million to 91.8 million [20]. In 2015, 2.1 million individuals reported using prescription pain relievers nonmedically for the first time within the last year—nearly 5,800 per day [24]. Approximately 97.5 million individuals 12 years of age or older were past-year users of prescription pain relievers in 2015 [24].

DEMOGRAPHICS OF ILLICIT OPIOID USERS

Male-to-female ratios for lifetime heroin-only users and lifetime heroin and oxycodone users show that use is higher for men than for women [20]. However, within the 65 or older age group, the proportion of female admissions reporting primary abuse of oxycodone was nearly three times that of men (7.2% vs. 2.8%) [31]. Male opioid users are more likely to also use other illicit drugs; female opioid users are more likely to also abuse other prescription drugs [32]. There is a high incidence of mood/anxiety disorders among opioid users, and this incidence is significantly greater among women than men.

In 2016, the percentages of past-year nonmedical use of pain relievers among the predominant racial and ethnic groups were [20]:

- White: 4.5%

- Hispanic or Latino: 4.3%

- Native Hawaiian or Pacific Islander: 4.2%

- American Indian/Alaska Native: 3.9%

- Black or African American: 3.9%

- Asian: 1.8%

Lifetime oxycodone-only users and lifetime heroin and oxycodone users are similarly distributed racially and ethnically, with both groups being predominantly white (66.9% and 67.8%, respectively) [24]. A small percentage of these users are black or African American, and an even smaller proportion are other minority races/ethnicities.

Past-year heroin-only users and past-year heroin and oxycodone users are predominantly 18 to 34 years of age (7% and 7.3%, respectively) [24]. Past year oxycodone-only users are more likely to be 26 years of age or older (11.2%) [24]. As of 2016, individuals 18 to 34 years of age have the highest percentage of past year (7.25%) and past month (2%) illicit pain medication use [24].

The increase in opioid analgesic abuse is particularly troubling because respiratory depression and death can result from the doses at which these agents are frequently abused, especially when mixed with other central nervous system depressants [33]. The two populations for whom prescription opioid abuse is especially problematic are adolescents, due to the uncertain implication of future dependence, and the elderly, due to the increased vulnerability to toxicity. Early exposure to opioids in adolescent users may cause neurobiologic changes and behavioral consequences that differ from adults [33].

GEOGRAPHIC PATTERNS OF MISUSE

Nonmedical use of opioid analgesics has been observed in both rural and urban areas. Small metro (4.4%), large metro (4.5%), and urbanized nonmetro (4.0%) areas have the highest percentage of past-year illicit pain medication users; however, less urbanized (4.0%) and completely rural areas (3.9%) have significant rates as well [24]. Research data also suggest a rising problem with injecting among rural opioid users, a problem more typically associated with urban drug users [10]. The Mountain (17.9%) and Pacific West (15.7%) areas have the highest percentage of lifetime users, followed by the Eastern Central South (15.5%), Eastern North Midwest (14.0%), and New England (13.9%).

RISK FACTORS FOR OPIOID USE DISORDER

Persons at heightened risk for heroin experimentation include those who abuse alcohol or marijuana, those with first-degree relatives addicted to alcohol or other drugs, and those with friends and associates addicted to heroin or at high risk of heroin experimentation [8]. Of course, not all persons who use drugs regarded as having a high liability of abuse and dependence end up becoming addicted to the drug. Among persons who try heroin, an estimated 23% develop heroin dependence, a rate comparable to cocaine but greater than marijuana [34].

The expected drug effect and the setting of use (context of administration) play important roles in the social learning of drug use. Because opioids, like other drugs that increase dopamine turnover, lead to conditional responses, the use of opioids may become conditioned to the activities of daily living. As a result, environmental stimuli become powerfully associated with opioid use, which can trigger cravings for the drug [33]. The visibility of pharmaceutical marketing and advertising of medications may also play a role by changing the attitudes towards ingestion of these agents [33]. For youth, a social learning aspect to drug use is likely, based on the modeling of drug use by adults in their families and social networks [33].

Individuals who use nonmedical prescription opioids before 13 years of age are more likely to become addicts than those who initiated use at 21 years of age or older. The odds of becoming an addict are reduced 5% each year after 13 years of age [35]. Additionally, it is a commonly held view among adolescents (27%) that prescription drugs are "much safer" than street drugs [36]. This belief is undoubtedly shared with much of the adult population and has led to the extraordinary rise in recreational prescription drug users.

Evidence Based Practice Recommendation

The Institute for Clinical Systems Improvement recommends considering screening patients for substance use disorders when there is an unclear etiology of pain.

https://www.guideline.gov/summaries/summary/50568

Last Accessed: March 21, 2018

Level of Evidence: Expert Opinion/Consensus Statement

Marked increases in prescriptions written for opioids in the United States and Internet access to prescription drugs may explain a portion of the increase in opioid use disorder. However, although Internet access is a major problem and accounts for some of the increase in opioid drug abuse, the same rate of increase has not been observed for other prescription drugs, such as stimulants, suggesting that other factors are involved [33]. Changes in the way medicine is practiced also influence prescription practices. Primary care physicians provide a greater proportion of care for pain patients rather than pain specialists, increasing the potential of diversion and abuse [33].

The increase in emergency department mentions is not solely accounted for by an increase in prescriptions; for example, from 1994–2002, fentanyl mentions increased more than 50-fold while the number of prescriptions increased only 7.2-fold. Similar excessive increases in emergency department mentions relative to prescriptions have been observed with oxycodone but not morphine or hydrocodone [33].

Risk Factors for Prescription Opioid Abuse Among Pain Patients

Long-term use of prescription opioids for chronic pain results in abuse or dependence in 2.8% to 18.9% of patients [33]. Predictors of dependence on opioid medications among pain patients include substance abuse-related diagnoses, positive toxicology for opioids, and other medical diagnoses, including diagnosis of comorbid psychiatric conditions [37]. Other patients at risk include those with idiopathic pain (no clear etiology) or high levels of psychologic distress or disability [7]. Alcoholism and other drug dependence are often viewed as contraindications for opioid medications in chronic noncancer pain.

EPIDEMIOLOGY OF OVERDOSE

Overdose is a major cause of premature death among opioid drug users. Nonfatal overdoses (defined as instances in which loss of consciousness and respiratory depression occur but are not fatal) are highly prevalent among heroin users, occurring in 50% to 70% of this population [38]. According to the ASAM and the Centers for Disease Control and Prevention (CDC), there were 20,101 overdose fatalities attributable to prescription painkillers in 2015 and 12,990 overdose fatalities attributable to heroin. Men 25 to 44 years of age had the highest heroin death rate at 13.2 per 100,000, which was an increase of 22.2% from 2014 [39,40].

Regional differences have been found in fatal drug overdose involving opioids. In 2016, the five states with the highest rates of death per 100,000 population due to overdose were West Virginia (52.0), Ohio (39.1), New Hampshire (39.0), Pennsylvania (37.9), and Kentucky (33.5) [41]. Significant increases from 2015 to 2016 were seen in the Northeast, Midwest, and South Census Regions. Twenty-six states reported statistically significant increases in drug overdose death rates from 2015 to 2016 [41].

The opioid overdose rate among women has increased faster than it has in men. From 1999 to 2015, overdose fatality increased 471% in women, compared with 218% for men. There has been an alarming increase in the rates of synthetic opioid-related deaths, which increased 850% in women between 1999 and 2015 [42]. In aggregate, women tend to possess background characteristics and opioid analgesic use patterns that may contribute to overdose vulnerability. Women are more likely to experience chronic pain, receive prescriptions for opioid analgesics, receive higher doses of opioids, and use opioids for longer periods than men. Substance use disorders involving opioid analgesics are thought to develop more rapidly in women, and women may be more likely to obtain opioid prescriptions from multiple prescribers than men [39].

Risk Factors for Heroin/Opioid Overdose

Identified risk factors for fatal heroin overdose include male gender, single status, unemployment, history of heroin dependence, no current treatment for heroin dependence, intravenous (IV) use, and concomitant use of alcohol or benzodiazepines. An unexplained and consistent finding is that victims of fatal heroin overdose are generally older, experienced users. Also, at autopsy, a large proportion of overdose fatalities have relatively low blood morphine concentrations [38]. (Heroin is rapidly metabolized into morphine once administered.) Demographic patterns among overdose fatalities suggest that polydrug use and loss of tolerance are key factors, which partially explains low blood opioid concentrations. However, this does not explain the strong association of fatal overdose with age [38].

Risk factors for prescription opioid overdose are similar to those for heroin overdose, but also include obtaining overlapping prescriptions from multiple providers/pharmacies, taking high daily doses of prescription pain relievers, self-medication, polypharmacy, living in a rural area, and mental illness [43]. Most people who abuse prescription opioids get them free from a friend or relative. However, those at highest risk of overdose (i.e., those who use the drugs nonmedically 200 or more days per year) obtain them differently. Twenty-seven percent of those at highest risk of overdose obtain opioids using their own prescriptions; 26% obtain them from friends or relatives for free; 23% purchase the drugs from friends or relatives; and 15% purchase them from a drug dealer. Individuals at highest risk of overdose are four times more likely than the average user to buy the drugs from a dealer or other stranger [44].

Risk Factors for Methadone Overdose

Historically, methadone was used primarily as pharmacotherapy for heroin addiction. During the 1990s, however, methadone gained increased acceptance for use as an analgesic, and methadone began to be prescribed to outpatients with moderate-to-severe noncancer pain. Prescribing rates soared over the next decade; comparison of methadone sales quantity between 1997 and 2007 shows an increase of 1293% [45,46]. This rising use of methadone occurred simultaneously with concerns over the abuse potential of other opioids and the search for a relatively inexpensive long-acting opioid analgesic alternative [47,48].

Since the mid-2000s, methadone has become disproportionately represented in cases of opioid analgesic fatality. Based on data showing that 70% of fatalities among those prescribed methadone occurred in the first seven days of treatment, the FDA changed the methadone labeling in 2006 to lengthen dosing intervals from every 3 to 4 hours to every 8 to 12 hours; the initial recommended dose of 2.5–10 mg was unchanged [49]. In 2008, use of the highest oral dose preparations, 40 mg, was prohibited from use in pain treatment and restricted to addiction therapy [50].

In addition to the general risk factors for opioid overdose, specific factors that contribute to methadone fatality include [50]:

- Payer policies that encourage or mandate methadone as first-line therapy

- Methadone prescribing in opioid-naïve patients

- Lack of prescriber knowledge of methadone pharmacology

5. CLASSIFICATION

Opioid broadly refers to all compounds related to opium. The term opium is derived from opos, the Greek word for "juice," as the drug is derived from the latex sap of the opium poppy Papaver somniferum. Drugs derived from opium, including the natural products morphine, codeine, and thebaine, may be referred to as opiates [9]. However, for the purposes of simplification, all compounds will be referred to as opioids throughout this course.

The narcotic analgesics can be categorized into three groups. The first group includes the natural opium derivatives (heroin, morphine, and codeine) and the semisynthetic derivatives from this group, including hydromorphone, oxymorphone, hydrocodone, oxycodone, dihydrocodeine, and buprenorphine. The two other groups are synthetic chemicals: the phenylpiperidines, including meperidine and fentanyl, and the pseudo-piperidines, including methadone and propoxyphene [51].

6. OPIOID SYNTHESIS

As noted, opium is obtained from the unripe seed capsules of the poppy plant P. somniferum. The sides of the unripe seed pod are slit, and the milky sap that emerges is dried to make powdered opium. Although raw opium contains numerous alkaloids, only a few, such as morphine, codeine, thebaine, and papaverine, have clinical utility. Because morphine synthesis is difficult, the drug is still primarily obtained from opium or extracted from poppy straw [9].

Heroin, or diacetylmorphine, is synthesized by collecting and converting powdered opium to heroin hydrochloride in clandestine laboratories [8]. Impurities in the processing, particularly in heroin from Mexico, result in some street heroin being brown in color. This type of heroin, often referred to as "black tar," is the predominant type available in the western United States. The purity of Colombian and Mexican heroin powder averages 40% to 60% [8]. From the point of entry in the United States to the consumer, heroin hydrochloride is adulterated by the addition of quinine, lactose, mannitol, dextrose, or talc at each level of distribution, to the point that bags costing $10 ("dime bags") may contain only 6% heroin hydrochloride [8].

The numerous synthetic derivatives of morphine and thebaine are made by relatively simple modifications of the molecule. Examples of this include the transformation of morphine to diacetylmorphine by acetylation at the 3 and 6 positions. The main goals of opioid structural modification are to increase the affinity for various species of opioid receptors, alter the activity of the drug from agonist to antagonist, change the lipid solubility, and alter the resistance to metabolic breakdown [9].

7. PHARMACOLOGY

Opioids have been the mainstay of pain treatment for thousands of years, exerting their effects by mimicking naturally occurring endogenous opioid peptides or endorphins [9]. Although many new opioids have been developed with pharmacologic properties similar to morphine, morphine remains the standard against which new analgesics are measured [9].

ENDOGENOUS OPIOID PEPTIDES

The endogenous opioid system is complex and subtle, with diverse functions. The system plays a sensory role, which is prominent in inhibiting response to painful stimuli; a modulatory role in gastrointestinal, endocrine, and autonomic functions; an emotional role evidenced by the powerful rewarding and addicting properties of opioids; and a cognitive role involving modulation of learning and memory [9].

There are three distinct families of classical opioid peptides: enkephalins, endorphins, and dynorphins. Each of these families is derived from a distinct precursor protein and has a characteristic anatomical distribution. The precursor proteins, preproenkephalin, prepro-opiomelanocortin (POMC), and preprodynorphin are encoded by three corresponding genes. The primary opioid peptide derived from POMC is beta-endorphin. The POMC precursor is also processed into the non-opioid peptides adrenocorticotropic hormone (ACTH), melanocyte-stimulating hormone (alpha-MSH), and beta-lipotropin (beta-LPH), suggesting a common precursor for the stress hormone ACTH and the opioid peptide beta-endorphin. This association indicates a shared physiologic linkage between the stress axis and opioid systems, which has been validated by the observation of stress-induced analgesia [9].

OPIOID RECEPTORS

Opioids produce their effects through activity at three major receptor subtypes: mu, kappa, and delta. These G-protein-coupled receptors are linked to adenylate cyclase. The endogenous ligands for these receptors, beta-endorphin, enkephalin, and dynorphin, are expressed heterogeneously throughout the central and peripheral nervous systems, with a distribution pattern parallel with that of opioid receptors. Opioid receptors are also found in the central respiratory centers. Functional studies have revealed substantial parallels between mu and delta receptors and dramatic contrasts between mu/delta and kappa receptors [52].

Most opioid therapeutics, and all opioids with abuse potential, are selective for mu receptors, reflecting their similarity to morphine. However, drugs that are relatively selective at standard doses can interact with additional receptor subtypes at higher doses, resulting in divergent pharmacologic profiles [9]. A large number of endogenous ligands activate a small number of opioid receptors, a pattern strikingly different from most other neurotransmitter systems, in which a single ligand interacts with a large number of receptors that have different structures and second messengers [9].

ABSORPTION, DISTRIBUTION, METABOLISM, AND ELIMINATION

Typically, opioids are readily absorbed from the gastrointestinal tract. The more lipophilic opioids are easily absorbed through the nasal or buccal mucosa. The most lipophilic opioids can be absorbed transdermally [9]. Most opioids, including morphine, undergo variable but significant hepatic first-pass metabolism, limiting oral bioavailability relative to parenteral administration. Most opioids act quickly when given intravenously. Compared with more lipid-soluble opioids, such as codeine, heroin, and methadone, morphine crosses the blood-brain barrier at a considerably lower rate [9].

8. CLINICAL EFFECTS

Morphine and most other opioid agonists share in common the following physiologic effects [9]:

- Analgesia

- Changes in mood and reward behavior

- Disruption of neuroendocrine function

- Alteration of respiration

- Changes in gastrointestinal and cardiovascular function

ANALGESIA

Morphine-like drugs produce analgesia, drowsiness, changes in mood, and mental clouding, all without loss of consciousness. Patients in pain report that the pain is less intense, less discomforting, or entirely gone when given therapeutic doses of these drugs. The pain relief is fairly selective, and other sensory modalities are not affected. Some patients experience euphoria. When morphine in the same dose is given to a pain-free individual, the experience may be unpleasant. Nausea and vomiting is common, and drowsiness, difficulty in mentation, apathy, and decreased physical activity may occur. The subjective analgesic and toxic effects, including respiratory depression, become more pronounced as the dose is increased. Morphine-class drugs seldom cause slurred speech, emotional lability, or significant motor incoordination [9].

EFFECT ON MOOD AND REWARD

Although the mechanisms by which opioids induce euphoria, tranquility, and other alterations of mood (including rewarding properties) have not been entirely determined, the neural systems mediating opioid reinforcement are distinct from those involved in physical dependence and analgesia [53]. Behavioral and pharmacologic data point to the probable role of dopaminergic pathways, with interactions between opioids and dopamine mediating the opioid-induced reinforcement [9].

NEUROENDOCRINE SYSTEM

Morphine acts in the hypothalamus to inhibit the release of gonadotropin-releasing hormone and corticotropin-releasing hormone (CRH), which decrease circulating luteinizing hormone (LH), follicle-stimulating hormone (FSH), ACTH, and beta-endorphin. This in turn reduces the plasma concentrations of testosterone and cortisol [9].

RESPIRATION

Morphine-like opioids depress respiration in part through a direct effect on the brainstem respiratory centers. Therapeutic doses of morphine depress all phases of respiratory activity and possibly induce irregular and periodic breathing. Clinically significant respiratory depression seldom occurs at standard therapeutic doses. The primary mechanism of respiratory depression involves a diminished responsiveness of the brainstem respiratory centers to carbon dioxide [9].

GASTROINTESTINAL TRACT

Morphine-like drugs directly stimulate the chemoreceptor trigger zone for emesis in the area postrema of the medulla, resulting in the nausea and vomiting experienced by some patients [9]. Morphine also decreases gastric motility; diminishes biliary, pancreatic, and intestinal secretions; and delays digestion of food in the small intestine. In the colon, peristaltic waves are diminished or abolished and tone is increased to the point of spasm, delaying the passage of bowel contents [9].

CARDIOVASCULAR SYSTEM

There are no opioid receptors on the heart, so morphine does not act directly on the heart muscle. However, opioid agonists indirectly affect cardiovascular processes through suppression of reflex vasoconstriction, which may result in bradycardia and hypotension [54]. In cases of injecting use, bacterial endocarditis can develop [54].

OTHER EFFECTS

Opioid agonists may also affect reflexes, particularly swallow/cough reflexes and pupillary dilation. Morphine and related opioids depress the cough reflex by direct action on the cough center in the medulla [9]. Morphine and most mu and kappa agonists also constrict the pupils through excitation of the parasympathetic nerve stimulating the pupil [9].

9. SPECIFIC OPIOID DRUGS

FULL AGONISTS

Heroin

Heroin, or diacetylmorphine, is a highly potent, semisynthetic analgesic produced by the anhydrous acetylation of morphine. Heroin is generally believed to have no significant opioid receptor activity; however, heroin is rapidly metabolized to 6-monoacetylmorphine (6-MAM) and then to morphine. While diacetylmorphine and 6-monoacetylmorphine readily cross the blood-brain barrier, morphine itself is much slower to do so; thus, heroin can be considered a prodrug that facilitates the brain entry of morphine [52]. The drug rapidly enters the brain after IV administration, where it binds to mu, kappa, and other stereospecific opioid-receptor binding sites in the locus coeruleus [8]. The onset of euphorigenic action is approximately 30 minutes after intranasal ingestion, 15 minutes after subcutaneous injection, and almost instantaneously after IV injection, with a duration of about three to four hours [8]. As with many other opioids, heroin reduces the anticipatory anxiety associated with emotional or physical pain and alters the perception of pain [8].

Heroin is rapidly deacetylated in the microsomes of the endoplasmic reticulum in the liver to 6-MAM, which is further deacetylated to morphine. It is excreted in the urine over a 30- to 40-hour period as free morphine and morphine 3-glucuronide [8]. Other drugs, including tricyclic antidepressants (TCAs), can inhibit the metabolism of heroin. Genetic variation in the expression of the enzymes involved in opioid metabolism and the potential for drug interactions at these sites may contribute to variation in response to heroin administration both among various individuals and within one individual [52].

The sought-after effects of heroin include intense tranquility, euphoria, analgesia, and a clouding of the sensorium, with the state of ecstasy and contentment immediately following IV injection being the most desired. Many novice heroin users experience adverse effects, such as mild nausea and vomiting. However, tolerance to these effects is soon achieved [8].

The lifestyle of the heroin addict seriously decreases life expectancy. Age-adjusted mortality rates have been found to be least seven times greater than that of the general population, adjusting for age, with death usually attributable to violence or drug effects. Also, the desire to replicate the most intense rush may compel the heroin addict to escalate the dose, resulting in acute heroin overdoses [8].

Codeine

Codeine is approximately 60% as effective orally versus parenterally as an analgesic and respiratory depressant. Several codeine analogs, such as levorphanol, oxycodone, and methadone, have a high ratio of oral-to-parenteral potency, with the greater oral bioavailability reflecting lower hepatic first-pass metabolism [9].

Approximately 10% of ingested codeine is O-demethylated to morphine. Free and conjugated morphine can be found in the urine after therapeutic doses of codeine. Codeine has an exceptionally low affinity for opioid receptors, and the analgesic effect of codeine is due to its conversion to morphine. However, the antitussive effects of this drug may involve distinct receptors that bind codeine itself. The plasma half-life of codeine is two to four hours [9].

Codeine and promethazine syrup is the active component of the recreational drug "purple drank;" other common names include "syrup" and "lean" [55]. The combination of the purple antitussive, soft drinks, and in some cases candy has been mentioned in hip-hop music since the late 1990s and has been particularly popular in the South [55]. All opioid/soft drink concoctions may colloquially be referred to as "sizzurp."

Tramadol

Tramadol is a synthetic codeine analog and a weak mu-opioid receptor agonist. Tramadol is unusual among opioids in that a portion of its analgesic effect is produced by norepinephrine and serotonin uptake inhibition [9]. Tramadol is as effective as morphine or meperidine in the treatment of mild-to-moderate pain. It is 68% bioavailable following a single oral dose and 100% available following intramuscular administration. The affinity of tramadol for the mu-opioid receptor is only 1/6000th that of morphine. However, the primary O-demethylated metabolite of tramadol is two to four times as potent as the parent drug and may partially explain the analgesic effect. Physical dependence with tramadol has been reported [9].

Levorphanol

Levorphanol (brand name Levo-Dromoran) is the only commercially available opioid agonist of the morphinan series, and it possesses pharmacologic effects very similar to those of morphine. Levorphanol is metabolized less rapidly than morphine and has a half-life of 12 to 16 hours [9,56].

Meperidine

Meperidine is predominantly a mu-receptor agonist. This agent, available under the brand name Demerol, is no longer recommended for treatment of chronic pain due to concerns of metabolic toxicity. Meperidine should not be used for longer than 48 hours or in doses greater than 600 mg/day [56]. The central nervous system effects are similar but not identical to that of morphine. In equianalgesic doses, meperidine produces comparable sedation, respiratory depression, and euphoria as morphine. Some patients may experience dysphoria. Meperidine can cause central nervous system excitation, characterized by tremors, muscle twitches, and seizures, primarily due to accumulation of the metabolite normeperidine [1]. Large doses repeated at short intervals by addicts who have developed a tolerance to the sedative effects can produce an excitatory syndrome characterized by hallucinations, tremors, muscle twitches, dilated pupils, hyperactive reflexes, and convulsions [9]. Meperidine is primarily abused by healthcare professionals [9].

Diphenoxylate and Loperamide

Diphenoxylate (in combination with atropine as Lomotil) and loperamide (Imodium) are meperidine congeners that are approved by the U.S. Food and Drug Administration (FDA) for the treatment of diarrhea [56]. These drugs slow gastrointestinal motility by affecting the circular and longitudinal muscles of the intestine, presumably through interaction with opioid receptors in the intestine [9].

Fentanyl and Congeners

Fentanyl is a synthetic opioid related to the phenylpiperidines. The actions of fentanyl and its congeners (sufentanil, remifentanil, and alfentanil) are similar to those of other mu-receptor agonists. Fentanyl is a popular drug in anesthesia practice because of its relatively short time to peak analgesic effect, rapid termination of effect after small bolus doses, and relative cardiovascular stability. Fentanyl is approximately 100 times more potent than morphine, and sufentanil is approximately 10 times more potent than fentanyl. These drugs are usually administered intravenously and are substantially more lipophilic than morphine. Time to peak analgesia is rapid, usually within five minutes. Respiratory depression potential is similar to other mu-receptor agonists with a more rapid onset. Fentanyl and sufentanil treatment of chronic pain has become more widespread, and transdermal patches that provide sustained release for 48 hours or more are available [9].

Fentanyl is delivered via the transdermal route for up to 72 hours, with patches containing 2.5, 5, 7.5, or 10 mg of fentanyl. Abuse of both the injectable formulation of fentanyl (Sublimaze) and the transdermal patch is primarily, but not exclusively, a problem among healthcare professionals due to availability and proximity. Fentanyl may be extracted from the patch and injected, or the patch contents may be chewed, ingested, or inhaled. Even a patch that has been used for three days contains sufficient fentanyl to be abused [1].

Methadone

Methadone was first synthesized as an analgesic in Germany during World War II as a response to the difficulty in obtaining raw opium [57]. Methadone is a long-acting mu-receptor agonist with pharmacologic properties quantitatively similar to those of morphine [9]. Methadone is well-absorbed from the gastrointestinal tract and can be detected in plasma within 30 minutes of oral ingestion. Peak concentrations occur in the brain within one or two hours of subcutaneous or intramuscular administration [9]. Oral bioavailability approaches 90% [56,57].

In contrast to heroin, the activity of methadone is due almost exclusively to the parent drug rather than its metabolites. The drug is characterized by a long, but highly variable, half-life. One of the primary elimination pathways of methadone is N-demethylation, with cytochrome P450 3A4 (CYP 3A4) the major enzyme involved [56]. Inhibition of CYP 3A4 with drugs such as ketoconazole and erythromycin may enhance and prolong the effect of methadone. Its induction with drugs such as rifampin, carbamazepine, and phenytoin will have the opposite effect [52,56]. Liver disease can increase the half-life of methadone, but renal failure will not [57]. Additionally, CYP 2D6 may be involved in the metabolism of the active enantiomer of methadone; less than 7% of white persons and more than 25% of Ethiopian persons are ultrarapid metabolizers at CYP 2D6. Individuals with this polymorphism may be more likely to experience methadone overdose [52,58].

Following absorption, methadone is distributed to the brain, liver, kidneys, muscles, and lungs. Tissue binding predominates over binding to plasma proteins, and accumulation of the drug occurs in these tissues with repeated dosing. Plasma concentrations are maintained by this peripheral reservoir. Methadone reabsorption from the tissues may continue for weeks after administration has ceased. It has an elimination half-life of about 22 hours, but metabolism varies in each person [59].

One of the most significant advantages of methadone is that it alleviates cravings for opioids (a primary reason for relapse) and blocks many of the pleasurable effects of heroin, which helps reinforce abstinence [57]. Some of the characteristic properties of methadone are its analgesic activity, its efficacy by the oral route, its extended duration of action in suppressing withdrawal symptoms in physically dependent individuals, and its ability to demonstrate persistent effects with repeated administration [9]. Accidental overdose fatalities can occur when pain patients re-administer methadone when the analgesia wears off and pain returns, potentially elevating plasma concentrations to life-threatening levels. These same pharmacologic properties also imperil those who use it illicitly. Opioid abusers often co-administer benzodiazepines, which greatly elevates lethality risk with methadone. Concurrent use of alcohol poses the same risk [47,48].

In methadone clinics, methadone is usually dispensed in prepared individual doses mixed with fruit juice to discourage IV use. Methadone is also prescribed for pain. Until recently, there had been little evidence that diversion of methadone from pain management was occurring on any substantial scale. The majority of diverted methadone is used by heroin addicts to self-medicate symptoms of opioid withdrawal. To date, there is no evidence that diversion of methadone from methadone clinics has resulted in significant numbers of new opioid addicts [1].

More frequent adverse effects associated with methadone use include sweating, decreased libido, weight gain, constipation, and irregular menstrual periods, all occurring primarily during the initial stabilization process. Uncommon side effects include facial flushing, pruritus, euphoria or dysphoria, insomnia, urinary retention, and bradycardia [56]. Rarely observed side effects include biliary spasm, urticaria, syncope, overdose death, and torsades de pointes [57]. These effects are more common at higher doses and when methadone is combined with certain other drugs [60]. Risk of QTc prolongation and arrhythmia led to a 2006 black box warning [56].

Tolerance to the opioid properties of methadone develops within four weeks. The minimal effective dose is regarded as 40 mg, but some patients require much greater doses [56,57]. Subcutaneous administration of 10-20 mg methadone to former opioid addicts unambiguously produces euphoria similar in duration and magnitude to that of morphine. Methadone's overall abuse potential is comparable to that of morphine [9].

Hydrocodone

Hydrocodone is a semi-synthetic codeine derivative first used clinically as an antitussive and analgesic in the 1920s. Following a 10-mg oral dose, maximum serum level is observed in 1.3 hours [61]. Hydrocodone exhibits a complex pattern of metabolism, including O-demethylation, N-demethylation, and 6-keto reduction to the corresponding 6-a- and 6-b-hydroxymetabolites. The 2D6 enzyme demethylates hydrocodone at the 3-carbon position into hydromorphone, which has much stronger mu binding than hydrocodone. Similar to codeine, it has been proposed that hydrocodone is a prodrug. Its analgesic properties are generally considered equipotent to codeine [62,63].

Oxycodone

Oxycodone is similar in structure to hydrocodone, with the addition of a hydroxyl group at the 14-carbon. Oxycodone, as a hydrochloride salt, is a pure agonist opioid that has been in clinical use since 1917. Unlike codeine and hydrocodone, oxycodone is a potent analgesic in its own right and not a prodrug, although 2D6 activity creates the active opioid analgesic metabolite oxymorphone (synthesized and marketed as the analgesic Opana). Oxycodone is suitable for oral administration due to high bioavailability (60%) but may also be taken intramuscularly, intravenously, subcutaneously, or rectally; however, oxycodone is only commercially available in oral preparations [56]. In terms of analgesic potency and lipophilicity, oxycodone is comparable to morphine, and both drugs possess similar abuse potential. With the exception of hallucinations, which occur more rarely with oxycodone than with morphine, the side effects of these drugs are highly similar [64].

Oxycodone is metabolized by demethylation to noroxycodone and oxymorphone followed by glucuronidation [56]. A urine screen may reveal oxycodone alone, oxycodone and oxymorphone, or oxymorphone alone [65].

Since 1995, oxycodone has been marketed in the United States as OxyContin, a Schedule II controlled-release oral tablet formulation. Oxycodone is also available in immediate-release tablets in combination with aspirin or acetaminophen under various trade names, including Percodan and Percocet, which contain 2.5–10 mg of oxycodone [56]. The oxycodone content of OxyContin ranges from 10 mg to 80 mg. When taken orally, OxyContin tablets release oxycodone over a 12-hour period. However, when the controlled-release mechanism is destroyed by crushing the tablet, the oxycodone can be snorted, ingested, or injected. It is this delivery of a large amount of the active drug in a relatively brief time period (compared to the intact tablet and the low-dose immediate-release form) that underlies addicts' interest in OxyContin [1].

In 2014, the FDA approved an extended-release version of oxycodone that is formulated to include naloxone in order to deter misuse [66]. If crushed and snorted or crushed, dissolved, and injected, the naloxone will block the euphoric effects of oxycodone, potentially deterring this type of abuse. This combination drug is intended for patients for whom alternative treatment options for chronic pain are ineffective or not tolerated [66]. The drug is no longer available in the United States [56].

Hydromorphone

Hydromorphone is a semi-synthetic hydrogenated ketone of morphine and shares the pharmacologic properties typical of mu-opioid agonists. Hydromorphone is a more potent analgesic than morphine; on a milligram basis, hydromorphone is 5 times as potent orally and 8.5 times as potent intravenously. Hydromorphone can be administered by infusion, intramuscularly, orally, or rectally [67].

Following oral administration of conventional-release hydromorphone, the drug is rapidly absorbed and undergoes hepatic first-pass elimination of approximately 50%. The terminal elimination half-life after IV administration is 2.5 to 3 hours. The primary mode of elimination is by urinary excretion as hydromorphone-3-glucuronide, the primary metabolite. Some metabolites may have greater analgesic activity than hydromorphone itself but are unlikely to contribute to the pharmacologic activity. Side effects are comparable to morphine [67].

MIXED AGONISTS/ANTAGONISTS

Discovery of an opioid analgesic with the efficacy but not the side effects or abuse potential of mu-agonists has been the ultimate goal of analgesic research for the past 60 years [29]. Mixed agonist-antagonist compounds have been developed with the hope that they would have less addictive potential and create less respiratory depression than morphine and related drugs. However, achieving the same degree of analgesia produces a similar magnitude of side effects, and a "ceiling effect," limiting the amount of analgesia attainable, is often seen with these drugs. Also, mixed agonist-antagonist drugs (e.g., pentazocine) can produce side effects not often seen with pure agonists, including severe, irreversible psychotomimetic effects [9].

Drugs such as nalbuphine and butorphanol are competitive mu-receptor antagonists, with their kappa receptor agonist action mediating the analgesic effect. Pentazocine qualitatively resembles these drugs but is a weaker mu-receptor antagonist or partial agonist while retaining its kappa-agonist activity. Buprenorphine is a partial mu-receptor agonist [9].

Pentazocine

Pentazocine was developed in an effort to synthesize an effective analgesic with little or no abuse potential. With agonistic actions and weak opioid antagonistic activity, the pattern of central nervous system effects is similar to that of morphine-like opioids, including analgesia, sedation, and respiratory depression. Dysphoric and psychotomimetic effects can be precipitated by higher doses (60 to 90 mg) [9].

In the 1970s and early 1980s, pentazocine (Talwin) was combined with the crushed, blue-colored antihistamine tablet tripelennamine and used intravenously, known as "Ts and Blues." Factors contributing to its widespread abuse included placement outside Schedule II and the erroneous belief that the drug was not abusable. Pentazocine was also widely abused by physicians because it could be prescribed in large quantities outside the stringent Schedule II monitoring system. At one point, pentazocine abuse became so prevalent that the manufacturer contemplated removing the drug from the market. Pentazocine was ultimately reformulated by the inclusion of the opioid antagonist naloxone. Similar to buprenorphine formulations containing naltrexone, when this formulation is taken as directed, the user experiences only the pentazocine effect because of poor oral naloxone absorption. However, if the tablet is dissolved and injected, the naloxone blocks the opioid effects of the pentazocine and precipitates acute opioid withdrawal [1].

Nalbuphine

Nalbuphine is an agonist-antagonist opioid related to naloxone and oxymorphone, with a spectrum of effects that qualitatively resembles that of pentazocine but with a lower potential to produce dysphoric side effects. Although doses of 10 mg or less produce few side effects, much higher doses (70 mg) can produce psychotomimetic side effects such as dysphoria, racing thoughts, and distorted body image. Prolonged administration of nalbuphine can produce physical dependence and withdrawal [9].

Butorphanol

Butorphanol is a morphinan congener with a profile of actions similar to those of pentazocine. It is generally more suitable for the relief of acute pain than chronic pain. Major side effects include drowsiness, weakness, sweating, feelings of floating, and nausea. Although the incidence of psychotomimetic side effects is lower than that with equianalgesic doses of pentazocine, they are qualitatively similar. Physical dependence to butorphanol can develop from regular use [9,56].

Buprenorphine

Buprenorphine was initially suggested in 1978 as an alternative oral opioid substitution therapy for opioid addicts. Buprenorphine and methadone are the two most widely used and effective pharmacotherapies for opioid use disorder, and both have regulatory approval in the United States for this indication [68]. Buprenorphine is a semi-synthetic opioid derivative made from thebaine, one of the naturally-occurring alkaloids in opium [69]. Buprenorphine, sold as Buprenex, Subutex, Belbuca, or Sublocade, is a long-acting partial opioid agonist that is classified as a Schedule III narcotic, in contrast to methadone and LAAM, which are Schedule II [56,57,70].

Buprenorphine has a very low oral bioavailability due to substantial intestinal and hepatic metabolism. The sublingual formulation used to treat opioid dependence is well-absorbed and produces opioid agonistic effects comparable to subcutaneous administration. Maximum plasma level is achieved 70 to 90 minutes after sublingual administration, and absolute bioavailability is 35% to 50% [69]. Following absorption, buprenorphine initially accumulates in the liver, kidneys, muscular tissue, and fatty tissue. It is released from fatty tissue when the plasma level drops and is then available at the opioid receptor. The slow dissociation kinetics explains the prolonged period of effectiveness. Buprenorphine is metabolized through the hepatic cytochrome P450 pathway. Approximately 80% is eliminated through binary excretion of the glucuronidated metabolites and 20% via the urinary route [69].

The minimum daily dose needed to suppress opioid use is about 4 mg. Larger doses of buprenorphine (32 mg) result less in an increase in therapeutic effect but more in an extension of the effect, which can last for up to 48 hours [69].

In 2014, the FDA approved a buccal film containing both buprenorphine and naloxone [71]. This combination therapy is applied once daily to suppress signs and symptoms of opioid withdrawal [56]. In 2016, the FDA approved the first buprenorphine implant (Probuphine) for opioid dependence [72]. The implant provides a constant, low-level dose of buprenorphine for six months. It is designed for use in patients who are already stable on a low dose of other forms of buprenorphine, as part of a complete treatment program. Because Probuphine must be inserted and removed surgically, healthcare providers are required to complete training and certification through the Probuphine Risk Evaluation and Mitigation Strategy (REMS) program [72]. In 2017, the FDA approved a once-monthly subcutaneous injection (Sublocade) for opioid use disorder [73]. Sublocade is intended for use in adult patients with moderate-to-severe opioid use disorder who have been on a stable dose of buprenorphine treatment for a minimum of seven days. The drug must be administered in a healthcare setting to avoid inadvertent IV administration that could result in death [73].Buprenorphine use is contraindicated for patients with alcohol intoxication, delirium tremens, and treatment with monoamine oxidase inhibitors. Cases of lethal buprenorphine intoxication almost always involve polyintoxication [69]. Buprenorphine contains a black box warning regarding the potential for serious, life-threatening, or fatal respiratory depression, especially during initiation or dose escalation [56]. Upon discontinuation, a withdrawal syndrome develops, with a delayed emergence in two days to two weeks. Signs and symptoms of buprenorphine withdrawal are typical of a milder morphine-type withdrawal and last roughly one to two weeks [9]. The more benign withdrawal syndrome is due to its partial agonist property at the mu receptor and weak antagonist property at the kappa receptor [57].

OPIOID ANTAGONISTS

Opioid antagonists have obvious therapeutic value in the treatment of opioid overdose. Relatively minor changes in the structure of an opioid can convert an agonist drug into one with antagonistic actions at one or more opioid receptor types. Opioid antagonists include naloxone, naltrexone, and nalmefene. Nalmefene is not approved in the United States [56]. Interestingly, naloxone also appears to block the analgesic effects of placebo medications and acupuncture. Naltrexone and naloxone have little or no potential for abuse [9].

10. NATURAL HISTORY OF OPIOID DEPENDENCE

Although the time from initiation to daily use and serious physiologic and psychologic dependence is highly variable, the different stages of opioid dependence are clearly delineated [8]. These stages include initiation, continuation, withdrawal, and relapse. Each stage is characterized by specific neurotransmitter action, involvement of specific brain structures, and activation of specific neural circuits. An understanding of these different processes is crucial to develop an understanding of the therapeutic strategies [13].

INITIATION

During the initiation phase, acute reinforcement of the initial drug effect is mediated by mu-opioid receptors and dopamine that inhabit the ventral tegmental area and nucleus accumbens. This results in conditioned responses and drug craving [13].

CONTINUATION

The second phase of continued drug use is characterized by diverse neurotransmitter involvement, including dopamine in the nucleus accumbens, corticotrophin-releasing hormone in the amygdala, and glutamate in the frontal-cingulate circuit. As tolerance develops, the dose and route of administration often change, with progression to IV use a frequent outcome [8].

DETOXIFICATION AND WITHDRAWAL

During detoxification and withdrawal from opioids and other central nervous system depressants, glutamate and norepinephrine in the locus coeruleus are primarily involved in causing the associated symptoms [13].

RELAPSE FOLLOWING SUSTAINED ABSENCE

Brain regions implicated in relapse to opioid use include the orbitofrontal cortex, anterior cingulate gyrus, and amygdala. Norepinephrine and corticotrophin-releasing hormones are involved in stress-induced relapse. Gamma-aminobutyric acid (GABA) and glutamate mediate brain systems that are involved in compulsive and habitual behavior and mediate cue-induced relapse [13].

11. PATHOPHYSIOLOGY

OPIOID TOLERANCE

Tolerance refers to a decrease in effectiveness of a drug with repeated administration. Tolerance to opioid effects is encountered in both the clinical use of opioids for pain relief and in recreational use of heroin [52]. Tolerance (as well as withdrawal and physiologic dependence) are expected responses to opioids and other controlled substances when given in sufficient doses over time and are not, by themselves, indicative of addiction [74,75]. Acute tolerance stems from transient administration of opioids; sustained administration leads to the development of classical or chronic tolerance. Short-term receptor desensitization may underlie the development of tolerance, probably involving phosphorylation of the mu and delta receptors by protein kinase C, protein kinase A, and beta-adrenergic receptor kinase (beta ARK). Long-term tolerance is believed to be associated with increases in adenylyl cyclase activity, a counter-regulation to the decrease in cyclic adenosine monophosphate levels [9].

The degree of tolerance can be influenced by changes in the environment in which drug use occurs. In the presence of cues previously associated with drug ingestion, tolerance is markedly enhanced, compared to the tolerance observed in a novel environment. Thus, administration of an opioid in an environment not previously associated with administration of the drug will be associated with lower tolerance and therefore a higher risk of overdose [52].

OPIOID DEPENDENCE

Opioid dependence is best described as a central nervous system disorder characterized by neurobiologic changes leading to compulsive drug-taking behaviors. As the result of chronic use, the cells producing endogenous opioids cease to function and degenerate, causing the user to become physically dependent on exogenous opioids [76].

According to the classical theory of addiction, opioid dependence results from the need to reduce distress, as withdrawal is a physical expression of distress. This is referred to as negatively reinforced behavior. This hypothesis has been challenged by the finding that the degree of physical dependence does not predict the intensity of subsequent craving, nor does detoxification and recovery from physical dependence prevent recidivism. Additionally, the motivational aspects of withdrawal are independent of the intensity and pattern of the physical symptoms of withdrawal [77].

Alternative hypotheses focus on the role of the mesocorticolimbic dopamine system, an anatomical pathway that originates from the ventral tegmental area in the midbrain and projects to several forebrain regions, including the nucleus accumbens and medial prefrontal cortex [77]. Dependence on most drugs of abuse is characterized by an altered physiologic state inferred from the emergence of a withdrawal syndrome following cessation of drug administration. Alleviation of an increasingly severe, withdrawal-induced negative affective state may reinforce continued drug taking and directly contribute to the development of dependence [78].

Molecular Basis

The diverse biologic effects of opioids are manifested through specific opioid receptors distributed throughout the central and peripheral nervous system. Opioid receptors, upon the binding of opioid drugs (or endogenous opioid peptides), regulate a multitude of intracellular signaling pathways. Involvement of opioid receptors in opioid dependence is unequivocal. This is reliably demonstrated by the rapid precipitation of withdrawal syndromes in opioid addicts by opioid receptor antagonists such as naloxone [79].

Repeated exposure to short-acting opioids can result in durable alterations in opioid receptor kinetics, transmembrane signaling, and postreceptor signal transduction [80]. Opioid dependence requires sustained activation of opioid receptors, and this chronic signaling process ultimately leads to changes in protein functions of gene transcription [79].

Opioid receptors are members of the G-protein receptor family, and each opioid receptor uses inhibitory G-proteins for signal transduction. Opioid receptors have the capacity to interact with five different forms of G-proteins, regulating a diverse spectrum of effectors ranging from adenylyl cyclases and ion channels to mitogen-activated protein kinases. These isoform-specific and differential regulations of various classes of effectors are combined into a sophisticated signaling network that mediates opioid actions. The enormous diversity in opioid signaling stems from the array of effectors and signaling molecules that functionally interact with the G-protein beta gamma complex [79].

Prolonged administration of opioids causes molecular and cellular adaptations that rapidly develop into tolerance and dependence. An upregulation of adenylyl cyclase responsiveness, referred to as adenylyl cyclases superactivation, is a classic sign of this tissue adaptation [79].

G-protein signals lead to changes in gene expression, and opioid-induced, long-term functional alterations of the nervous system involve changes in gene expression. Many opioid-induced signals converge at the level of transcription factors, although little is known about the exact mechanisms of gene transcription in the development of opioid tolerance and dependence [79].

Mechanism of Reinforcement

Drugs with an abuse liability have habit-forming actions that can be localized in a variety of brain regions. Drugs of abuse mimic or enhance the actions of endogenous chemical messengers in the brain [81]. The mesolimbic dopamine system is the likely substrate upon which opioids act to produce their reinforcing effects. Both the positive (rewarding) and negative (aversive) reinforcement of opioid mu- and kappa-receptor agonists are mediated by the mesolimbic dopamine system [77].

Opioids produce reinforcement by inhibition of the GABA neurons that normally inhibit dopaminergic neurons in the ventral tegmental area. This results in a surge of dopamine in the nucleus accumbens and other mesolimbic-mesocortical brain regions [82]. The neurochemical cascade begins with activation of mu- or kappa-opioid receptors differentially distributed on GABAergic cells in the ventral tegmental area and nucleus accumbens and dopamine terminals in the nucleus accumbens. This activation produces rewarding and aversive effects by increasing or decreasing dopamine release in the nucleus accumbens. Inhibition of medium spiny GABAergic neurons in the nucleus accumbens by dopamine and opioids can synergistically facilitate opioid reinforcement. Increases in glutamatergic afferents into the ventral tegmental area may facilitate opioid reinforcement by activating dopamine neurons. An increase in glutamate activity in the nucleus accumbens may decrease opioid action by activating nucleus accumbens GABAergic cells. Also, an increase in nucleus accumbens 5-HT by opioids modulates opioid reinforcement by activation of 5-HT1 and/or 5-HT3 receptors [77].

12. EFFECTS OF OPIOID USE DISORDER

The misuse of opioids results in several acute and long-term effects. Signs and symptoms of acute opioid intoxication include drowsiness, decreased respiration, euphoria, and impaired judgment (Table 1).

Table 1: SIGNS AND SYMPTOMS OF ACUTE OPIOID INTOXICATION

Constricted pupils (or dilated pupils with meperidine)

Euphoria

Apathy

Dysphoria

Drowsiness

Loss of consciousness

Coma

Psychomotor agitation or retardation

Decreased respiration

Decreased heart rate

Pulmonary edema

Impaired social judgment

Slurred speech

Impaired attention and memory

Impaired occupational functioning

Source: [83]

INFECTIOUS DISEASE

Infectious complications from opioid use generally stem from injection use, primarily of heroin, in which bloodborne pathogens are transmitted via contaminated needles. An estimated 60% to 90% of injection users have hepatitis C virus infection [84,85]. Other common infectious diseases include human immunodeficiency virus (HIV) and hepatitis B [8]. Common bacterial infections include Staphylococcus aureus, cellulitis and abscesses around the injection site, pneumonia, bacteremia, and endocarditis. Of HIV-positive persons in the United States, more than 33% have injected opioids and more than 25% report sharing needles with other users [10]. Injection drug users represented 4.2% of new HIV infections in 2016 and 17% of those living with HIV in 2016 [86].

ENDOCRINE/METABOLIC EFFECTS

Opioid use affects multiple endocrine functions and is associated with hypogonadism, adrenal dysfunction, reduced bone mineral density, and growth hormone abnormalities [87].

Hypothalamic-Pituitary-Gonadal (HPG) Axis

Opioid use has been implicated in gonadal dysfunction [88]. Central hypogonadism can result from opioid receptor activation in the vicinity of the hypothalamus. Resultant diminished secretion of gonadotropin-releasing hormone can lead to decreases in gonadotropin and testosterone levels. This effect may decrease over time secondary to the development of tolerance [87].

Metabolic Effects

Heroin use has been associated with abnormalities in glucose metabolism by multiple mechanisms. Fasting insulin levels can be substantially higher in heroin addicts than in control subjects, and insulin resistance stemming from opioid use may be coupled with beta cell dysfunction [89]. Heroin addicts often have lower acute insulin response than control patients evaluated by oral glucose tests and response to a standard meal. This blunted glucose response suggests an association between opioid use and abnormal glucose metabolism [87]. The use of highly active anti-retroviral therapy (HAART) for the treatment of HIV infection is also associated with a number of metabolic problems, including increased prevalence of insulin resistance, dyslipidemia, and changes in fat distribution. Because opioid use can also result in metabolic abnormalities, the presentation of patients who are both HIV-positive and opioid dependent may be complicated.

Chronic heroin use may also complicate dyslipidemia, evidenced by elevated total cholesterol levels, hypertriglyceridemia, decreased total cholesterol and high-density lipoprotein, and elevated triglyceride levels relative to controls [87].

Hypothalamic-Pituitary-Adrenal (HPA) Axis

Opioid addicts may also have impaired adrenal function, documented by a high prevalence of adrenal insufficiency and abnormal response to the cosyntropin test [88]. The action of heroin on neurotransmitters that regulate the secretion of corticotrophin-releasing factor, leading to disturbances in cortisol levels, has been hypothesized as the underlying pathophysiology. This is supported by the observation of lower plasma cortisol levels concurrent with depressed ACTH levels in heroin addicts [87].

In addition, chronic opioid use may contribute to low bone mineral density through reduction in lumbar bone mineral density. Growth hormone axis abnormalities are also seen in heroin addicts [87].

NEUROCOGNITIVE EFFECTS

Cognitive impairment resulting from chronic drug use may contribute to abuse and dependence in at least two ways. The first involves increasing the likelihood of drug-seeking behavior through various induced cognitive deficits, such as failure of impulse control mechanisms. The second involves the interference with users' ability to assimilate and participate in rehabilitation programs that have an educative and cognitive emphasis [90,91].

The chronic use of illicit drugs is often associated with a generalized profile of neuropsychologic deficit. However, it is thought that important differences in the patterns of interaction associated with various neurotransmitter systems, coupled with corresponding differences in the distributions of receptor subtypes, are responsible for the distinct neurocognitive effects of specific drugs of abuse [90].

Compared with marijuana and stimulants, there has been substantially less research into neuropsychologic deficits in chronic opioid abusers. Early studies found relatively little impairment in tasks involving abstraction and reasoning, leading investigators to conclude that chronic opioid use was not associated with deficient frontal lobe functioning. However, newer studies, utilizing more sensitive measures, have demonstrated that opioid abusers do possess marked deficits in frontal lobe functioning relative to healthy control subjects. These deficits may include problems with altered attentional control, altered decision making, or problems with choices involving motivationally significant outcomes [90]. Additional research is needed to establish whether this pattern reflects increased impulsivity. It should be noted that determining causation in studies involving drug users is difficult due to comorbid psychiatric disorders and polysubstance abuse [90].

Cognitive-Motor Effects of Methadone Maintenance

While under the influence of acute opioid ingestion, the ability to work safely or drive a car can be impaired. This does not appear to be the case with methadone patients who have adapted to the effects of opioids for months or even years, a reflection of the substantial tolerance to the central depressing effect when opioids are taken regularly on a long-term basis [92].

A review of the cognitive functioning of methadone patients found that [92]:

- On measures of concentration and attention, methadone patients tended to perform less well than controls.

- Methadone patients performed equally or slightly faster in speed of information processing and equally or slightly worse in motor reaction on measures of simple reactions and simple-choice reactions.

- Performance was inconsistent on complex-choice reactions under reactive stress.

- No evidence for inferior performance of methadone patients in vigilance tasks has been found.

- Methadone patients have performed worse than control groups in visual orientation.

- In tests combining tracking with a reaction task, slower reaction to peripheral signals have been observed in methadone patients together with equal accuracy and greater tracking deviation or smaller number of correct responses and equal tracking deviation.

Researchers concluded that among methadone-maintained patients without complicating comorbidity, visual structuring and reaction are not impaired [92]. Performance of attention, visual orientation, and eye-hand coordination are worsened. In general, performance of methadone patients and comparable healthy subjects overlap to a substantial degree. The study results may be better explained by sociodemographic factors than by the grouping factor; age, gender, and educational attainment showed a greater influence than methadone use. The authors concluded that being a methadone patient does not necessarily mean that impairment of cognitive-motor skills performance is inevitable [92]. Authors of more recent studies have reported similar findings [93,94].

The practical application of these findings suggests that methadone-maintained patients may be as capable as healthy persons in job performance. If job demands encompass skills with no differences found between healthy subjects and methadone patients, if minimum prerequisites are not extraordinarily high, or if patients exhibit favorable features exclusive of their methadone dependence, job performance is unlikely to be affected [92].

13. OPIOID OVERDOSE

In 2016, there were 63,600 drug-overdose deaths in the United States. This was 21% higher than the rate in 2015, including 20,032 deaths that involved synthetic opioid analgesics (other than methadone) and 15,831 that involved heroin. The 2016 overdose death rates were highest for persons 35 to 44 years of age (35.0 per 100,000), whereas the greatest increase in death rates occurred among adults 25 to 34 years of age [95]. Between 1999 and 2016, the age-adjusted death rate from drug overdose more than tripled (from 6.1 per 100,000 in 1999 to 19.8 in 2016). Overdose death rates from synthetic opioids other than methadone (e.g., fentanyl/fentanyl analogs, tramadol) increased from 0.3 per 100,000 in 1999 to 6.2 in 2016. The rate increased on average by 18% each year from 1999 to 2006, did not statistically change from 2006 to 2013, then increased by 88% per year from 2013 to 2016 [95]. The heroin overdose death rate increased from 0.7 per 100,000 in 1999 to 4.9 per 100,000 in 2016. The rate was steady from 1999 to 2005, then increased on average by 10% per year from 2005 to 2010, by 33% per year from 2010 to 2014, and by 19% per year from 2014 to 2016 [95].

Overdose death rates involving natural and semisynthetic opioids (e.g., oxycodone, hydrocodone) increased from 1.0 per 100,000 in 1999 to 4.4 per 100,000 in 2016. This was an average increase per year of 13% from 1999 to 2009 and 3% per year from 2009 to 2016 [95]. Overdose deaths involving methadone increased from 0.3 per 100,000 in 1999 to 1.8 in 2006, then declined to 1.0 in 2016 [95]. Methadone was involved in 3,231overdose deaths in 2016 [95]. Most methadone fatalities occur when the drug is prescribed for pain rather than for addiction treatment [60].

RISK FACTORS

Heroin purity has only a moderate relationship to heroin-related fatalities, and despite the increasing incidence of heroin ingestion by smoking, almost all overdose deaths remain the result of injection. In fatal overdoses, instantaneous death is uncommon, indicating that there is time to intervene in the majority of cases. However, public responsiveness to overdoses is often poor, with the most common reason for delayed response being fear of police involvement [96]. The time following release from prison has also been identified as a very high-risk period for both fatal and nonfatal overdose [96].

Methadone overdose decedents are more likely than other pharmaceutical opioid abusers to not have had a prescription for the overdose drug. They are also significantly more likely to be male [97,98].

Tolerance in Overdose

Variation has been found in the acquisition of tolerance to different opioid effects, including respiratory depression [38]. The role of tolerance in heroin overdose is suggested by the rigors of the heroin lifestyle, which often results in a reduction in use after a decade or more of use. Often, heroin addicts increase the use of other drugs, such as alcohol, to compensate for reduced heroin use. Both of these factors increase the risk for overdose.

Polysubstance Use

Polysubstance use in cases of fatal heroin overdose is so frequent that polydrug toxicity is often a better description of the cause of death. The primary drugs associated with fatal and nonfatal overdose are alcohol, benzodiazepines, and TCAs. The risk of nonfatal heroin overdose is increased significantly by TCA use but not by selective serotonin reuptake inhibitor (SSRI) use [17].

Alcohol and benzodiazepines are relatively weak respiratory depressants but can act synergistically with opioid agonists to produce substantial respiratory depression. Stimulants act as functional or physiologic opioid antagonists and may therefore minimize the respiratory depressant effects of opioids [52].

SYMPTOMS

In the case of opioid overdose, symptoms include mental clouding, stupor or coma, miotic pupils, bradypnea, diminished response to painful stimuli, and mottled, cooled skin. Respiratory depression is the most feared acute adverse effect. Direct suppression of the brain stem respiratory center leads to bradypnea, shallow respirations, and a significant overall reduction of tidal volume. Death from opioid overdose is almost always caused by respiratory depression [8,99].

Sequelae of nonfatal overdose include [38]:

- Pulmonary conditions, most frequently edema

- Pneumonia

- Cardiac complications such as arrhythmia, acute cardiomyopathy, and hemoglobinemia

- Rhabdomyolysis (disintegration or dissolution of muscle cells leading to myoglobinuria)

- Neurologic damage through prolonged hypoxia

14. OPIOID WITHDRAWAL

A withdrawal syndrome can be precipitated in humans after even a single dose of morphine. Physical dependence to opioids is assessed by observing the emergence of a withdrawal syndrome following discontinuation of opioid administration or through the administration of a competitive opioid antagonist, such as naloxone [100]. Signs and symptoms of opioid withdrawal include [83,101]:

- Dilated pupils

- Rhinorrhea

- Epiphora/lacrimation

- Piloerection

- Nausea

- Vomiting

- Diarrhea

- Yawning

- Muscle cramps

- Restlessness

- Elevated vital signs

Although the neurophysiology underlying opioid withdrawal is incompletely understood, several neurotransmitter systems are believed to play a role, including dopaminergic, cholinergic, noradrenergic, and glutamatergic systems [100]. The extended amygdala is robustly implicated in affective signs of withdrawal from chronic exposure to opioids. Less is known about the cellular mechanisms underlying acute dependence [78]. The progressive escalation of withdrawal severity that occurs across repeated acute opioid exposure separated by prolonged intervals suggests the involvement of long-term cellular plasticity in acute dependence [78]. The involvement of central mechanisms of the endothelin system in opioid withdrawal is also being investigated [102,103].

There are a number of useful opioid withdrawal scales that can assist the clinician's evaluation of patients by identifying and quantitating the severity of opioid withdrawal symptoms. These include the Objective Opioid Withdrawal Scale (OOWS), the Subjective Opioid Withdrawal Scale (SOWS), and the Clinical Opioid Withdrawal Scale (COWS). The OOWS is useful for measuring and documenting measurable symptoms of opioid withdrawal. The SOWS records the patient's rating of withdrawal on a 16-item scale. The COWS includes 11 items and contains signs and symptoms (both objective and subjective) of withdrawal [104].

In 2014, the FDA cleared the Bridge Neurostimulation System (an electroauricular device) for use in acupuncture. In 2017, the FDA approved a new indication for the device for use in helping to reduce the symptoms of opioid withdrawal [105]. The NSS-2 Bridge is placed behind the patient's ear and emits electrical pulses to stimulate branches of certain cranial nerves. It can be used for up to five days during the acute phase of withdrawal. In one study, within 30 minutes of using the device, all patients showed a reduction in COWS score of nearly 31% [105].

In 2018, the FDA approved lofexidine for the management of opioid withdrawal symptoms [205]. This agent may be incorporated into the treatment of adults with opioid withdarawl symptoms for up to 14 days.

ACUTE OPIOID WITHDRAWAL

Most research regarding acute withdrawal from an opioid has been conducted with heroin users. Withdrawal symptoms are the result of mu-agonist withdrawal in the case of heroin and begin approximately eight hours after the last dose. The symptoms begin slowly, peak at 48 to 72 hours, and then gradually taper during the next four to seven days [101]. As noted, typical symptoms of withdrawal include agitation, anxiety, piloerection, tachycardia, mild hypertension, and pupillary mydriasis. Approximately 8 to 12 hours after the last dose, increases in vital signs, pulse, blood pressure, and respiratory vital rate are observed. At the peak, pronounced anxiety, tremors, shakes, smooth and skeletal muscle cramps, and joint and deep bone pain begin to manifest [8].

PROTRACTED WITHDRAWAL

Withdrawal symptoms may persist long after elimination of the opioid agent. Such persistent behavioral change suggests plastic alternation within the nervous system, some of which may be mediated by the regulation of gene expression [100]. Chronic exposure to opioids may be associated with changes to the mu receptor, resulting in the propagation of signal transduction in the absence of an agonist. The withdrawal phase can be extended due to the cellular changes that occur after long-term opioid exposure [76].

PERSISTENT NEUROADAPTATION AND RELAPSE VULNERABILITY

Opioid dependence is a chronic relapsing disorder characterized by compulsive drug seeking and use. More than 80% of addicts relapse to drug seeking and use after a period of abstinence during the protracted withdrawal phase, underscoring the long-standing nature of the compulsion and high rates of recidivism [106]. Two important brain alterations occur following dependence and withdrawal that are believed to underlie the heightened vulnerability to relapse: conditioned responses of norepinephrine A1/A2 neuron release in the extended amygdala and changes in the mesocorticolimbic dopamine system and its afferents that alter hedonic processing. At the same time, motivation or learning for drug reward and drug-associated cues is increased [106].

Abstinence from chronic drug use unmasks neuroadaptation in brain function that contributes to an ill-defined feeling of dysphoria, anxiety, or malaise that can only be alleviated by renewed administration of the drug. Continued drug use is rewarding because it stimulates the natural reward circuitry and also because the action offsetting the anti-reward response (stress hypersensitivity and anxiety) produces an additional reinforcing effect that increases the sum of positive reinforcement. The protracted withdrawal period is often characterized by elevated anxiety involving alterations in the noradrenergic input to the bed nucleus of the stria terminalis or amygdala. Drug-associated stimuli activate noradrenergic A1/A2 neurons during protracted withdrawal, leading to elevated anxiety through the ensuing release of noradrenergic neurons in the extended amygdala. In turn, additional reinforcing properties are produced via the alleviation of anxiety when these noradrenergic neurons are inhibited, reflecting negative reinforcement [106,107].

Additionally, chronic drug exposure results in a generalized hedonic deficit for natural rewards and an incentive value for drugs. This deficit in the capacity for obtaining reinforcement from non-drug sources generates symptoms such as anhedonia and depression [107]. The sensitized hedonic drug value is also believed to increase motivation for drug use. Furthermore, the changes that occur in hedonic processing mechanisms following chronic opioid exposure may involve multiple systems that recover at different rates. Changes in the afferents to the ventral tegmental area or in plasticity within the ventral tegmental area itself could play a vital role in altered hedonic processing during protracted withdrawal [106,107].

Taken together, these findings suggest that elevated drug seeking during protracted withdrawal may involve two processes: prolonged and elevated anxiety leading to a negative reinforcement mechanism for opioids and increased incentive motivation for drug reward through a sensitization mechanism [106,107].

15. LIABILITY OF ABUSE/DEPENDENCE OF LEGITIMATELY PRESCRIBED OPIOID DRUGS

There is broad consensus that patients with acute and chronic pain have often received inadequate pain control out of a fear of creating dependence. This is typified by the results of a survey in which 35% of Canadian family physicians reported they would never prescribe opioids for moderate-to-severe chronic pain and 37% identified dependence as a major barrier to prescribing opioids [108]. Prescriber knowledge deficit has been identified as a key obstacle to appropriate opioid prescribing and, along with gaps in policy, treatment, attitudes, and research, contributes to widespread inadequate treatment of pain [109]. A 2013 survey measured primary care physician understanding of opioids and addiction. Of the 200 participants, [110]:

- 35% admitted knowing little about opioid addiction.

- 66% and 57% viewed low levels of education and income, respectively, as causal or highly contributory to opioid addiction.

- 30% believed opioid addiction "is more of a psychologic problem," akin to poor lifestyle choices rather than a chronic illness or disease.

- 92% associated prescription analgesics with opioid addiction, but only 69% associated heroin with opioid addiction.

- 43% regarded opioid dependence and addiction as synonymous.

These statistics reflect knowledge and attitude gaps among physicians that lead to undertreatment of pain and unnecessary suffering among patients experiencing pain [108]. In response to this, the Joint Commission and other organizations have enacted accreditation standards that consider pain to be the fifth vital sign, assessed whenever other vital signs are measured [1].

However, with the growing concern about the undertreatment of pain and the underuse of opioids in pain treatment, there is also a renewed concern about prescription opioid dependence and overdose deaths [1]. The disparate concerns regarding undertreatment of pain and facilitation of dependence is underscored by the fact that, until recently, pain management and addiction specialists rarely communicated. Pain management physicians rightly concern themselves with alleviation of pain and have traditionally underestimated dependence among their patients, with such patients often simply dismissed from further care. Addiction specialists, on the other hand, seldom encounter pain patients whose quality of life is vastly improved by opioids, but instead see failed patients from pain treatment programs [1]. Additionally, there is a shortage of pain specialist physicians in the United States that is expected to worsen. This has resulted in most of the medical care for patients with chronic pain being delivered by primary care physicians, despite, as stated, significant and widespread knowledge deficits among these practitioners in the medical skills necessary for providing optimal pain management, managing drug abuse and addiction, and utilizing risk evaluation and mitigation strategies when prescribing opioids [111]. Until the 1990s, Schedule II opioid analgesics were primarily used in operating rooms and inpatient settings because they required intravenous or intramuscular administration. In response to the increasingly permissive climate and by genuine unmet patient need, several nonparenteral Schedule II opioids have been approved by the FDA for use in the treatment of moderate-to-severe pain. Many of these newer agents are high-dose, extended-release formulations of pre-existing opioids, including OxyContin (a controlled-release oral formulation of oxycodone), MS Contin (a formulation of morphine sulfate), and Exalgo (a formulation of hydromorphone hydrochloride), all of which have fulfilled a genuine clinical need by providing an elevated, constant plasma level for extended periods without the fluctuations seen with the short-acting versions. These long-acting formulations may both reduce euphoric effects of the drug and reduce pain more effectively by treating pain before it becomes established (pre-emptive effect) rather than after, when higher doses may be required. However, these formulations can be abused by crushing the tablet or capsule and ingesting the powder intranasally, sublingually, or orally or dissolving the powder in water and injecting the substance. These approaches to ingestion alter the pharmacokinetics by disabling the slow-release mechanism and make a very high dose of the substance available, which substantially increases the reinforcing effects compared with oral consumption of the drug in its unaltered form [29].

Abuse liability is related to the ease of extraction and modification to produce the desired psychologic effect. Medication tends to be more readily abusable if it has a rapid onset and short duration of action, is highly potent, and is smokable or easily ingested. Examples of opioids with high abuse liability include hydromorphone (Dilaudid) tablets, which can be easily dissolved in water and injected, and OxyContin tablets, which can be crushed to disable the controlled-release properties and then snorted or dissolved in solution and injected. A specific black box warning on the labeling of a medication can alert potential substance abusers of the abuse liability. Also, brand name drugs, which carry a higher street value, are more likely to be abused and diverted than generic equivalents [1].

In studies of trends in medical use and abuse of opioid analgesics, a corresponding increase in the rate of abuse with prescription rates has been apparent [15,112,113]. Thus, the increased medical use of opioid analgesics for the treatment of pain has contributed to an increase in opioid analgesic abuse and overdose fatalities. The abuse of hydrocodone and oxycodone products, which has increased disproportionately to their availability since 2000, is an extreme example of this trend [1]. Results of epidemiologic studies indicate a high prevalence of lifetime abuse of other substances and of substance-related disorders in patients with OxyContin dependence, suggesting that substance abuse predated the use of OxyContin [114].

Legitimate pain clinics offer large amounts of drugs with a high potential for abuse, often with little evaluation and follow-up [112]. In some states (e.g., Florida, Texas), increasingly liberal prescribing practices have been linked to rising overdose death rates. A study evaluating opioid overdose in a sample of more than 5.7 million patients found that, irrespective of medical or nonmedical use, the rate of fatal overdose increased in proportion to the amount of prescriptions filled [113]. Furthermore, the risk of fatal overdose increased with prescription strength (morphine dose equivalent), particularly with equivalent doses greater than 50 mg/day. According to the CDC, 40% of all opioid overdose deaths involved a prescription opioid in 2016 [115].

DEVELOPMENT OF DEPENDENCE

The dependence of a patient to a drug initially prescribed for a medical condition is referred to as iatrogenic dependence. Opioid prescriptions fall into two major subgroups: treatment of acute pain with short-term opioids and treatment of chronic pain with long-term opioids. In contrast to the rare association of dependence with short-term use, long-term administration of opioids is estimated to result in opioid abuse or dependence in 2.8% to 18.9% of patients, which typically parallels the rate of abuse or dependence among opioid users in the general population [33].

There is no adequately validated instrument to differentiate pain patients who are at risk of dependence from those who are not. Research suggests that patients, even alcoholics, with no history of opioid dependence are not at heightened risk of becoming addicted with short-term opioid exposure. However, those with a positive history of dependence would benefit from active recovery efforts while receiving such medications [1].

One way to gauge the adequacy of pain control is to consider whether the use of added opioids has resulted in improvements in the functional restoration, physical capacity, psychologic well-being, family/social interactions, and healthcare resource use, which are weighed against unwanted effects, such as daytime sedation, mental confusion, constipation, and other side effects.

Despite the rise in the prescribing and abuse of opioid analgesics, definitive data on the rate of dependence among patients administered opioids for acute pain does not yet exist. There is, however, agreement on how to minimize the risk of iatrogenic dependence. These steps include screening for dependence risk potential based on a family history of substance abuse and the exploration of different delivery systems that adequately treat pain but minimize abuse potential [34]. Although a pattern of aberrant behavior may be grounds for caution, a history of opioid abuse does not necessarily preclude a patient from successful treatment with an opioid [1]. Screening for psychologic disorders is also advisable, including psychosomatic causes of pain.

The final word on the dilemma of balancing the desire for patient pain relief with the desire to minimize the chance of iatrogenic abuse or dependence comes from the authoritative pharmacology textbook The Pharmacological Basis of Therapeutics, which states, "neither the presence of tolerance and dependence nor the fear that they may develop should ever interfere with the appropriate use of opioids for pain relief" [9].

16. MANAGEMENT OF OPIOID USE DISORDER

In 1914, the Harrison Act was passed, which had the effect of criminalizing addiction and led to significant apprehension among physicians in treating narcotic addicts. Treatment for opioid dependence was basically non-existent until 1935, when U.S. Public Health Services opened a hospital in Lexington, Kentucky, devoted to the treatment of opioid dependence. However, treatment was entirely detoxification-based at that time. In 1963, the New York Academy of Sciences recommended that clinics be established to dispense narcotics to opioid-dependent patients. During this time, research identified methadone as a possibly efficacious agent because of its long half-life, which allowed once-daily dosing. In 1972, the FDA created stringent regulations governing methadone, reducing the flexibility of practitioners caring for opioid-dependent patients. The Office of National Drug Control Policy subsequently made changes in the 1995 Federal Regulations of Methadone Treatment to encourage the development of a less restrictive approach and to give physicians more latitude in prescribing methadone [57].

Today, management of opioid dependence entails different methods to achieve different goals, depending on the health situation and treatment history of the patient. These treatment approaches include [13]:

- Crisis intervention: Directed at immediate survival by reversing the potentially lethal effects of overdose with an opioid antagonist.

- Harm reduction: Intended to reduce morbidity and mortality associated with use of dirty needles and overdose.

- Detoxification/withdrawal: Aims to remove the opioid of abuse from the patient's body, either through gradual taper and substitution of a long-acting opioid or through ultra-rapid opioid detoxification.

- Maintenance treatment or opioid (agonist) replacement therapy: Aimed at reduction/elimination of illicit opioid use and lifestyle stabilization. Maintenance follows detoxification/withdrawal, whereby the patient is tapered from short-acting opioids and introduced to a long-acting opioid agonist, such as methadone or buprenorphine. Patients remain on agonist therapy short-term, long-term, or indefinitely depending on individual needs.

- Abstinence-oriented therapy: Treatment directed at cure. The patient is tapered off of short-acting opioids during the detoxification/withdrawal process and may be placed on an opioid antagonist with the goal of minimizing relapse.

All treatment approaches share the common goal of improving health outcomes and reducing drug-related criminality and public nuisance [13].

CRISIS INTERVENTION

Evidence Based Practice Recommendation

According to the World Health Organization, people likely to witness an opioid overdose should have access to naloxone and be instructed in its administration to enable them to use it for the emergency management of suspected opioid overdose.

https://www.guideline.gov/summaries/summary/48893

Last Accessed: March 21, 2018

Strength of Recommendation/Level of Evidence: Strong/very low

In response to acute overdose, the short-acting opioid antagonist naloxone is considered the criterion standard. Naloxone is effective in reversing respiratory depression and coma in overdose patients. There is no evidence that subcutaneous or intramuscular use is inferior to intravenous naloxone. This prompted discussion of making naloxone available to the general public for administration outside the healthcare setting to treat acute opioid overdose, and in April 2014, the FDA approved naloxone as an autoinjector dosage form for home use by family members or caregivers [116]. The autoinjector delivers 0.4 mg naloxone intramuscularly or subcutaneously. The autoinjector comes with visual and voice instruction, including directs to seek emergency medical care after use [116]. In November 2015, the FDA approved intranasal naloxone after a fast-track designation and priority review. Intranasal naloxone is indicated for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or CNS depression. It is available in a ready-to-use 4-mg single-dose sprayer [117,118].

HARM REDUCTION

Harm reduction measures are primarily employed to minimize the morbidity and mortality from opioid abuse and to reduce public nuisance [96]. As a part of this effort, measures to prevent and minimize the frequency and severity of overdoses have been identified. Enrollment in opioid substitution therapy, with agents such as methadone and buprenorphine, substantially reduces the risk of overdose as well as the risk for infection and other sequelae of illicit opioid use [96].

Education

Reducing the risk for harm involves education on polydrug use and needle-exchange programs [96]. The authors of one review noted that there was positive evidence, though limited, to support education regarding noninjecting routes of administration, brief interventions, and supervised injecting facilities [119]. Given that a harm-reduction approach can address risk behaviors that may occur alongside drug use, the authors of one paper suggest that risk-reduction education be based on harm reduction philosophy as a whole rather than on the specific harms of drug use and harm reduction strategies (e.g., needle-exchange programs) [120]. The authors defined six principles—humanism, pragmatism, individualism, autonomy, incrementalism, and accountability without termination—and generalized them for use in healthcare settings with patients beyond those who use illicit substances. Each principle was defined and providers were given descriptions of how to deliver interventions informed by the principles as well as examples of how to apply each principle in the healthcare setting [120].

To improve response to overdoses, opioid abusers and their friends and families should be taught simple cardiopulmonary resuscitation skills to keep comatose users alive until emergency medical personnel arrive. Associates of users should be encouraged to call an ambulance when overdose occurs. The provision of naloxone to opioid users should be tested and evaluated; naloxone could be distributed through existing outlets, such as needle and syringe exchanges, pharmacies, urgent care facilities, or treatment agencies. Heroin users should also be encouraged to switch to noninjecting routes of administration to reduce related morbidity and mortality [96].

Needle-Exchange Programs

Needle-exchange programs, also referred to as syringe services programs, have been shown to be effective in reducing drug-related health problems, reducing injection frequency, and increasing entry and retention in drug treatment [13]. According to one review, there is sufficient evidence of efficacy, effectiveness, and financial benefit to recommend needle-exchange and outreach programs [119]. It is important to note that information regarding infection prevention strategies be provided to all participants in needle-exchange programs, as increased incidences of HIV and other bloodborne pathogens have been noted in this population [121]. The Consolidated Appropriations Act of 2016 gives states and local communities, under limited circumstances, the opportunity to use federal funds to support certain components of needle-exchange programs. Although federal funds cannot be used to purchase sterile needles or syringes for illegal drug injection, these funds can be used to support a comprehensive set of services as part of a needle-exchange program [122].

Injection Rooms

Medically supervised injecting rooms are officially designated areas where injecting opioid users, often persons who use heroin, can inject without fear of arrest and with knowledge that medical assistance is available if overdose occurs. Such facilities have existed in Switzerland since 1986, in Germany since 1994, and in the Netherlands since 1996. The goal of user rooms is to promote health and reduce risk behaviors and public nuisance, with a specific focus on overdose reduction and hygiene [123]. Several descriptive studies have shown significant effects on harm reduction and reduction of public nuisance [13].

Heroin Maintenance

Heroin maintenance, also referred to as heroin-assisted treatment, is the implementation of heroin prescriptions under medical supervision. This option may improve health and reduce heroin overdoses, illicit opioid use, and crime. However, formidable barriers to heroin maintenance exist in the United States [96].

One systematic review compared heroin maintenance to methadone or other substitution treatments of opioid dependence for efficacy and acceptability; retaining patients in treatment; reducing the use of illicit substances; and improving health and social functioning [124]. Eight studies involving 2,007 patients met the inclusion criteria. Five studies compared supervised injected heroin plus flexible dosages of methadone to oral methadone alone. Results suggest an added value of heroin prescribed alongside flexible doses of methadone for long-term, treatment-refractory, opioid users to reduce use of illicit substances and sustain treatment [124].

DETOXIFICATION AND WITHDRAWAL

The process of tapering opioid-dependent patients from agonist therapy is often referred to as detoxification, or more accurately, medically supervised withdrawal [57,125]. Its purpose is to eliminate physical dependence on opioid medications. It can be considered the medically supported transition to a medication-free state or to antagonist therapy. A careful and thorough review of the risks and benefits of detoxification should be provided and informed consent obtained from patients prior to choosing this option [125,126]. Detoxification alone should not be considered a treatment and should only be promoted in the context of a well-planned relapse-prevention program [13,125].

Discontinuation of opioid use must be implemented slowly and cautiously to avoid a marked abstinence syndrome. Withdrawal symptoms may not begin for days after abrupt discontinuation of methadone or buprenorphine given their longer half-lives. Protracted abstinence, or post-acute withdrawal, may last for several months and is characterized by asthenia, depression, and hypotension. Post-acute withdrawal is more likely to occur with methadone than other opioids [57].

The three primary treatment modalities used for detoxification are opioid agonists, non-opioid medications, and rapid and ultra-rapid opioid detoxification [57]. The most frequently employed method of opioid withdrawal is a slow, supervised detoxification during which an opioid agonist, usually methadone, is substituted for the abused opioid [76]. Methadone is the most frequently used opioid agonist due to the convenience of its once-a-day dosing [57]. Methadone is highly bound to plasma proteins and accumulates more readily than heroin in all body tissues. Methadone also has a longer half-life, approximately 22 hours, which makes withdrawal more difficult than from heroin. Substitution therapy with methadone has a high initial dropout rate (30% to 90%) and an early relapse rate. Alternative pharmacologic detoxification choices include clonidine (with or without methadone), midazolam, trazodone, or buprenorphine [76].

Many opioid withdrawal symptoms, such as restlessness, rhinorrhea, lacrimation, diaphoresis, myosis, piloerection, and cardiovascular changes, are mediated through increased sympathetic activation, the result of increased neuron activity in the locus coeruleus. Non-opioid agents (such as clonidine), which inhibit hyperactivation of noradrenergic pathways stemming from the locus coeruleus nucleus, have been used to manage acute withdrawal [76,104]. The first non-opioid treatment approved for the management of opioid withdarawl symptoms is lofexidine [205]. In studies, patients treated with lofexidine reported less severe withdrawal symptoms and were more likely to complete treatment.

However, some withdrawal symptoms, including anxiety and myalgias, are resistant to clonidine; benzodiazepines and nonsteroidal anti-inflammatory agents may be necessary to treat these symptoms. To mitigate withdrawal symptoms and assist in detoxification, alpha2-agonists, opioid agonist-antagonists, benzodiazepines, and antidepressants have been used [76].

Following detoxification, patients may feel exhausted and weak. Other complications, such as slight variations in hemodynamic status and gastrointestinal tract symptoms, follow quickly and may take several days to resolve. Muscle cramps and low back pain can be treated with nonsteroidal anti-inflammatory drugs. However, the newer cyclooxygenase-2 (COX-2) inhibitors may be advantageous because they produce fewer gastrointestinal side effects [76]. Insomnia is a frequent aspect of acute and protracted withdrawal, as opioids disrupt the normal sleep-wake cycle and many addicts require narcotics to sleep. Although long-term disruption of the normal sleep-wake cycle cannot be corrected rapidly, melatonin (3 mg), benzodiazepines, or antihistamines can be used with beneficial effects. Hypnosis and relaxation techniques are nonpharmacologic methods that may also be used [76]. Psychosocial treatments offered in addition to pharmacologic detoxification treatments positively impact treatment retention and completion, results at follow-up, and compliance [127,128].

Ultra-Rapid Opioid Detoxification

Ultra-rapid opioid detoxification (UROD) has been developed as a means of avoiding the physical symptoms of withdrawal from opioids through the use of general anesthesia. UROD consists of naltrexone-assisted detoxification under heavy sedation or full anesthesia. Chemical sedation has been used since the early 1940s in the management of drug withdrawal. The major breakthrough in the management of opioid withdrawal occurred with the addition of an opioid antagonist during chemical sedation [129]. UROD was introduced in 1990 primarily by private practitioners in a for-profit setting [130].

Traditional withdrawal management utilizes the substitution of the short-acting opioid with a long-acting opioid and subsequent tapering or use of non-opioids. This may involve substantial discomfort to patients, who often terminate the detoxification process and return to opioid use. Some may not even attempt to quit due to fears of the discomfort of the withdrawal process. Thus, attempts have been made to induce and shorten opioid withdrawal through the use of UROD [130].

UROD is also referred to as rapid or anesthesia-assisted detoxification. One reason for the proliferation of terms is that the anesthesia-assisted procedure was commercially used and was submitted as a registered trademark or patent. Therefore, other researchers had to devise novel names for the process. Suggested classification is [130]:

- Ultra-rapid opioid detoxification (UROD): General anesthesia; duration <6 hours

- Rapid opioid detoxification (ROD): Deep sedation; duration 6 to 72 hours

- Compressed opioid detoxification (COD) and naltrexone-compressed opioid detoxification (NCOD): Duration three to six days; preceded by a period of abstinence from opioids under sedation prior to introduction of naltrexone

The common underlying themes in all UROD techniques are a desire to condense the detoxification process into a shorter period to blunt the awareness of physical discomfort and to shorten the time lag between a patient's last dose of opioid and transfer to naltrexone maintenance [130]. This is accomplished by precipitating withdrawal following the administration of opioid antagonists under deep sedation or anesthesia.

A highly specific subgroup of patients may benefit more from UROD. This includes patients unable to abstain with methadone substitution despite adequate motivation, patients unable to stop methadone, and patients who are socially and occupationally active and cannot go through a lengthy detoxification. Patient preference is also an important variable [130].

Absolute contraindications include pregnancy; a history or clinical suspicion of cardiac disease; chronic renal impairment; liver disease; current dependence on benzodiazepines, alcohol, or stimulants; and history of psychotic illness [130]. Relative contraindications include a history of treatment for depression and unstable social circumstances. A comprehensive plan to stabilize such patients should be undertaken before the procedure [130]. Patients with chronic pain syndromes requiring opioid medication are not good candidates unless their pain can be controlled by alternative methods [76].

UROD is best performed in an intensive care unit with full resuscitative equipment and monitoring available [76]. Initiation of opioid withdrawal is precipitated by IV injection of a high-dose antagonist, usually naloxone. Antagonists are chosen that have high binding coefficients relative to agonists (naltrexone binds at the mu receptor 34 times more than morphine) [76]. Parameters that indicate adequacy of withdrawal include a 20% decrease of ventilation below the maximum minute ventilation, an electrocardiogram (ECG) detection of decreased QQ variability, and electroencephalogram (EEG) normalization [76].

Detoxification and withdrawal are rarely complete following UROD, and residual withdrawal symptoms can include drug craving, sympathetic hyperactivity, muscle pain, bone pain, nausea, vomiting, diarrhea, and insomnia. UROD does little to prevent protracted abstinence syndrome, which can last 3 to 10 weeks. Naltrexone may reduce opioid craving during the post-UROD period, with 50 mg per day recommended for relapse prevention [76]. However, patients undergoing long-term naltrexone therapy can become sensitized to opioid drugs, heightening the risk of fatal overdose if opioid use is resumed. Patients with a history of pre-existing liver dysfunction should undergo naltrexone maintenance therapy only under careful supervision. Clonidine may diminish sympathetic hyperactivity and should be continued through the protracted abstinence syndrome [76].

The withdrawal syndrome observed in many of the published studies on UROD was protracted, as reflected in the duration of inpatient stay, which varied from 24 hours to eight days, with a mean duration of three to four days. Therefore, alternatives to UROD are considered to be more cost-effective [130]. Krabbe et al. compared abstinence rates and withdrawal effects of UROD with standard methadone tapering in a prospective three-month trial [131]. They found significantly higher abstinence rates and fewer withdrawal symptoms in UROD patients versus methadone patients at one and two months, with no differences at three months.

A major shortcoming of UROD is the lack of evidence that an opioid antagonist can accelerate the restoration of neurobiologic homeostasis following opioid withdrawal [130]. Although significant drawbacks and questionable long-term efficacy exist with UROD, popular demand has proven difficult to restrain, in part due to the marketing of the procedure as a painless cure for opioid dependence. Marketing and the media have also blurred the fact that the original purpose of the procedure was to induce patients as rapidly as possible onto naltrexone and not to magically and permanently terminate years of opioid dependence [129].

There are a number of drawbacks to UROD relative to other detoxification methods. For example, one study found that, when used alone, naloxone has a high relapse rate in the long term [132]. The study included 64 opioid-dependent men 18 years of age and older (mean age: 31.1 years) at the time of UROD. One month after UROD, 48 patients (75%) reported relapse and 16 patients (25%) reported abstinence. There was no significant difference between the two groups regarding marital status, level of education, and family history of opioid dependence. Four patients from the nonrelapsed group reported on episode of opiate use [132]. Another study was conducted to assess UROD efficacy with naltrexone and estimate the relapse rate in a two-year follow-up period [133]. A total of 424 opioid-addicted self-reporting patients were enrolled in the study and entered the UROD program; 400 patients completed the program. Of the total patients, 303 (75.75%) were successful and 97 (24.25%) relapsed. No patients in the relapse group continued naltrexone maintenance at six-month follow-up. The relapse rate was 14% at the first month visit and 24% at the six-month visit and thereafter. All relapsed patients had discontinued use of naltrexone before relapse occurred [133].

Serious adverse events related to the anesthetic procedure also have been reported. A randomized, controlled trial directly comparing naltrexone-assisted detoxification with and without full anesthesia clearly stated that heavy sedation or full anesthesia should not be used because it does not confer any advantages in withdrawal symptom severity or increased rates of initiation or maintenance and it increases the potential for life-threatening adverse events [13]. A trial comparing naltrexone-induced, anesthesia-assisted detoxification with buprenorphine- or clonidine-assisted detoxification found no difference in withdrawal severity and rates of completion. However, potentially life-threatening adverse events associated with the UROD anesthesia were observed. The authors concluded that the data do not support use of anesthesia for detoxification [134]. Heavy sedation compared to light sedation does not confer additional benefits in terms of less severe withdrawal or increased rates of initiation and retention on naltrexone maintenance treatment. The risk for adverse events, the high monetary cost, and use of scarce intensive care resources suggest that this form of treatment should not be pursued [135,136]. Additionally, UROD has not undergone the processes of therapeutic protocols, which are recognized as essential in scientific medicine, and no animal studies have been conducted with the procedure [129].

AGONIST REPLACEMENT OR ABSTINENCE THERAPY

Two principle treatment modalities are offered for opioid-dependent patients: agonist maintenance or detoxification followed by outpatient or residential drug-free treatment. Both can be effective, with no clear indication for each, although agonist maintenance leads to greater treatment retention [137]. A reasonable approach is initial outpatient or residential treatment referral for patients relatively new to treatment, with agonist maintenance appropriate for patients with history of treatment failures, greater disease severity, or a history of drug overdoses. Naltrexone is best reserved for patients with strong legal incentives to abstain, family involvement to monitor treatment, or concurrent enrollment and involvement in a psychosocial intervention [138].

At present, there are no direct interventions that are capable of reversing the effects of drugs of dependence on learning and motivation systems [34]. Instead, the management of opioid dependence often consists of pharmacotherapy with methadone and buprenorphine, which do not eliminate physical dependence on opioids. These medications instead reduce the use of illicit opioids and produce very strong positive health outcomes as measured by decreased mortality, improved mental and physical health, and reduced risk of disease transmission [34]. Considering the high rate of relapse after detoxification, maintenance therapy with methadone or buprenorphine is currently considered to be the first-line treatment for opioid-dependent patients [13].

Any treatment for opioid dependence must take into consideration the chronic relapsing nature of opioid dependence, characterized by a variable course of relapse and remission in many patients. Treatments should emphasize patient motivation, psychoeducation, continuity of care, integration of pharmacotherapy and psychosocial support, and improved liaison between the treatment staff and the judicial system. Pharmacotherapy must be offered in a comprehensive healthcare context that also addresses the psychosocial aspects of dependence [13]. Opioid-dependent patients frequently suffer from physical and psychiatric disorders, and targeted interventions of psychiatric comorbidity are essential in improving treatment outcome for these patients [13]. Polysubstance abuse is the rule rather than the exception in opioid dependence, and concurrent use of other substances should be carefully monitored and treated when necessary [13]. Incarceration should never automatically result in discontinuation of an existing treatment; imprisonment offers a window of opportunity to initiate or restart treatment with a necessary continuation after release [13].

Agonist Replacement Therapy

The goal of opioid replacement therapy is to reduce illicit drug use and associated health risks, with secondary goals of reducing unsafe sexual practices, improving vocational and psychosocial functioning, and enhancing quality of life [57]. The theoretical basis of opioid replacement stems from the finding that chronic opioid use results in an endogenous opioid deficiency as a result of the down-regulation of opioid production. This creates overwhelming cravings and necessitates interventions that shift the dependent patient's attention and drive from obsessive preoccupation with the next use of opioids to more adaptive areas of focus, such as work, relationships, and non-drug leisure activities [57].

The neurobiologic changes resulting from prolonged opioid exposure provide a rationale for specific pharmacotherapies, such as long-acting opioid agonists, that are aimed at stabilizing these complex systems [80]. Opioid agonist maintenance treatment stabilizes brain neurochemistry by replacing short-acting opioids, which can create rapid changes in opioid levels in the serum and brain, with a long-acting opioid that has relative steady-state pharmacokinetics. Opioid agonist maintenance treatment is designed to have minimal euphoric effect, block the euphoria associated with administration of exogenous opioids (competitive antagonism), eliminate the risk of infectious disease and health consequences associated with injection drug use, and prevent opioid withdrawal [80].

Successful maintenance treatment entails stabilization of opioid dependence through opioid receptor occupation. Positron emission tomography studies have revealed that only 25% to 35% of brain opioid receptors are occupied during steady-state methadone maintenance, suggesting that unoccupied opioid receptors disrupted during cycles of opioid abuse could normalize during methadone maintenance [57]. Additionally, opioid replacement therapy blocks much of the euphoria from illicit heroin use. Long-term opioid agonist treatment also has a positive impact on public health, through significantly reducing overdose deaths, criminal activity, and the spread of infectious disease [57].

As of 2016, 417,057 patients in the United States were enrolled in opioid replacement therapy in 1,308 opioid treatment programs [139]. However, this represents only an estimated 19% of all opioid-dependent patients. Although some have criticized the practice of methadone and buprenorphine therapy on the grounds that one opioid is merely being substituted for another, the clinical benefits strongly support this treatment modality [57]. When compared to active street heroin users, these benefits include a four-times lower HIV seroprevalence rates, 70% fewer crime-days per year, and a one-year mortality rate of 1% (versus 8%) [60].

Methadone

The first demonstrated efficacy of methadone treatment for opioid dependence was published in 1965. Methadone is now the most inexpensive and empirically validated agent available for use in opioid replacement therapy. Studies have shown one-year treatment retention rates of 80%, with significant reductions in illicit opioid use [57]. Individual and group counseling are the main ancillary therapies and consist primarily of cognitive-behavioral and supportive-expressive approaches. There is some evidence that augmentation of methadone with intensive psychosocial therapy significantly improves outcomes [57]. Efforts to provide methadone in an office-based setting have been successful, although federal regulation has limited the flexibility of providers [80,104].

Evidence Based Practice Recommendation

When considering initiation of methadone, the American Pain Society recommends that clinicians perform an individualized medical and behavioral risk evaluation to assess risks and benefits of methadone, given methadone's specific pharmacologic properties and adverse effect profile.

https://www.guideline.gov/summaries/summary/49245

Last Accessed: March 21, 2018

Strength of Recommendation/Level of Evidence: Strong/low

As noted, methadone maintenance treatment offers substantial benefits over no treatment, including reduced risk of death and disease, reduced heroin use, reduced criminal involvement, and improved well-being. However, the benefits are less with poor-quality or under-funded programs. The quality of the staff-patient interaction, attitudes of staff, good management of clinics, and good record-keeping characterize higher-quality programs [140].

Methadone maintenance is also cost-effective [57]. A 1997 study of Veterans' Affairs patients showed that the estimated six-month costs are about $21,000 for an untreated drug abuser, $20,000 for an incarcerated drug abuser, and $1750 for a patient enrolled in a methadone maintenance program [141]. A 2010 study using data from one healthcare plan reached a similar conclusion regarding cost-effectiveness (albeit with differing cost estimates) [142]. The annual costs (in 2004 dollars) were $18,694 for patients receiving no methadone with 0 or 1 outpatient addiction treatment visits; $14,157 for patients receiving no methadone with 2 or more visits; and $7,163 for patients receiving methadone.

There is an unrealistic expectation that opioid users should be able to stop using all drugs. Although some do successfully stop, dependence is a chronic problem for most patients, associated with frequent relapses, serious health risks, and psychosocial impairment [140]. Unfortunately, a serious stigma surrounds methadone treatment, which is experienced most acutely by patients but also by professionals. This may pose a barrier to treatment support [140].

Treatment is initiated with a dose of 25–30 mg and is gradually titrated in 5- to 10-mg increments per day to a desired range of 60–120 mg. Low-dose treatment is associated with less positive outcomes than doses of 60–120 mg/day or greater [57,60]. One published review of efficacy literature concluded that high doses of methadone (>50 mg daily) are more effective than low doses (<50 mg daily) in reducing illicit opioid use. This may be due to the increased availability of highly pure heroin [60]. Additionally, high doses of methadone are more effective than low doses of buprenorphine (<8 mg daily). High dosages of methadone are comparable to high dosages of buprenorphine (>8 mg daily) on measures of treatment retention and reduction of illicit opioid use [13]. Methadone is contraindicated for the following patients [104]:

- Those with known hypersensitivity to methadone hydrochloride

- Those experiencing respiratory depression

- Those with acute bronchial asthma or hypercapnia

- Those with known or suspected paralytic ileus

Buprenorphine

Buprenorphine offers several advantages over methadone, including lower cost, milder withdrawal symptoms following abrupt cessation, lower risk of overdose, and longer duration of action, allowing alternate-day dosing [57,143]. Identifying subpopulations of opioid addicts who differentially respond to buprenorphine versus methadone has not been clearly established. However, patients with less chronic and less severe heroin dependence benefit more fully from buprenorphine than from a pure opioid agonist like methadone [57].

Studies support buprenorphine as a viable alternative for opioid maintenance therapy. However, its mixed agonist/antagonist action entails special considerations. Buprenorphine may precipitate opioid withdrawal, and patients being switched from short-acting opioids must abstain from illicit opioid use for at least 24 hours before initiating buprenorphine therapy [57,104]. Another drawback is associated with the sublingual route of administration. This administration presents some difficulties because the tablet is relatively large and slow to dissolve under the tongue and swallowing diminishes its effectiveness. Also, the transition to buprenorphine from long-acting opioids is difficult [34]. The ASAM warns that diversion and misuse are possible with buprenorphine, as is physical dependence. Respiratory depression may occur if buprenorphine is used with CNS depressants including alcohol, other opioids, and illicit drugs. Neonatal withdrawal has also been reported after use of buprenorphine during pregnancy. Buprenorphine is not recommended for patients with severe hepatic impairment [104].

Higher doses of buprenorphine (12 mg or greater) are more effective than lower doses in reducing illicit opioid use, with some studies reporting similar efficacy to methadone on major treatment-outcome measures. One systematic review was conducted to evaluate buprenorphine maintenance compared to placebo and methadone maintenance in the management of opioid dependence [144]. Outcomes considered were treatment retention, suppression of illicit drug use, and reduction in criminal activity and mortality. A total of 31 trials involving 5,430 participants with moderate- to high-quality evidence were included in the review. According to the data reviewed, buprenorphine retained participants better than placebo at low doses (2–6 mg), at medium doses (7–15 mg), and at high doses (≥16 mg). Only high-dose (≥16 mg) buprenorphine was more effective than placebo at suppressing illicit opioid use (as measured by urinanalysis). Buprenorphine in flexible doses (i.e., adjusted to participant need) was less effective than methadone in retaining participants, and for those retained in treatment, no difference was observed in suppression of illicit opioid use. In low fixed-dose studies, methadone (≤40 mg) was more likely to retain participants than low-dose (2–6 mg) buprenorphine. However, there was no difference between medium-dose (7–15 mg) buprenorphine and medium-dose (40–85 mg) methadone in retention or in suppression of illicit opioid use. Similarly, there was no difference between high-dose (≥16 mg) buprenorphine and high-dose (≥85 mg) methadone in retention or suppression of self-reported heroin use [144]. In a 2011 study of 34,000 Massachusetts Medicaid beneficiaries, the incidence of relapse was greater with buprenorphine than with methadone [143]. The primary advantage of buprenorphine over methadone is its superior safety profile [34].

Slow-Release Oral Morphine

Slow-release formulations of morphine that are effective with once-daily dosing are a viable alternative in the treatment of opioid dependence. These formulations considerably delay time to peak concentration after oral administration, resulting in delayed onset of action and making the reinforcing effects very weak when it is administered orally. Several trials have suggested that slow-release morphine has approximately equal efficacy with methadone; however, there is no definitive evidence of this effect [34,145,146]. Slow-release oral morphine may be a viable alternative for patients who are intolerant to methadone [147].

Diacetylmorphine (Heroin)

The pharmacokinetic properties of heroin make it less than ideal for use as a maintenance drug, and the main rationale for heroin maintenance has been the treatment of patients who simply do not respond to any other treatment modality. Although preliminary results seem to be positive, before suggesting that heroin treatment may have a place with a subpopulation of patients, further studies using standardized protocols are needed. Significantly, studies so far clearly indicate that heroin maintenance, with or without methadone, can be implemented safely. The relatively high cost of heroin maintenance compared with standard methadone or buprenorphine treatment is a drawback of this approach. However, at least one study suggests that heroin combined with methadone may be more cost-effective than methadone alone [34].

The results of medically prescribed heroin administration to chronic, treatment-refractory, heroin-dependent patients have been detailed in two reports. One report from Switzerland concluded that supervised medical prescription of heroin was associated with favorable treatment retention, reduced illicit drug use, reduced criminality, and improved health outcomes and social functioning. These findings were also reported in a controlled trial from Spain and Germany [13]. Research projects were also performed in the Netherlands, Canada, and England, and others are planned in Belgium and Denmark. Based on the positive outcomes thus far, heroin maintenance has become routine treatment for otherwise untreatable heroin addicts in Switzerland, the Netherlands, Germany, and England and is being recommended in Canada [148,149].

Agonist Replacement and Psychosocial Therapy

The addition of any psychosocial support modality to agonist replacement therapy significantly reduces illicit use during treatment, and treatment retention and results at follow-up are also improved [127,128]. There are two general types of psychosocial therapy used for treating addictive disorders. The first includes therapies developed for treating depression and anxiety that were later adapted for treating persons with addictive disorders, examples of which include cognitive behavioral therapy, supportive expressive therapy, and interpersonal therapy. The second type includes therapies developed specifically for persons with addictive disorders, such as the closely-related motivational interviewing and motivational enhancement therapy [150].

Drug counseling, another approach specific to addictive disorders, emphasizes abstinence, involvement in 12-step programs, and assistance with social, family, and legal problems. Drug counseling is not considered psychotherapy because it focuses on behaviors and external events rather than the intrapsychic processes [150].

Most studies of psychotherapy with opioid-dependent patients have been conducted in methadone programs and are actually pharmacotherapy/psychotherapy studies. In addition to pharmacologic intervention, methadone programs typically use behavioral contingencies that are based on cessation of illicit drug use and other improvements [150].

A review of the literature on psychosocial therapy outcomes with opioid-dependent patients receiving methadone has found evidence of an interaction between measures of psychiatric symptoms, therapy assignment, and outcomes [150]. Patients with minimal psychiatric symptoms did equally well with drug counseling alone or with drug counseling plus supportive expressive therapy or cognitive-behavioral therapy. Patients with moderate-level symptoms did somewhat better if they received additional psychotherapy, and patients with more severe psychiatric symptoms had substantially better outcomes with additional psychotherapy than with drug counseling alone. Improvements were observed in employment, legal, psychiatric, and drug use indices. Patients with opioid dependence and antisocial personality disorder did not benefit from additional psychosocial therapy beyond drug use reduction, but patients with opioid dependence, antisocial personality, and depression exhibited improvement in multiple areas [150].

Therapist variables played an important role in outcome, with better results associated with therapists who formed a positive, helping relationship with the patient. There is also some evidence that the best patient outcomes come from methadone programs with a higher level of services that include counseling, medical, and psychiatric services [150].

Abstinence-Oriented Therapies

The primary goal of abstinence-oriented interventions is cure, which is defined as long-term, stable abstinence from all opioids. Abstinence is achieved in two phases: detoxification and relapse prevention. Outcomes in abstinence-oriented programs are generally poor [13].

The primary goal of pharmacotherapy during detoxification is to alleviate opioid withdrawal severity and associated distress/medical complications and to enhance patient motivation to continue treatment. Withdrawal can also be reduced by psychosocial measures, such as contingency management or counseling, and as discussed, the addition of psychosocial therapy to pharmacologic treatment increases efficacy. Buprenorphine and clonidine are both used to manage withdrawal symptoms, but buprenorphine's advantages, compared with clonidine, are related to its favorable side effect profile and positive effects on well-being and psychosocial variables [13].

Opioid Antagonist Therapy

Relapse-prevention programs have traditionally involved long-term residential placement of nine months or more, often using the therapeutic community format. More recently, pharmacotherapeutic agents, such as naltrexone, have been added to reduce relapse risk. A drawback with opioid antagonist therapy is the high dropout rate during detoxification, which results in highly selective patient samples in most of the naltrexone maintenance studies. Naltrexone maintenance or relapse-prevention treatment should be reserved only for those patients who are highly motivated for long-term total abstinence and who are otherwise psychosocially stable [104]. Relapse prevention with naltrexone may also be suitable for pregnant women who are unable to stabilize on methadone or buprenorphine. Patients should be warned that reduced tolerance following naltrexone treatment may increase the risk of overdose [13].

The primary problem with naltrexone treatment is low compliance, with retention in treatment ranging from 6% to 45% [34,104]. Strategies to improve treatment compliance include combining naltrexone maintenance with contingency management, involving the provision of vouchers redeemable for goods and services contingent on naltrexone intake and drug-free urines [82]. The authors of one investigation evaluated prescribing patterns for opioid use disorder medications among a commercially insured population in the United States from 2010 to 2014. The evaluation revealed consistently low treatment completion rates for two forms (e.g., injectable, oral) of naltrexone. At 30 days post-initiation, 52% of individuals treated with injectable naltrexone had discontinued treatment, and 70% of individuals treated with oral naltrexone had discontinued treatment. The proportion of patients treated with either form of naltrexone grew over time, but the discontinuation rates were significantly higher compared with individuals treated with sublingual or oral-mucosal buprenorphine/naloxone [151]. Although the focus of this investigation was not on the reasons for treatment discontinuation, it did highlight the poor treatment compliance with naltrexone. The extended-release injectable naltrexone formulation may help overcome the compliance issues associated with the oral formulation [104].

Naltrexone is contraindicated in patients with hypersensitivity reactions to the agent, in patients with current physical and physiologic dependence on opioids, and in patients in acute opioid withdrawal [104]. At present, reviewers conclude "there is no sufficient evidence of efficacy of naltrexone to justify its use in the maintenance treatment of opioid dependence" [152].

Psychosocial Monotherapy

Evidence Based Practice Recommendation

In opioid treatment program settings, the Department of Veterans Affairs Work Group suggests offering individual counseling and/or contingency management, with consideration of patient preferences and provider training/competence.

https://www.guideline.gov/summaries/summary/49968

Last Accessed: March 21, 2018

Strength of Recommendation: Weak for

There is no data to support psychosocial interventions as a sole intervention for opioid dependence [127,128]. Psychosocial treatments alone are not adequately proven treatment modalities, nor are they superior to any other type of treatment for opioid dependence [153]. However, psychosocial treatments offered in addition to pharmacologic detoxification treatments are effective in terms of treatment completion, opioid use, and participant abstinence at follow-up [128].

12-Step/Self-Help Programs

Twelve-step programs for opioid abuse and dependence include Narcotics Anonymous (NA) and Methadone Anonymous (MA) and are modeled after Alcoholics Anonymous (AA), an abstinence-based support and self-improvement program that is based on the 12-step model of recovery. AA is widely considered the most successful treatment for alcoholism and has helped hundreds of thousands of alcoholics achieve sobriety [154]. The 12-step model emphasizes acceptance of dependence as a chronic, progressive disease that can be arrested through abstinence but not cured. Additional elements include spiritual growth, personal responsibility, and helping other addicted persons. By inducing a shift in the consciousness of the addict, 12-step programs offer a holistic solution and are a resource for emotional support [154]. Although research on efficacy and patient outcomes in NA and MA is very limited, many prominent researchers emphasize the important role ongoing involvement in 12-step programs plays in recovery from substance abuse [155].

The understanding of drug dependence as a chronic and relapsing disorder has helped professionals gain a better comprehension of the vital role played by 12-step programs. Every patient attempting to recover from a substance use disorder will encounter a time when he or she faces urges to use without the resources or assistance of healthcare professionals. Twelve-step programs are not considered treatment, nor are they intended as substitutes for treatment. Instead, they are organizations that provide ongoing and indefinite support in the achievement and maintenance of abstinence and in personal growth and character development [155].

Part of the effectiveness of NA and MA is related to their ability to provide a competing and alternative reinforcer to drug use. Involvement in 12-step programs can enhance the quality of social support and the social network of the member, a potentially highly reinforcing aspect the person stands to forfeit if they resume drug using. Other reinforcing elements of 12-step involvement include recognition for increasingly durable periods of abstinence and frequent awareness of the consequences of drug and alcohol use through attendance of meetings [156]. Research shows that establishing a pattern of 12-step program attendance early in treatment predicts the level of ongoing involvement. Emphasis and facilitation of early engagement in a 12-step program involvement are key [157].

Narcotics Anonymous

Relative to the more established AA, there are few studies published on NA. However, some research has revealed important information about how NA functions to help both new and long-term members abstain from opioids and other drugs. Being active as an NA sponsor over a one-year period was found to be strongly associated with substantial improvements in sustained abstinence rates for the sponsors. This suggests that providing direction and support to other newer addicts is a way to enhance the likelihood of one's own abstinence [158]. In addition to being a sponsor, having a sponsor also is associated with positive outcomes. One analysis explored the predictors and outcomes of having a 12-step sponsor among individuals receiving treatment for stimulant use disorders [159]. Four types of 12-step groups were evaluated: NA, AA, Cocaine Anonymous, and Crystal Meth Anonymous. Factors evaluated were the extent to which participants obtained sponsors, the extent to which other predictors (e.g., beliefs, expectations) were associated with having a sponsor, and the effect of sponsorship at the end of treatment. Participants in the 12-step facilitation intervention had higher sponsorship rates at the end of treatment and at three-month follow-up, and end-of-treatment sponsorship predicted a higher likelihood of abstinence and no drug-related problems at follow-up [159].

Improvement in psychologic functioning as a result of NA involvement has been observed by Christo and Sutton [160]. Among the 200 NA members in their study, those who had been off drugs and involved with NA for longer periods tended to have lower trait anxiety and higher self-esteem scores, with those abstinent for more than three years exhibiting levels of anxiety and self-esteem similar to those of a comparison group of 60 students from a vocational training college [160].

Methadone Anonymous

MA was begun in 1991 when a staff member of a methadone maintenance treatment clinic in Baltimore attended an NA meeting and observed a woman receiving an "Anniversary Chip" in recognition of abstinence from heroin, only to be told to return the chip when she shared that methadone maintenance helped make it possible. This staff person went on to develop a 12-step program for methadone patients [161].

MA is based on the belief that "methadone is a therapeutic tool of recovery that may or may not be discontinued in time, dependent upon the needs of the individual," and that continued abstinence from drugs of abuse, including alcohol, is the foremost goal of recovery [162]. Most MA meetings are hosted by methadone clinics, and there are more than 1,000 MA clinics worldwide [163].

There are very few published studies involving MA. One study found that, similar to other 12-step programs, MA members undergo a spiritually-mediated transformation in their recovery process, with members describing methadone as the core of the group experience and an aid to spiritual transformation [164]. Length of time in MA has been found to be associated with reductions in the use of other substances as well, including alcohol, cocaine, and marijuana. Clients in methadone maintenance programs have rated components of MA to be significantly more helpful to recovery than methadone treatment components, suggesting that MA participation has benefits not available in professionally-driven methadone therapy programs [161].

ACUPUNCTURE

Auricular acupuncture is the most common acupuncture approach for substance abuse, including opioid abuse and dependence, in the United States and the United Kingdom. This technique consists of bilateral insertion of acupuncture needles in the outer ears [165]. There is controversy surrounding the presumed mechanism of action of acupuncture. Western scientists attempt to explain its action on the body's electromagnetic system, with the acupuncture needle creating a difference in electrical potential that stimulates extracellular ion flow. Chinese practitioners, who have been using acupuncture for several thousand years to treat a wide range of maladies, attribute its effects to unblocking or removing an excess of qi, or life energy, along key channels referred to as meridians [166].

Results from well-designed studies indicate that auricular acupuncture treatment is not sufficient in efficacy as a stand-alone treatment for opioid dependence. The placebo response rate is substantial, and the body of evidence does not demonstrate the type of qualitative and quantitative rigor needed to validate acupuncture efficacy in the treatment of opioid-addicted patients. Common adverse events from acupuncture include needle pain, fatigue, and bleeding; fainting and syncope are uncommon. Feelings of relaxation are reported by as many as 86% of patients [165]. There is some evidence that differences in efficacy may be influenced by racial physiologic differences among persons of European and Asian descent [165].

A 2016 review of 199 studies found that contradictory results, intergroup differences, and acupuncture placebo effects made it difficult to evaluate the effectiveness of acupuncture for drug addiction treatment [167]. The authors of another review looked at clinical trials of 100-Hz electroacupuncture for detoxification treatment. They found a potential for the treatment to allay opioid-associated depression and anxiety but no effect for opioid craving [168].

INTERVENTIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

For those who are not proficient in English, it is important that information regarding the risks associated with the use of opioids and available resources be provided in their native language, if possible. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required. Interpreters can be a valuable resource to help bridge the communication and cultural gap between patients and practitioners. Interpreters are more than passive agents who translate and transmit information back and forth from party to party. When they are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers, who ultimately enhance the clinical encounter. In any case in which information regarding treatment options and medication/treatment measures are being provided, the use of an interpreter should be considered. Print materials are also available in many languages, and these should be offered whenever necessary.

17. MANAGEMENT OF COMORBID PSYCHOPATHOLOGY

Psychiatric comorbidity often accompanies opioid dependence and plays an important role in treatment outcome. Multiple national population surveys have found that roughly 50% of those who experience mental illness during their lives will also experience a substance use disorder and vice versa [169,170]. More than 60% of adolescents in community-based substance abuse treatment programs also meet diagnostic criteria for another mental illness [171]. An estimated 43% of individuals in treatment for nonmedical use of prescription opioids have a diagnosis or symptoms of a mental health disorder, particularly depression and anxiety [172].

Major depression prevalence among opioid-dependent patients is estimated to be 20% to 30% lifetime and 10% to 20% at enrollment in treatment. Depression is also associated with the use of prescription opioids for chronic pain and worse treatment outcomes. Approximately 50% of patients with chronic pain have a comorbid psychiatric condition, and 35% of patients with chronic back and neck pain have a comorbid depression or anxiety disorder [37,138,173,174]. The prevalence of depression is lower in out-of-treatment patients than in those seeking treatment and is associated with increased retention in methadone treatment. Thus, depression has a mixed effect on prognosis. It appears to be a motivating factor in treatment-seeking while at the same time interfering with treatment effectiveness [37,138,173,174]. In addition, opioid-dependent patients with Axis I psychiatric comorbidity often require significantly higher methadone doses [57].

Psychiatric comorbidity is especially pronounced with serious mental illness, which is defined by the Substance Abuse and Mental Health Services Administration as individuals 18 years of age or older having, at any time during the past year, a diagnosable mental, behavior, or emotional disorder that causes serious functional impairment that substantially interferes with or limits one or more major life activities [175]. Approximately one in four individuals with a serious mental illness (e.g., major depression, schizophrenia, bipolar disorder) have a comorbid substance use disorder [176].

A main issue in managing comorbid conditions is the differentiation of independent versus substance-induced disorders, as therapeutic plans differ for the two conditions [173]. Substance abuse can result in changes in mood, appetite, sleep patterns, beliefs, and perceptual experiences, all of which may present as psychiatric disorders but resolve with stabilization of drug use. Treatment should not focus solely on the non-substance-use psychiatric diagnosis, as symptom reduction will not translate into reduced drug use. Active substance use can also alter the presentation of personality and diagnosis of a personality disorder [177].

ASSESSMENT

It is important to assess dependent opioid users for other psychiatric and substance use disorders, especially alcohol and cocaine dependence because they are frequent comorbidities in opioid-dependent patients and can aggravate depressive symptoms [104,176]. Bipolar illness is rare but has substantial treatment implications. Anxiety disorders frequently co-occur with depression, and traumatic experiences and post-traumatic stress disorder are common and should be thoroughly evaluated and treated [138,176]. Independent disorders are psychiatric conditions occurring during periods of sustained abstinence or having an onset before the substance-use disorder. A positive family history can aid in identifying an independent psychiatric disorder.

Comprehensive assessment tools can reduce the chance of a missed or incorrect diagnosis. Patients with psychiatric comorbidities often exhibit symptoms that are more persistent, severe, and resistant to treatment compared to patients who have either disorder alone [178,179,180,181]. Assessment is critical to identify concomitant medical and psychiatric conditions that may need immediate attention and require transfer to a higher level of care [104]. The ASAM recommends that clinicians also assess social and environmental factors to identify facilitators and barriers to treatment, specifically to pharmacotherapy [104].

TREATMENT APPROACH

Treatment should initially focus on stabilization of the patient's substance use disorder, with an initial goal of two to four weeks abstinence before addressing comorbidities. Patients who persistently display symptoms of a psychiatric disorder during abstinence should be considered as having an independent disorder and should receive prompt psychiatric treatment [177].

Although depressive symptoms often improve following treatment admission, significant symptoms will persist in some patients [138]. Antidepressant medications can be effective in patients dually diagnosed with opioid dependence and depression when used at adequate doses for at least six weeks [182]. Factors emphasizing prompt antidepressant treatment include greater severity of depression, suicide risk, and co-occurring anxiety disorders [138].

SSRIs are generally safe and well-tolerated, but clinical trials with these agents in methadone patients have been negative [138]. Therefore, SSRIs may be considered first-line treatment based on their safety profile, but if the patient does not respond, then TCAs or newer generation agents should be considered. SSRIs in combination with cognitive-behavioral therapy have been found to be highly effective for treating clients with comorbid depression [170]. More stimulating antidepressants, such as venlafaxine and bupropion, may be suitable in patients with prominent low energy or past or current symptoms consistent with attention deficit hyperactivity disorder (ADHD) [138]. The utility of nonpharmacologic treatments should be emphasized. Psychosocial therapies are as effective as pharmacotherapy in the treatment of mild-to-moderate depressive and anxiety symptoms. Treatment of personality disorders is nonpharmacologic [177]. If depression persists, psychosocial modalities, such as cognitive therapy, supportive therapy, or contingency management, have some evidence to support their efficacy in opioid-dependent patients [138,170].

In the treatment of insomnia and anxiety, trazodone and nefazodone are helpful agents, although nefazodone should be used with caution because of reports of liver toxicity. Mirtazapine, a sedating antidepressant, is a logical alternative. A baseline ECG is recommended prior to a TCA trial in opioid users [138]. Benzodiazepines for anxiety should be avoided due to the liability of abuse and the potential of drug-seeking behavior, which is detrimental to treatment. Effective alternatives to benzodiazepines include antidepressants and anticonvulsant mood stabilizers. Sedating atypical antipsychotics may also be useful but should be used with caution due to potential side effects [138].

Medical comorbidities that may impact mental status and treatment response include [138]:

- Hypothyroidism

- HIV infection

- Hepatitis C and B

- Chronic lung disease

- Hypertension

- Diabetes

- Cardiovascular disease

The presence of comorbid conditions increases severity and complicates recovery. Patients with comorbid disorders demonstrate poorer treatment adherence and higher rates of treatment dropout [180,183]. A natural outgrowth of increased severity has been greater interest in and use of integrated treatment, compared with separate treatment of combined conditions [170]. Integrated treatment refers to a treatment focus on two or more conditions and the use of multiple treatments (e.g., combination of psychotherapy and pharmacotherapy). It is an approach supported by research that demonstrates the superiority of an integrated approach [184,185,186,187,188].

TREATING POLYSUBSTANCE ABUSE/DEPENDENCE

As noted, polysubstance use is the norm rather than the exception among opioid-dependent patients. The optimal approach to treating multiple substance abuse depends on the substances being used, the severity of the abuse, the treatment setting, familiarity of the clinician with treatment of the substance problem, and available resources for treatment. Optimal patient outcomes occur with pharmacologic and psychosocial combination therapy [177].

18. OPIOID USE DURING PREGNANCY

A portion of pregnant women with substance dependence continue using addictive substances despite awareness of the potential harm to the fetus [189]. Infants can sustain adverse effects from maternal opioid use, although it is difficult to separate factors due to opioid use from those due to the abuse of other drugs, poor prenatal care, poor nutrition, or other complications [100,190]. Reports of adverse effects of opioid use on fetuses and neonates include [189]:

- Fetal growth restriction

- Intrauterine withdrawal with increased fetal activity

- Depressed breathing movement

- Preterm delivery

- Preterm rupture of the membranes

- Meconium-stained amniotic fluid

- Perinatal death

- Neonatal abstinence syndrome (NAS)

Opioid withdrawal is a physiologic rebound from the chronic drug effects on brain function. In pregnant women, rapid opioid withdrawal may precipitate preterm labor; in neonates, it may be fatal [189]. NAS occurs when an infant becomes dependent on opioids or other drugs used by the mother during pregnancy [191]. It is an expected and treatable condition seen in 30% to 80% of infants born to women taking opioid agonist therapies [190]. NAS increased fivefold nationally between 2000 to 2012, coinciding with rising rates of opioid prescribing to pregnant women [192]. NAS may result in disruption of the mother-infant relationship, sleep-wake abnormalities, feeding difficulties, weight loss, and seizures [191,193]. Withdrawal symptoms in neonates can include tremors, diarrhea, fever, irritability, jitteriness, sweating, fever, vomiting, and generalized convulsions [191,194].

The optimal treatment for NAS has not been established. Opioids are considered the first-line therapy [194]. Opioid treatment of NAS reduces the time to regain birth weight, reduces the duration of supportive care, and increases the length of hospital stay. There is no evidence of effect on treatment failure [195]. Treatment with long-acting opioids has been shown to be superior to phenobarbital and diazepam in infants with NAS [195].

Evidence Based Practice Recommendation

The World Health Organization recommends that healthcare providers should, at the earliest opportunity, advise pregnant women dependent on opioids to cease their use and offer, or refer to, detoxification services under medical supervision where necessary and applicable. Detoxification can be undertaken at any stage in pregnancy, but at no stage should antagonists (e.g., naloxone, naltrexone) be used to accelerate the detoxification process.

https://www.guideline.gov/summaries/summary/48894

Last Accessed: March 21, 2018

Strength of Recommendation/Level of Evidence: Strong/very low

Phenobarbital is generally considered a second-line agent and is effective for the treatment of withdrawal and polydrug exposure. Clonidine is also a safe second-line option for treatment of NAS symptoms that are refractory to opioid therapy [194,196]. Buprenorphine and methadone have both been shown to be safe and effective treatments for opioid use disorder during pregnancy [197]. A 2014 meta-analysis showed that methadone was associated with higher treatment retention and buprenorphine resulted in a 10% lower incidence of NAS, decreased neonatal treatment time of 8.46 days, and less morphine (3.6 mg) needed [198]. Infants whose mothers receive these medications may still experience NAS; however, it is less severe than in the absence of treatment [198].

In treating pregnant women with substance dependence, psychologic and pharmacologic treatments are often combined. Psychosocial treatments include contingency treatment, community reinforcement, behavioral marital therapy, cognitive-behavioral skills training, motivational enhancement therapy, and 12-step approaches [189].

HEROIN

Heroin rapidly crosses the placental blood barrier. Between 55% and 94% of infants born to IV heroin users exhibit signs of neonatal withdrawal, with a small minority showing neonatal seizure activity [199]. Methadone maintenance has been found to be an effective harm-reduction strategy and can reduce acute neonatal withdrawal problems, including seizures [200].

METHADONE

Pregnant women who are opioid dependent should be maintained on the lowest effective dose of methadone; detoxification, if attempted, should be done in the second trimester [189]. Outcomes are poor for patients who leave treatment. Fetal exposure can result in lower birth weight, smaller head circumference, jaundice, and thrombocytosis, although the cause of these conditions is difficult to distinguish between methadone and other concurrently-used substances. Methadone in the newborn infant will produce physical dependence and subsequent withdrawal symptoms that may not emerge until 48 hours after birth, regardless of maternal dose. Methadone-exposed infants function within a normal range of cognition at one- and two-year evaluations [189]. Methadone levels in breast milk appear to be small [201].

BUPRENORPHINE

Buprenorphine has been administered successfully to opioid-dependent pregnant women as a maintenance replacement opioid. Placental transfer may be less than methadone, reducing fetal exposure and subsequent dependence and withdrawal. Buprenorphine has a low incidence of labor and delivery complications and of neonatal abstinence syndrome [189]. Multiple small case series have examined maternal buprenorphine concentrations in breast milk and all concur that the amounts are small and unlikely to have short-term negative effects on the developing infant [202].

OXYCODONE

Oxycodone is metabolized to noroxycodone, oxymorphone, and their glucuronides and primarily excreted through urine. Oxycodone has been detected in breast milk, and although not found to be a teratogenic in experimental animals, it is not recommended for use in pregnancy [56]. Management of infants born to mothers abusing oxycodone is of particular concern because the drug and its metabolites are difficult to detect by the enzyme immunoassay methods typically used for urine and meconium opioid screens [203].

NALTREXONE

The literature is limited and equivocal regarding naltrexone and pregnancy. The substantial drop-out rates due to the reward-blocking and dysphoric effects of this drug have resulted in limited reports on pre- and perinatal complications. One Australian study showed no obstetric complications and healthy-appearing infants, leading the authors to conclude naltrexone is a safe alternative in select pregnant patients [189]. However, other authors have found that naltrexone can cause premature labor and fetal death, and it is considered to be pregnancy category C [8,56]. The manufacturer recommends that nursing mothers either discontinue the drug or discontinue nursing [56].

19. PROGNOSIS OF TREATMENT FOR OPIOID USE DISORDER

The relapse rate among patients receiving treatment for opioid dependence and other substance abuse is high (25% to 97%), comparable to that of other patients with chronic relapsing conditions, including hypertension and asthma [204]. Many cases of relapse are attributable to treatment noncompliance and lack of lifestyle modification [83].

Duration of agonist replacement therapy is usually recommended as a minimum of one year, and some patients will receive agonist replacement therapy indefinitely. Longer durations of treatment are associated with higher rates of abstinence from illicit opioids [34].

Much remains unknown about patient outcomes following termination of long-term opioid replacement therapy. Some patients aim to achieve total abstinence from all opioids, but little is known about patient characteristics and strategies used among those who remain abstinent. It is likely that at least some of the patients who remain abstinent from all opioids do so with the help of a 12-step support program, such as NA [34].

20. CONCLUSION

Dependence on opioids is associated with serious morbidity and mortality, and advances in the understanding of the dependence have led to the development of effective treatments. More recently, the abuse of prescription opioids has become considerably more widespread, fueled in part by the availability of such drugs over the Internet. This has resulted in opioid abuse and dependence in populations seldom afflicted in the past. Thus, medical, mental health, and other healthcare professionals in a variety of settings may encounter patients with an opioid use disorder. The knowledge gained from the contents of this course can greatly assist the healthcare professional in identifying, treating, and providing an appropriate referral to patients with opioid use disorders.

21. GLOSSARY

Acetylation: the process of introducing an acetyl group into a compound.

Adenylate cyclase: an enzyme that converts adenosine triphosphate to cyclic adenosine monophosphate (cAMP).

Anhydrous: having no water.

Axis I mental disorders: clinical syndromes, including major mental disorders such as depression, schizophrenia, and obsessive-compulsive disorder.

Bioavailability: the amount of active drug that reaches systemic circulation after ingestion.

Congener: a compound of the same kind or category.

Cosyntropin test: a test to determine how well the adrenal glands respond to the hormone ACTH. Involves the measurement of cortisol in the blood before and after injection of cosyntropin.

Effectors: a molecule that binds to and changes the activity of a protein.

Enantiomer: either of a pair of isomers that are mirror images of each other.

Endogenous opioid: an opioid that occurs naturally in the body, such as endorphin.

Equianalgesic: having the same analgesic effect.

First-pass metabolism: reduction of drug concentration prior to systemic circulation, often due to hepatic metabolism.

Free morphine: unmetabolized morphine.

Full agonist: chemicals or drugs that bind to and activate a receptor and display full efficacy (response) at that receptor.

Glucuronidation: a detoxification pathway in the liver whereby glucuronic acid is conjugated with toxins.

Hedonic: having a positive or pleasurable effect.

Ketone: water-soluble compound produced when fatty acids are metabolized in the liver and kidney.

Kinase: an enzyme that largely acts to transmit signals and control the complex activities of cells.

Ligand: a signal-triggering molecule.

Lipophilic: fat-soluble.

Metabolite: a substance involved in metabolism, either as a by-product or as a necessary component.

Parent drug: the drug initially consumed or administered prior to metabolization.

Peptide: a short chain of amino acids.

Phosphorylation: the addition of a phosphate group to an organic molecule.

Plastic alternation: pliable or alterable exchange.

Polymorphism: genetic variation within a population.

Prodrug: a pharmacologically inactive compound that converts to an active form within the body.

Pseudoaddiction: preoccupation with and pursuit of opioid medication driven by a desire for pain relief and not for the drug's mood-altering effects. Results from poorly treated pain.

Sensorium: an individual's perception and entire sensory environment.

Works Cited

1. Epstein DH, Philips KA, Preston KL. Opioids. In: Ruiz P, Strain E (eds). Lowinson and Ruiz's Substance Abuse: A Comprehensive Textbook. 5th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2011: 161-190.

2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013.

3. Federation of State Medical Boards. Model Policy for the Use of Opioid Analgesics in the Treatment of Chronic Pain. Washington, DC: Federation of State Medical Boards; 2013.

4. Prince V. Pain management in patients with substance-use disorders. In: Chronic Illnesses I, II, and III– PSAP-VII, Book 5. Lenexa, KS: American College of Clinical Pharmacology; 2011.

5. Utah Department of Health. Utah Clinical Guidelines on Prescribing Opioids for Treatment of Pain. Salt Lake City, UT: Utah Department of Health; 2009.

6. American Society of Addiction Medicine. Definition of Addiction. Available at https://www.asam.org/quality-practice/definition-of-addiction. Last accessed March 7, 2018.

7. Miller NS, Greenfeld A. Patient characteristics and risks factors for development of dependence on hydrocodone and oxycodone. Am J Ther. 2004;11(1):26-32.

8. Schwartz RH. Adolescent heroin use: a review. Pediatrics. 1998;102(6):1461-1466.

9. Yaksh T, Wallace M. Opioids, analgesia, and pain management. In: Brunton L, Hilal-Dandan R, Knollmann BC (eds). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 13th ed. New York, NY: McGraw-Hill; 2017: 355-386.

10. Havens JR, Walker R, Leukefeld CG. Prevalence of opioid analgesic injection among rural nonmedical opioid analgesic users.Drug Alcohol Depend. 2007;87(1):98-102.

11. World Drug Report 2017. Available at https://www.unodc.org/wdr2017. Last accessed March 7, 2018.

12. Owen GT, Burton AW, Schade CM, Passik S. Urine drug testing: current recommendations and best practices. Pain Physician. 2012;15:ES119-ES133.

13. van den Brink W, Haasen C. Evidence-based treatment of opioid-dependent patients. Can J Psychiatry. 2006;51(10):635-646.

14. Kenan K, Mack K, Paulozzi L. Trends in prescriptions for oxycodone and other commonly used opioids in the United States, 2000–2010. Open Med. 2012;6(2):e41-e47.

15. Manchikanti L, Singh A. Therapeutic opioids: a ten-year perspective on the complexities and complications of the escalating use, abuse, and nonmedical use of opioids. Pain Physician. 2008;11(2 Suppl):S63-S88.

16. Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality. The DAWN Report: Highlights of the 2011 Drug Abuse Warning Network (DAWN) Findings on Drug-Related Emergency Department Visits. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2013.

17. Substance Abuse and Mental Health Services Administration, Office of Applied Studies. Drug Abuse Warning Network, 2011: National Estimates of Drug-Related Emergency Department Visits. Available at https://www.samhsa.gov/data/sites/default/files/DAWN2k11ED/DAWN2k11ED/DAWN2k11ED.pdf. Last accessed March 7, 2018.

18. Vivolo-Kantor AM, Seth P, Gladden RW, et al. Trends in suspected nonfatal opioid overdoses in the United States, July 2016–September 2017. MMWR. 2018;67(9);279-285.

19. National Institute on Drug Abuse. Heroin: What is the Scope of Heroin Use in the United States? Available at https://www.drugabuse.gov/publications/research-reports/heroin/scope-heroin-use-in-united-states. Last accessed March 7, 2018.

20. Substance Abuse and Mental Health Services Administration. Results from the 2016 National Survey on Drug Use and Health: Detailed Tables. Available at https://www.samhsa.gov/data/sites/default/files/NSDUH-DetTabs-2016/NSDUH-DetTabs-2016.pdf. Last accessed March 7, 2018.

21. National Institute on Drug Abuse. Monitoring the Future Survey: Trends in Prevalence of Various Drugs. Available at https://www.drugabuse.gov/trends-statistics/monitoring-future/monitoring-future-study-trends-in-prevalence-various-drugs. Last accessed March 7, 2018.

22. Zacny JP, Gutierrez S, Bolbolan SA. Profiling the subjective, psychomotor, and physiological effects of a hydrocodone/acetaminophen product in recreational drug users. Drug Alcohol Depend. 2005;78(3):243-252.

23. Substance Abuse and Mental Health Services Administration. Results from the 2004 National Survey on Drug Use and Health: National Findings. Available at https://medicalmarijuana.procon.org/sourcefiles/2k4results.pdf. Last accessed March 7, 2018.

24. Hughes A, Williams MR, Lipari RN, et al. Prescription Drug Use and Misuse in the United States: Results from the 2015 National Survey on Drug Use and Health. Available at https://www.samhsa.gov/data/sites/default/files/NSDUH-FFR2-2015/NSDUH-FFR2-2015.htm. Last accessed March 7, 2018.

25. Crane EH. Emergency Department Visits Involving Narcotic Pain Relievers. Available at https://www.samhsa.gov/data/sites/default/files/report_2083/ShortReport-2083.html. Last accessed March 7, 2018.

26. Throckmorton DC. Re-scheduling Prescription Hydrocodone Combination Drug Products: An Important Step Toward Controlling Misuse and Abuse. Available at https://blogs.fda.gov/fdavoice/index.php/2014/10/re-scheduling-prescription-hydrocodone-combination-drug-products-an-important-step-toward-controlling-misuse-and-abuse. Last accessed March 7, 2018.

27. Burke J. Hydrocodone Prescribing and Quotas. Available at http://www.pharmacytimes.com/publications/issue/2017/january2017/hydrocodone-prescribing-and-quotas. Last accessed March 7, 2018.

28. Drug Enforcement Administration Diversion Control Division. Rules—Available at https://www.deadiversion.usdoj.gov/fed_regs/rules/2014/fr0822.htm. Last accessed March 7, 2018.

29. Woolf CJ, Hashmi M. Use and abuse of opioid analgesics: potential methods to prevent and deter non-medical consumption of prescription opioids. Curr Opin Investig Drugs. 2004;5(1):61-66.

30. Ruetsch C. Empirical view of opioid dependence. J Manag Care Pharm. 2010;16(1 Suppl B):S9-13.

31. Substance Abuse and Mental Health Services Administration. The TEDS Report. Available at https://www.samhsa.gov/data/sites/default/files/sr077-gender-differences-2014.pdf. Last accessed March 7, 2018.

32. Wu LT, Woody GE, Yang C, Blazer DG. Subtypes of nonmedical opioid users: results from the national epidemiologic survey on alcohol and related conditions. Drug Alcohol Depend. 2010;112(1-2):69-80.

33. Compton WM, Volkow ND. Major increases in opioid analgesic abuse in the United States: concerns and strategies. Drug Alcohol Depend. 2006;81(2):103-107.

34. Wasan AD, Correll DJ, Kissin I, O'Shea S, Jamison RN. Iatrogenic addiction in patients treated for acute or subacute pain: a systematic review. J Opioid Manag. 2006;2(1):16-22.

35. McCabe SE, West BT, Morales M, Cranford JA, Boyd CJ. Does early onset of non-medical use of prescription drugs predict subsequent prescription drug abuse and dependence? Results from a national study. Addiction. 2007;102(12):1920-1930.

36. The Partnership for a Drug-Free America. 2012 Partnership Attitude Tracking Study: Teens and Parents. Available at https://drugfree.org/wp-content/uploads/2013/04/PATS-2012-FULL-REPORT2.pdf. Last accessed March 7, 2018.

37. Jamison RN, Serraillier J, Michna E. Assessment and treatment of abuse risk in opioid prescribing for chronic pain. Pain Res Treat. 2011:941808.

38. Warner-Smith M, Darke S, Lynskey M, Hall W. Heroin overdose: causes and consequences. Addiction. 2001;96(8):1113-1125.

39. American Society of Addiction Medicine. Opioid Addiction: 2016 Facts and Figures. Available at https://www.asam.org/docs/default-source/advocacy/opioid-addiction-disease-facts-figures.pdf. Last accessed March 7, 2018.

40. Centers for Disease Control and Prevention. Opioid Overdose: Heroin Overdose Data. Available at https://www.cdc.gov/drugoverdose/data/heroin.html. Last accessed March 7, 2018.

41. Centers for Disease Control and Prevention. Opioid Overdose: Drug Overdose Death Data. Available at https://www.cdc.gov/drugoverdose/data/statedeaths.html. Last accessed March 7, 2018.

42. Office on Women's Health. Final Report: Opioid Use, Misuse, and Overdose in Women: 2017. Available at https://www.womenshealth.gov/files/documents/final-report-opioid-508.pdf. Last accessed March 7, 2018.

43. Centers for Disease Control and Prevention. Opioid Overdose: Prescription Opioids. Available at https://www.cdc.gov/drugoverdose/opioids/prescribed.html. Last accessed March 7, 2018.

44. Centers for Disease Control and Prevention. Opioid Overdose: Prescribing Data. Available at https://www.cdc.gov/drugoverdose/data/prescribing.html. Last accessed March 7, 2018.

45. Manchikanti L, Abdi S, Atluri S, et al.; American Society of Interventional Pain Physicians. American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic noncancer pain: Part 2—guidance. Pain Physician. 2012;15(3 Suppl):S67-S116.

46. Manchikanti L, Singh A. Therapeutic opioids: a ten-year perspective on the complexities and complications of the escalating use, abuse, and nonmedical use of opioids. Pain Physician. 2008;11(2 Suppl):S63-S88.

47. Boyles S. CDC: Alarming Increase in Methadone Deaths: Deaths from Opioid Painkillers have Tripled since 1999. Available at https://www.webmd.com/pain-management/news/20090930/alarming-increase-in-methadone-deaths#1. Last accessed March 7, 2018.

48. Manchikanti L, Fellows B, Ailinani H, Pampati V. Therapeutic use, abuse, and nonmedical use of opioids: a ten-year perspective. Pain Physician. 2010;13:401-435.

49. Webster LR, Cochella S, Dasgupta N, et al. An analysis of the root causes for opioid-related overdose deaths in the United States. Pain Medicine. 2011;12(Suppl 2):S26-S35.

50. Centers for Disease Control and Prevention. Vital Signs: risk for overdose from methadone used for pain relief—United States, 1999–2010. MMWR. 2012;61(26):493-497.

51. Armstrong SC, Cozza KL. Pharmacokinetic drug interactions of morphine, codeine, and their derivatives: theory and clinical reality, part II. Psychosomatics. 2003;44(6):515-520.

52. White JM, Irvine RJ. Mechanisms of fatal opioid overdose. Addiction. 1999;94(7):961-972.

53. Gruber SA, Silveri MM, Yurgelun-Todd DA. Neuropsychological consequences of opiate use. Neuropsychol Rev. 2007;17(3): 299-315.

54. Ghuran A, van der Wieken LR, Nolan J. Cardiovascular complications of recreational drugs. BMJ. 2001;323(7311):464-466.

55. National Institute on Drug Abuse. Emerging Trends: "Syrup," "Purple Drank," "Sizzurp," "Lean." Available at https://www.drugabuse.gov/videos/emerging-trends-syrup-purple-dranksizzurp-lean. Last accessed March 7, 2018.

56. LexiComp Online. Available at https://online.lexi.com. Last accessed March 7, 2018.

57. Krantz MJ, Mehler PS. Treating opioid dependence: growing implications for primary care. Arch Intern Med. 2004;164(3):277-288.

58. Gasche Y, Daali Y, Fathi M, et al. Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med. 2004;351(27):2827-2831.

59. Fredheim OM, Moksnes K, Borchgrevink PC, Kaasa S, Dale O. Clinical pharmacology of methadone for pain. Acta Anaesthesiol Scand. 2008;52(7):879-889.

60. Kleber HD. Methadone maintenance 4 decades later: thousands of lives saved but still controversial. JAMA. 2008;300(19):2303-2305.

61. Homsi J, Walsh D, Nelson KA. Important drugs for cough in advanced cancer. Support Care Cancer. 2001;9(8):565-574.

62. Drugs.com. Hydrocodone Comparative Strength. Available at https://www.drugs.com/forum/drug-information/hydrocodone-comparative-strength-35421.html. Last accessed March 7, 2018.

63. Cone EJ, Heit HA, Caplan YH, Gourlay D. Evidence of morphine metabolism to hydromorphone in pain patients chronically treated with morphine. J Anal Toxicol. 2006;30(1):1-5.

64. Benyamin R, Trescot AM, Datta S, et al. Opioid complications and side effects. Pain Physician. 2008;11(2 Suppl):S105-S120.

65. Moeller KE, Lee KC, Kissack JC. Urine drug screening: practical guide for clinicians. Mayo Clin Proc. 2008;83(1):66-76.

66. U.S. Food and Drug Administration. [Archive}. FDA Approves Targiniq ER with Abuse-Deterrent Properties. Available at http://wayback.archive-it.org/7993/20170111080314/http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm406290.htm. Last accessed March 7, 2018.

67. Sarhill N, Walsh D, Nelson KA. Hydromorphone: pharmacology and clinical applications in cancer patients. Support Care Cancer. 2001;9(2):84-96.

68. Tetrault JM, Fiellin DA. Current and potential pharmacological treatment options for maintenance therapy in opioid-dependent individuals. Drugs. 2012;72:217-228.

69. Davids E, Gastpar M. Buprenorphine in the treatment of opioid dependence. Eur Neuropsychopharmacol. 2004;14(3):209-216.

70. Moukaddam N, Herin DV, Stotts A, et al. Comparison of 3 L-α-acetyl-methadol (LAAM) Maintenance Strategies for Heroin Dependence. Addictive Disord Treatment. 2009;8(4):191-200.

71. U.S. Food and Drug Administration. Bunavail: Highlights of Prescribing Information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205637s000lbl.pdf. Last accessed March 7, 2018.

72. U.S. Food and Drug Administration. FDA News Release. FDA Approves First Buprenorphine Implant for Treatment of Opioid Dependence. Available at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm503719.htm. Last accessed March 7, 2018.

73. U.S. Food and Drug Administration. FDA News Release. FDA Approves First Once-Monthly Buprenorphine Injection, a Medication-Assisted Treatment Option for Opioid Use Disorder. Available at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm587312.htm. Last accessed March 7, 2018.

74. Oliver J, Coggins C, Compton P, et al. American Society for Pain Management Nursing position statement: pain management in patients with substance use disorders. Pain Management Nursing. 2012;13:169-183.

75. McPherson ML. Opioids: fears, myths, and misconceptions. Pain View. 2011;7:16-18.

76. Kaye AD, Gevirtz C, Bosscher HA, et al. Ultrarapid opiate detoxification: a review. Can J Anaesth. 2003;50(7):663-671.

77. Xi ZX, Stein EA. GABAergic mechanisms of opiate reinforcement. Alcohol Alcohol. 2002;37(5):485-494.

78. Harris AC, Gewirtz JC. Acute opioid dependence: characterizing the early adaptations underlying drug withdrawal. Psychopharmacology (Berl). 2005;178(4):353-366.

79. Tso PH, Wong YH. Molecular basis of opioid dependence: role of signal regulation by G-proteins. Clin Exp Pharmacol Physiol. 2003;30(5-6):307-316.

80. Fiellin DA, Friedland GH, Gourevitch MN. Opioid dependence: rationale for and efficacy of existing and new treatments.Clin Infect Dis. 2006;43(Suppl 4):S173-S177.

81. Wise RA. Neurobiology of addiction. Curr Opin Neurobiol. 1996;6:243-251.

82. van den Brink W, van Ree JM. Pharmacological treatments for heroin and cocaine addiction. Eur Neuropsychopharmacol. 2003;13(6):476-487.

83. Vukmir RB. Drug seeking behavior. Am J Drug Alcohol Abuse. 2004;30:551-575.

84. Wood E, Kerr T, Stoltz J, et al. Prevalence and correlates of hepatitis C infection among users of North America's first medically supervised safer injection facility. Public Health. 2005;119(12):1111-1115.

85. Bruce RD, Altice FL. Clinical care of the HIV-infected drug user. Infect Dis Clin North Am. 2007;21(1):174-179.

86. Centers for Disease Control and Prevention. HIV Surveillance Report: Diagnoses of HIV Infection in the United States and Dependent Areas, 2016. Available at https://www.cdc.gov/hiv/pdf/library/reports/surveillance/cdc-hiv-surveillance-report-2016-vol-28.pdf. Last accessed March 7, 2018.

87. Cooper OB, Brown TT, Dobs AS. Opiate drug use: a potential contributor to the endocrine and metabolic complications in human immunodeficiency virus disease. Clin Infect Dis. 2003;37(Suppl 2):S132-S136.

88. Colameco S, Coren JS. Opioid-induced endocrinopathy. J Am Osteopath Assoc. 2009;109(1):20-25.

89. Pereska Z, Bozinovska C, Dimitrovski C, et al. Heron dependence duration influences the metabolic parameters: mechanisms and consequences of impaired insulin sensitivity in hepatitis C virus seronegative heroin dependents. J Addict Med. 2012;6(4):304-310.

90. Rogers RD, Robbins TW. Investigating the neurocognitive deficits associated with chronic drug misuse. Curr Opin Neurobiol. 2001;11(2):250-257.

91. Bates ME, Buckman JF, Voelbel GT, Eddie D, Freeman J. The mean and the individual: integrating variable-centered and person-centered analyses of cognitive recovery in patients with substance use disorders. Front Psychiatry. 2013;4:177.

92. Specka M, Finkbeiner T, Lodemann E, Leifert K, Kluwig J, Gastpar M. Cognitive-motor performance of methadone-maintained patients. Eur Addict Res. 2000;6(1):8-19.

93. Liao DL, Huang CY, Hu S, et al. Cognitive control in opioid dependence and methadone maintenance treatment. PLoS One. 2014;9(4):e94589.

94. Henry PK, Umbricht A, Kleykamp BA, et al. Comparison of cognitive performance in methadone maintenance patients with and without current cocaine dependence. Drug Alcohol Depend. 2012;124(1-2):167-171.

95. Hedegaard H, Warner M, Miniño AM. NCHS Data Brief No. 294. Drug Overdose Deaths in the United States, 1999-2016. Available at https://www.cdc.gov/nchs/data/databriefs/db294.pdf. Last accessed March 7, 2018.

96. Darke S, Hall W. Heroin overdose: research and evidence-based intervention. J Urban Health. 2003;80(2):189-200.

97. Centers for Disease Control and Prevention. Prescription Painkiller Overdoses Infographic. Available at https://www.cdc.gov/vitalsigns/methadoneoverdoses/infographic.html. Last accessed March 7, 2018.

98. Centers for Disease Control and Prevention. Unintentional Drug Poisoning in the United States. Available at https://www.cdc.gov/medicationsafety/pdfs/cdc_5538_ds1.pdf. Last accessed March 7, 2018.

99. Substance Abuse and Mental Health Services Administration. SAMHSA Opioid Overdose Toolkit. Available at https://store.samhsa.gov/shin/content/SMA13-4742/Overdose_Toolkit_2014_Jan.pdf. Last accessed March 7, 2018.

100. Noda Y, Nabeshima T. Opiate physical dependence and N-methyl-D-aspartate receptors. Eur J Pharmacology. 2004;500(1-3):121-128.

101. McKeown NJ. Withdrawal Syndromes. Available at https://emedicine.medscape.com/article/819502-overview. Last accessed March 7, 2018.

102. Bhalla S, Andurkar SV, Gulati A. Neurobiology of opioid withdrawal: role of the endothelin system. Life Sci. 2016;159:34-42.

103. Bhalla S, Pais G, Tapia M, Gulati A. Endothelin ETA receptor antagonist reverses naloxone-precipitated opioid withdrawal in mice. Can J Physiol Pharmacol. 2015;93(11):935-944.

104. American Society of Addiction Medicine. National practice guideline for the use of medications in the treatment of addiction involving opioid use. Available at https://www.asam.org/docs/default-source/practice-support/guidelines-and-consensus-docs/asam-national-practice-guideline-supplement.pdf. Last accessed March 7, 2018.

105. U.S. Food and Drug Administration. FDA Grants Marketing Authorization of the First Device For Use in Helping to Reduce the Symptoms of Opioid Withdrawal. Available at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm585271.htm. Last accessed March 7, 2018.

106. Aston-Jones G, Harris GC. Brain substrates for increased drug seeking during protracted withdrawal. Neuropharmacology. 2004;47(Suppl 1):167-179.

107. Substance Abuse and Mental Health Services Administration. National Survey of Substance Abuse Treatment Services (N-SSATS): 2012. Data on Substance Abuse Treatment Facilities. BHSIS Series S-66, HHS Publication No. (SMA) 14-4809. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2013.

108. Kahan M, Srivastava A, Wilson L, Gourlay D, Midmer D. Misuse of and dependence on opioids: study of chronic pain patients. Can Fam Physician. 2006;52(9):1081-1087.

109. Institute of Medicine, Committee on Advancing Pain Research, Care, and Education. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: The National Academies Press; 2011.

110. PRNewswire. U.S. Public and Doctors' Misperceptions Revealed in National Survey Demonstrate Urgent Need for Increased Opioid Dependence Awareness. Available at https://www.prnewswire.com/news-releases/us-public-and-doctors-misperceptions-revealed-in-national-survey-demonstrate-urgent-need-for-increased-opioid-dependence-awareness-210981471.html. Last accessed March 7, 2018.

111. Breuer B, Pappagallo M, Tai JY, Portenoy RK. U.S. board-certified pain physician practices: uniformity and census data of their locations. J Pain. 2007;8:244-250.

112. Centers for Disease Control and Prevention. Vital signs: overdoses of prescription opioid pain relievers—United States, 1999–2008. MMWR. 2011;60(43):1487-1492.

113. Bohnert AS, Valenstein M, Bair MJ, et al. Association between opioid prescribing patterns and opioid overdose-related deaths. JAMA. 2011;305(13):1315-1321.

114. Potter JS, Hennessy G, Borrow JA, Greenfield SF, Weiss RD. Substance use histories in patients seeking treatment for controlled-release oxycodone dependence. Drug Alcohol Depend. 2004;76(2):213-215.

115. Centers for Disease Control and Prevention. Opioid Overdose. Available at https://www.cdc.gov/drugoverdose. Last accessed March 7, 2018.

116. Cassels C. FDA Okays Handheld Autoinjector for Opioid Overdose. Available at https://www.medscape.com/viewarticle/823039. Last accessed March 7, 2018.

117. Narcan Nasal Spray (naloxone intranasal) [package insert]. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208411lbl.pdf. Last accessed March 7, 2018.

118. Journal of Hematology Oncology Pharmacy. FDA Moves Quickly to Approve Easy-To-Use Nasal Spray to Treat Opioid Overdose. Available at http://jhoponline.com/in-the-news-oncology-december-2015/16608-fda-moves-quickly-to-approve-easy-to-use-nasal-spray-to-treat-opioid-overdose. Last accessed March 7, 2018.

119. Ritter A, Cameron J. A review of the efficacy and effectiveness of harm reduction strategies for alcohol, tobacco and illicit drugs. Drug Alcohol Rev. 2006;25(6):611-624.

120. Hawk M, Coulter RWS, Egan JE, et al. Harm reduction principles for healthcare settings. Harm Reduct J. 2017;14(1):70.

121. Des Jarlais DC, Semaan S. HIV prevention for injecting drug users: the first 25 years and counting. Psychosom Med. 2008;70(5):606-611.

122. Centers for Disease Control and Prevention. HIV/AIDS. Syringe Services Programs. Available at https://www.cdc.gov/hiv/risk/ssps.html. Last accessed March 7, 2018.

123. Drug Policy Alliance. Supervised Injection Facilities. Available at http://www.drugpolicy.org/issues/supervised-injection-facilities. Last accessed March 7, 2018.

124. Ferri M, Davoli M, Perucci CA. Heroin maintenance for chronic heroin-dependent individuals. Cochrane Database Syst Rev. 2011;12:CD003410.

125. Substance Abuse and Mental Health Services Administration. Federal Guidelines for Opioid Treatment Programs. HSS Publication No. (SMA) PEP15-FEDGUIDEOTP. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2015.

126. Substance Abuse and Mental Health Services Administration. SAMHSA Opioid Overdose Prevention Toolkit. HHS Publication No. (SMA) 16-4742. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2016.

127. Amato L, Minozzi S, Davoli M, Vecchi S, Ferri M, Mayet S. Psychosocial and pharmacological treatments versus pharmacological treatments for opioid detoxification. Cochrane Database Syst Rev. 2008;(4):CD005031.

128. Amato L, Minozzi S, Davoli M, Vecchi S. Psychosocial and pharmacological treatments versus pharmacological treatments for opioid detoxification. Cochrane Database Syst Rev. 2011;9:CD005031.

129. Streel E, Verbanck P. Ultra-rapid opiate detoxification: from clinical applications to basic science. Addict Biol. 2003;8(2):141-146.

130. Singh J, Basu D. Ultra-rapid opioid detoxification: current status and controversies. J Postgrad Med. 2004;50(3):227-232.

131. Krabbe PF, Koning JP, Heinen N, Laheij RJ, van Cauter RM, De Jong CA. Rapid detoxification from opioid dependence under general anaesthesia versus standard methadone tapering: abstinence rates and withdrawal distress experiences. Addict Biol. 2003;8(3):351-358.

132. Forozeshfard M, Hosseinzadah ZB, Saberi Zafarghandi MB, Bandari R, Foroutan B. Six-month follow-up study of ultrarapid opiate detoxification with naltrexone. Int J High Risk Behav Addict. 2014;3(4):e20944.

133. Salimi A, Safari F, Mohajerani SA, Hashemian M, Kolahi AA, Mottaghi K. Long-term relapse of ultra-rapid opioid detoxification.J Addict Dis. 2014;33(1):33-40.

134. Collins ED, Kleber HD, Whittington RA, Heitler NE. Anesthesia-assisted vs. buprenorphine- or clonidine-assisted heroin detoxification and naltrexone induction: a randomized trial. JAMA. 2005;294(8):903-913.

135. Gowing L, Ali R, White J. Opioid antagonists under heavy sedation or anaesthesia for opioid withdrawal. Cochrane Database Syst Rev. 2006;(2):CD002022.

136. Gowing L, Ali R, White JM. Opioid antagonists under heavy sedation or anaesthesia for opioid withdrawal. Cochrane Database Syst Rev. 2010;1:CD002022.

137. Fiellin DA, O'Connor PG. Office-based treatment of opioid-dependent patients. N Engl J Med. 2002;347(11):817-823.

138. Nunes EV, Sullivan MA, Levin FR. Treatment of depression in patients with opiate dependence. Biol Psychiatry. 2004;56(1):793-802.

139. Substance Abuse and Mental Health Services Administration. National Survey of Substance Abuse Treatment Services (N-SSATS): 2016. Data on Substance Abuse Treatment Facilities. BHSIS Series S-93, HHS Publication No. (SMA) 17-5039. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2017.

140. Bell J, Zador D. A risk-benefit analysis of methadone maintenance treatment. Drug Saf. 2000;22(3):179-190.

141. Kraft MK, Rothbard AB, Hadley TR, McLellan AT, Asch DA. Are supplementary services provided during methadone maintenance really cost-effective? Am J Psychiatry. 1997;154(9):1214-1219.

142. McCarty D, Perrin NA, Green CA, Polen MR, Leo MC, Lynch F. Methadone maintenance and the cost and utilization of health care among individuals dependent on opioids in a commercial health plan. Drug Alcohol Depend. 2010;111(3):235-240.

143. Clark RE, Samnaliev M, Baxter JD, Leung GY. The evidence doesn't justify steps by state Medicaid programs to restrict opioid addiction treatment with buprenorphine. Health Aff (Millwood). 2011;30(8):1425-1433.

144. Mattick RP, Breen C, Kimber J, Davoli M. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Syst Rev. 2014;2:CD002207.

145. Jegu J, Gallini A, Soler P, Montastruc JL, Lapeyre-Mestre M. Slow-release oral morphine for opioid maintenance treatment: a systematic review. Br J Clin Pharmacol. 2011;71(6):832-843.

146. Ferri M, Minozzi S, Bo A, Amato L. Slow-release oral morphine as maintenance therapy for opioid dependence. Cochrane Database Syst Rev. 2013;6:CD009879.

147. Bond AJ, Reed KD, Beavan P, Strang J. After the randomized injectable opiate treatment trial: post-trial investigation of slow-release oral morphine as an alternative opiate maintenance medication. Drug Alcohol Rev. 2012;31(4):492-498.

148. Uchtenhagen AA. Heroin maintenance treatment: from idea to research to practice. Drug Alcohol Rev. 2011;30(2):130-137.

149. Schechter MT, Kendall P. Is there a need for heroin substitution treatment in Vancouver's Downtown Eastside? Yes there is, and in many other places too. Can J Public Health. 2011;102(2):87-89.

150. Woody GE. Research findings on psychotherapy of addictive disorders. Am J Addict. 2003;12(Suppl 2):S19-S26.

151. Morgan JR, Schackman BR, Leff JA, Linas BP, Walley AY. Injectable naltrexone, oral naltrexone, and buprenorphine utilization and discontinuation among individuals treated for opioid use disorder in a United States commercially insured population. J Subst Abuse Treat. 2018;85:90-96.

152. Minozzi S, Amato L, Vecchi S, Davoli M, Kirchmayer U, Verster A. Oral naltrexone maintenance treatment for opioid dependence. Cochrane Database Syst Rev. 2011;(4):CD001333.

153. Amato L, Davoli M, Perucci CA, Ferri M, Faggiano F, Mattick RP. An overview of systematic reviews of the effectiveness of opiate maintenance therapies: available evidence to inform clinical practice and research. J Sub Abuse Treat. 2005;28(4):321-329.

154. Humphreys K, Wing S, McCarty D, et al. Self-help organizations for alcohol and drug problems: toward evidence-based practice and policy. J Substance Abuse Treat. 2004;26(3):151-165.

155. Ronel N, Gueta K, Abramsohn Y, Caspi N, Adelson M. Can a 12-step program work in methadone maintenance treatment?Int J Offender Ther Comp Criminol. 2011;55(7):1135-1153.

156. Stoops WW, Lile JA, Glaser PE, Hays LR, Rush CR. Alternative reinforcer response cost impacts cocaine choice in humans.Prog Neuropsychopharmacol Biol Psychiatry. 2012;36(1):189-193.

157. Donovan DM, Ingalsbe MH, Benbow J, Daley DC. 12-step interventions and mutual support programs for substance use disorders: an overview. Soc Work Public Health. 2013;28(3-4):313-332.

158. Crape BL, Latkin CA, Laris AS, Knowlton AR. The effects of sponsorship in 12-step treatment of injection drug users. Drug Alcohol Depend. 2002;65:291-301.

159. Wendt DC, Hallgren KA, Daley DC, Donovan DM. Predictors and outcomes of twelve-step sponsorship of stimulant users: secondary analyses of a multisite randomized clinical trial. J Stud Alcohol Drugs. 2017;78(2):287-295.

160. Christo G, Sutton S. Anxiety and self-esteem as a function of abstinence time among recovering addicts attending Narcotics Anonymous. Br J Clin Psychol. 1994;33:198-200.

161. Ginter W. Methadone Anonymous and mutual support for medication-assisted recovery. J Groups Addict Recovery. 2012;7(2-4): 189-201.

162. Methadone is Recovery. Available at http://www.druglibrary.org/schaffer/heroin/methadone/dont/m_isreco.htm#Recovery. Last accessed March 7, 2018.

163. Opiate Addiction and Treatment Resource. Methadone Clinic Directory. Available at http://www.opiateaddictionresource.com/treatment/methadone_clinic_directory. Last accessed March 7, 2018.

164. Glickman L, Galanter M, Dermatis H, Dingle S. Recovery and spiritual transformation among peer leaders of a modified Methadone Anonymous group. J Psychoactive Drugs. 2006;38(4):531-533.

165. Jordan JB. Acupuncture treatment for opiate addiction: a systematic review. J Subst Abuse Treat. 2006;30(4):309-314.

166. Otto KC. Acupuncture and substance abuse: a synopsis, with indications for further research. Am J Addict. 2003;12(1):43-51.

167. Motlagh FE, Ibrahim F, Rashid RA, Seghatoleslam T, Habil H. Acupuncture therapy for drug addiction. Chin Med. 2016;11:16.

168. Wu SL, Leung AW, Yew DT. Acupuncture for detoxification in treatment of opioid addiction. East Asian Arch Psychiatry. 2016;26(2):70-76.

169. Ross S, Peselow E. Co-occurring psychotic and addictive disorders: neurobiology and diagnosis. Clin Neuropharmacol. 2012;35(5):235-243.

170. Kelly TM, Daley DC. Integrated treatment of substance use and psychiatric disorders. Soc Work Public Health. 2013;28(0):388-406.

171. Hser YI, Grella CE, Hubbard RL, et al. An evaluation of drug treatments for adolescents in 4 U.S. cities. Arch Gen Psychiatry. 2001;58(7):689-695.

172. Goldner EM, Lusted A, Roerecke M, Rehm J, Fischer B. Prevalence of Axis-1 psychiatric (with focus on depression and anxiety) disorder and symptomatology among non-medical prescription opioid users in substance use treatment: systematic review and meta-analyses. Addict Behav. 2014;39(3):520-531.

173. Wasan AD, Michna E, Edwards RR, et al. Psychiatric comorbidity is associated prospectively with diminished opioid analgesia and increased opioid misuse in patients with chronic low back pain. Anesthesiology. 2015;123(4):861-872.

174. Howe CQ, Sullivan MD. The missing 'P' in pain management: how the current opioid epidemic highlights the need for psychiatric services in chronic pain care. Gen Hosp Psychiatry. 2014;36(1):99-104.

175. U.S. Department of Health and Human Services, Substance Abuse and Mental Health Services Administration. Estimation methodology for adults with serious mental illness (SMI). Fed Regist. 1999;64(121):33890-33897.

176. National Institute on Drug Abuse. Common Physical and Mental Health Comorbidities with Substance Use Disorders. Available at https://www.drugabuse.gov/publications/research-reports/common-physical-mental-health-comorbidities-substance-use-disorders/part-1-connection-between-substance-use-disorders-mental-illness. Last accessed March 7, 2018.

177. Strain EC. Assessment and treatment of comorbid psychiatric disorders in opioid-dependent patients. Clin J Pain. 2002;18(4 Suppl):S14-S27.

178. Ross S, Peselow E. Co-occurring psychotic and addictive disorders: neurobiology and diagnosis. Clin Neuropharmacol. 2012;35(5):235-243.

179. Morojele NK, Saban A, Seedat S. Clinical presentations and diagnostic issues in dual diagnosis disorders. Curr Opin Psychiatry. 2012;25(3):181-186.

180. Mueser KT, Gingerich S. Treatment of co-occurring psychotic and substance use disorders. Soc Work Public Health. 2013;28(3-4):424-439.

181. Torrens M, Rossi PC, Martinez-Riera R, Martinez-Sanvisens D, Bulbena A. Psychiatric co-morbidity and substance use disorders: treatment in parallel systems or in one integrated system? Subst Use Misuse. 2012;47(8-9):1005-1014.

182. Nunes EV, Levin FR. Treatment of depression in patients with alcohol or other drug dependence: a meta-analysis. JAMA. 2004;291(15):1887-1896.

183. DeMarce JM, Lash SJ, Stephens RS, Grambow SC, Burden JL. Promoting continuing care adherence among substance abusers with co-occurring psychiatric disorders following residential treatment. Addict Behav. 2008;33(9):1104-1112.

184. Kelly TM, Daley DC, Douaihy AB. Treatment of substance abusing patients with comorbid psychiatric disorders. Addict Behav. 2012;37(1):11-24.

185. Baker AL, Hides L, Lubman DI. Treatment of cannabis use among people with psychotic or depressive disorders: A systematic review. J Clin Psychiatry. 2010;71:247-254.

186. Mangrum LF, Spence RT, Lopez M. Integrated versus parallel treatment of co-occurring psychiatric and substance use disorders.J Subst Abuse Treat. 2006;30(1):79-84.

187. van der Bosch LM, Verheul R. Patients with addiction and personality disorder: Treatment outcomes and clinical implications.Curr Opin Psychiatry. 2007;20(1):67-71.

188. Weiss RD, Connery HS. Integrated Group Therapy for Bipolar Disorders and Substance Abuse. New York, NY: Guilford Press; 2011.

189. Rayburn WF, Bogenschutz MP. Pharmacotherapy for pregnant women with addictions. Am J Obstet Gynecol. 2004;191(6):1885-1897.

190. American College of Obstetricians and Gynecologists. Opioid use and opioid use disorder in pregnancy. Committee Opinion No. 711. Obstet Gynecol. 2017;30:e81-e94.

191. National Institute on Drug Abuse. Treating Opioid Use Disorder During Pregnancy. Risks of Opioid Misuse During Pregnancy. Available at https://www.drugabuse.gov/publications/treating-opioid-use-disorder-during-pregnancy/treating-opioid-use-disorder-during-pregnancy#ref. last accessed March 7, 2018.

192. Patrick SW, Schumacher RE, Benneyworth BD, et al. Neonatal abstinence syndrome and associated health care expenditures United States, 2000-2009. JAMA. 2012;307(18):1934-1940.

193. Osborn DA, Jeffery HE, Cole MJ. Opiate treatment for opiate withdrawal in newborn infants. Cochrane Database Syst Rev. 2010;(6):CD002059.

194. Hamdan AH. Neonatal abstinence syndrome. Available at https://emedicine.medscape.com/article/978763-overview. Last accessed March 7, 2018.

195. Ferri M, Davoli M, Perucci CA. Heroin maintenance for chronic heroin dependents. Cochrane Database Syst Rev. 2010;(8):CD003410.

196. Grim K, Harrison TE, Wilder RT. Management of neonatal abstinence syndrome from opioids. Clin Perinatol. 2013;40(3):509-524.

197. Jones HE, Kaltenbach K, Heil SH, et al. Neonatal abstinence syndrome after methadone or buprenorphine exposure. N Engl J Med. 2010;363(24):2320-2331.

198. Brogly SB, Saia KA, Walley AY, Du HM, Sebastiani P. Prenatal buprenorphine versus methadone exposure and neonatal outcomes: systematic review and meta-analysis. Am J Epidemiol. 2014;180(7):673-686.

199. Bell J, Harvey-Dodds L. Pregnancy and injecting drug use. BMJ. 2008;336(7656):1303-1305.

200. Hudak ML, Tan RC, The Committee on Drugs, The Committee on Fetus and Newborn. Neonatal drug withdrawal. Pediatrics. 2012;129(2):e540-e560.

201. Jansson LM, Choo RE, Harrow C, et al. Concentration of methadone in breast milk and plasma in the immediate perinatal period. J Hum Lact. 2007;23(2):184-190.

202. Reece-Stremtan S, Marinelli KA. ABM clinical protocol #21: guidelines for breastfeeding and substance use or substance use disorder, revised 2015. Breastfeed Med. 2015;10(3):135-141.

203. Rao R, Desai NS. OxyContin and neonatal abstinence syndrome. J Perinatol. 2002;22(4):324-325.

204. Dixon DW. Opioid Abuse Follow-Up. Prognosis. Available at https://emedicine.medscape.com/article/287790-followup#e4. Last accessed March 7, 2018.

205. U.S. Food and Drug Administration. FDA Approves the First Non-Opioid Treatment for Management of Opioid Withdrawal Symptoms in Adults. Available at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm607884.htm. Last accessed May 24, 2018.

Evidence-Based Practice Recommendations Citations

1. Hooten M, Thorson D, Bianco J, et al. Pain: Assessment, Non-Opioid Treatment Approaches and Opioid Management. Bloomington, MN: Institute for Clinical Systems Improvement; 2016. Summary retrieved from National Guideline Clearinghouse at https://www.guideline.gov/summaries/summary/50568. Last accessed March 21, 2018.

2. World Health Organization. Community Management of Opioid Overdose. Geneva: World Health Organization; 2014. Summary retrieved from National Guideline Clearinghouse at https://www.guideline.gov/summaries/summary/48893. Last accessed March 21, 2018.

3. Chou R, Cruciani RA, Fiellin DA, et al. Methadone safety: a clinical practice guideline from the American Pain Society and College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society. J Pain. 2014;15(4):321-337. Summary retrieved from National Guideline Clearinghouse at https://www.guideline.gov/summaries/summary/49245. Last accessed March 21, 2018.

4. Management of Substance Use Disorders Work Group. VA/DoD Clinical Practice Guideline for the Management of Substance Use Disorders. Version 3.0. Washington, DC: Department of Veterans Affairs, Department of Defense; 2015. Summary retrieved from National Guideline Clearinghouse at https://www.guideline.gov/summaries/summary/49968. Last accessed March 21, 2018.

5. World Health Organization. Guidelines for the Identification and Management of Substance Use and Substance Use Disorders in Pregnancy. Geneva: World Health Organization; 2014. Summary retrieved from National Guideline Clearinghouse at https://www.guideline.gov/summaries/summary/48894. Last accessed March 21, 2018.