GAL22 • Nurses 2022

Table of Contents

GAL22 • Nurses 2022

How to Receive Credit

NetCE 15 Hour Course #30830 • Pituitary and Adrenal Disorders

30830 • Pituitary and Adrenal Disorders

1. INTRODUCTION

2. ANATOMY AND PHYSIOLOGY

3. NURSING ASSESSMENT

4. NURSING DIAGNOSES

5. DIABETES INSIPIDUS

6. SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION (SIADH)

7. GROWTH HORMONE DEFICIENCY

8. DISORDERS OF HYPERSOMATOTROPISM

9. ADDISON DISEASE

10. CUSHING SYNDROME

11. PRIMARY ALDOSTERONISM

12. PHEOCHROMOCYTOMA

13. PSYCHOSOCIAL/LIFESTYLE INFLUENCES AND EFFECTS

14. CASE STUDIES

15. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 10 Hour Course #96963 • Opioid Use Disorder

96963 • 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 MISUSE 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

Works Cited

Evidence-Based Practice Recommendations Citations

GAL22 • Nurses 2022

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

Amanda Perkins, MSN, DNP

www.netce.com

Copyright © 2024 NetCE, All rights reserved.

GAL22 • Nurses 2022

Expiration Date: 02/28/2022

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.

30830 • Pituitary and Adrenal Disorders

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

Amanda Perkins, MSN, DNP

www.netce.com

Copyright © 2021 NetCE, All rights reserved.

The pituitary and adrenal glands play a significant role in many functions in the body, and proper functioning is essential for the maintenance of health. Dysfunction in these glands can have detrimental effects and may lead to death if untreated. Although disorders of the pituitary or adrenal glands are not as easy to see or identify as many conditions, they are nonetheless relatively common among many patient populations. This course will provide a brief overview of the anatomy and physiology of the pituitary and adrenal glands, assessment, common disorders, and care of the patient with pituitary/adrenal dysfunction. Nurses have a responsibility and duty to identify the signs and symptoms of these disorders and to care for patients appropriately and fully.

Table of Contents

30830 • Pituitary and Adrenal Disorders

Course Overview

Audience

Accreditations & Approvals

Designations of Credit

Individual State Nursing Approvals

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planner

Division Planner Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. ANATOMY AND PHYSIOLOGY

HYPOTHALAMUS

PITUITARY GLAND

ADRENAL GLANDS

HORMONES

3. NURSING ASSESSMENT

PHYSICAL ASSESSMENT

DIAGNOSTIC TESTS

4. NURSING DIAGNOSES

INEFFECTIVE INDIVIDUAL COPING

ALTERATION IN THOUGHT PROCESSES

ALTERATION IN COMFORT

DISTURBANCE IN SELF-CONCEPT

ALTERATION IN NUTRITION AND BOWEL ELIMINATION

ALTERATION IN FLUID VOLUME

5. DIABETES INSIPIDUS

PATHOPHYSIOLOGY

SIGNS AND SYMPTOMS

DIAGNOSIS

TREATMENT

6. SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION (SIADH)

PATHOPHYSIOLOGY

SIGNS AND SYMPTOMS

DIAGNOSTIC TESTS

TREATMENT AND NURSING INTERVENTIONS

7. GROWTH HORMONE DEFICIENCY

PATHOPHYSIOLOGY

SIGNS AND SYMPTOMS

DIAGNOSTIC TESTS

TREATMENT AND NURSING INTERVENTIONS

8. DISORDERS OF HYPERSOMATOTROPISM

ACROMEGALY

GIGANTISM

9. ADDISON DISEASE

PATHOPHYSIOLOGY

SIGNS AND SYMPTOMS

DIAGNOSTIC TESTS

TREATMENT AND NURSING INTERVENTIONS

10. CUSHING SYNDROME

PATHOPHYSIOLOGY

SIGNS AND SYMPTOMS

DIAGNOSTIC TESTS

TREATMENT

11. PRIMARY ALDOSTERONISM

SIGNS AND SYMPTOMS

DIAGNOSIS

TREATMENT

12. PHEOCHROMOCYTOMA

SIGNS AND SYMPTOMS

DIAGNOSIS

TREATMENT

13. PSYCHOSOCIAL/LIFESTYLE INFLUENCES AND EFFECTS

SELF-CONCEPT AND SELF-ESTEEM

SEXUAL EXPRESSION AND REPRODUCTION

OCCUPATIONAL AND ECONOMIC FACTORS

DIETARY FACTORS

CULTURAL CONSIDERATIONS

14. CASE STUDIES

ACUTE ADRENAL INSUFFICIENCY (ADDISON DISEASE)

DIABETES INSIPIDUS

SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION

15. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

30830 • Pituitary and Adrenal Disorders

Education Category. Medical / Surgical

Release Date. 08/01/2021

Expiration Date. 07/31/2024

Course Overview

The pituitary and adrenal glands play a significant role in many functions in the body, and proper functioning is essential for the maintenance of health. Dysfunction in these glands can have detrimental effects and may lead to death if untreated. Although disorders of the pituitary or adrenal glands are not as easy to see or identify as many conditions, they are nonetheless relatively common among many patient populations. This course will provide a brief overview of the anatomy and physiology of the pituitary and adrenal glands, assessment, common disorders, and care of the patient with pituitary/adrenal dysfunction. Nurses have a responsibility and duty to identify the signs and symptoms of these disorders and to care for patients appropriately and fully.

Audience

This course is designed for nurses in all practice settings.

Accreditations & Approvals

In support of improving patient care, NetCE is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. NetCE is accredited by the International Accreditors for Continuing Education and Training (IACET). NetCE complies with the ANSI/IACET Standard, which is recognized internationally as a standard of excellence in instructional practices. As a result of this accreditation, NetCE is authorized to issue the IACET CEU.

Designations of Credit

NetCE designates this continuing education activity for 15 ANCC contact hour(s). NetCE designates this continuing education activity for 5 pharmacotherapeutic/pharmacology contact hour(s). NetCE designates this continuing education activity for 18 hours for Alabama nurses. NetCE is authorized by IACET to offer 1.5 CEU(s) for this program. AACN Synergy CERP Category A.

Individual State Nursing Approvals

In addition to states that accept ANCC, NetCE is approved as a provider of continuing education in nursing by: Alabama, Provider #ABNP0353, (valid through July 29,2025); Alabama, Provider #ABNP0353, (valid through July 29, 2025); Arkansas, Provider #50-2405; California, BRN Provider #CEP9784; California, LVN Provider #V10662; California, PT Provider #V10842; District of Columbia, Provider #50-2405; Florida, Provider #50-2405; Georgia, Provider #50-2405; Kentucky, Provider #7-0054 through 12/31/2025; South Carolina, Provider #50-2405; South Carolina, Provider #50-2405. West Virginia RN and APRN, Provider #50-2405.

Course Objective

As health care becomes more complex, it is essential that the theoretical concepts of the basis of illness (pathophysiology) be well understood. The purpose of this course is to reinforce the scientific rationales for the interventions nurses perform and the decisions nurses make as patients move through the ever-changing struggle with their pituitary or adrenal illness.

Learning Objectives

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

1. Describe the anatomy and physiology of the pituitary and adrenal glands.

2. Outline the action of the hormones excreted by the pituitary and adrenal glands.

3. Describe key aspects of the assessment of patients with pituitary or adrenal disorders, including appropriate diagnostic tools.

4. Discuss the presentation and diagnosis of diabetes insipidus.

5. Outline the options for the treatment of diabetes insipidus.

6. Review the presentation and management of syndrome of inappropriate antidiuretic hormone secretion (SIADH).

7. Evaluate the signs/symptoms, diagnosis, and treatment of growth hormone deficiency.

8. Identify acromegaly and gigantism and appropriate approaches to their treatment.

9. Describe the clinical presentation and diagnosis of Addison disease.

10. Evaluate approaches to the treatment of Addison disease, including identification and management of adrenal crises.

11. Discuss the identification and diagnosis of Cushing syndrome.

12. Evaluate various treatment options for Cushing syndrome, including surgical considerations.

13. Review the signs/symptoms, diagnosis, and treatment of primary aldosteronism.

14. Analyze the clinical presentation, diagnosis, and treatment of pheochromocytoma.

15. Identify psychosocial/lifestyle considerations for patients with pituitary or adrenal disorders.

Faculty

Amanda Perkins, MSN, DNP, is a DNP-prepared registered nurse with a focus in healthcare leadership. Prior to obtaining her DNP, she obtained an MSN with a focus on nursing education. She currently works full-time as an Associate Professor of Nursing at Vermont Tech and per-diem at Gifford Medical Center on the medical-surgical unit and in the long-term care facility. Dr. Perkins also sits on the editorial board, writes, and peer-reviews for the journal Nursing Made Incredibly Easy! She has experience in a variety of settings, including long-term care, residential care, medical-surgical, women and children, intensive care, and inpatient psychiatric units.

Jane C. Norman, RN, MSN, CNE, PhD, received her undergraduate education at the University of Tennessee, Knoxville campus. There she completed a double major in Sociology and English. She completed an Associate of Science in Nursing at the University of Tennessee, Nashville campus and began her nursing career at Vanderbilt University Medical Center. Jane received her Masters in Medical-Surgical Nursing from Vanderbilt University. In 1978, she took her first faculty position and served as program director for an associate degree program. In 1982, she received her PhD in Higher Education Administration from Peabody College of Vanderbilt University. In 1988, Dr. Norman took a position at Tennessee State University. There she has achieved tenure and full professor status. She is a member of Sigma Theta Tau National Nursing Honors Society. In 2005, she began her current position as Director of the Masters of Science in Nursing Program.

Faculty Disclosure

Contributing faculty, Amanda Perkins, MSN, DNP, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Contributing faculty, Jane C. Norman, RN, MSN, CNE, PhD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planner

Sharon Cannon, RN, EdD, ANEF

Division Planner Disclosure

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

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has 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.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION

Body activities, homeostasis, and the response to stress are controlled by two distinct, but interacting systems: the nervous system and the endocrine system. The nervous system creates an immediate but short-lived response, operating on the principles of electricity, through impulse conduction. The endocrine system has a slightly slower onset and a longer duration of action and uses highly specific hormones to control its response chemically.

The endocrine system is composed of many glands scattered throughout the body; these glands secrete unique and potent hormones directly into the bloodstream. Most hormones direct their action to target glands or tissues at distant receptor sites, thereby regulating critical body functions such as urinary output, cellular metabolic rate, and growth and development. Hormonal secretions typically are regulated by negative feedback; information about the hormone level or its effect is fed back to the gland, which then responds accordingly.

Endocrine diseases result from an abnormal increase or decrease in the secretion of hormones. This divergence from normal hormone quantities may be the result of hyperplasia, hypertrophy, or atrophy of an endocrine gland. Changes in gland size that affect the gland's production and secretion of a hormone often result from an insult to the gland, such as infection, radiation, trauma, surgical intervention, or inflammation.

As noted, the principal functional units in the system are the endocrine glands: the pituitary, thyroid, parathyroid, adrenal, and pineal glands; the cells of the islets of Langerhans in the pancreas; the gonads (ovaries and testes); and the thymus. The kidneys also perform an endocrine function. Some of these glands are solely endocrine in function, whereas others form parts of larger organs that may have both endocrine and nonendocrine functions. The pituitary, thyroid, parathyroid, pineal, and adrenal glands have distinct endocrine functions. This course will focus on the pathophysiology of the pituitary and adrenal glands.

Because of the complex actions of the pituitary and adrenal glands, as well as their interaction with each other and with other body systems, their dysfunctions have a variety of causes and clinical manifestations. Pituitary disorders encompass a diverse set of conditions, including diabetes insipidus, SIADH (syndrome of inappropriate antidiuretic hormone secretion), acromegaly, and growth hormone deficiency. Common adrenal disorders include Cushing syndrome, Addison disease, hypoaldosteronism, and hyperaldosteronism. Because the pituitary and adrenal glands work together closely, there is often overlap in the pathophysiology of these disorders.

Dysfunction of the pituitary or adrenal gland is associated with many physical and mental symptoms, with significant impact on patients, families, health services, and society. When caring for patients with these types of disorders, there are key skills necessary to accurately interpret diagnostic testing, identify comorbidities, and effectively manage care.

2. ANATOMY AND PHYSIOLOGY

HYPOTHALAMUS

The hypothalamus plays an important role in the regulation of homeostasis within the body. It is necessary for automatic functions of the nervous system, regulation of the glands of the endocrine system, emotional responses, and behaviors [1]. It may help to think of the hypothalamus as a control center—it monitors information about the body and makes necessary changes based on the information obtained.

The hypothalamus functions as an integral part of both the endocrine and nervous systems. In its neural role, it receives and processes innervations from the thalamus, cerebral cortex, spinal cord, and brainstem. This results in the control of such bodily functions as temperature, respiration, arterial blood pressure and circulation, and metabolism. The hypothalamus also controls certain behavioral functions, including the emotional states of fear, anxiety, anger, rage, pleasure, and pain, as well as the states of sleep, wakefulness, and alertness. The hypothalamus, as it is influenced by the autonomic nervous system, affects all the unconscious actives of the body [2,3]. In its endocrine role, the hypothalamus has two regulatory functions:

- Regulating the anterior pituitary gland by producing and secreting releasing factors

- Producing and secreting two hormones (oxytocin and antidiuretic hormone [ADH]) stored in the posterior pituitary gland

Hypothalamic-releasing factors are proteins that act on the anterior pituitary gland to stimulate or inhibit the release of tropic hormones. Other inhibiting factors and releasing factors have been identified; it is thought, although still unproven, that the hypothalamus may produce both an inhibiting and a releasing factor for each of the anterior pituitary hormones [2,3].

The release or inhibition of these hypothalamic hormones is controlled by various neurotransmitters, such as serotonin, acetylcholine, norepinephrine, and dopamine. The tropic hormones released from the anterior pituitary gland then act upon a target gland or tissues to produce a specific response. In regulating the secretion of these releasing factors, the hypothalamus processes input from both the circulatory and nervous systems [2,3].

PITUITARY GLAND

The pituitary gland (hypophysis) is located in the sella turcica at the base of the skull. It lies just below the hypothalamus and is connected to it by a stalk containing blood vessels and nervous tissue. The pituitary gland is composed of an anterior and posterior lobe (adenohypophysis and neurohypophysis, respectively), each of which performs specific functions, as well as a rudimentary intermediate lobe [4].

In response to the releasing factors from the hypothalamus, the anterior pituitary gland secretes several hormones, some of which control hormonal secretions by other glands. The anterior pituitary hormones secreted include thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), growth hormone, luteinizing hormone (also called interstitial cell-stimulating hormone in men), follicle-stimulating hormone, and prolactin. In general, growth hormone, ACTH, and TSH are concerned with metabolic activities, whereas luteinizing hormone, follicle-stimulating hormone, and prolactin are concerned with reproduction. ACTH, TSH, follicle-stimulating hormone, and luteinizing hormone exert their effects on target glands, either increasing their size or their secretions. Prolactin and growth hormone directly affect the metabolism of specific target tissues [5].

Most of the disorders affecting the pituitary gland originate in the anterior lobe. The effects of pathology on the anterior pituitary gland can be broadly summarized as hyperpituitarism and hypopituitarism [6,7].

The most common cause of hyperfunction of the anterior pituitary gland is a neoplastic secreting tumor, usually a benign adenoma. Tumors of the pituitary gland exert their effects through either pressure on structures in the brain, causing visual symptoms and headaches, or excessive secretion of one or more of the anterior pituitary hormones, which results in increased stimulation of one or more target glands.

One of the pathophysiologic manifestations of these tumors is hypersomatotropism, which can result in acromegaly in adults and gigantism in children. Other effects of hypersomatotropism include goiter (from stimulation of the thyroid) and diabetes mellitus (from the diabetogenic effect of growth hormone). Cardiomegaly and hypertension can also occur. Visual impairment and eventual blindness are possible because of compression of tissues by an expanding tumor. Amenorrhea in women and loss of libido and potency in men may occur because compression from the expanding tumor leads to gonadal deficiencies from loss of healthy gonadotropin-producing cells [6,7].

Hyperfunction of the anterior pituitary gland can be secondary to pathology of the anterior pituitary gland or to injury to the hypothalamus resulting in a decrease or absence of hypothalamic-releasing factors. Hypothalamism may be manifested by isolated hormonal deficiencies or by a deficiency of both the anterior and posterior pituitary hormones (panhypopituitarism). The exact hormonal deficit and its etiology are important to understanding patients' symptoms and signs [6,7].

ADRENAL GLANDS

The adrenal glands are paired and located in the retroperitoneal space at the upper pole of the kidney. Because of this position, they may be referred to as the suprarenal glands. Each adrenal gland consists of an outer portion (the cortex) and an inner portion (the medulla), which differ in both anatomic structure and function [8].

The adrenal cortex is composed of three zones, or groups of different cells: the zona glomerulus (the outer layer of cortical cells that secretes the mineralocorticoids), the zona fasciculate (the middle layer of cortical cells that secretes the glucocorticoids), and the zona reticularis (the layer of cortical cells proximal to the medulla that secretes the adrenal sex hormones androgens and estrogen). The adrenal glands receive an abundant blood supply. The medulla of the adrenal gland functions as part of the sympathetic nervous system, whereas the cortex has only minimal nervous system innervation [8].

In response to stimulation by ACTH from the anterior pituitary gland, the adrenal cortex secretes three major types of hormones: glucocorticoids (cortisol), mineralocorticoids (aldosterone), and sex hormones (androgens, estrogen, and progesterone). These hormones affect metabolism, fluid balance, and the development of secondary sex characteristics, respectively. All three types of hormones secreted by the adrenal cortex are structurally similar steroids, which results in some overlapping of their effects [5,9].

The primary causes of hypercortisolism (Cushing syndrome), originating from within the adrenal cortex itself, include neoplastic and bilateral hyperplasia. In iatrogenic hypercortisolism, an exogenous source (e.g., prolonged use of glucocorticoids or ACTH) is responsible for the hypercortisolism. The normal adrenal glandular tissue may be atrophic, and ACTH levels are suppressed [10].

Hyperfunction of the adrenal cortex results in three major disorders: Cushing syndrome, primary aldosteronism, and excessive production of sex hormones characterized by virilizing changes in women, feminizing changes in men, and precocious sexual development in children. These changes often cause serious psychologic issues related to self-esteem and body image.

Hypofunction of the adrenal cortex, or adrenal insufficiency, results in a decreased secretion of glucocorticoids, mineralocorticoids, and sex hormones. The causes of adrenal insufficiency can be grouped into two categories: primary (based on pathology occurring within the gland itself) and secondary (arising from an undersecretion of ACTH due to pathology in the pituitary gland or the hypothalamus). Primary causes may be acute or chronic [11].

Primary adrenal insufficiency (Addison disease) is characterized by a failure of the adrenal cortex to produce sufficient corticosteroids. Acute severe symptoms of Addison disease are referred to as addisonian or acute adrenal crisis.

The adrenal medulla is considered a part of the sympathetic division of the autonomic nervous system, which controls the secretion of its hormones. Because the functions of the sympathetic nervous system and the functions of the hormones of the adrenal medulla are the same, they can compensate for each other. Thus, the medullary hormones are not essential to life but play an important role in the body's response to stress. About 15% of the hormonal secretion by the adrenal medulla is norepinephrine and 75% is epinephrine [5].

Pathophysiology of the adrenal medulla is rare and is usually associated with hyperfunction. The clinical manifestations seen in hyperfunction of the adrenal medulla are related to the excessive secretion of epinephrine and norepinephrine [12]. Pheochromocytoma is the most common cause of adrenal medulla hyperfunction. Other disorders associated with hyperfunction of the adrenal medulla include neurofibromatosis carcinomas (of the thyroid) and hyperparathyroidism [12].

HORMONES

A hormone may be defined as a "chemical substance synthesized by an endocrine gland and secreted into the bloodstream, which carries it to other sites in the body where its actions are exerted" [5]. Hormones may function independently, in conjunction with other hormones, or as a step in a series of related actions. They may influence the action, metabolism, synthesis, and/or transport of another hormone, which is one of the integrative aspects of the endocrine system. Hormones can be differentiated into two major categories: local (with specific local effects) and general (transported by the circulation to distant sites, where they have a physiologic effect) [13].

Only target cells have the capability to respond to a specific hormone in a characteristic way. Their response depends on the presence of specific receptors for a particular hormone. This response is called hormone-target cell specificity, and the process is known as hormone-receptor binding. The initial interaction between a hormone and its target cell receptor initiates a chain of biochemical events that eventually provokes a cellular response. This often involves a hormone-induced change in the activity of a specific enzyme found in the target cell that might change the rate of reactions within the cell, change the growth of the cell, or control the cell's secretion. Because cells are exposed to many hormones, complex hormone-hormone interactions can occur in target cells. These interactions may be inhibitory, synergistic, or permissive (i.e., one hormone, by its presence, potentiates the effect of the second hormone) [13].

Hormones include steroid, polypeptide, amino acid, catecholamine, or iodothyronine structures. The steroidal hormones are aldosterone, cortisol, and the estrogens and androgens. The receptors involved in hormonal-receptor binding differ for steroidal and nonsteroidal hormones. The receptors for most nonsteroidal hormones are located on the outer surface of the plasma membrane of the target cells, whereas the receptors for the steroidal hormones are soluble proteins within the cytoplasm of the target cell. The physiology of hormone receptors is an expanding area of research in endocrinology [13].

Most hormones are not secreted at a constant rate. After secretion into the bloodstream, they circulate in a free form or are bound to proteins. Polypeptide hormones and the catecholamines are essentially unbound in the circulation. These free hormones are directly available to the target tissues, and only they can affect the target cells. The protein-bound forms are thought to represent a hormonal reserve, because the protein binding may prevent excretion of the hormone by the kidney. The amount of circulating free hormone is usually quite small and exists in equilibrium with the bound fractions [13].

There are five major influences of the secretion of hormones by the endocrine glands: the hypothalamus, hypothalamic-releasing factors, anterior pituitary hormones, the autonomic nervous system, and nutrient and ion concentrations in the plasma. The hypothalamus affects hormone secretion by secreting a series of peptides called releasing factors, which stimulate or inhibit the release of hormones by the anterior pituitary gland. The hypothalamus also directly manufactures oxytocin and antidiuretic hormones (ADH or vasopressin). The hypothalamic-releasing factors cause the interior pituitary gland to secrete growth hormone, prolactin, TSH, the gonadotropic hormones follicle-stimulating hormone, luteinizing hormone, and ACTH. The anterior pituitary hormones directly control the release of thyroid hormone (T3 and T4), cortisol, testosterone in men, and estrogen and progesterone in women [13]. In some patients with excessive hormone levels caused by a tumor of the involved endocrine gland, feedback inhibition does not suppress the overproduction of the hormone, and the tumor functions autonomously [14,15].

Diurnal variation is another of the control mechanisms affecting hormonal secretion. A 24-hour cyclical variation in the secretory rates of certain hormones can be seen. For example, growth hormone levels are highest in the first 90 minutes after sleep begins. These circadian rhythms have been found to be different for each hormone. It is evident that the endocrine system affects all aspects of the organism. Through the hormonal secretion of its glands, the system controls and regulates the metabolic processes of anabolism and catabolism, the function of muscles, growth and reproduction, energy production, stress reactions, electrolyte balances, and personality development [14,15].

Antidiuretic Hormone (ADH)

The storage and release of ADH are influenced by such factors as plasma osmolality, blood volume, physiologic and psychological stress, and input from the central nervous system. ADH is produced in the hypothalamus and then transported to the posterior pituitary gland where it is stored. In the posterior pituitary gland, oxytocin and ADH are bound to the protein neurophysin and released into the circulation in response to specific physiological stimuli [3].

ADH plays an important role in the reabsorption of water by the kidneys; decreased ADH leads to diuresis, and increased ADH leads to fluid retention [16]. ADH is typically responsible for osmoregulation, but this changes when a person has a reduction in blood volume, which shifts ADH from osmoregulation to blood volume regulation [17]. ADH induces water reabsorption via vasopressin 2 receptors in the kidneys [18]. The main osmotic stimulus for ADH secretion is increased plasma osmolality and the main non-osmotic stimulus is hypovolemia [18]. The osmotic threshold for ADH is approximately 280–290 mOsm/Kg [17]. As such, ADH levels will significantly decrease when plasma osmolality drops below this level. Plasma osmolality greater than 280–290 mOsm/kg will lead to increased ADH release [17].

Growth Hormone

Growth hormone, also referred to as somatotropin, is produced in the pituitary gland [19]. An estimated 50% of the cells in the anterior pituitary are somatotrophs (cells that secrete growth hormone) [20]. Secretion of growth hormone by the anterior pituitary gland occurs in a pulsatile manner, and the majority (up to 70%) occurs at night during non-REM (typically stage 3) sleep [21,22]. Therefore, the amount and quality of sleep plays an important role in growth and development.

Growth hormone-releasing hormone (GHRH) is secreted from the hypothalamus, so growth hormone levels are primarily under hypothalamic control [22,23]. Growth hormone activates hormone-sensitive lipase (which results in metabolism of fat for energy), affects insulin sensitivity, and stimulates the formation of insulin-like growth factor in the liver [20,24].

Growth hormone can first be detected in the fetus near the end of the first trimester, with levels peaking at 20 weeks and decreasing after birth [21]. It will fall to adult levels until puberty, when levels increase [21]. After puberty, the levels decrease again and remain relatively stable until mid-adulthood, when they undergo another drop [21]. Levels of growth hormone may be increased during fasting or exercising and decreased in those with central obesity [21,23].

In addition to its role in normal development, growth hormone is necessary for the maintenance of bone health. It stimulates osteoblast differentiation and proliferation and increases calcium absorption in the intestines [23]. Further, it plays a role in appetite, cognitive function, energy, memory, mood, neuroprotection, and sleep [25].

Glucocorticoids

The glucocorticoids function in carbohydrate, fat, and protein metabolism and play an important role in the body's response to stress and emotional well-being. The principal glucocorticoid secreted by the adrenal cortex is cortisol, which constitutes 95% of cortical production; corticosterone and cortisone are also produced.

Glucocorticoids act on all cells in the body [26]. Cortisol, the main glucocorticoid, is secreted based on the circadian rhythm and in response to stress; for this reason, it is also known as the stress hormone. When the body is experiencing stress, the pituitary gland secretes ACTH, which stimulates the production and release of cortisol [27]. Cortisol also plays a role in nutrient metabolism, immune response to inflammation, regulation of blood pressure, blood glucose levels, and body fluid homeostasis [28,29].

Mineralocorticoids

The principal and most potent mineralocorticoid secreted by the adrenal cortex is aldosterone. Desoxycorticosterone and corticosterone are also secreted, but their actions are of minor importance. Aldosterone enters the circulation and travels to the kidney, where it binds to a specific receptor in the cytoplasm of the epithelial cells of the distal convoluted tubules. This receptor initiates a series of biochemical events that result in the major physiologic action of aldosterone [5,9].

Aldosterone increases the reabsorption of sodium and the secretion of potassium. This is accomplished as an exchange of sodium ions for potassium or hydrogen ions, which results in the excretion of potassium and hydrogen into the urine and the retention of sodium. As sodium is reabsorbed into the blood, it brings with it water and chlorides, which mechanically increases the blood volume. This action of aldosterone is vital to the maintenance of the extracellular fluid volume. Aldosterone also promotes sodium reabsorption to a lesser degree from the sweat glands, salivary glands, and gastrointestinal (GI) tract [2,3].

Aldosterone is an important factor in the maintenance of circulatory blood volume homeostasis through its effect on the electrolyte balance and its control of blood volume. It is the most potent hormonal regulator of electrolyte excretion. The secretion of aldosterone is regulated by three (or possibly four) major mechanisms: the renin-angiotensin system, ACTH, plasma potassium levels, and perhaps prostaglandins.

Although chiefly affecting the secretion of cortisol, ACTH is also thought to affect aldosterone production for short periods. This appears to be related to crises, during which ACTH causes an increase in the secretion of glucocorticoids and stimulates the production of aldosterone. This effect of ACTH is thought to be minor and secondary to that of the renin-angiotensin system and serum potassium levels [3].

The ratio of serum sodium levels to serum potassium levels is another important regulator of aldosterone secretion. If the serum potassium level rises or the serum sodium level decreases, changing the sodium-potassium ratio, the adrenal cortex will be stimulated to produce aldosterone. Prostaglandins are also thought to be involved in aldosterone secretion through the relation of sodium and water excretion and the release of renin [5,9].

Adrenal Medullary Hormones

The primary hormones secreted by the adrenal medulla are norepinephrine and epinephrine. Norepinephrine increases the contraction of the blood vessels, which increases peripheral resistance and causes the blood pressure to rise. This hormone also dilates the pupils of the eyes, increases the force and rate of myocardial contraction, and inhibits the activity of the GI system. It causes peripheral vasoconstriction, which diverts blood away from less-needed areas (e.g., the GI tract) toward the heart and skeletal muscles in a "fight-or-flight" response. Because of the length of time norepinephrine is retained in the circulation (two to three circulation times), it has an effect ten times larger than that of the sympathetic nervous system [5].

Epinephrine increases body metabolism and, in conjunction with glucagon, elevates the plasma glucose levels by glycogenolysis (the conversion of glycogen to glucose). Epinephrine also inhibits the secretion of insulin and elevates blood lipid levels by promoting lipolysis. These actions provide the body with a plasma glucose source for increased energy expenditure. Epinephrine is also able to constrict the arterioles of the skin selectively (causing pallor) while dilating the blood vessels of the heart and skeletal muscles, again vital to the stress response [5].

It is important to remember the permissive role of the glucocorticoids with respect to catecholamines. In the absence of cortisol, the vasoconstrictive and metabolic responses mediated by norepinephrine and epinephrine will not occur [5,9].

Through innervation from the sympathetic nervous system, the secretion of the adrenal medullary hormones is influenced by emotional stresses (e.g., fear, anxiety) and physiologic stresses (e.g., childbirth, injury, cold, hypoxia, immobilization, physical exercise). The relation between the psychologic-emotional state and the endocrine system is one of the body's major homeostatic mechanisms for protecting the individual from harm and physiologic stresses in a way that preserves integrity [9].

3. NURSING ASSESSMENT

Assessment of pituitary and adrenal issues should begin with a nursing history, followed by a physical examination. Exams should include determination of the patient's signs and symptoms, past medical history, family history, and any medications or supplements that the patient is taking. During the physical assessment, nurses should use the skills of inspection, olfaction, auscultation, percussion, and palpation. Vital signs and the patient's weight should also be obtained during the patient assessment.

PHYSICAL ASSESSMENT

Vital Signs

Patients with suspected pituitary or adrenal disorder should have their height and weight assessed and compared with growth charts. A careful developmental and familial growth history may help in the interpretation of abnormalities. Blood pressure should be measured in both arms initially and in at least two positions (e.g., supine and seated). Apical and radial pulse rates, rhythm, and quality should be evaluated, along with respiratory rate, rhythm, and depth. The patient's temperature should also be recorded [30].

General Appearance

Whether a patient's appearance closely matches his or her chronologic age should be noted. The symmetry and proportionality of the body parts should be assessed. Weight distribution and any abnormal movements of the extremities or face (e.g., spasms or twitching of facial muscles) should be noted. A plethoric (round, erythematous), "moon" face suggests Cushing syndrome [30].

Skin, Hair, and Nails

Pituitary and adrenal dysfunction can affect the temperature and texture of the skin. For example, pheochromocytoma is associated with increased skin temperature with sweating. Ecchymoses often accompany Cushing syndrome, and vitiligo has been seen in patients with adrenal insufficiency. Other possible skin lesions include skin infections (e.g., furuncles, carbuncles), ulcerations, and diabetes-related skin changes (e.g., candidiasis, diabetic dermopathy, diabetic xanthoma) [30]. The texture and distribution of body hair should also be considered.

Eyes

Nurses should pay careful attention to any changes in visual acuity or visual fields defects. Patients whose disorders induce hyperglycemia may display diabetic retinopathy (e.g., retinal edema, microaneurysms, retinal hemorrhages, exudates). Patients with these conditions require immediate referral to an ophthalmologist [30].

Cardiorespiratory System

The patient's heart rate and rhythm should be assessed, with attention to murmurs or extra heart sounds. In pheochromocytoma, hypertension, tachycardia, and atrial fibrillation may be noted. Cushing syndrome often leads to congestive heart failure, as manifested by lethargy, dyspnea on exertion, paroxysmal nocturnal dyspnea, and cough. Hypertension can accompany Cushing syndrome, and hypotension can accompany adrenal insufficiency. Because of the interrelation between cardiac and respiratory systems, cardiac pathology often produces changes in the lungs (e.g., pleural effusions, congestive heart failure). Therefore, the lungs should be assessed for abnormal breath sounds, rales, rhonchi, wheezes, and pleural friction rubs [30].

Abdomen and Genitals

The abdomen should be assessed for any asymmetry that might indicate ascites, enlargement of an organ, or a mass. Auscultation may detect bruits (especially over the renal arteries), and palpation can uncover abdominal pain [30].

Assessment of the genitalia is important in the evaluation of patients with pituitary/adrenal dysfunction, because changes in sexual development and reproductive function often occur. The appearance and any abnormalities of the patient's genitals should be noted. The presence or absence of secondary sex characteristics is recorded, including agreement between the genital, hormonal, and psychologic sex of the patient [30].

Neuromuscular System

Patients should be evaluated for current and past fractures, as may be seen in Cushing syndrome. Other issues may include bone pain, joint pain, and generalized muscle weakness. The neurologic and endocrine systems work closely together to maintain the homeostasis of the internal environment and to help cope with stress. Therefore, pathology in the nervous system often affects endocrine function (e.g., a benign tumor of the pituitary gland can cause hypersecretion of anterior pituitary hormones) and pathology in the endocrine system can be reflected in the nervous system [30].

Nurses should conduct a careful neurologic evaluation, including assessment of mental status, cranial nerves (as dysfunction of cranial nerves I and II is associated with enlargement of the pituitary gland), motor and sensory function, the cerebellum, and deep tendon and superficial reflexes. Ataxia can occur in hypocalcemia and acromegaly. Thoroughness in examination and accuracy in recording findings are essential, and all abnormal findings require additional evaluation [30].

DIAGNOSTIC TESTS

Single measures of endocrine function are rarely sufficient to support a diagnosis but nevertheless should be an integral part of the whole data base. In pituitary and adrenal testing, be aware of the importance of patient preparation and adhere strictly to the testing protocols. Patient and environmental influences that might modify the test results are important nursing considerations [31]. This section will focus on some of the most commonly used tests; general screening tests, such as complete blood count and basic metabolic panel, will not be discussed but are usually part of the workup.

Serum and Urine Osmolality

Serum osmolality testing provides information about the number of particles dissolved in the serum, while urine osmolality provides information about the kidney's ability to concentrate urine [32]. Serum and urine osmolality are controlled by ADH [33]. The release of ADH reduces the amount of fluid output by the kidneys, increasing blood volume and decreasing serum osmolality while simultaneously increasing urine osmolality. Serum osmolality is also increased in patients with hypernatremia and decreased in those with hyponatremia. The opposite is true for urine osmolality—it is increased with hyponatremia and decreased with hypernatremia. Certain medications can affect serum and urine osmolality (Table 1).

Table 1: MEDICATIONS THAT IMPACT SERUM AND URINE OSMOLALITY

Effect

Medications/Drugs

Increased serum osmolality

Corticosteroids

Glycerin

Insulin

Mannitol

Decreased serum osmolality

Carbamazepine

Chlorpromazine

Hydrochlorothiazide

Cyclothiazide

Doxepin

Lorcainide

MDMA/Ecstasy

Increased urine osmolality

Anesthetic drugs

Furosemide

Mannitol

Octreotide

Vincristine

Decreased urine osmolality

Captopril

Demeclocycline

Glyburide

Lithium

Octreotide

Tolazamide

Verapamil

Source: [32]

Cumulatively, serum and urine osmolality will help to estimate the ability of the kidney tubules to concentrate or dilute urine and can be used to aid in the diagnosis of diabetes insipidus and SIADH [33]. The normal range for serum osmolality is 280–300 mOsm/kg, and the normal range for urine osmolality is approximately 250–900 mOsm/kg [32,33]. Normal reference ranges may vary slightly depending on the source or laboratory. Diabetes insipidus is associated with elevated serum osmolality, while decreased values would be indicative of SIADH.

Urine osmolality tests use the first-voided urine specimen, which is thought to represent the maximum concentration ability of the kidneys [34]. Prior to this test, the patient should be asked about recent alcohol use and blood transfusions, as both can interfere with the results [33]. Alcohol should be avoided for at least 12 hours prior to the collection of the serum sample [33].

Water Deprivation Test

A water deprivation test involves withholding water from the patient for 6 to 17 hours while monitoring body weight, vital signs, urine volume, and urine osmolality every 1 to 2 hours [16,35]. Blood samples are also obtained two hours after the start of fluid deprivation and before giving desmopressin [35]. At the end of the test, desmopressin is given and urine osmolality is tested [18]. Water deprivation typically leads to more concentrated urine and increased weight [16]. Extended deprivation results in a urine osmolality level greater than 800 mOsm/kg (considered maximally concentrated) [18]. In patients with complete central diabetes insipidus, urine osmolality will remain less than 300 mOsm/kg during water deprivation but will increase by more than 50% after the administration of desmopressin [18]. With nephrogenic diabetes insipidus, urine osmolality will remain less than 300 mOsm/kg throughout the test and administration of desmopressin will not induce an increase in urine osmolality [18]. Although the test is fairly easy, interpreting the results can be a challenge [35].

If any of the following develop during a water deprivation, the test should be halted [35]:

- Body weight decreased by more than 3%

- Symptoms of orthostatic hypotension, with a heart rate increase of 15% or a mean arterial blood pressure decrease of 15%

- Increase in plasma sodium level to 150 mmol/L or more

Hypertonic Saline Test

The hypertonic saline test can be used to aid in the diagnosis of diabetes insipidus. This procedure involves the administration of a 250-mL bolus of 3% hypertonic saline; the patient is given a 5% glucose infusion and is instructed to drink 30 mL of water per kg of body weight within one hour. Rapid sodium measurements are taken every 30 minutes; plasma osmolality, serum sodium, urea, and glucose are also monitored [18,35]. If the sodium level rises above 147 mmol/L, the infusion should be stopped. If copeptin is being measured, it should be done at this point [18]. With the hypertonic saline test, a plasma copeptin measurement of 4.9 pmol/L or less indicates complete or partial central diabetes insipidus [35].

The advantages of measuring copeptin are that small amounts of serum are needed, the samples collected are stable for one week at room temperature, and results are available within two hours [18,35]. The release of copeptin is triggered by osmotic stimuli and volume depletion [18]. Research has shown that measuring osmotically stimulated copeptin is a useful diagnostic tool [35]. Levels may be measured with a water deprivation or hypertonic saline test, but results are more accurate with hypertonic saline than water deprivation [35]. Baseline copeptin levels should be obtained followed by levels prior to desmopressin [35]. Basal plasma copeptin levels of less than 2.6 pmol/L are indicative of complete central diabetes insipidus [35]. If the ratio of copeptin to plasma sodium is less than 0.02 pmol/L, partial central diabetes insipidus is suggested [35].

Growth Hormone Stimulation Test

As noted, growth hormone is secreted by the anterior pituitary gland periodically throughout the day, with levels highest at night. Due to the episodic nature of growth hormone secretion, random checks are rarely useful [32]. However, to assess for growth hormone deficiency or acromegaly, a growth hormone test is often completed together with a growth hormone suppression test, growth hormone stimulation test, and insulin-like growth factor test [33]. Before testing, the patient should avoid eating, drinking, and exercising for 10 hours [33]. The typical normal value is less than 5 ng/mL in men, less than 10 ng/mL in women, and 0–10 ng/mL in children [33]. Decreased levels are associated with a deficiency, and increased levels are associated with acromegaly.

The growth hormone stimulation typically takes two to five hours to complete and is typically started in the morning with a baseline blood sample [36]. Medication (arginine, glucagon, or insulin) will be given intravenously to stimulate the pituitary gland to release growth hormone [36]. Blood samples may be obtained at baseline and 30, 60, 90, and 120 minutes after administration of the testing agent [33]. Prior to growth hormone stimulation and suppression tests, patients should avoid strenuous activity for at least 12 hours [32]. If the patient has normal values throughout this test, growth hormone deficiency can be ruled out. However, failure of growth hormone levels to increase as expected is an indicator that the patient may have a growth hormone deficiency.

Insulin Tolerance Test

Because hypoglycemia stimulates growth hormone secretion, an insulin tolerance test may also be used to assess growth hormone sufficiency [21]. An insulin tolerance test involves hypoglycemia induced by an intravenous (IV) injection of insulin [37]. With this test, regular insulin is administered intravenously to drop the patient's glucose levels below 40 mg/dL [21]. Within 30 to 60 minutes, growth hormone levels are measured and should reflect a peak. Throughout the course of this test, the patient may experience signs and symptoms of hypoglycemia, including dizziness, anxiety, tremors, sweating, and tachycardia. Seizure and/or loss of consciousness are possible, so close monitoring during the test is necessary [21].

Cortisol Levels

The body typically responds to stress by triggering the pituitary to make ACTH, with a resultant elevation in cortisol [37]. Blood is drawn at the start of the test and every 30 minutes for 2 hours [37]. In patients with Cushing syndrome, cortisol levels are higher than expected [32]. This test is not appropriate for persons taking insulin or on hemodialysis [32]. Patients should be instructed to report signs and symptoms of hypoglycemia.

Growth Hormone Suppression Test

Growth hormone suppression tests are used to aid in the diagnosis of acromegaly. After the baseline blood sample is obtained, the patient is instructed to drink a solution containing glucose within five minutes [38]. Blood samples are then obtained after 60 and 120 minutes [33]. If possible, glucocorticoids should be halted prior to the test [38]. In general, this test is not used for screening—it is only ordered if a patient presents with signs and symptoms of acromegaly [38]. If growth hormone levels stay the same or increase during the test, acromegaly is suggested [38].

Insulin-like growth factor regulates the effects of growth hormone, but it remains stable throughout the day [39]. Testing Insulin-like growth factor levels is indicated for patients with suspected acromegaly or to monitor the effectiveness of growth hormone treatment [39,40]. Elevated levels in the presence of elevated growth hormone levels are indicative of acromegaly [39].

ACTH Stimulation Test

ACTH stimulation testing involves the infusion of cosyntropin (a synthetic form of ACTH) as either intravenous or intramuscular injection [32]. Cortisol levels are collected at baseline, 30 minutes, and (in some cases) 60 minutes after the medication bolus [32]. Normal baseline cortisol levels are greater than 5 mcg/dL; normal levels at 30 to 60 minutes are 18–20 mcg/dL [32]. In response to the cosyntropin infusion, the adrenal cortex should release two to five times the amount of normal plasma cortisol levels within 30 minutes [24]. Prior to undergoing ACTH stimulation testing, patients should abstain from nicotine, alcohol, cortisol-affecting medications, and strenuous activity for at least 12 hours [32]. Some patients may be instructed to remain in bed for one hour prior to the test [32].

Urinary Free-Cortisol Test

For the 24-hour urinary free-cortisol test, urine is collected over 24 hours to measure the amount of unbound cortisol filtered by the urinary system [41]. The accuracy of this test is dependent on the patient's glomerular filtration rate and urinary volume [41]. Normal cortisol levels in a 24-hour urine collection are 450–700 nmol/L [42]. Elevated levels indicate Cushing syndrome, while low levels could indicate Addison disease.

Low-Dose Dexamethasone Suppression Test

The low-dose dexamethasone suppression test (LDDST) is completed by administering low doses of dexamethasone at night, followed by a blood draw in the morning [28]. For this test, the patient is given 1 mg of dexamethasone orally at 11 p.m. and cortisol levels are measured at 8 a.m. [32]. Alternately, dexamethasone may be given every 6 hours for 48 hours, followed by a blood sample 6 hours after the last dose [28]. Cortisol levels are expected to be less than 1.8 mcg/dL when the sample is taken [32]. Administration of dexamethasone decreases cortisol levels, so an elevated finding is indicative of abnormality. This test is used to distinguish between Cushing syndrome and Cushing disease (specifically caused by a pituitary tumor that secretes excessive ACTH) [32]. However, certain medical conditions can affect the results of the test, including severe obesity, pregnancy, dehydration, uncontrolled diabetes, severe weight loss, alcohol withdrawal, severe injury, and stress [33].

Corticotropin-Releasing Hormone Stimulation Test

The corticotropin-releasing hormone stimulation test can help to distinguish between Cushing syndrome and Cushing disease [32]. Corticotropin-releasing hormone is given intravenously and eight cortisol and ACTH levels are collected, one at baseline and the others at 5, 15, 30, 60, 120, and 180 minutes after administration [32]. The expected result in healthy individuals is a peak in cortisol (greater than 20 mcg/dL) and a two- to four-fold increase in ACTH within 30 to 60 minutes [32]. Higher cortisol levels are associated with Cushing disease; cortisol levels that fail to increase may indicate ectopic ACTH secretion [32].

Inferior Petrosal Sinus Sampling

Bilateral inferior petrosal sinus sampling (IPSS) can be used to distinguish Cushing disease from ectopic ACTH secretion [43]. This test is guided by fluoroscopy, typically while the patient is under general anesthesia, and will take 60 to 90 minutes [43,44]. Catheters are inserted through both the left and right femoral veins and advanced to the petrosal sinuses [43]. Samples are drawn simultaneously from the inferior petrosal sinus and the peripheral veins for plasma ACTH five minutes and one minute before administration of 1–100 mcg corticotropin-releasing hormone in a peripheral vein. Samples for plasma ACTH are collected at 2, 5, and 10 minutes after administration. A peripheral sample for plasma cortisol is also taken along with each sample for plasma ACTH.

ACTH should be in higher concentrations when measured from a sample collected close to the gland [43]. Possible complications associated with this test include a groin hematoma and rarely subarachnoid hemorrhage, brainstem injury, brainstem stroke, and infection [43]. Though less accurate, jugular vein sampling is a less-invasive alternative to IPSS [43].

If a tumor is the cause of excess ACTH, this test will help to identify the location [44]. Additionally, comparing results from the right and left sides can help identify the best approach to remove the tumor while maintaining some functional pituitary tissue [44].

Other Tests and Imaging

The late-night salivary cortisol test measures cortisol in the saliva at night, when the levels typically drop; levels will remain elevated in patients with Cushing syndrome [28]. Serum or urinary cortisol, aldosterone, and/or ACTH may also be assessed.

The diagnostic investigation of anterior pituitary dysfunction often involves an x-ray, computed tomography (CT), or most commonly, magnetic resonance imaging (MRI) scan of the skull. A cerebral flow brain scan or echoencephalogram also may be used. In the presence of a pituitary tumor, a widening of the sella turcica (the bony seat of the pituitary gland) may be visualized. To further detect the presence of a brain tumor, a complete neurologic evaluation may be done, including assessment of the patient's visual fields [34].

4. NURSING DIAGNOSES

The nursing diagnosis forms the basis of the plan of care for the patient and provides guidelines for its implementation and evaluation. Because pituitary/adrenal dysfunction has widespread effects, many nursing diagnoses can be used in caring for these patients. Each patient's actual problem is unique, however, and requires a skillful assessment. Recognition of the specific problem and its etiology is integral to a comprehensive, well-executed nursing care plan [46].

INEFFECTIVE INDIVIDUAL COPING

Because of the profound physiologic and psychosocial stresses on the patients with these conditions, it is not unusual for them to be fearful and have difficulty coping. Feelings of anxiety can be directly related to the disorder (as in pheochromocytoma) or exogenous, resulting from feelings of unexplained apprehension about the situation [46].

Pituitary/adrenal disorders often require the patient and family to make major changes in lifestyle. Patients may require lifelong pharmacotherapy and medical/nursing supervision. They also may face the possibility of major surgery and may have some degree of transitory or permanent sensory loss [46].

ALTERATION IN THOUGHT PROCESSES

Central nervous system involvement may produce a variety of problems in patients, ranging from headaches and lethargy (e.g., with pheochromocytoma) to outright psychosis (e.g., Cushing syndrome). Alterations in thought processes and perception pose difficulties not only for patients but for their families and friends as well [47].

ALTERATION IN COMFORT

Some patients with pituitary or adrenal dysfunction will have problems with thermal regulation. For example, patients with pheochromocytoma or hypoglycemia often experience excessive sweating. Those with acromegaly often experience joint pain [46,47].

DISTURBANCE IN SELF-CONCEPT

Changes in the skin and hair occur in patients with pituitary or adrenal dysfunction and can contribute to disturbances in body image. Increases in skin pigmentation may occur in patients with Addison disease. Ecchymosis develops in patients with Cushing syndrome due to changes in the fragility of the capillaries. Facial flushing is often a sign of pheochromocytoma. Hirsutism is a problem for patients with adrenal tumor or hyperplasia and is an especially bothersome body image issue for women [46,47].

Patients with these disorders may have an impaired ability to manage self-care or maintain their home environment. They are at increased risk for injury because of weakness, fatigue, and visual disturbances. For example, weakness of the musculoskeletal system is seen in patients with acromegaly and Cushing syndrome. Patients with Cushing syndrome have an increased incidence of fractures. Fatigue often accompanies adrenal insufficiency, hypoglycemia, and acromegaly. Patients with pituitary tumors may have some level of visual impairment [46,47].

Sexual dysfunction may occur as loss of libido or impotence. Menstrual problems are also relatively common [46,47].

ALTERATION IN NUTRITION AND BOWEL ELIMINATION

Anorexia and weight loss are common in patients with adrenal insufficiency, pheochromocytoma, and hyperkalemia [46,47]. Alteration in bowel elimination, specifically diarrhea, may be seen in patients with Addison disease, while constipation can occur in patients with hypercalcemia and pheochromocytoma [46,47].

ALTERATION IN FLUID VOLUME

Actual or potential fluid volume deficits occur in patients with posterior pituitary disorders. In addition, patients with Cushing syndrome may develop congestive heart failure. Patients with hypercalcemia and hyperaldosteronism may have polydipsia and polyuria [46,47].

5. DIABETES INSIPIDUS

Diabetes insipidus is a rare disorder of the posterior pituitary caused by insufficient production or utilization of ADH and characterized by polyuria, polydipsia, and hypernatremia. It is seen in approximately 1 out of 25,000 people and is more common in adults but can develop in individuals of all ages [45]. Risk factors for the development of diabetes insipidus include tumors, trauma, medications, and alcohol consumption [16].

PATHOPHYSIOLOGY

The underlying cause of diabetes insipidus is generally either pituitary (central) or nephrogenic. More rarely, it may develop during pregnancy or related to a mental disorder.

Central Diabetes Insipidus

Approximately 50% of patients have primary central diabetes insipidus, also known as pituitary or primary diabetes insipidus. This form is associated with familial and congenital factors as well as with subclinical encephalitis. Secondary diabetes insipidus is diabetes insipidus arising from a variety of causes, including hypophysectomy, tumors (e.g., metastatic carcinoma of the breast, craniopharyngiomas), trauma (e.g., basilar skull fractures), vascular lesions (e.g., hemorrhage, aneurysm), infection (e.g., syphilis, encephalitis, meningitis), histiocytosis, and granulomatous disease (e.g., sarcoidosis, tuberculosis) [46,47].

Patients with central diabetes insipidus have an impaired ability to synthesize and secrete vasopressin (ADH) [26]. In most healthy people, ADH is secreted by the pituitary gland when plasma osmolality increases, but this does not occur in those with central diabetes insipidus [48]. Central diabetes insipidus is classified as either complete or partial, depending on the level of ADH present in the body [18].

A variety of factors can lead to central diabetes insipidus, including genetic mutation, medications (e.g., beta-adrenergic agents, ethanol, halothane, phenytoin, opioid antagonists), head (pituitary) trauma, intracranial tumor, infection (e.g., meningitis, encephalitis, tuberculosis), autoimmune disease, disorders of the hypothalamus or pituitary gland, and brain surgery [26,48]. Rarely, central diabetes insipidus may be the result of snakebite. One genetic cause is Wolfram syndrome, an autosomal dominant disorder associated with diabetes mellitus, diabetes insipidus, optic nerve atrophy, and sensorineural hearing loss [48]. The most common causes are trauma and malignancy.

Lesions and autoimmune disorders can lead to the destruction of vasopressin neurons in the hypothalamus, while surgery and trauma can damage or destroy the vasopressin neurons [49]. It is important to note that the body's ability to synthesize vasopressin is greater than the body's needs, so up to 80% to 90% of the vasopressin neurons in the hypothalamus can be destroyed before diabetes insipidus develops [49].

A transient form of polyuria may develop in patients post-trauma or post-surgery, but it usually resolves within four days [49]. In rare cases, these patients may develop a permanent form of diabetes insipidus [49].

Nephrogenic Diabetes Insipidus

In patients with nephrogenic diabetes insipidus, the kidneys do not respond normally to vasopressin [26]. The underlying etiology of this condition may be genetic/congenital, medication-induced kidney damage (e.g., with amphotericin, cisplatin, clozapine, demeclocycline, furosemide, lithium [most common], methicillin), renal or urinary tract infection, or chronic disease processes (e.g., amyloidosis, chronic renal failure, polycystic kidney disease, sickle cell disease, Sjögren syndrome) [18; 26; 50]. Acquired nephrogenic diabetes insipidus is more common than the hereditary form [50].

The genes associated with the hereditary form of nephrogenic diabetes insipidus prevent the kidneys from responding to ADH [50]. Infants with hereditary nephrogenic diabetes insipidus will develop signs and symptoms of the disease within a few months of birth [50].

Gestational Diabetes Insipidus

Gestational diabetes insipidus is a type of transient diabetes insipidus that develops in 2 to 4 of every 100,000 pregnancies [51]. During pregnancy, ADH production is increased and plays a role in the increased blood volume. At the same time, placental vasopressinase, which metabolizes ADH, is increased [51]. This is more commonly seen in pregnancies with multiple fetuses because of the increased placental mass [18,51]. In the majority of cases, the patient will have a normal delivery and healthy newborn [51]. After delivery, vasopressinase levels will decrease by approximately 25% each day, reaching undetectable levels at four to six weeks postpartum and resulting in resolution of the disorder [51].

It is important to note that some patients may have undiagnosed diabetes insipidus prior to pregnancy, with symptoms not becoming apparent until after they become pregnant [51]. If the patient has undiagnosed diabetes insipidus discovered during pregnancy, it is classified as central or nephrogenic, depending on the underlying pathophysiology.

Psychogenic Diabetes Insipidus

In rare cases, patients may develop a psychiatric condition involving the consumption of large amounts of fluids [26]. This is not true diabetes insipidus, but it can be life-threatening and has been associated with increased morbidity and mortality. In psychogenic cases, the function of the pituitary gland and kidneys remain intact, and extracellular fluid dilution develops and inhibits ADH secretion, leading to diuresis [52]. The increased fluid intake leads to functional diabetes insipidus [52].

This condition can be seen in patients with a variety of mental health disorders, including autism, schizophrenia, schizoaffective disorder, and bipolar disorder [53]. Schizophrenia is a common cause, with 11% to 20% of patients with schizophrenia developing psychogenic diabetes insipidus [53].

For some patients, increased fluid intake is a compulsion rather than a response to thirst [53]. Another subset of patients believes that increased water intake is healthy [53]. These individuals typically do not have a mental health disorder but are rather misinformed about the risks of overconsumption of water.

SIGNS AND SYMPTOMS

Patients with diabetes insipidus present with polyuria, nocturia, polydipsia, increased serum osmolality, decreased urine osmolality, and decreased urine specific gravity [16,26]. Many report extreme thirst, even at night, leading to increased fluid intake at all hours [52]. In addition to drinking throughout the day, patients with diabetes insipidus often have a preference for cold or ice water [18]. An intact thirst drive will often prevent severe dehydration and maintain homeostasis in those affected [48]. In some cases, the thirst mechanism is faulty because of damage to osmoreceptors in the hypothalamus, leading to decreased fluid intake and severe dehydration [49].

Patients with diabetes insipidus will have dilute and light-colored urine. Polyuria will develop regardless of normal contributing factors to urine output, such as fluid intake. Patients may urinate as much as 10–20 L/day [26]. In most cases, the urine will be hypotonic and serum osmolality will increase [16,26]. In patients with a serum osmolality of 300–330 mOsm/kg, symptoms may not be apparent [49]. Patients with severe dehydration may develop weakness, postural dizziness, confusion, azotemia, hyperglycemia, secondary hyperaldosteronism with hypokalemia, and coma [49]. Under normal circumstances, an increase in serum osmolality would result in a drop in blood pressure and subsequent secretion of ADH [16]. Additionally, when a patient has increased serum osmolality they will often be very thirsty [16]. Thirst will lead to increased fluid intake, which increases fluid in the vasculature and restores fluid balance. However, in patients with diabetes insipidus, this does not occur, further increasing the risk for dehydration and hypovolemic shock [16].

Serum sodium levels will be normal or increased, with hypernatremia typically developing if the patient does not drink enough water to account for the increased urine output [26]. Patients with hypernatremia may present with altered mental status, myoclonus (muscle jerking), seizures, and focal deficits [26]. If untreated, the patient may progress to an altered level of consciousness or death [16].

Infants with congenital nephrogenic diabetes insipidus present with enuresis, poor intake, poor weight gain, poor growth (failure to thrive), irritability, fevers, diarrhea, and vomiting [50]. If a child with this condition develops dehydration on multiple occasions, it can lead to problems with growth and development [50].

As many as 50% of patients with underlying diabetes insipidus will have increased signs and symptoms during pregnancy [51]. Patients with underlying diabetes insipidus do not have increased levels of ADH during pregnancy, so the symptoms of diabetes insipidus may become apparent [51]. Patients are at increased risk for dehydration and hypernatremia if they experience diabetes insipidus during pregnancy [51]. However, during pregnancy, thirst is triggered at lower serum osmolality levels, which can act as a protective factor [51].

Patients with an exacerbation of a mental illness may also increase their fluid intake; this increase is not related to the regulation or maintenance of homeostasis [53]. Patients with psychogenic diabetes insipidus drink more than 3L of fluids per day [52]. In patients with compulsive fluid intake, drinking fluids calms an acute anxiety and the compulsion can be so strong that they will drink from inappropriate and unhealthy water sources (e.g., toilets) [53]. Individuals who compulsively drink fluids may also have comorbid nicotine, alcohol, and/or eating disorders [53]. Patients with psychogenic diabetes insipidus urinate as often as every 30 minutes, and the urine is dilute, with decreased specific gravity and decreased osmolality [52]. These patients may also report fatigue and constipation [52].

Patients with psychogenic diabetes insipidus typically do not drink fluids at night, which can help differentiate it from true cases of diabetes insipidus [53]. Most patients with diabetes insipidus will develop hypernatremia due to the fluid deficit, but patients with psychogenic diabetes insipidus may develop hyponatremia [53]. If hyponatremia develops in these patients, it is important to determine if it is the result of excessive fluid intake or another cause (e.g., medication) [53]. Patients with schizophrenia and diabetes insipidus typically have lower body weight and increased rates of alcohol consumption and smoking compared with patients without diabetes insipidus [53].

DIAGNOSIS

The diagnosis of diabetes insipidus can be a challenge, and misdiagnosis carries the risk for severe complications [35]. Diabetes insipidus is diagnosed by routine screening tests, such as specific gravity of urine, plasma sodium levels, osmolality tests, and water-deprivation and water-loading tests. If serum osmolality is greater than 300 mOsm/kg and urine osmolality is less than 300 mOsm/kg, the diagnosis is likely diabetes insipidus [48]. Diagnosis is confirmed if a deficiency of ADH is demonstrated and the patient's kidneys are shown to respond normally to ADH. In response to a water-deprivation challenge, patients with diabetes insipidus will demonstrate an inability to increase the specific gravity and osmolality of the urine [54,55]. Differential diagnosis involves other causes of polyuria. A brain scan, skull x-rays, visual field testing, and full neurologic examination may be indicated to rule out the presence of a tumor.

Differentiation between the types of diabetes insipidus can be a challenge but is essential because treatment will vary based on the type identified [18]. Patients with central diabetes insipidus will respond to vasopressin with decreased urine output and increased urine osmolality [48]. If the patient has nephrogenic diabetes insipidus, there will be no response to the vasopressin [48].

A newer diagnostic tool is copeptin, a surrogate marker for ADH [18]. High basal copeptin levels are accurate in diagnosing nephrogenic diabetes insipidus [18]. The copeptin test can also be used during pregnancy, unlike the water deprivation test [51]. In nonpregnant patients, the copeptin test can be combined with the water deprivation test, which increases diagnostic accuracy of both tests [18]. It can also be combined with the administration of hypertonic saline [18].

Diagnosis of psychogenic diabetes insipidus usually requires a multidisciplinary approach [52]. The care team may include primary care, endocrinologists, nephrologists, and psychologists.

TREATMENT

The treatment plan for patients with diabetes insipidus depends on the type and the associated signs and symptoms.

Central Diabetes Insipidus

Evidence Based Practice Recommendation

The Society for Endocrinology recommends that for those patients with central diabetes insipidus and normal serum sodium and who require maintenance intravenous fluid therapy, the type and volume administered should be equivalent to the daily requirements appropriate for other patients without central diabetes insipidus. This should be given together with the agreed, prescribed dose of desmopressin.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013691

Last Accessed: August 5, 2021

Level of Evidence: Expert Opinion/Consensus Statement

For patients with mild cases of central diabetes insipidus, treatment may be as simple as increasing fluid intake [56]. However, most patients will require ADH replacement therapy. In acute cases, patients are given intravenous or subcutaneous vasopressin [16]. Long-term treatment involves the administration of desmopressin orally, subcutaneously, or intranasally [16]. The most common adverse effect of desmopressin administration is hyponatremia, although fluid retention can also develop [48]. Intranasal desmopressin can result in eye irritation, headaches, dizziness, rhinitis, epistaxis, coughing, and flushing [48]. If diabetes insipidus is caused by pituitary tumor, hypophysectomy may be required [16].

For infants with congenital central diabetes insipidus, the preferred treatment is usually thiazide diuretics [48]. Thiazide diuretics work by inhibiting the amount of sodium lost by the kidneys, which can lead to decreased water loss [57]. However, thiazide diuretics can paradoxically decrease urine flow in some [16]. As such, urine output should be closely monitored in these patients.

Nephrogenic Diabetes Insipidus

Poorly managed nephrogenic diabetes insipidus can cause pain, infection, damage to the genitourinary system, and kidney failure [50]. Appropriate treatment will help to prevent these complications. In many cases, treatment is palliative [57]. A low-sodium diet may be prescribed to help decrease the amount of urine made by the kidneys [56]. As with all types of diabetes insipidus, fluid intake should be increased. Hydrochlorothiazide may be given to help manage symptoms and decrease urine output [56]. Patients may also be prescribed indomethacin, a nonsteroidal anti-inflammatory drug that increases urine concentration [57].

Most of the secondary causes of nephrogenic diabetes insipidus can be reversed [18]. If medications are the cause, their use should be reconsidered. If the underlying cause is lithium, it can take months to years for renal function to recover completely [18].

Infants with nephrogenic diabetes insipidus should intermittently be offered water. Patients unable to take in enough fluid to replace urine output may require a feeding tube [57]. School-aged children should have a plan in place with their school to ensure adequate access to a bathroom and to fluids. The school nurse and teachers should be included in the plan.

Gestational Diabetes Insipidus

Desmopressin is the treatment of choice for gestational diabetes insipidus, with minimal side effects for the patient and fetus [51]. It is important to consider that the dosage should usually be increased as the pregnancy progresses [51]. It is also important to correct any hypernatremia that develops. Patients with diabetes insipidus during pregnancy are at increased risk for recurrence during any future pregnancies [51].

Psychogenic Diabetes Insipidus

For patients with psychogenic diabetes insipidus, behavioral therapy may be beneficial [52]. Medication reconciliation should be done to eliminate agents that impair water excretion, if possible [53]. The treatment of psychogenic diabetes insipidus in children should involve parents/caregivers [52]. In general, adequately addressing the underlying mental health issue will help to resolve the diabetes insipidus. Patients with psychogenic diabetes insipidus due to health misinformation should be given education on appropriate water intake [53].

In some cases, clozapine may be given to help normalize sodium levels and decrease fluid intake [53]. The choice to use this medication should be made carefully, because it is associated with significant side effects [53]. Vasopressin V2 receptor (V2R) antagonists (vaptans) may also be given to normalize serum sodium levels [53]. These medications should be used cautiously and the patient observed closely because they can lead to dehydration and renal damage [53].

Unlike the treatment of other diabetes insipidus types, these patients may be placed on fluid restriction [53]. Weight measurements can help identify patients who will benefit from fluid restriction. If the patient's weight increases, it may be an indicator for fluid restriction. Providing ice chips may also help control fluid intake for patients with psychogenic diabetes insipidus [53].

Surgical Resection

If diabetes insipidus is caused by a pituitary tumor, this must be addressed in order to resolve symptoms. Hypophysectomy can involve the resection of a small tumor or the complete removal of the pituitary gland. The major indications for hypophysectomy are a primary neoplasm of the pituitary gland (adenoma) and the need to halt the growth and spread of other endocrine-dependent malignancies (e.g., breast, ovary, or prostate cancer).

Though historically used, transcranial and transsphenoidal approaches to hypophysectomy are major surgical procedures and have largely been replaced by less invasive options, such as radiation therapy. However, in some cases, surgical resection is required. Because of the risk of damaging the pituitary and the proximity of the optic nerves, optic chiasm, carotid arteries, cavernous sinus, and hypothalamus to the operative area, the surgery involves some risk.

The surgical approach is most commonly transsphenoidal selective tumor resection guided by fluoroscopy [58]. With this type of surgery, the tumor is approached through the sphenoid sinus, avoiding brain tissue. A cut is made along the nasal septum or under the upper lip, near the base of the nose. In addition to the avoidance of brain tissue, this procedure is often associated with fewer side effects and cosmetic effects compared with other surgery types [59]. Drawbacks are that it is more time-consuming and is difficult to perform on large tumors, which often require craniotomy for removal [59]. After a transsphenoidal approach, the patient may report sinus congestion and headaches lasting for one to two weeks postoperatively [59].

Transfrontal craniotomy is indicated when the tumor extends beyond the pituitary fossa and is impinging on the optic chiasm, because this procedure provides the best view of the operative field [60]. With this technique, an opening is made in the skull and the pituitary is accessed through the brain, increasing the risk of brain injury [59]. Complications can include brain damage, stroke, blindness, meningitis, leakage of cerebrospinal fluid, bleeding, diabetes insipidus, and adverse reactions to anesthesia [59].

Transient cerebrospinal fluid leaks can occur following removal of the nasal packings. Most leaks respond to conservative measures aimed at keeping the intracranial pressure low. Lifelong hormonal replacement is necessary if the entire gland is removed [60].

Prior to surgery, patients with diagnosed pituitary tumors should be observed for symptoms and signs of pituitary apoplexy, including severe headache, changes in level of consciousness, diplopia, loss of vision, and shock. Pituitary apoplexy occurs when there is spontaneous hemorrhage into the tumor secondary to rupture of the blood vessels or rapid enlargement of the adenoma with resulting infarction [61].

Postoperative care of patients who have undergone transfrontal craniotomy should also be closely observed for signs/symptoms of [61]:

- Increased intracranial pressure (e.g., hypertension, bradycardia, change in pupil size and reaction to light, changes in level of consciousness, changes in mental or neurologic status)

- Adrenal insufficiency

- Hypothyroidism (which may develop over several weeks)

- Meningitis (e.g., elevated temperature, headache, motor restlessness, photophobia, nuchal rigidity)

- Fluid imbalance (which may indicate transient or permanent diabetes insipidus)

Most patients recover rapidly from transsphenoidal surgery. Patients may report a temporary loss of smell. Oral hygiene is important to keep the oral mucosa moist. Tooth brushing is usually contraindicated because of possible tension on the suture line. Nasal packs are usually removed in 48 to 72 hours [62]. Headache may be a problem in the postoperative period and should be assessed as a possible symptom of meningitis.

A major complication in the postoperative period is hypopituitarism, which may develop into Addisonian crisis and transient or permanent diabetes insipidus. As such, these patients should be watched closely for symptoms and signs of Addisonian crisis (e.g., weakness, lethargy, fever, nausea, hypotension, dizziness) and diabetes insipidus. In the immediate postoperative period, intake and output should be measured and used as a guide to fluid balance; the specific gravity of urine should be checked after each voiding [62].

After total ablation of the pituitary gland, amenorrhea and infertility will result. For men, testosterone may relieve changes in libido and impotence secondary to the surgery. Estrogen may be prescribed for women to relieve atrophy of the vaginal mucosa. Human pituitary gonadotropins have been successful in treating infertility in patients posthypophysectomy, especially women [62].

Postoperative teaching should focus on medications prescribed, including their purpose and side effects, and the importance of regular follow-up care.

Nursing Interventions

When caring for any patient with diabetes insipidus, close monitoring of the patient's fluid balance is necessary. Nurses should also monitor the patient for dehydration, especially if the patient is confused, unconscious, or otherwise unable to communicate (e.g., infants), because these patients are unable to make their needs known regarding fluid intake. This is best done with daily weights and frequent intake and output monitoring. Patients should be assessed for signs and symptoms of fluid deficit, such as poor skin turgor and dry mucous membranes.

Treatment of diabetes insipidus may include the administration of hypotonic intravenous fluids to increase fluid in the vasculature without increasing serum sodium levels [16]. These patients should be closely monitored for fluid overload [16]. Oral fluids should be encouraged for most patients with diabetes insipidus, except those with psychogenic diabetes insipidus. Nurses should also be vigilant for signs of hypovolemic shock, including hypotension and tachycardia. Any of these potential complications should be addressed promptly.

6. SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION (SIADH)

Clinically, SIADH is the opposite of diabetes insipidus, with ADH levels increased as opposed to decreased. It is seen more commonly as an individual ages but can develop at any age [17]. A major risk factor for SIADH is hospitalization, and a high number of SIADH cases develop in hospitalized patients older than 30 years of age [24].

PATHOPHYSIOLOGY

The syndrome of inappropriate antidiuretic hormone, or SIADH, is a condition characterized by autonomous release of ADH without regard to plasma osmolality. The body is unable to dilute the urine appropriately, so fluid is retained, which expands the extracellular fluid compartment and leads to hyponatremia. There may also be sodium loss by the kidneys because of a lack of aldosterone [26].

The cause of SIADH is multifactorial and may include genetic, nervous system, malignancy, pulmonary disease, surgery, and medication factors [16]. Hereditary SIDAH is referred to as nephrogenic SIADH and is the result of a functional mutation in the vasopressin 2 receptors in the kidneys that leads to these receptors staying in an active state [17].

Conditions that increase intracranial pressure can lead to the development of SIADH, including head trauma, stroke, meningitis, lesions, hemorrhage, and hydrocephalus [16,24,26]. Vasopressin-secreting tumors of the lung and brain are another potential cause of SIADH; small cell lung cancer is responsible for 70% of the cancer-related causes of SIADH [16,26,63]. Pulmonary disease (e.g., cystic fibrosis, chronic obstructive pulmonary disease) can lead to SIADH, although the exact mechanism is not fully understood [16].

Medications associated with SIADH include carbamazepine, oxcarbazepine, chlorpropamide, cyclophosphamide, selective serotonin reuptake inhibitors (SSRIs), antipsychotics, hormones (i.e., vasopressin, desmopressin, and oxytocin), and antihistamines [16,26]. Of these medications, SSRIs and carbamazepine are the most commonly associated medications [24]. The illicit drug 3,4-methylenedioxy-methamphetamine (MDMA or Ecstasy/E/Molly) induces release of ADH and increases thirst, which causes SIADH and is linked to more severe signs and symptoms [17].

SIGNS AND SYMPTOMS

SIADH is also associated with serum hypo-osmolality, concentrated urine, increased urine specific gravity, decreased urine output, weakness, lethargy, headache, anorexia, nausea, vomiting, mental status changes, seizures, cerebral edema, cerebral hemorrhage, asterixis, myoclonus, pulmonary edema, and coma [26,64]. Hyponatremia and decreased extracellular fluid volume lead to a fluid shift into the cells [17]. The osmotic fluid shifts associated with this condition cause cerebral edema and subsequent increased intracranial pressure [26]. When cerebral edema occurs, there is also a loss of potassium and amino acids from brain cells [24].

In patients with chronic SIADH, solute loss is more prominent than water retention [17]. This can lead to the development of hyponatremia in a euvolemic state. In those with SIADH, ADH is secreted even in instances in which the ADH should be decreased, leading to the reabsorption of water, increased fluid in the bloodstream, dilutional hyponatremia, and an increase in the extracellular fluid volume. Dilutional hyponatremia may be manifested by a bounding pulse, increased or normal blood pressure, muscle weakness, headache, personality changes, nausea, diarrhea, convulsions, and coma [16]. The patient with hyponatremia may also develop gait disturbance, memory and cognition problems, dizziness, and an increased risk for falls.

Hyponatremia can be classified as mild (130–134 mEq/L), moderate (125–129 mEq/L), or profound (less than 125 mEq/L) [64]. In patients with mild-to-moderate hyponatremia, the only signs and symptoms may be nausea and malaise [17]. As hyponatremia worsens, patients will develop additional signs and symptoms, and serum sodium levels less than 120 mEq/L can lead to coma and respiratory arrest [17]. The speed at which the hyponatremia develops is correlated with the neurologic manifestations [26]. If the patient develops acute hyponatremic encephalopathy, the condition may be reversible, but it could also lead to permanent deficits [17]. Vomiting is considered an ominous sign [17].

Hyponatremia that develops quickly can lead to cerebral edema and potential brain herniation [63]. When the body has time to adapt to the cerebral edema, it displaces solutes (e.g., potassium) from the brain and into the extracellular spaces [63]. In those with chronic hyponatremia, the body adapts and the condition can be asymptomatic, even with serum sodium levels less than 120 mEq/L [17]. Although these patients may be asymptomatic, nausea and vomiting are seen in approximately one-third of patients [17]. However, rapid drops in sodium levels can result in delirium, confusion, and seizures, even if the drop is minimal [17].

DIAGNOSTIC TESTS

Evidence Based Practice Recommendation

The European Society of Endocrinology recommends that if clinical assessment indicates that the volume of extracellular fluid is not overtly increased and the urine sodium concentration is >30 mmol/L, other causes of hypotonic hyponatremia should be excluded before implicating SIADH.

https://eje.bioscientifica.com/view/journals/eje/170/3/G1.xml

Last Accessed: August 5, 2021

Level of Evidence: Expert Opinion/Consensus Statement

In all patients with suspected SIADH, hypothyroidism and adrenal insufficiency should be ruled out [17]. Patients should be asked about a history of head injury, chronic pain, smoking, weight loss, respiratory symptoms, drug use, and any new symptoms experienced [17]. The physical exam should include an assessment of the patient's volume status, skin turgor, mucous membranes, neurologic status, and vital signs. There is no specific diagnostic tool or test for SIADH, but the Bartter-Schwartz criteria, developed in 1967, are still used today to aid in diagnosis [17]. The following are the criteria for this tool [17]:

- Serum sodium <135 mEq/L

- Serum osmolality <275 mOsm/Kg

- Urine sodium >40 mEq/L

- Urine osmolality >100 mOsm/kg

- Absence of clinical evidence of volume depletion

- Absence of other causes of hyponatremia

- Correction of hyponatremia with fluid restriction

Selection of appropriate diagnostic tests is vital, because it will affect the successful correction of hyponatremia and patient success rates [65]. Although a variety of tests are used, the three cardinal tests assess urine osmolality, plasma osmolality, and urine sodium [65]. Patients with SIADH will have decreased serum sodium, increased urine sodium, decreased serum osmolality, increased urine osmolality, decreased blood urea nitrogen (BUN), and concentrated urine [16,66]. Urine osmolality will be greater than 50 mOsm/Kg, and often greater than 100 mOsm/kg [64]. Serum ADH will also be increased.

TREATMENT AND NURSING INTERVENTIONS

Treatment of SIADH is directed toward its underlying cause. Approaches will differ for acute and chronic disease [63]. One of the main goals of treatment is the correction of hyponatremia, with a target serum sodium level of more than 130 mEq/L [17]. Even mild cases of hyponatremia are associated with a variety of safety risks, including gait instability, falls, osteoporosis, bone fractures, attention deficit, and increased mortality [67]. Although these risks are known, many patients admitted to the hospital with SIADH are discharged with continued hyponatremia [65].

In elderly patients a common cause of hyponatremia is chronic SIADH, and these patients may have aging-related safety risks exacerbated by low serum sodium levels [67]. Additionally, chronic SIADH is associated with a decreased bone mass, increasing the risk for fractures [63].

It is important to slowly increase sodium levels, because increasing the concentration too quickly can lead to osmotic demyelination syndrome and poor outcomes [17,64]. Osmotic demyelination syndrome, also known as central pontine myelinolysis, is seen more often in those treated with hypertonic saline or tolvaptan [65,68]. Rapid correction of sodium leads to a fluid shift and essentially dehydration of the brain cells, which causes degeneration and demyelination of the myelin [68]. Patients with euvolemic hyponatremia (as opposed to hypervolemic hyponatremia) have an increased risk for rapid sodium correction and the development of osmotic demyelination syndrome [66]. Other risk factors include alcohol use disorder, malnutrition, liver disease, hypokalemia, hyponatremia lasting longer than two days, and decreased serum sodium concentration in conjunction with decreased BUN prior to the start of therapy [66,68]. With this in mind, these laboratory values should be assessed/considered prior to initiating treatment.

The signs and symptoms associated with osmotic demyelination typically arise in two to six days. The first signs and symptoms include changes in level of consciousness and difficulty or inability to speak [68]. Patients may also develop dysarthria, dysphagia, paraparesis, quadriparesis, spastic quadriplegia, confusion, disorientation, obtundation, pseudobulbar palsy, encephalopathy, and coma [68]. These signs and symptoms are the result of noninflammatory demyelination of the pons [68]. In severe cases, a type of locked-in syndrome can develop, whereby the patient is paralyzed and unable to communicate but fully awake [17]. The effects of this condition may be partially reversible, but in many instances, they are permanent. Prevention involves avoidance of sodium increases of more than 8 mEq/L in 24 hours or 0.5–1 mEq/L per hour [17]. Treatment focuses on addressing symptoms and lowering the serum sodium concentration [68].

Patients with mild-to-moderate SIADH may require fluid restriction, which will lead to the release of aldosterone and the conservation of sodium by the kidneys [17,24]. The recommended fluid intake is often 600–800 mL per day, which can be a significant challenge for many patients [24,67]. In fact, the major challenge with fluid restriction is non-compliance, and patient education will play an important role in the patient's plan of care. Fluid restriction should be used cautiously in patients with an increased risk for hypovolemia.

If fluid restriction is unsuccessful or if the patient is acutely ill and symptomatic, hypertonic 3% saline may be administered to help increase serum sodium levels; this is typically reserved for patients with severe hyponatremia [17]. This intervention should be completed cautiously, because when the solution is administered too rapidly the fluid shifts can damage the brain [24]. The initial dose is 100 mL hypertonic 3% saline bolus in the first three to four hours [17]. Serum sodium levels are then checked within two to three hours, and the results will help to guide continued treatment [17]. These patients should be closely monitored for fluid overload. Because of the risks of severe side effects, isotonic saline should only be used in hyponatremic emergencies [65].

In some cases, loop or thiazide diuretics may be ordered to help rid the body of excess fluid. Use of diuretics is often reserved for patients with cardiac symptoms [24]. Patients prescribed diuretics may take oral salt tablets or increase dietary salt intake to decrease the urine concentration [17].

Conivaptan is a vasopressin 2 receptor antagonist that may be ordered for severe cases of hyponatremia [16]. This agent is given intravenously and blocks the action of ADH at the kidney level [16,66].

Tolvaptan is also a vasopressin 2 receptor antagonist, but it is given orally [17]. This medication is hepatotoxic and should be avoided in patients with pre-existing liver disease. Tolvaptan increases sodium levels at a faster rate than other methods, but it can increase the rates too rapidly, leading to osmotic demyelination syndrome [65]. Potential side effects include dry mouth, polydipsia, liver toxicity, and polyuria [63]. It is also important to consider that this medication can be quite costly.

Other medications that may be used in the treatment of this condition are lithium and demeclocycline [17]. Demeclocycline, an antibiotic that blocks the action of ADH at the tubules of the kidney, is administered at a dose of 600–1,200 mg/day in divided doses [24]. Both of these medications are nephrotoxic and associated with undesirable side effects.

If a secreting tumor is the underlying cause of SIADH, the tumor may need to be removed [16]. The removal and additional treatment of the tumor will depend on a variety of factors, including whether the tumor is malignant or benign. If medications are associated with this condition, they should be stopped, if possible.

Patients with SIADH should be monitored for patent airway. For patients without respiratory symptoms, the head of the bed should be kept low (i.e., 10 degrees or less) [24]. Keeping the head of the bed low will enhance venous return and left atrial filling pressure, leading to a decrease in the release of ADH [24].

Other nursing interventions include closely monitoring intake and output, daily weight checks, assisting with hemodynamic monitoring, and neurologic checks. Because the most common indicator of SIADH is decreased serum sodium levels, the patient's laboratory values should be monitored closely [24]. Urinary output may be monitored hourly, with notation of color, clarity, and odor. In most patients with SIADH, urinary output will be decreased and urine will appear concentrated. If the patient on fluid restrictions complains of a dry mouth, hard candies, dry mouth lozenges, or moisturizing mouth swabs may be offered. Patients should also be educated on SIADH and treatment, with an emphasis on the importance of adhering to fluid restriction and increased salt intake.

7. GROWTH HORMONE DEFICIENCY

Growth hormone deficiency is usually the result of genetic mutations or structural defects in the brain and can affect children and adults [69]. Acquired growth hormone deficiency in adults is due to malnutrition, trauma (e.g., traumatic brain injury [TBI], Sheehan syndrome), infection (e.g., meningitis, encephalitis), radiation therapy, brain tumors, or the treatment of acromegaly [69; 70]. In children, malnutrition, neglect, and/or emotional stress can lead to a growth hormone deficiency [16]. Cases in which there is no identifiable cause are classified as idiopathic.

Worldwide, malnutrition is the most common cause of growth hormone deficiency [16]. The prevalence of growth hormone deficiency in children is 1.8 to 2.9 per 10,000 population [71]. Approximately 6,000 new cases of adult-onset growth hormone deficiency are diagnosed each year in the United States [21].

PATHOPHYSIOLOGY

Congenital growth hormone deficiency can be genetic or the result of structural changes in the brain. It appears to have a hereditary factor; approximately 5% to 30% of children with growth hormone deficiency have a first-degree relative with the disorder [20]. These patients have an increased risk for other pituitary hormone abnormalities and anatomic differences of the pituitary gland [20]. Three abnormalities are commonly seen in patients with congenital growth hormone deficiency: interrupted or thin pituitary stalk; absent or ectopic posterior pituitary gland (i.e., the posterior portion of the pituitary gland is in an abnormal position); and anterior hypoplasia or aplasia of the pituitary gland [20].

Genetic causes of growth hormone deficiency include growth hormone deficiency IA, IB, IIB, and III [69]. Growth hormone deficiency IA is an autosomal recessive disorder in which the fetus develops growth retardation in utero [69]. When these children are initially given growth hormone, they respond appropriately, but over time, they create antibodies to the growth hormone [69]. Growth hormone deficiency IB is an autosomal recessive disorder in which the child has some growth hormone and will respond to the administration of growth hormone [69]. Growth hormone IIB is an autosomal dominant disorder, and III is an x-linked disorder [69]. Both of these genetic disorders are similar to growth hormone deficiency IB [69].

Adult-onset growth hormone deficiency is typically caused by a pituitary tumor or brain trauma, but less common causes include surgery, radiation, infection, and hemorrhage [23,69]. These contributing factors cause damage to the pituitary gland, leading to a growth hormone deficiency. Deficiency in adults can also be caused by persistent childhood growth hormone deficiency [23]. It is also important to consider that growth hormone secretion decreases with age [22].

Treatment of acromegaly suppresses growth hormone secretion and reduces insulin-like growth factor levels [22]. An estimated 30% to 75% of patients undergoing radiation therapy for acromegaly develop growth hormone deficiency, with increased risk associated with younger age, high doses of radiotherapy, and extended treatment [22]. This effect will be discussed in greater detail later in this course.

TBI has been associated with growth hormone deficiency; more severe TBI increases this risk [70]. However, growth hormone deficiency after a TBI is not well-known and can be easily missed [70]. The reported prevalence is variable due to a multitude of factors, but an estimated 2% to 30% of patients who have experienced a TBI will develop growth hormone deficiency within one month [25]. Further, an estimated 10% to 63.6% of patients in the chronic phase of TBI will develop growth hormone deficiency [25]. The underlying cause in these patients is ischemic injury to the pituitary gland, particularly the pituitary stalk, which is fragile and prone to injury [25]. In the secondary phase of TBI, ischemic, cytotoxic, and inflammatory changes can increase the risk for the development of a growth hormone deficiency [25].

In some cases, malnutrition, neglect, and/or emotional/environmental stress can lead to delayed growth [71]. This may be related to inflammation that develops due to chronic stress; increased inflammation is associated with decreased levels of insulin-like growth factor and growth hormone resistance [71].

Sheehan Syndrome

Sheehan syndrome is a rare postpartum pituitary dysfunction caused by pituitary necrosis [70]. This condition develops after severe hypotension and shock associated with hemorrhage during delivery [70]. A variety of hormonal deficiencies can develop in the patient with Sheehan syndrome, but growth hormone deficiency is one of the most common [72]. Although relatively rare in the United States, this disorder is still seen frequently in developing countries due to the lack of obstetric care [72].

Sheehan syndrome is characterized by hypopituitarism caused by ischemic pituitary necrosis developing after blood loss associated with childbirth [72]. The pituitary gland is susceptible to injury during and immediately after pregnancy because the anterior pituitary gland enlarges during pregnancy but does not develop an increased blood supply [72].

SIGNS AND SYMPTOMS

The signs and symptoms observed with growth hormone deficiency will vary depending on the age of the individual affected.

Children

Growth hormone deficiency can present in a variety of ways in children. Growth retardation, short stature, and delays in maturation are common signs [69]. Children with this deficiency typically have delays in longitudinal bone growth, and untreated growth hormone deficiency results in an average maximal height of 3–4 feet, although body proportions are normal. These children will also display slowed sexual maturation and, in some cases, cognitive deficits. Excess weight and a younger than expected appearance and voice may also be noted [73].

Children with growth hormone deficiency are typically within normal range for size at birth [69]. However, infants with anatomic changes in the pituitary gland are more likely to be born breech and to have jaundice, hypoxia, and hypoglycemia [20]. As these children grow, they will present with delayed development of the facial bones, slowed tooth eruption, fine hair, poor nail growth, and delayed lengthening of the long bones [69]. If the growth hormone deficiency is associated with malnutrition, changes in the child's weight will often be observed before delayed growth [71]. In infants, the fontanelles may take longer than expected to close [69]. Additional signs and symptoms include poor appetite, decreased strength, decreased muscle development, low energy, poor endurance, sleep difficulties, trouble concentrating, and fatigue [73].

Growth hormone deficiency can impact a child's daily, emotional, and social life [73]. The child may report a decreased ability to play sports or participate in social activities [73]. Short stature may lead to bullying, leaving the child to feel as if he or she is different and socially isolated.

Adults

Adults with a growth hormone deficiency may present with fatigue, weakness, obesity, decreased muscle mass, weakened bones, sexual dysfunction, elevated cholesterol levels, and insulin resistance [16,69]. Decreased bone turnover and decreased bone mass are common, and adults with a growth hormone deficiency have a risk for fracture that is two to three times higher than their counterparts without growth hormone deficiency [23]. Early onset of deficiency (i.e., in childhood) and cigarette smoking can further increase this risk [23].

These patients are at an increased risk for cardiovascular and neurologic disorders. Growth hormone deficiency is associated with increased abdominal subcutaneous tissue, insulin resistance, hypercoagulability, increased total and low-density lipoprotein (LDL) cholesterol levels, decreased high-density lipoprotein (HDL) cholesterol levels, decreased exercise performance, and atherosclerosis [21]. All of these changes can increase the risk for cardiovascular complications.

As with pediatric patients, growth hormone deficiency can decrease adult patients' quality of life, and treatment has been shown to improve satisfaction with life [21,22]. These individuals are more likely to be unemployed, on sick leave, or on disability [21]. Patients who develop a growth hormone deficiency after a TBI are more likely to develop depression and report a decreased quality of life [25].

DIAGNOSTIC TESTS

Evidence Based Practice Recommendation

The Endocrine Society recommends that the insulin tolerance test and the GHRH-arginine test have sufficient sensitivity and specificity to establish the diagnosis of growth hormone deficiency in adults.

https://academic.oup.com/jcem/article/96/6/1587/2833853

Last Accessed: August 5, 2021

Strength of Recommendation/Level of Evidence: 1/⊕⊕⊕⊕ (Strong recommendation based on high-quality evidence)

The diagnosis of congenital causes of growth hormone deficiency is often delayed until slow growth is observed in a child [69]. It is common to see initial diagnosis around 5 years of age, when children start school or when puberty is delayed (10 to 13 years of age for girls, 12 to 16 years of age for boys) [69]. Diagnostic tests for a growth hormone deficiency include serum growth hormone levels, growth hormone stimulation test, pituitary MRI, and bone density tests.

Although growth hormone levels can be measured, these tests can be unreliable because hormones are not secreted in consistent amounts throughout the day. Additionally, a variety of medications can affect growth hormone levels and interfere with diagnostic testing [32]. As such, a medication review should be conducted to determine if any could interfere with testing. Medications that can affect the results include insulin, estrogen, amphetamines, oral contraception, and corticosteroids; the herbal supplement St. John's wort can also impact findings [33].

A more reliable test is the growth hormone stimulation test, which measures the response of growth hormone to hypoglycemia [16]. Medications that may be used in stimulation testing are clonidine, arginine, and glucagon [20]. In the patient with a growth hormone deficiency, growth hormone levels would not elevate as expected.

An MRI is usually completed to assess for tumors, and a bone density test will provide information about bone strength and possible disorders (e.g., osteopenia, osteoporosis). In patients with congenital growth hormone deficiency, an MRI will help to identify abnormal pituitary anatomy rather than for definitive diagnosis. However, conducting an MRI can be challenging for pediatric patients and may require sedation to remain calm and still for approximately 45 minutes.

Diagnosis of a growth hormone deficiency after TBI can be challenging because many of the signs and symptoms associated with each condition overlap [25]. It is important to consider that increases in the severity of TBI likewise increase the risk of growth hormone deficiency [25]. As such, patients with a severe TBI should be evaluated. In these patients, plasma insulin growth factor is not a useful measure, because it lacks sensitivity and accuracy [25]. Instead, an insulin tolerance test, GHRH levels, and/or glucagon stimulation test should be used [25].

The diagnosis of growth hormone deficiency due to Sheehan syndrome is often delayed, in some instances for many years [72]. This is often because it is overlooked by healthcare professionals, and it should be considered as part of the differential diagnosis in women presenting with suggestive signs and symptoms [72].

TREATMENT AND NURSING INTERVENTIONS

The treatment of growth hormone deficiency is most commonly the administration of synthetic human growth hormone. If hormone replacement is initiated during childhood, the patient will usually reach a normal height in adulthood; even those with short stature can catch up [71,74]. The goal is to start hormone replacement before the child drops below the third percentile for height [21].

Growth hormone replacement is also appropriate therapy for adults and can lead to increased bone turnover, expanded remodeling space, decreased fracture risk, and over time, increased bone density [23]. It is interesting to note that some research has shown that the positive effect on bone density is more pronounced in men than women [23].

Somatropin, a recombinant growth hormone, may be used for both children and adults with a growth hormone deficiency. This medication increases skeletal growth in children and increases bone density in adults [75]. Somatropin is administered as a subcutaneous injection, usually in the evening to mimic the body's normal rhythm [21]. The onset of action is typically within three months of the initiation of treatment [75]. Starting treatment early will help prevent delayed growth in children. In most cases, somatropin is administered to children when delayed growth is identified, with doses increased when the child is going through puberty and discontinued when skeletal maturation is reached [69]. However, testing should be completed to determine if the patient should continue treatment, as early cessation can lead to negative consequences in adulthood [69]. Adverse effects of somatropin include edema of the hands and feet, hyperglycemia, hypothyroidism, insulin resistance, pancreatitis, pain at the injection site, lipodystrophy, carpal tunnel syndrome, and arthralgia [21,75]. Lipodystrophy can be prevented by rotating injection sites. Concurrent use of corticosteroids can decrease the effectiveness of somatropin [75].

During somatropin treatment, children should have growth (height and weight) assessed every three to six months [75]. In adolescence, patients' growth and puberty should be monitored every six months [74]. Because this medication has been linked to hypothyroidism, thyroid function should be periodically checked. Somatropin treatment is ineffective in the presence of hypothyroidism, so treatment of the condition is vital [75]. Patients should also be monitored for hyperglycemia, especially patients diagnosed with diabetes. In addition, patients given somatropin after epiphyseal closure should be monitored for signs and symptoms of acromegaly.

Somapacitan, a long-acting human growth hormone analog, was approved for use in adults with growth hormone deficiency in 2020 [76]. This medication is administered as a once-weekly injection [76,77]. The initial dose is 1.5 mg, but the dose can be increased by 0.5–1.5 mg per week (to a maximum 8 mg per week) every two to four weeks based on clinical response and insulin-like growth factor-1 levels. Potential adverse effects include back pain, joint pain, indigestion, sleep disorders, dizziness, tonsillitis, edema of the extremities, vomiting, adrenal insufficiency, hypertension, increased blood creatinine phosphokinase, weight gain, and anemia [76]. The dose should be reduced if needed for adverse reactions or elevated insulin-like growth factor-1 levels. Somapacitan is contraindicated in patients with malignancy, diabetic retinopathy, and acute critical illness [76,77]. Discontinuation of therapy should be considered if no apparent benefits are achieved after 12 to 18 months.

Growth hormone replacement therapy should continue over a prolonged period of time, in some cases for the patient's entire life. Patients receiving this treatment should be taught self-administration techniques.

Due to the length of treatment, adherence can be a challenge. Factors that may affect adherence include cost, length of treatment, and decreased understanding of treatment. Transition to adolescence is an important challenge to adherence [74]. Factors that may negatively affect adherence in adolescence include peer group conflict and loss of a sense of control. This is also a period of increased independence during which adolescents may want to take a more central role in managing their own care.

Poor compliance with or delayed therapy can lead to poor growth in children and to increased weight, changes to bone metabolism and density, and changes to cardiac structure and function (e.g., exercise intolerance, bradycardia, dilated cardiomyopathy) in adults [74]. Cognitive/psychological changes associated with poor compliance may include fatigue, sleep disturbance, decreased motivation, decreased self-esteem, and isolation [74].

With adherence in mind, empowering patients is important. For pediatric patient, parents/caregivers and the patient should be educated, offering choices (whenever possible), rewards, and age-appropriate educational materials [74]. Adolescent patients should be asked how they feel about their treatment and allowed to make decisions so they feel a sense of control. Adult patients should be encouraged to attend regular follow-up appointments and be provided with education on the benefits of treatment. Phone alerts or text or e-mail reminders may be beneficial [74]. Because cigarette smoking can increase the risk for fracture in adults with a growth hormone deficiency, patients should be advised to quit smoking and provided with cessation tools and resources.

8. DISORDERS OF HYPERSOMATOTROPISM

Hypersecretion of somatotropin by the anterior pituitary results in gigantism (before puberty) or acromegaly (after puberty). The crucial factor is the time onset of the disorder. If the hypersecretion of growth hormone occurs during the individual's growth period before the epiphyses of long bones have closed, gigantism will occur. Acromegaly occurs after epiphyseal closure [78,79].

ACROMEGALY

Acromegaly is a rare condition, with approximately 3 to 14 of every 100,000 people diagnosed [80]. It is seen most commonly in adults between 30 and 40 years of age and more frequently in women than men [16,24]. Acromegaly is most commonly caused by pituitary tumors (e.g., adenomas, hypothalamic adenomas), but pituitary hyperplasia and genetic mutation are other possible etiologies.

Pathophysiology

As noted, acromegaly develops when there is excessive growth hormone after the closure of the growth plates [80]. Bones will specifically increase in width rather than length. Subcutaneous connective tissues, organs, and glands may also enlarge [16].

Patients with acromegaly have increased levels of somatotropin and insulin-like growth factor [22]. Insulin-like growth factor alters the metabolism of blood glucose and lipids, increasing the risk for type 2 diabetes, hypertension, and cardiovascular disease [80]. Patients with acromegaly may also have an abnormal production of glucocorticoids, mineralocorticoids, and gonadotropins [24].

The majority of cases of growth hormone hypersecretion (more than 90%) are caused by benign pituitary adenomas [19]. In the United States, it is estimated that about 16% of the population (more than 50 million people) have pituitary tumors, although most are undiagnosed. Approximately 13,000 people are diagnosed with pituitary tumors each year; 25% of these tumors will lead to acromegaly [21]. It is possible for patients to develop a malignant pituitary adenoma that is responsible for acromegaly, but this occurs in less than 1% of cases [24]. The disorder may also be caused by hypothalamic adenomas that increase the amount of GHRH, which, in turn, increases growth hormone levels [19]. Other types of tumors, such as those found in the hypothalamus, pancreas, lungs, chest, or abdomen, can also lead to acromegaly [80]. These tumors can secrete their own growth hormone, although it is more common for them to produce GHRH [80]. Additional possible causes include pituitary hyperplasia and excess GHRH [16].

Acromegaly has been shown to run in families, and several mutated genes have been associated with acromegaly, including AIP, MEN1, CDKN1B, PRKARIA, SDHx, GPR101, and GNAS [81]. The most common genetic cause of acromegaly is familial isolated pituitary adenoma syndrome [81]. Less common causes are Carney complex, multiple endocrine neoplasia, and sporadic acromegaly [81]. The exact mechanisms behind familial isolated pituitary adenoma are not fully understood [81].

Signs and Symptoms

The term acromegaly refers to enlargement of the acral parts—the head, hands, and feet—and these patients often present with enlargement of facial features, excessive growth of the hands and feet, and hypertrophy of soft tissues. The signs and symptoms may develop slowly and not become apparent for years [19].

Patients with acromegaly will have lateral changes to the bones of the face, and the mandible will enlarge and protrude. The space between the patient's teeth may widen and teeth may become displaced, which can lead to problems chewing and eating. The tongue and salivary glands often enlarge, leading to trouble with speaking and eating [16,21]. In addition to the tongue thickening, the lips and nose also enlarge, impeding breathing and possibly causing sleep apnea [80]. The patient's hair and skin may become thick, coarse, and oily [80]. Approximately 70% of patients with acromegaly report oily skin with increased sweating and unpleasant odor [21]. Some patients describe skin tags that become larger and darker [80]. Joint changes are seen in approximately 70% of patients with acromegaly, and joint pain and osteoarthritis often develop [19]. Growth hormone can increase bone resorption and turnover, increasing the risk for fracture [21].

Evidence Based Practice Recommendation

The Endocrine Society suggests evaluating all patients presenting with acromegaly for associated comorbidities, including hypertension, diabetes mellitus, cardiovascular disease, osteoarthritis, and sleep apnea.

https://academic.oup.com/jcem/article/99/11/3933/2836347

Last Accessed: August 5, 2021

Strength of Recommendation/Level of Evidence: 2|⊕⊕○○ (Weak recommendation based on low-quality evidence)

Patients with pituitary enlargement may complain of headaches and visual disturbances (e.g., diplopia) as a result of the adenoma pushing on the brain and cranial nerves III, IV, and VI [16,19,24]. If the tumor presses on other pituitary tissue, it can lead to menstrual changes, erectile dysfunction, thyroid hormone changes, and decreased circulating cortisol [80]. The headaches may be severe and can interfere with the patient's ability to perform daily tasks [21]. If cranial nerve V is involved, the patient may also complain of facial pain [21].

Patients with acromegaly often have a reduced life expectancy because of associated cardiovascular, respiratory, metabolic, and neoplastic conditions [22]. Cardiac disease, including cardiomyopathy, arrhythmias, hypertension, and diastolic overload, is seen in approximately 60% of patients with acromegaly [21]. As many as 50% of patients will develop hypertension [21].

Diagnosis

The slow progression of acromegaly often delays diagnosis and treatment [80]. This is a problem, because associated health conditions can develop and cause significant damage during this period [80]. The first step is in an accurate physical exam and history. Patients should be observed for any enlargement in facial features; it may be helpful to ask the patient to bring in an older photograph for comparison [24]. Patients should also be asked about any changes that they have noticed, such as an increase in ring or shoe size [16]. An oral exam may be significant for an enlarged tongue; if present, respiratory issues may be a concern. Patients should be asked about any problems chewing, eating, or swallowing or with sleep (e.g., snoring and excessive daytime sleepiness, which may be signs of sleep apnea). When speaking with the patient, assess for and note any difficulty speaking. The nurse should ask the patient about skin changes, sweating, increased body odor, changes to body hair, and skin tags, and an assessment of the patient's integumentary system should be conducted. Patients should be asked about a history of headaches or visual changes, either of which would warrant additional investigation.

Appropriate diagnostic tests include serum insulin-like growth factor, growth hormone levels, serum glucose, MRI, CT scan, bone density scans, and x-rays [24]. Insulin-like growth hormone levels are more than five times greater in patients with acromegaly than in those without the disease [24,80]. For patients with moderately elevated insulin-like growth factor, an oral glucose tolerance test may also be ordered. This test consists of the patient drinking a sugary liquid, typically containing 75 mg of glucose, and blood samples taken after one and two hours to measure growth hormone [24,80]. Under normal conditions, growth hormone levels would drop after consumption of glucose, but this will not occur in patients with acromegaly. Theoretically, blood tests of growth hormone levels would also be elevated, but these tests may be unreliable. Elevated blood glucose levels are also common in these patients.

Bone density testing is completed to identify any weakening of the patient's bones, and x-rays are done to identify bone enlargement. An MRI should be conducted to visualize pituitary and any other tumors.

Treatment and Nursing Interventions

The changes associated with acromegaly usually develop over 7 to 10 years, but the best outcomes are associated with early identification and treatment [24]. Left untreated, this condition can result in early mortality and decreased quality of life [80]. However, treatment allows patients with acromegaly a normal life expectancy and quality of life [80].

In most cases, the goal of treatment is to control the size of the underlying tumor, to return growth hormone and insulin-like growth factor levels to normal, and to improve symptoms and manage any associated conditions [80]. It is particularly important to address any cardiovascular complications, as these are the main cause of excess mortality [21].

Surgical Intervention

A common treatment option is the surgical removal of the pituitary adenoma by endoscopic, transnasal, or transsphenoidal route [24]. For 60% of patients, surgery will result in cure, and in many cases, pituitary function may be preserved [24]. However, some may require hypophysectomy, with fluoroscopy-guided removal of the pituitary gland along with any adenoma or other tumors [80].

Possible postoperative complications include bleeding, cerebrospinal fluid leaks, sodium imbalances, fluid imbalances, decreased pituitary hormones, diabetes insipidus, hypopituitarism, and meningitis [24,80]. Postsurgical nursing interventions include [24]:

- Assess neurologic status

- Assess for pain

- Assess for nasal drainage

- Elevate the head of the bed

- Educate about the avoidance of activities that increase intracranial pressure

- Check blood glucose and serum sodium levels

If present, clear nasal drainage should be checked for glucose to ensure that it is not cerebral spinal fluid [24]. The head of the bed should be elevated to promote drainage and to make breathing easier. Patients should be advised to avoid coughing, straining for a bowel movement, or any other activity that can increase intracranial pressure for up to two months following the procedure. Tooth brushing can cause damage to the surgical incision site and should also be avoided. After the removal of pituitary adenoma, hypoglycemia may develop as growth hormone and insulin-like growth factor levels drop [24]. Approximately 20% of patients have associated pituitary damage and may require replacement of glucocorticoids, gonadotropins, and thyroid hormone [24].

Radiation Therapy

Radiation therapy is another treatment option for patients with acromegaly caused by malignancy. It is typically a second-line option if surgery and/or pharmacotherapy are ineffective [80]. It is important to understand that it can take years for this treatment to improve symptoms [80]. Further, this therapy can impair fertility and approximately 50% of patients will require hormone replacement [80].

Pharmacotherapy

Medications used in the treatment of acromegaly include somatostatin analogs, dopamine agonists, and growth hormone-receptor antagonists [80]. These medications are initiated in patients who do not have remission following surgical removal of adenoma or in patients for whom surgery and/or radiation therapy is contraindicated [24].

Somatostatin analogs (e.g., octreotide, lanreotide) work by slowing the release of growth hormone [80]. In some cases, these medications can effectively reduce the size of the pituitary tumor [80]. Octreotide suppresses growth hormone, insulin, and glucagon and helps to normalize growth hormone and insulin-like growth factor levels in patients with acromegaly [75]. Octreotide is available in short- and long-acting forms [24]. The short-acting form is given as a 100-mg subcutaneous injection three times daily; the long-acting form is given as a 10- to 30-mg intramuscular injection once monthly [24]. Lanreotide is a treatment option for patients with acromegaly who are not candidates for or who have not responded to other treatment options [75]. Lanreotide is given as a 60- to 120-mg subcutaneous injection monthly and is intended to be administered by a healthcare professional [75]. Potential side effects of somatostatin analogs include cramps, bradycardia, orthostatic hypotension, gas, diarrhea, gallstones, and hair loss [80]. Octreotide has been linked to dizziness, bradycardia, and orthostatic hypotension, so pulse and blood pressure should be monitored in these patients prior to and periodically throughout treatment. Patients should be advised to move slowly and not operate vehicles or heavy machinery until they know how they respond to the medication. Octreotide can also increase fertility in ovulating patients, so precautions to prevent pregnancy are necessary [75]. GI side effects are common when starting lanreotide but will often decrease with time [75].

Dopamine agonists (e.g., bromocriptine) are a treatment option to inhibit growth hormone production and tumor growth, but they are not as effective as somatostatin analogs [80]. Growth hormone-receptor antagonists (e.g., pegvisomant) decrease growth hormone levels and may be given orally. Potential side effects include GI upset, nausea, vomiting, headache, postural hypotension, dizziness, nasal congestion, and cold-induced vasospasm [21]. Laboratory changes may also be noted, including increased serum BUN, aspartate transaminase (AST), alanine transaminase (ALT), creatine phosphokinase (CPK), alkaline phosphatase, and uric acid levels [75]. Due to the risk of severe hypotension with the first dose, patients should be supervised when treatment is initiated.

Growth hormone antagonists (e.g., pegvisomant) are given to lower insulin-like growth factor levels [24]. Pegvisomant is used for patients with acromegaly who do not respond to other therapies and are not candidates for surgery or radiation [75]. It binds to growth hormone receptor sites and blocks the effects of growth hormone, decreasing the manifestations of acromegaly [75]. Pegvisomant is given as a daily subcutaneous injection and takes two weeks to start working [24,75]. Insulin-like growth factor levels should be checked within four to six weeks of the onset of therapy and every six months thereafter [75]. Side effects include hypertension, peripheral edema, lipohypertrophy, increased glucose tolerance, elevated liver enzymes, increased fertility, dizziness, and back pain [75].

If the therapy regimen includes injectable medications, patients should receive instruction on injection technique and should be able to demonstrate appropriate medication administration. Patients with acromegaly often experience changes to their self-concept [24]. Nurses should inquire about how the condition is affecting their life and help develop a plan of care based on the information obtained from the patient.

GIGANTISM

Gigantism starts in infancy or childhood and is characterized by continuous growth of the body until epiphyseal closure occurs. In adults, it is defined as a height greater than 80 inches; in children, it is defined as three standard deviations above the mean for the child's age as measured on a growth curve. Adults with gigantism may be as tall as 8 feet and weigh more than 300 pounds. Some individuals may develop associated acromegaly features (i.e., very large heads, hands, and feet) in adulthood [79].

Signs and Symptoms

Untreated, patients with gigantism have an increased death rate of approximately twice the normal average for the population. These patients experience progressive debilitation, but treatment can be very effective [78,79]. They generally present with [78,79]:

- Extremely large size

- Enlargement of the heart, liver, spleen, kidneys, pancreas, thyroid, parathyroid, adrenals, soft tissues, and/or peripheral nerves

- Increased metabolic rate

- Incomplete or slow development of secondary sex characteristics

- Glucose intolerance with resulting hyperglycemia and diabetes mellitus

- Possible excess secretion of other anterior pituitary hormones (e.g., prolactin, ACTH)

More advanced signs include extreme muscular weakness and crippling osteoarthritis, which may be associated with a severe kyphosis [78,79].

The symptoms of gigantism are usually attributable to the effects of compression of the adjacent tissues by the pituitary tumor or by metabolic changes. Symptoms include headache, which may be mild to severe and persistent; bitemporal hemianopia and other visual field defects (e.g., changes in color perception, diplopia) due to pressure in the optic chiasm; and seizures and stroke resulting from increased intracranial pressure [78,79].

Treatment

Because the underlying pathophysiology of gigantism is similar to acromegaly (usually pituitary tumor), the approach to treatment is generally the same. However, because most of these patients are children, patient and family education should be adjusted. Patients should be allowed opportunities to discuss their feelings and ask questions about the changes in their physical appearance. Children with gigantism require information about the reasons for the changes in physical appearance and also what might occur in the future. These patients are often coping with major differences in body size and shape as compared with peers, and this can result in bullying and insecurity [55].

9. ADDISON DISEASE

Addison disease, also known as primary adrenal insufficiency, develops when the adrenal glands do not produce enough of the hormones cortisol and aldosterone. In the United States, Addison disease affects approximately 4 out of every 100,000 people and is seen more commonly in women than men [27,37]. This disorder is typically diagnosed among individuals 30 to 50 years of age, but it can develop at any age [37]. Addison disease may be caused by an autoimmune disease, genetics, infections, adrenalectomy, hemorrhage, cancer, amyloidosis, adrenoleukodystrophy (ALD), or medications, or as a side effect of the treatment of Cushing syndrome [45].

PATHOPHYSIOLOGY

As discussed, the adrenal glands are found above each kidney and produce cortisol, a glucocorticoid and aldosterone, a mineralocorticoid. In patients with Addison disease, an abnormality of the adrenal cortex leads to inadequate amounts of circulating cortisol and, in some cases, aldosterone [82].

Autoimmune disease is the most common cause of Addison disease, accounting for approximately 80% to 90% of all cases [37]. Autoimmune Addison disease, also referred to as autoimmune adrenalitis, results in atrophied adrenal glands and an inability to produce hormones in sufficient amounts. Cells destroyed by the inflammatory response are replaced by fibrotic tissue [83]. In these patients, the cells in the adrenal cortex are damaged but the medulla remains intact [83].

Risk for Addison disease is increased in those with a family history of the disease, with heritability accounting for 97% of cases in a Swedish twin study [24]. In addition, other autoimmune conditions have been associated with an increased risk of Addison disease, including vitiligo, type 1 diabetes, and hypothyroidism [45].

Viral, bacterial, or fungal infection or parasitic infestation of the adrenal glands can lead to changes, and childhood infections may predispose a patient to Addison disease [83]. Worldwide, tuberculosis is the most common cause of Addison disease, although this is not routinely seen as a cause in developed countries [45,83]. Many infections that damage the adrenal glands are opportunistic, meaning they develop in immunocompromised individuals [83]. Serious infections (e.g., sepsis) require that the body be able to rapidly activate glucocorticoid production, which can lead to adrenal failure and, in some instances, adrenal crisis [83]. However, it has been hypothesized that infections highlight or exacerbate existing adrenal insufficiency rather than initiating it [83].

Patient who undergo bilateral adrenalectomy, as may occur with Cushing syndrome treatment, require steroid replacement or they will develop adrenal insufficiency and subsequent adrenal crisis. However, unilateral adrenalectomy rarely causes Addison disease unless the patient experiences severe adrenal stress, in which case the reduced adrenal reserve may be depleted [84]. Conditions that increase the risk for adrenal stress include sepsis, cardiopulmonary disturbance, trauma, and postoperative complications [84].

Hemorrhage (usually in response to infection or trauma) or malignant cells in the adrenal glands can cause damage and negatively affect the glands' ability to secrete cortisol and aldosterone [45]. Amyloidosis is a condition whereby the protein amyloid accumulates and causes damage to the adrenal glands, leading to decreased amounts of cortisol in the body [45]. Medications (e.g., antifungals, general anesthesia) can also lead to the development of Addison disease [37,45].

Adrenal crisis is a serious complication of Addison disease that can result in death if not identified and treated appropriately. Anything that increases the cortisol needs of the body can lead to this condition. In the patient with Addison disease, the body is unable to increase the amount of circulating cortisol in the body, leading to a cortisol deficit. The decline in cortisol and aldosterone directly affects the liver, stomach, and kidneys [85].

SIGNS AND SYMPTOMS

Addison disease is associated with vague, gradually developing (insidious) symptoms that can make diagnosis a challenge [37]. Signs and symptoms associated with this disorder are due to hormone deficiency, with the majority being attributable to decreased cortisol levels, although aldosterone plays a role as well [82]. In many cases, signs and symptoms do not develop until approximately 90% of the adrenal cortex is destroyed, and in some patients, symptoms are not recognized until adrenal crisis develops [45,82].

The most common signs and symptoms of Addison disease are chronic fatigue, lethargy, muscle weakness, loss of appetite, weight loss, increased urination, increased thirst, and abdominal pain [37,45]. Other potential signs and symptoms include nausea, vomiting, diarrhea, hypotension, irritability, depression, joint pain, salt cravings, hypoglycemia, dizziness, reduction in underarm and pubic hair, muscular pain, irregular or no menstruation, decreased libido, darkening of the skin, slowed growth in children, neurologic disturbances, depression, impaired concentration, and hypersensitivity to tastes and smells [37,86].

Cortisol plays a significant role in glucose metabolism, and decreases in cortisol levels can lead to hypoglycemia. Aldosterone acts on the kidneys to increase water retention and blood volume, and decreases in aldosterone levels can lead to hypotension, tachycardia, and salt cravings [16,32,82].

Melanodermia, color changes of the skin, is a potential side effect of Addison disease and most often presents in areas of the body most exposed to sunlight, such as the face, neck, knuckles, elbows, knees, and creases of the palms [24,86]. Darkening of scars may also be seen [85]. Pigment changes seen with Addison disease are due to the stimulant effect of excess ACTH on the melanocytes to produce melanin [82].

Electrolyte changes (e.g., hyponatremia, hyperkalemia, hypercalcemia) may occur with Addison disease [86]. As such, these patients should be closely monitored and may require supplementation and/or a modified diet. The patient with this disorder may also develop lymphocytosis and anemia [82].

Late symptoms of adrenal insufficiency are hypotension, dizziness, syncope, nausea, vomiting, diarrhea, abdominal pain, joint pain, back pain, muscle cramps, chronic exhaustion, skin changes, and decreased libido [45]. Signs and symptoms of adrenal crisis are hypotension, hypoglycemia, hyponatremia, hyperkalemia, vomiting, diarrhea, weakness, confusion, severe dehydration, severe pain in the lower back and abdomen, GI pain, and loss of consciousness [37,86]. Patients with later stage Addison disease may present with pale, cold, clammy skin; sweating; rapid, shallow breathing; and severe muscle weakness [45]. Untreated, adrenal crisis can lead to coma and death.

Patients in adrenal crisis lose large amounts of sodium and water, causing a fluid deficit with resulting hypotension and tachycardia [16]. The patient will often present with hyperkalemia, which can lead to cardiac abnormalities. The decreased cortisol levels in Addison disease will cause decreased glucose output by the liver and decreased digestive enzymes [85].

DIAGNOSTIC TESTS

For most patients with Addison disease, diagnosis will be made around 40 years of age, and it is not uncommon for these patients to see multiple physicians before a diagnosis is made [82]. In cases of primary adrenal insufficiency, diagnosis of Addison disease may be delayed up to one year in as many as half of all cases [86]. Misdiagnosis is also common due to the vague signs and symptoms associated with the condition [82].

As discussed, the diagnostic tests that may be used for suspected Addison disease include ACTH stimulation test, serum cortisol levels, insulin tolerance test, antibody testing, and a CT scan or MRI. Aldosterone, serum cortisol, urine cortisol, blood glucose, and electrolyte levels may also be assessed [16,45]. In these patients, cortisol, aldosterone, sodium and glucose levels would all be low in persons with Addison disease; potassium will be elevated [45]. If the patient becomes dehydrated, BUN and hematocrit levels should be checked and will likely both be elevated. A complete blood count may be checked to determine if the patient has lymphocytosis or anemia.

After completion of the ACTH stimulation and insulin tolerance tests, an antibody test may be ordered. If the antibody test is positive, diagnosis of autoimmune Addison disease may be made with no further testing [37]. The CT scan or MRI may be helpful to evaluate the adrenal glands and/or pituitary gland. These imaging studies can determine if the glands are small in size or if they are enlarged due to infection, bleeding, or malignancy [37]. If tuberculosis is suspected, testing to rule out tuberculosis should be conducted.

TREATMENT AND NURSING INTERVENTIONS

When a patient develops Addison disease, glucocorticoids are typically prescribed. Those with autoimmune Addison disease will require lifelong glucocorticoid treatment, and even with steroid replacement, these patients have an increased risk for morbidity, mortality, and decreased quality of life [83].

Hormone replacement should be carefully planned to ensure the best outcome for the patient. Under typical circumstances, two-thirds of the daily dose is given in the morning and one-third in the evening to mimic the natural circadian rhythm of cortisol levels [16]. Increased doses of hormones are required during times of stress, as this will mimic what normally happens in the body; this includes during illness, infection, accident, injury, invasive medical procedures, and strenuous exercise [45]. If the patient is vomiting, IV or intramuscular hydrocortisone may be necessary [27]. Patients should be educated on self-administration of injectable medications.

The most often prescribed corticosteroid for the treatment of Addison disease is hydrocortisone; however, prednisone or dexamethasone may be used [37]. In patients who are deficient in both cortisol and aldosterone, fludrocortisone is the agent of choice [37]. Fludrocortisone aids in the retention of sodium and loss of potassium, and patients taking this medication should be monitored for signs and symptoms of fluid overload. This involves daily weights and assessment of new onset of edema in the lower extremities. Patients who do not make sufficient amounts of aldosterone should be advised to consume high-salt foods, especially if they are craving salt and on hot days.

One side effect of long-term corticosteroid therapy is an increased risk for osteoporosis [37]. As such, calcium and vitamin D supplementation may be necessary, and patients should be educated about incorporating these nutrients into the diet. Corticosteroids can also lead to mood swings and insomnia [45]. Treatment for these side effects is guided by impact on the patient's life and patient preference.

It may also be necessary to restore fluid, electrolyte, and hormone imbalances [24]. The IV fluid typically used for these patients is 5% dextrose in 0.9% sodium chloride to address glucose and sodium imbalances [24]. Electrolyte disturbances are addressed by adding electrolytes to IV fluid, hanging individual bags of specific electrolyte(s), or oral supplementation.

Nursing assessments should include questions about any recent stressors, such as illness, infection, or traumatic events. It is important to inquire regarding the use of steroids or recent surgery, particularly on the adrenal and/or pituitary glands. Identifying associated signs and symptoms (e.g., increased urination, salt cravings) is important. Standard nursing care includes monitoring vital signs, daily weights, intake and output, and laboratory values. Patients who report increased urination should be monitored for dehydration and signs/symptoms of hypovolemia (e.g., hypotension, tachycardia). Understanding that stress can play a role in this disorder, patients should be assessed for coping abilities and educated about stress reduction strategies. It may also be helpful to ask about the patient's support systems. Patients should be encouraged to wear a medical alert bracelet or necklace to help ensure appropriate care, such as the administration of glucocorticoids if the patient is ill or injured and unable to provide a medical history [45].

Adrenal Crisis

When at all possible, it is important to prevent an adrenal crisis. Risk factors for adrenal crisis include GI infection, febrile infection, surgery, strenuous physical activity, discontinuation of glucocorticoids, psychiatric distress, and accidents [86]. If untreated, these patients can go into shock, followed by coma and death [85]. If adrenal crisis is suspected, treatment should be started quickly to restore fluid balance and cortisol levels [16,87]. Replacement fluids should contain glucose. Cortisol levels are restored with the administration of intravenous glucocorticoids. If IV access is not readily available, glucocorticoids can be given intramuscularly [87]. Glucocorticoids are administered either on an around-the-clock schedule or as a continuous infusion [87]. If necessary, electrolytes should be replaced. For children with adrenal crisis, additional challenges include an increased incidence of hypoglycemia, ensuring weight-based dosing for medications, and difficulty attaining IV access [87].

Patient education is essential for the prevention of adrenal crisis. Patients should be aware of the risk factors in addition to associated signs and symptoms. Specific medication orders should be given for sick/stress days, and an emergency hydrocortisone kit should be available at all times [87].

10. CUSHING SYNDROME

As discussed, Cushing syndrome is a disorder of excess cortisol, and the effects of this disorder can be seen in nearly every body system [24]. It is most commonly seen in individuals between 20 and 50 years of age and is three times more common in women than men [88]. Cushing syndrome affects 40 to 70 people per 1 million population in the United States [28]. Nearly 90% of cases are among adults, but children can be affected [24].

PATHOPHYSIOLOGY

Cushing syndrome is further classified as iatrogenic (or exogenous), primary, secondary, or ectopic [24]. Iatrogenic Cushing syndrome is the most common form and is the result of long-term glucocorticoid therapy [21]. Both primary and secondary Cushing syndrome develop as a result of endogenous causes (e.g., adrenal tumor). Primary Cushing syndrome is typically caused by adrenal gland malignancy, while secondary Cushing syndrome (also referred to as Cushing disease) is the result of excessive secretion of ACTH by a pituitary tumor, usually an adenoma [24]. Ectopic Cushing syndrome arises from the endogenous production of ACTH by one of at least 25 different extrapituitary malignancies, including carcinoma of the lung and of several organs in the GI tract. Secondary Cushing syndrome is the most common (66%) endogenous type of the disease. When this condition is seen in infants, it is most commonly caused by an adrenal carcinoma [24].

As noted, Cushing syndrome is most commonly caused by long-term, high-dose glucocorticoid (e.g., prednisolone, dexamethasone) therapy, often used for the treatment of chronic conditions, such as asthma and chronic obstructive pulmonary disease (COPD) [21,28]. Symptoms associated with exogenous Cushing syndrome typically do not develop until the patient has been taking corticosteroids for at least one month [24].

In comparison, endogenous Cushing syndrome is relatively rare, occurring in 2 to 3 out of every 1 million people [41]. Cushing disease (secondary Cushing syndrome) makes up approximately 70% of all endogenous cases [21]. It is important to note that the terms Cushing syndrome and Cushing disease are not synonymous. Cushing syndrome encompasses cortisol changes from a variety of internal (endogenous) or external (exogenous) causes, while Cushing disease is only endogenous disease caused by a pituitary tumor or hyperplasia of the pituitary gland [29,88].

SIGNS AND SYMPTOMS

A variety of signs and symptoms may be observed in patients with Cushing syndrome, including round ("moon") face; flushed face; weight gain above the collarbone and/or on the back of neck ("buffalo hump"); purple striae on the chest, armpits, and abdomen; acne; excessive facial hair; easy bruising; thin skin; rapid central weight gain; thin extremities; hypertension; skin ulcers; headache; muscle weakness; weak bones; menstrual irregularities; decreased libido; erectile dysfunction; hyperglycemia; emotional disturbances; and slowed growth in children [29,88,89]. Visceral fat deposits are one of the most common and often one of the first symptoms [21]. The distribution of fat deposits is different than what is typically seen with obesity [21]. For example, fat deposits are commonly seen on the face and clavicular area, both anterior and posterior; extremities often remain thin unless edema develops [21].

Many of the signs and symptoms associated with this disorder are due to the protein-wasting effect of cortisol [21]. Muscle wasting, thin skin, and striae develop because of the catabolic effect of cortisol on the tissues [16]. Purple/red striae occur then the skin becomes thin and stretched over areas of fat deposits [21]. This sign is most commonly seen on the abdomen, flank, breast, hips, and axillae [21]. The patient's skin may be red and warm to the touch due to inflammatory changes [21]. Patients with Cushing syndrome bruise easily and have fragile skin that is prone to tears. Wound healing is slowed due to the increased cortisol levels and subsequent hyperglycemia [21]. Lower extremity edema may develop and is often due to increased capillary permeability and sodium/fluid retention [21].

Children and adolescents with Cushing syndrome may present with growth delay or arrest (most common), weight gain/obesity, virilism, hirsutism, delay of secondary sexual development, and muscle weakness [90].

Women with Cushing syndrome may display signs of androgen imbalance, including oligomenorrhea or amenorrhea; infertility; excess hair on the face, neck, chest, abdomen, and thighs; thinning of the hair on the scalp; and polycystic ovary syndrome [16,28,90]. In addition to increasing the risk for infertility, Cushing syndrome may also increase the risk for miscarriage, perinatal death, premature birth, intrauterine growth restriction, pre-eclampsia, and eclampsia [21,58]. Men may experience erectile dysfunction and decreased fertility and libido [28].

The symptoms of Cushing syndrome often overlap significantly with metabolic syndrome [41]. These symptoms include obesity, glucose impairment, insulin resistance, dyslipidemia, and hypertension, all of which may persist after diagnosis and treatment of Cushing syndrome [41]. Patients with Cushing syndrome will have an increased risk for heart attack, cardiac failure, and left ventricular hypertrophy [41]. These persisting conditions can lead to a decreased quality of life and an increased risk morbidity and mortality.

Patients with this condition may also present with emotional, behavioral, and cognitive effects, such as mood changes, increased irritability, anxiety, depression, sleep problems, memory problems, and fatigue [29,89]. Anxiety and bipolar disorder are the most common psychiatric disorders associated with Cushing syndrome [41]. In children, obsessive compulsive disorder may be seen, as well as a declining school performance [41].

The catabolic effect of cortisol can cause changes to the patient's bones [16]. Up to 40% of patients with Cushing syndrome will develop osteoporosis and 20% of patients with this disorder will develop compression fractures of the spine [21]. Patients may also have a spontaneous rupture of the Achilles tendon [90]. The patient may also develop kyphosis and decreased height. Individuals with Cushing disease are more prone to opportunistic infections [90].

Many patients with Cushing syndrome report a decreased quality of life. Appropriate diagnosis and treatment can lead to improvements in patient health and well-being.

DIAGNOSTIC TESTS

Diagnosis of Cushing syndrome may be difficult because cortisol levels are variable and will fluctuate throughout the day [89]. Misdiagnosis is common because the disease typically progresses slowly, making symptom identification more difficult [88]. Diagnosis is based on a medical history, physical exam, and laboratory tests. Through the diagnostic process, differential diagnosis is a consideration, as several conditions can mimic the syndrome. Patients should be evaluated for recent use of oral, cream, or inhaled steroids, most commonly hydrocortisone, prednisone, and dexamethasone [88]. Estrogen-containing oral contraceptive pills can increase cortisol and glucose levels, making diagnosis a challenge [21]. When testing for Cushing syndrome, estrogen therapy should be discontinued for six weeks prior to the test, if possible [21].

Diagnosis is especially challenging during pregnancy, because cortisol and glucose levels normally increase during this time [21]. Understanding that pregnancy and oral contraceptives may increase blood glucose and cortisol levels, Cushing syndrome testing should utilize saliva or urine samples in these patients [21].

After Cushing syndrome is diagnosed, it is necessary to determine the underlying cause [41]. This can often be accomplished with a dexamethasone-corticotropin-releasing hormone test [28]. This test can distinguish Cushing syndrome from non-Cushing causes of elevated cortisol. Similarly, bilateral inferior petrosal sinus sampling can be used to differentiate pituitary from ectopic Cushing syndrome [41].

CT or MRI is necessary to identify pituitary or adrenal tumors; MRI is the preferred imaging technique for Cushing syndrome [21]. CT scan can be used, but it is less reliable and may lead to false positive findings [21]. Additional laboratory tests may show neutrophilia and decreased lymphocytes and eosinophils [21].

TREATMENT

Surgery

Evidence Based Practice Recommendation

The Endocrine Society recommends initial resection of primary lesion(s) underlying Cushing disease, unless surgery is not possible or is unlikely to significantly reduce glucocorticoid excess.

https://academic.oup.com/jcem/article/100/8/2807/2836065

Last Accessed: August 5, 2021

Strength of Recommendation/Level of Evidence: 1/⊕⊕⊕⊕ (Strong recommendation based on high-quality evidence)

As noted, the underlying cause of Cushing syndrome will guide the development of a plan of care [58]. If a tumor is the cause, surgery is often necessary. Surgery is effective and is associated with decreased morbidity and mortality [21]. Prior to surgery, hypertension and hyperglycemia should be well-controlled.

An adrenalectomy is the surgical removal or resection of one or both of the adrenal glands. In a subtotal adrenalectomy, only part of an adrenal gland is excised [60]. In most cases, the major goal of adrenalectomy is to reduce hyperfunction secondary to a tumor or hyperplasia of the glands (e.g., pheochromocytoma) or in advanced cases of cancer of the breast and prostate.

Laparoscopic adrenalectomy is the criterion standard for benign adrenal conditions [92]. A number of approaches are appropriate given the location of the adrenal glands, including posterior or lateral retroperitoneal, transthoracic, and lateral transperitoneal. Rarely, an open adrenalectomy may be required for large tumors or complicated cases.

Preoperative nursing care focuses on stabilization of the patient. In a patient with Cushing syndrome, this involves controlling hypertension, hyperglycemia, and hypokalemia. However, it also requires attention to decreased resistance to stress and infection, emotional liability, and edema [61]. The environment should be organized to provide maximum physical and emotional rest for the patient. Hyperadrenocorticism has an impact on the emotions, and patients may require additional support and reassurance. Patients should also be monitored for symptoms or signs of infection [61,92].

Serum electrolytes and urinary glucose and acetone levels will be monitored at regular intervals. Any fluid and electrolyte imbalances should be corrected in the preoperative period, because they may be exacerbated in the postoperative period. Intake, output, and weights should be recorded to assess the degree of fluid retention [54].

In the postoperative period, dietary selections should be centered on controlling hypertension, hyperglycemia, and hypokalemia. If a patient with excessive hyperadrenocorticism has protein depletion (hypoproteinemia), as reflected by a low serum albumin level, he or she may be prescribed a high-protein diet [93].

Corticosteroids are administered preoperatively as well as during surgery to prevent renal insufficiency in the postoperative period. Intravenous fluids are usually started and infused slowly to allow prompt administration of corticosteroids and vasopressors if needed [54].

Patient teaching before adrenalectomy should include [54]:

- What to expect in the immediate postoperative period (i.e., the patient will be in the recovery room or intensive care unit until stable, and vital signs will be monitored regularly)

- The importance of coughing, deep breathing, and early ambulation for prevention of complications

- The nature of the procedure, its indication, and its expected outcome, including the need for lifelong medication and medical supervision

The greatest postoperative concern after adrenalectomy is adrenal insufficiency. Also important are possible hypotension caused by the rapid withdrawal of mineralocorticoids, electrolyte imbalances, and infection resulting from suppression of the immune system. The surgical hazards associated with adrenalectomy include possible injury to the spleen, liver, duodenum, and common bile duct as well as hemorrhage [54].

Postoperative nursing care of the patient following adrenalectomy includes frequent monitoring of the vital signs, including level of consciousness and blood pressure. Blood pressure is monitored every 15 minutes in the immediate postoperative period until it is stabilized. Any unexplained or significant fall in blood pressure should be reported immediately, because it may indicate immediate impending adrenal insufficiency. Complaints of chest pain should also be reported, because they may indicate cardiac involvement or a pulmonary embolism [54].

Patients should also be monitored for signs and symptoms of Addisonian crisis. Early signs of adrenal insufficiency may be subtle, including restlessness, dehydration, and tachycardia. Later signs (preceding overt shock) are increased weakness, hypotension, increased temperature, and vomiting. Addisonian crisis requires prompt intervention with increased corticosteroids, hypertonic saline solution, or both. In rare cases, peripheral vasoconstrictors may be used [54,55].

If the tumor is removed but the gland remains, the gland may start to function again over time [29]. However, the patient may require supplemental cortisol until function returns [29]. Blood hormone levels should be checked at intervals after surgery to assess glandular function. In instances in which the gland is removed along with the tumor, lifelong cortisol replacement will be necessary. Surgery is often paired with radiation therapy and/or chemotherapy.

Pharmacotherapy

Three medication classes may be used in the treatment of Cushing syndrome: somatostatin analogs (central-acting inhibitors of ACTH), adrenal steroidogenesis inhibitors, and antiglucocorticoids [88]. Pasireotide, a somatostatin analog, is used to reduce ACTH to normal levels [88]. It is administered by subcutaneous or intramuscular injection and is effective in approximately 25% of patients; for others, it may decrease but not fully resolve symptoms [88]. It may take up to two months for the full effects of the agent to be seen [88]. Common side effects associated with pasireotide include fatigue, headache, hypertension, edema, alopecia, hyperglycemia, GI upset, anorexia, and injection-site reactions [75]. Ketoconazole, metyrapone, mitotane, and etomidate are adrenal steroidogenesis inhibitors that are used off-label to decrease cortisol levels in patients with Cushing syndrome [88]. For example, when administered at a dose of 400–1,200 mg per day, the antifungal ketoconazole effectively decreases cortisol production [58]. Mifepristone is a antiglucocorticoid commonly used to treat hypertension associated with Cushing syndrome [88]. A variety of side effects are associated with this medication, including but not limited to anxiety, headache, dizziness, fatigue, edema, hypothyroidism, hypocalcemia, GI upset, dry mouth, uterine bleeding, and dyspnea [75].

Radiation Therapy

Treatment of Cushing syndrome may also include targeted radiation therapy, known as stereotactic radiosurgery [88]. Stereotactic radiosurgery involves the application of x-ray beams to destroy the DNA of abnormal tissue [94]. This can reach small and/or difficult to reach areas in the body while decreasing the risk for damage to healthy tissue [94]. Stereotactic radiosurgery is associated with fewer side effects than other types of radiation therapy [94]. When side effects do develop, they may include fatigue, skin irritation at the site of treatment, hair loss at the site of treatment, headache, and GI upset [94].

Nursing Interventions

Standard nursing care for patients being treated for Cushing syndrome includes a medication review, vital signs, intake and output assessment, laboratory test monitoring, and infection prevention. Nurses should inquire about weight gain, paying particular attention to patient reports of the face becoming more "round" or a "hump on their back." Photographic comparison of the patient's previous appearance may be helpful. To assess for skin thinning, examine the skin on the back of the hand for striae, skin color, and skin texture [21]. The patient's muscle strength should be assessed by asking the patient to rise from sitting without using their hands or arms; the muscle wasting that occurs with Cushing syndrome tends to occur in the lower extremities [90]. The nurse should also examine the patient's extremities, noting if they appear thin or atrophied.

Electrolyte monitoring is important because potassium levels are often low and sodium levels are often high, requiring treatment and monitoring [42]. Patients may be encouraged to consume a high-potassium, low-sodium, and high-protein diet [16]. Patient education should include dietary recommendations and the importance of the various nutrients.

Patients with suspected Cushing syndrome should be asked about the use of steroids [90]. If Cushing syndrome is caused by long-term glucocorticoid use, the dose is usually decreased slowly over an extended period of time [28]. The nurse should also provide education to the patient about any medications and/or treatment ordered.

11. PRIMARY ALDOSTERONISM

Primary aldosteronism, also known as Conn syndrome or hyperaldosteronism, is a condition caused by excessive production of aldosterone by the adrenal cortex. It is characterized by hypertension, excessive urinary loss of potassium, and retention of sodium. Primary aldosteronism is thought to be the underlying cause in 1% to 2% of patients with diagnosed hypertension.

Primary aldosteronism originates from one of three sources: single adrenocortical tumor (generally a benign adenoma), bilateral hyperplasia of the adrenal cortices, or tumor of the juxtaglomerular cells of the kidney (which produce renin autonomously). A secondary form of aldosteronism occurs when increased renal secretion of renin leads to the increased production of aldosterone. The increase renin secretion results from other pathologic processes in the body, such as heart failure or cirrhosis. The production of aldosterone it triggers in turn initiates a cycle of pathologic changes, resulting in increased fluid retention, further compromising cardiac and hepatic function [95,96].

SIGNS AND SYMPTOMS

The major clinical manifestations of primary aldosteronism are hypertension, excessive urinary loss of potassium resulting in hypokalemia, and retention of sodium (hypernatremia). The hypertension is usually a moderate elevation in diastolic blood pressure. Patients may complain of headaches, and on physical examination, early hypertensive retinopathy and cardiomegaly may be noted [95,96].

Symptoms of hypokalemia range from mild fatigue to profound weakness. Patients may complain of paresthesia, loss of stamina, muscular weakness, and intermittent periods of paralysis. If hypokalemia alkalosis occurs, resulting in tetany, physical examination may elicit positive Trousseau and Chvostek signs [95,96].

Because of the increased reabsorption of sodium and water, hypernatremia and hypervolemia occur. Generally, edema is not present. The hematocrit may appear abnormally low as a result of the hemodilution. In addition to these major clinical signs, the patient with primary aldosteronism may also have severe polydipsia, polyuria, and nocturia resulting from the renal tubules' inability to respond appropriately to ADH [95,96].

Primary aldosteronism should be suspected in all patients with hypertension, particularly the young. Findings of comorbid hypertension, hypokalemia (potassium level less than 3.5 mEq/L), and excessive mineralocorticoid production (increased serum aldosterone levels) suggest the diagnosis. These findings become more significant if an excessive excretion of urinary potassium is found along with hypernatremia and decreased excretion of urinary sodium [95,96].

DIAGNOSIS

For the diagnosis of primary aldosteronism, a spironolactone test may be used in conjunction with assessment of serum potassium levels. Spironolactone is an aldosterone antagonist and, when given orally for three to four days, will stop the urinary excretion of potassium and restore serum levels to normal. Serum potassium levels have been shown to drop again five to seven days after the drug is halted [95,96].

To identify and localize an aldosterone-producing adenoma, various techniques may be used. Noninvasive procedures such as CT, MRI, and fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET)/CT are the most commonly used imaging studies to assess potential adrenal masses. Invasive procedures, such as arteriography and retrograde adrenal venography, are rarely used for this purpose [95,96].

TREATMENT

Evidence Based Practice Recommendation

In patients with primary aldosteronism due to bilateral adrenal disease, the Endocrine Society recommends medical treatment with a mineralocorticoid receptor antagonist (e.g., spironolactone).

https://academic.oup.com/jcem/article/101/5/1889/2804729

Last Accessed: August 5, 2021

Strength of Recommendation/Level of Evidence: 1|⊕⊕○○ (Strong recommendation based on low-quality evidence)

The two main approaches to the treatment of primary aldosteronism are surgery and pharmacotherapy. Surgery is indicated when there is a unilateral aldosterone-producing tumor. In cases of hyperplasia, a subtotal or total adrenalectomy may be performed. Postoperatively, the return of normal aldosterone secretion by the remaining adrenal tissue may take several months. Following resection of the tumor, blood pressure will return to normal in most patients, but in one-third it may be lowered only slightly [97,98].

If surgery is not possible or declined by the patient, mineralocorticoid receptor antagonists (e.g., spironolactone, eplerenone) and lifestyle changes may be necessary to help control symptoms [99,100]. Possible side effects of these medications include gynecomastia, hyperkalemia, and hyperglycemia. Lifestyle changes, including weight loss, exercise, and low-sodium diet, and smoking cessation, will also be necessary.

Nursing Interventions

The nursing care of patients with primary aldosteronism should include daily weights and measurement of intake and output to assess the degree of fluid retention and loss, as well as frequent assessment of blood pressure, pulse, and respiratory rate. Symptoms and signs of increased blood pressure (e.g., headaches, changes in visual acuity, hypertensive retinal changes) should also be noted. Patients should also be observed for symptoms and signs of cardiac decompensation and congestive heart failure (e.g., increasing shortness of breath, jugular venous distention, rales at lung bases, orthopnea, and paroxysmal nocturnal dyspnea), and irregularities in heart rate and rhythm [97,98].

Symptoms and signs of hypokalemia, muscle weakness, cramping, fatigue, and skin breakdown should also be noted. Patients should be assessed for paresthesia and tetany. It is vital that these individuals take adequate rest. The recommended diet is low in sodium and high in protein and potassium. Calories may be restricted if weight reduction is desired [97,98].

Patients with primary aldosteronism should receive instruction on the nature of the disorder (e.g., pathophysiology, symptoms and signs, prognosis) and the goals of the treatment plan. If pharmacotherapy is indicated, patients should be familiar with its purpose, action, dosage, administration, and side effects. Patient teaching on diet, physical activity, and regular medical follow-up should also be provided. If surgery is done, patients should be aware of the time frame for resumption of adrenal function, the potential need for postsurgical medication therapy, and signs of surgical complications [97,98].

Patients who are able should take and record their blood pressure and pulse regularly. Nurses can provide instruction on how to interpret the findings and when to report issues. If patients are unable to self-monitor, a caregiver or family member may be engaged in the capacity [97,98].

12. PHEOCHROMOCYTOMA

Pheochromocytomas are tumors that arise from chromaffin cells in the adrenal medulla. While tumors originate in the adrenal medulla, they may rarely develop in the sympathetic ganglia of the abdomen, bladder, or chest; these are referred to as extra-adrenal pheochromocytomas or catecholamine-secreting paragangliomas. Pheochromocytomas characteristically produce both catecholamines (epinephrine and norepinephrine), although some tumors may release only one of the catecholamines. Hypersecretion of epinephrine elevates blood pressure by increasing the strength of contractions of the heart and increasing cardiac output. Norepinephrine causes arteriolar vasoconstriction, increasing peripheral vascular resistance to blood flow. Both of these effects result in marked elevation of both diastolic and systolic blood pressure, which is characteristic of pheochromocytoma [101,102].

Pheochromocytomas are thought to occur more often than clinically recognized and are often diagnosed due to incidental findings when investigating other unrelated issues. Pheochromocytomas are also often asymptomatic or vaguely symptomatic for some time. Tumors that produce primarily epinephrine are typically associated with profuse diaphoresis, palpitations, tremors, anxiety, heat intolerance, and pallor followed by flushing. Tumors that produce primarily norepinephrine are associated with fewer symptoms; when symptoms are present, they are similar to those of essential hypertension [101,102].

Most (70%) pheochromocytomas are benign, unilateral adrenal tumors; however, 10% are benign bilateral or multiple, 10% are extra-adrenal, and 10% are malignant. Men and women are equally affected, and the peak incidence is in the fourth and fifth decades of life, although they can occur at any age. Pheochromocytomas can also be found in association with certain familial neurofibromatosis disorders (e.g., neurofibromatosis, hemangioblastoma), hyperparathyroidism, and thyroid medullary carcinoma [101,102].

SIGNS AND SYMPTOMS

Both epinephrine- and norepinephrine-producing tumors may secrete catecholamines paroxysmally, episodically, or continuously. The most severe symptoms are usually seen in patients with paroxysmally functioning tumors because of the rapid and marked changes in serum catecholamine levels. About 40% of patients with pheochromocytoma have paroxysmal hypertension, whereas the remainder experience either sustained or labile elevations in blood pressure [102].

Paroxysmal attacks vary in frequency, severity, and duration. Both the onset and resolution tend to be abrupt, with the average attack lasting a few minutes to a few hours. In many patients, these attacks may occur without warning, but others may be able to identify a prodrome of dermal paresthesia and increasing anxiety. Paroxysmal attacks may be precipitated by emotional changes (e.g., laughing, sexual activity, pain), postural changes (especially flexion or bending of the body), and/or physical exertion. Attacks may increase in frequency and duration over time and can result in pulmonary edema, cerebral hemorrhage, or ventricular fibrillation [102].

Symptoms of pheochromocytoma include headache, diaphoresis, and intense palpitations. The patient may also complain of extreme anxiety, tinnitus, excessive weakness, tremor, blurred vision, vertigo, dyspnea, and angina. After the attack, the patient may report a feeling of extreme weakness and exhaustion [97,103,104].

Signs of pheochromocytoma include marked elevation of the diastolic and systolic blood pressure (which may rise as high as 200 to 300/150 mm Hg), often with excessive diaphoresis, anxiety, dilation of the pupils, and tachycardia. Orthostatic hypotension and hypertensive retinopathy may occur in patients with persistently functioning tumors. Hyperglycemia and glycosuria are also frequently associated with pheochromocytoma because catecholamines can inhibit insulin production [97,103,104].

DIAGNOSIS

Pheochromocytoma should be suspected in patients with hypertension who have symptoms and signs of sympathetic hyperactivity, although only an estimated 0.2% of hypertension is related to pheochromocytoma. Diagnosis of pheochromocytoma is based on the presence of symptoms, laboratory confirmation, and imaging modalities. Biochemical testing of the serum and/or urine will reflect continuous production of catecholamines and their metabolites (metanephrines) [105]. In the past, pharmacologic tests (e.g., histamine test, phentolamine-blocking test) were used, but these have largely been replaced by more reliable and safer urinary assays [99].

After excessive catecholamine secretion has been determined, imaging studies are done to confirm the diagnosis and localize the tumor [97,104]. PET is the preferred approach, coupled with CT. The American College of Radiology recommends FDG-PET/CT scan to detect metastatic disease [106].

TREATMENT

The definitive treatment of pheochromocytoma is surgical excision of the tumor. In the 10% of patients who are not surgical candidates (because of malignant pheochromocytoma with metastases or serious medical problems), control of symptoms is attempted with cytoreductive techniques, radiopharmaceuticals, chemotherapy, radiotherapy, and experimental therapies.

Surgical resection of a pheochromocytoma is considered high-risk due to the potential impact on heart rate and blood pressure. The Endocrine Society recommends that all patients with hormonally functional pheochromocytoma undergo preoperative blockade to prevent perioperative cardiovascular complications. The recommended preoperative treatment of choice is alpha-adrenergic receptor blockers [107]. This treatment should continue for 7 to 14 days before surgery. During this period, patients should also be instructed to adhere to a high-sodium diet and to increase fluid intake. Adjustments should be made prior to surgery in response to blood pressure, heart rate, and blood glucose level monitoring.

The usual operative approach is minimally invasive (laparoscopic) adrenalectomy. Open resection is reserved for large (i.e., >6 cm) or invasive pheochromocytomas to ensure complete tumor resection, prevent tumor rupture, and avoid local recurrence [107]. Partial adrenalectomy may be appropriate for selected patients.

Evidence Based Practice Recommendation

For patients who have undergone treatment for pheochromocytoma, the Endocrine Society suggests lifelong annual biochemical testing to assess for recurrent or metastatic disease.

https://academic.oup.com/jcem/article/99/6/1915/2537399

Last Accessed: August 5, 2021

Strength of Recommendation/Level of Evidence: 2|⊕⊕○○ (Weak recommendation based on low-quality evidence)

Because of the possibility of extreme fluctuations in the blood pressure in the immediate postoperative period, blood pressure should be monitored every 15 minutes until stabilized; the time to stabilization may be extended in patients with pheochromocytoma. Nurses should be alert for sudden elevation in blood pressure in the early postoperative period, which may reflect a release of epinephrine and norepinephrine from the tumor as it was being excised. An alpha-adrenergic blocking agent may be used intravenously if the blood pressure rises excessively [60].

Severe hypotension may also develop postoperatively and can lead to shock. Metaraminol or norepinephrine, usually administered via IV infusion, may be used to help stabilize the patient. The dosage and flow rate will depend on accurate blood pressure measurements [60]. All patients who have undergone resection of a pheochromocytoma should be advised to change positions slowly to avoid orthostatic hypotension.

Discharge planning should stress the need for lifelong medical supervision. Following successful resection, patients should undergo regular follow-up, including measuring plasma or urine levels of metanephrines, to diagnose persistent (recurrent or metastatic) disease. Pheochromocytomas recur in 10% to 13% of cases [55].

13. PSYCHOSOCIAL/LIFESTYLE INFLUENCES AND EFFECTS

The pituitary and adrenal glands have far-reaching effects on both physiologic and psychological function, and dysfunction can contribute to major developmental and psychosocial crises. To provide comprehensive patient care, nurses should be aware of these potential crises and their manifestations [78,79].

Patients with pituitary and/or adrenal dysfunction may have to face the reality of coping with chronic illness or an acute life-threatening situation. Anger, fear, guilt, and denial are common initial reactions. Individual responses to this challenge vary according to the patient's past experiences, attitudes toward health and illness, coping patterns, and support system strength. It is not unusual to find patients with several years' history of a disease still working through their anger and denial. In pediatric cases, parents' feelings of guilt and denial should also be considered as part of a holistic plan of care [78,79].

In many patients, lifestyle changes are necessary to manage the disease, reduce symptoms, and perform activities of daily living and tolerate stress. However, these changes are often reminders to the patient and family that the illness is serious and that their lives will be affected [78,79].

SELF-CONCEPT AND SELF-ESTEEM

Patients with pituitary or adrenal dysfunction are often confronted with a change in self-concept and a loss of self-esteem arising from changes in body image, decreased functional abilities, sexual dysfunction, loss of autonomy, and limitations in the decision-making processes. Changes in self-concept and loss of self-esteem can interfere with the patient's ability to adhere with the treatment plan and accept the diagnosis and its implications. For example, patients with Cushing syndrome will often require time and support to adjust to the cosmetic implications of the "moon" face, upper back/neck fat deposits, and truncal obesity associated with that disorder. Some conditions will also affect patients' ability to participate in activities as they once had or wish to. Individuals with Addison disease are required to take steps to avoid stressful situations. These pathophysiologic changes affect the patient's ability to function in normal situations, causing further stress and anxiety [78,79].

Certain disorders, including pituitary tumor and dysfunction of the adrenal cortex and medulla, cause emotional liability and personality changes. This presents serious concerns for the patient, who often feels out of control or unrecognizable. The nurse can help both the patient and family to understand the relationship between the physiologic condition problem and the psychological changes [78,79].

SEXUAL EXPRESSION AND REPRODUCTION

Often in disorders affecting the creation of the adrenocortical sex hormones, changes in libido and sexual potency concern patients and their sexual partner. Sensitive intervention by the nurse may relieve anxiety in the couple [79]. Unfortunately, sexual dysfunction is rarely addressed in the treatment plan for these patients. Research indicates that different domains of sexual health are affected by different disease processes, particularly in women. Specifically, hypercortisolism is associated with impaired lubrication, orgasm, sexual arousal, and satisfaction, while hyperprolactinemia and hypoandrogenism are associated with decreased sexual desire and arousal [108]. Treatment of the underlying condition may help, but if sexual dysfunction persists, it should be addressed by pharmacotherapy, adaptive practices, and psychotherapy. It is important to remember that pharmacotherapy cannot address important psychosocial factors of performance anxiety, poor self-confidence, partner sexual dysfunction, relationship conflict or poor communication, sexual factors in the relationship (e.g., sexual scripts, sexual satisfaction), and contextual factors (e.g., life stressors) [109]. Even when sexual dysfunction is primarily physiologic, virtually all patients experience negative psychologic and interpersonal effects. These include interpersonal conflict, depression, performance anxiety, and avoidance of sex.

OCCUPATIONAL AND ECONOMIC FACTORS

Occupational implications of pituitary/adrenal disorders include the possible need to change occupations or limitations in one's ability to work because of a physical disability. Patients with visual loss or changes in mentation often must make significant occupational adjustments. Patients may require adaptive equipment or may move to a different area to be closer to a source of health care or to access a special living environment. Economic factors may include the necessity for lifelong medications and medical supervision along with the increasing costs of diagnostic tests and hospitalizations [101,102].

DIETARY FACTORS

The adjustment to new dietary requirements is a major challenge for patients with pituitary/adrenal disease. Patients who previously gave little thought to nutrition or balanced meals are often introduced into a life of fluid restrictions, special diets, and dietary supplements. These changes add extra strain to an already stressful situation and can also be an economic burden. Nurses should acknowledge the importance of dietary challenges and understand how they affect the patient and family, with particular consideration of how food features in the patient's culture. Patient teaching should include an exploration of dietary customs and how changes will be linked to improved health and quality of life [101,102].

CULTURAL CONSIDERATIONS

As society becomes increasingly diverse, nurses are encountering a wide variety of cultural values and perceptions that influence health behavior in individuals and families. Because culture can have a strong influence on a patient's response to nursing interventions, nurses should be continually aware of these influences.

Cultural competence means being sensitive to differences in the values and beliefs that are shared by the members of an ethnic, cultural, racial, religious, or lifestyle preference of a group. Components of effective transcultural nursing include communication style, use of personal space, eye contact, and understanding of biologic variations. It is important to keep in mind, however, that there can be great variation among individuals within cultures. Therefore, stereotyping and making assumptions about an individual patient's beliefs based solely upon ethnic identification should be avoided.

In most cases, it is not necessary to develop a thorough understanding of each and every culture encountered in diverse healthcare settings. However, a certain degree of cultural competence can and should be developed. The first step in doing this is to recognize that cultural differences do exist. How these variations impact self-management can be explored in the needs assessment. This may include a sensitive exploration of the person's healthcare practices and the role of family members. Other culturally impacted areas may include beliefs about illness, diet, the role of the patient in self-care, gender roles, religious rituals, and communication styles.

Dietary preferences, meal preparation practices, and the symbolism of food represent an especially important area. When giving diet instructions, efforts should be made to consider the food preferences of the cultural group.

Cultural competence includes recognizing that cultural healthcare practices may differ from one's own beliefs about how an illness should be treated. Furthermore, cultural influences may not always be consistent with healthcare recommendations. This may be especially true for diseases that require significant behavioral adaptations. Americanized versions of traditional foods are high in salt, fat, and calories and are not recommended for people with restricted diets. Therefore, patients may experience a conflict between cultural values and those of the mainstream healthcare system.

14. CASE STUDIES

ACUTE ADRENAL INSUFFICIENCY (ADDISON DISEASE)

Present Illness

Patient A, a man 50 years of age, is admitted for diagnosis and initial management of suspected adrenal hypofunction with acute adrenal insufficiency. For the past five years, Patient A has been under considerable stress managing his failing contracting business. Initially, he dismissed his complaints of fatigue and weakness as job-related. Lately, the symptoms have been difficult to ignore and associated with anorexia, nausea, and vomiting. He has lost 30 pounds over the past three months without dieting. He complains of frequently feeling cold and has had two syncopal attacks in the month prior to admission. He reports that although he has spent essentially all this time indoors at the office, his skin has become as dark as his employees who work outdoors.

On the morning of admission, he did not wake at his usual early hour and told his wife that he felt gravely ill. His wife called the family physician, who instructed her to take Patient A to the emergency department. After evaluation in the emergency department, Patient A is admitted to the critical care unit (CCU).

Medical History

A medical history is obtained from Patient A's wife. She states that the patient has no allergies to medications but was very allergic to ragweed when they were first married. During the first 10 years of their marriage, Patient A had frequent asthma attacks requiring treatment with epinephrine injections. The asthma attacks diminished in frequency during his middle years, and his wife cannot remember when he last had an attack.

Patient A also has a history of coccidioidomycosis, which was active for several years late in adolescence and in early adulthood. Mrs. A has no recollection of being told of changes in the patient's routine chest x-rays for some time. Ten years previously, Patient A was diagnosed with hypertension, but his blood pressure has been well-controlled with daily exercise and dietary changes.

Patient A has been married to his wife for 35 years and has three grown children who live out of state. His contracting business had been successful until five years ago, when a decrease in housing starts resulted in a decline in business and increased financial stress.

Assessment and Diagnosis

Upon admittance to the CCU, a full physical exam is conducted (Table 2). A chest x-ray is done and shows normal lung fields and a smaller than expected heart. Several laboratory tests are ordered, with the following results:

- Serum chemistry results:

- Sodium: 125 mEq/L

- Potassium: 6.2 mEq/L

- Chloride: 89 mEq/L

- Carbon dioxide (CO_2): 19 mmol/L

- Blood glucose: 45 mg/dL

- BUN: 37 mg/dL

- Hematocrit: 50%

- White blood count: 3.5 x 10^9/L

Table 2: PATIENT A'S PHYSICAL EXAM RESULTS

Parameter

Findings

General appearance

A thin, well-tanned man who seemed mildly confused

Height: 6 feet 2 inches (188 cm)

Weight: 190 pounds (86 kg)

Head and eyes

Normocephalic

Numerous gray-brown freckles on forehead

Pupils equal (4 mm), round, reactive to light and accommodation

Normal fundoscopic exam

Extraocular muscles full

Nasal turbinates slightly reddened, with clear exudate

Brown freckles on oral mucosa

Pharynx clear

Ears

External ear canals clear

Tympanic membranes clear and retracted

Neck

Supple, without masses or thyromegaly

Nonpalpable cervical lymph nodes

Chest

Symmetrical excursion

Areolas darkly pigmented

Lungs clear to percussion and auscultation

Abdomen

Flat with active bowel sounds in all quadrants

Normally unexposed skin appears tanned

Soft, nontender, and without organomegaly or masses

Extremities

Pulses present, equal, and faint. Normal hair distribution

Genitourinary system

Within normal limits

Neurologic status

Oriented to person, place, and time but very slow to answer questions

Cranial nerves II–XII grossly intact

Deep tendon reflexes 1+ and symmetrical

Bilateral plantar flexor responses

Cardiovascular system

Cardiac rhythm sinus bradycardia without ectopy

Point of maximal impulse at sixth intercostal space 1 inch left of midclavicular line

Heart sounds quiet with normal S1 and S2, without gallops, rubs, or murmurs

Vital Signs

Blood pressure

100/60 mm Hg

Temperature

96.5° F

Heart rate

58 bpm

Respiratory rate

12 breaths per minute

Source: Author

Based on the results of the assessment, Patient A is diagnosed with possible acute adrenal insufficiency and possible Addison disease.

Management

Shortly after arriving in the CCU, Patient A vomits a large amount of bile-colored gastric contents and then develops coma and shock. His blood pressure is 60/10 mm Hg, his heart rate is 50 beats per minute, and his respiratory rate is 8 breaths per minute and gasping. He is quickly resuscitated with rapid IV infusion of normal saline, hydrocortisone sodium succinate (100 mg IV), tracheal intubation, and artificial ventilation. A double lumen nasogastric tube is inserted and connected to low constant suction. An indwelling urinary catheter is inserted and connected to a urine meter. Patient A's condition stabilizes as he becomes alert and orientated, has adequate spontaneous ventilation, and maintains adequate cardiac output and blood pressure. Efforts are made to confirm the diagnosis of Addison disease.

The physician orders diagnostic tests of adrenal, thyroid, and pituitary function. Results of the 24-hour urine collection assessed for 17-ketosteroids and 17-hydroxycorticosteroids indicates that adrenal secretion of cortisol, corticosterone, cortisone, and 11-hydroxycorticosternone is inadequate. The result of the plasma cortisol response to ACTH test confirms the diagnosis of Addison disease. The latest results of tests of thyroid and pituitary function are within normal limits.

Patient A is prescribed fludrocortisone acetate (0.1 mg daily) and hydrocortisone (20 mg daily) as replacement therapy. He responds well and is transferred out of the CCU four days after admission.

Study Questions

Consider the information that has been presented in this course regarding adrenal insufficiency and Addison disease.

1. What fluid and electrolyte imbalances are usually associated with adrenal insufficiency? How does the pathophysiology of adrenal insufficiently create these imbalances?

2. What are the expected results of the plasma cortisol response to ACTH test and 24-hour urine collection in adrenal insufficiency? How are the tests conducted?

3. What risks will subsequent critical illness pose for Patient A?

4. What nursing observation would be important in a critically ill patient with a history of adrenal insufficiency?

5. How might chronic adrenal insufficiency be managed during a critical illness?

6. What are the symptoms and signs of hypoadrenalism?

7. What is the most common type of hypoadrenalism?

8. What are the other causes of hypoadrenalism?

9. How is hypoadrenalism diagnosed?

DIABETES INSIPIDUS

Present Illness

Patient B, a man 26 years of age, is in the hospital recovering from surgical clipping of an aneurysm on the anterior communicating artery. Three days after surgery, he begins voiding large quantiles of very pale urine. His IV intake is 80 mL/hour, and his oral intake is minimal. The specific gravity of the urine is 1.002, and the patient's calculated urine output is more than 200 mL/hour for four consecutive hours. The nurse observes that during the past two hours Patient B's blood pressure has declined from 120/80 mm Hg to 110/70 mm Hg and that his heart rate has increased from 68 beats per minute to 110 beats per minute. The nurse notifies the neurosurgeon of the large unconcentrated urinary output and the changes in vital signs.

Medical History

Patient B has suffered chronic severe headaches, and the diagnosis of cerebral aneurysm led to the cerebrovascular procedure. The surgical procedure went well, and Patient B was recovering as expected.

Assessment and Diagnosis

Upon the onset of diuresis, a full physical exam is conducted (Table 3). Laboratory findings are:

- Plasma osmolality: 289 mOsm/L

- Urine osmolality: 108 mOsm/L

- Serum sodium level: 150 mEq/L

Table 3: PATIENT B'S PHYSICAL EXAM RESULTS

Parameter

Findings

General appearance

A young African American man who appears his stated age and is alert and oriented

Height: 5 feet 11 inches (180.5 cm)

Weight: 190 pounds (86 kg)

Head and eyes

Normocephalic

Dressing dry and intact

No ecchymosis visible

Pupils equal (4 mm), round, reactive to light and accommodation

Normal fundoscopic exam

Extraocular muscles full

Nasal turbinates and oral mucosa pink and moist

Pharynx clear

Ears

External ear canals clear

Tympanic membranes clear

Neck

Supple, without masses or thyromegaly

Chest

Symmetrical excursion

Lungs clear to percussion and auscultation

Abdomen

Flat with active bowel sounds in all quadrants

Soft, nontender, and without organomegaly or masses

Extremities

Pulses present, equal, and moderate

Genitourinary system

Within normal limits

Neurologic status

Oriented to person, place, and time

Cranial nerves II–XII grossly intact

Deep tendon reflexes 1+ to 2+ and symmetrical

Bilateral plantar flexor responses present

Cardiovascular system

Cardiac rhythm normal sinus without ectopy

Point of maximal impulse at fifth intercostal space 2 cm left of midclavicular line

Heart sounds normal S1 and S2, without gallops, rubs, or murmurs

Vital Signs

Blood pressure

110/70 mm Hg

Temperature

98.4° F

Heart rate

69 bpm

Respiratory rate

11 breaths per minute

Source: Author

Based on the findings of the assessment, Patient B is diagnosed with diabetes insipidus secondary to manipulation of the pituitary.

Management

The neurosurgeon orders 2.5 units of aqueous vasopressin to be administered immediately intramuscularly. Following administration, urine output is reduced to 60 mL/hr in 30 minutes. The urine osmolality level two hours later is 760 mOsm/L. Patient B continues to be monitored to determine if the pituitary damage is permanent and if he requires long-term desmopressin therapy.

Study Questions

Consider the information that has been presented in this course regarding diabetes insipidus.

1. What are the key signs and symptoms of diabetes insipidus? How did it present in Patient B?

2. What is the action of vasopressin?

3. What are the main types of diabetes insipidus? What type does Patient B have?

4. What causes central diabetes insipidus? What causes nephrogenic diabetes insipidus?

5. What diagnostic test(s) can reveal whether diabetes insipidus is central or nephrogenic? How are these conditions treated?

SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION

Present Illness

Patient C is a Hispanic man, 60 years of age. He is brought to the emergency department by his family because of acute mental confusion and combativeness. His wife and son report that he has been complaining of anorexia, a nonproductive cough, and unusual fatigue and weakness for the past seven months. During this time, he lost 40 pounds. In the past two weeks, Patient C has been unusually irritable and occasionally irrational. The day before admission, the patient's confusion and disorientation became so severe that he tried to hit his wife. Because she could not manage him alone, the patient's wife asked their son to come and stay with them.

The morning of the admission, Patient C has a seizure (with signs consistent with a tonic-clonic seizure), and the family transports the patient to the emergency department for evaluation.

Medical History

Patient C's wife reports that her husband drinks six 12-ounce beers daily and has smoked two to three packs of cigarettes per day for the 35 years of their marriage. She has no knowledge of Patient C's family medical history. In addition, Patient C has only rarely seen a physician for illnesses and has never had a routine physical examination.

Assessment and Diagnosis

Upon presentation to the emergency department, a full physical exam is conducted (Table 4). An electrocardiogram (ECG) is normal with nonspecific ST-T wave changes. Skull imaging is normal, but a chest x-ray visualizes a mass in the lower right lobe. Laboratory studies find:

- Blood chemistry levels:

- Sodium: 115 mEq/L

- Potassium: 3.8 mEq/L

- Chloride: 80 mEq/L

- Calcium: 7.2 mg/dL

- Total protein: 5.8 mg/dL

- CO_2: 25 mmol/L

- BUN: 15 mg/dL

- Blood glucose: 90 mg/dL

- Creatinine: 0.9 mg/dL

- Serum osmolality: 235 mOsm/L

- Urine osmolality: 260 mOsm/L

Table 4: PATIENT C'S PHYSICAL EXAM RESULTS

Parameter

Findings

General appearance

A thin, disoriented, and irritable man who appears older than his stated age and coughs frequently

Height: 5 feet 8 inches (173 cm)

Weight: 149 pounds (68 kg)

Head and eyes

Normocephalic

All structures normal

Ears

External ear canals clear

Tympanic membranes clear

Neck

Supple, without thyromegaly

Firm 2 x 3 cm lymph node in right supraclavicular area

Jugular vein distention to the angle of the jaw while sitting up 45 degrees

Chest

Increased anteroposterior diameter and increased curvature to thoracic spine curvature

Dullness to percussion in right base

Lungs have scattered rhonchi and diminished breath sounds in the right base

Abdomen

Flat with active bowel sounds in all quadrants

Soft with mild tenderness in right upper quadrant

Liver palpable 5 cm below right costal margin

Extremities

Peripheral pulses present, equal, and bounding

Normal hair distribution

Genitourinary system

Within normal limits

Neurologic status

Confused, oriented to self only

Unable to follow instructions for cranial nerve exam

Deep tendon reflexes symmetrically diminished, with bilateral plantar flexion

Cardiovascular system

Heart sounds are normal S1 and S2 with S3 with a soft systolic murmur the base

No pericardial friction rub

Vital Signs

Blood pressure

140/80 mm Hg, supine and standing

Temperature

98.9° F

Heart rate

100 bpm

Respiratory rate

18 breaths per minute

Source: Author

Based on the findings of the assessment, Patient C is diagnosed with severe hyponatremia secondary to water intoxication. A lack of history for excessive water intake suggests SIADH.

Management

The physician suspects that Patient C has SIADH, and further diagnostic studies are planned and carried out. The supraclavicular lymph node is biopsied. The pathology report identifies the node as small-cell lung cancer.

Patient C's serum cortisol is 10 mcg/dL in the morning. A 24-hour urine collection is completed, and 17-ketosteroids excretion is 9 mg per day and sodium excretion is 150 mEq per day. Patient C's fluid intake is restricted, furosemide is administered, and hypertonic saline is carefully infused. As the patient undergoes diuresis, his serum sodium gradually returns to normal and his sensorium improves. His wife is relieved at the return of her normally gentle husband.

Extended management includes assessment of the underlying cause of the SIADH, assumed to be metastatic small-cell lung cancer. The patient is referred to an oncologist for further testing and treatment.

Study Questions

Consider the information that has been presented in this course regarding SIADH.

1. What are the key signs and symptoms of SIADH? What pathophysiology underlies these effects?

2. How do diabetes insipidus and SIADH present differently? How are they similar?

3. What studies assist in confirming the diagnosis of SIADH? What are the nursing responsibilities in conducting these tests?

4. What safety precautions should be implemented for Patient C because he is confused and oriented to self only?

5. What nursing observations and actions are required to compensate for patients who are not alert and/or do not have access to food and water and therefore cannot use normal physiologic mechanisms to achieve fluid and electrolyte balance?

6. What typically causes SIADH?

7. How is SIADH treated?

15. CONCLUSION

The pituitary and adrenal glands play a significant role in many functions in the body, and proper functioning is essential for the maintenance of health. Dysfunction in these glands can have detrimental effects and may lead to death if untreated. Although disorders of the pituitary or adrenal glands are not as easy to see or identify as many conditions, they are nonetheless relatively common among many patient populations.

This course has provided a brief overview of the anatomy and physiology of the pituitary and adrenal glands, assessment, common disorders, and care of the patient with pituitary/adrenal dysfunction. Nurses have a responsibility and duty to identify the signs and symptoms of these disorders and to care for patients appropriately and fully.

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85. Rebar CR, Heimgartner NM, Gersch CJ (eds). Pathophysiology Made Incredibly Visual! 6th ed. Philadelphia, PA: Lippincott William Wilkins; 2018.

86. Saverino S, Falorni A. Autoimmune Addison's disease. Best Pract Res Clin Endocrinol Metab. 2020;34(1):101379.

87. Dineen R, Thompson CJ, Sherlock M. Adrenal crisis: prevention and management in adult patients. Therc Adv Endocrinol Metab. 2019;10:2042018819848218.

88. Brain Institute. Cushing Disease/Cushing Syndrome. Available at https://www.oshu.edu/brain-institute/cushing-disease-cushing-syndrome. Last accessed May 19, 2021.

89. Hormone Health Network. Cushing's Disease. Available at https://www.hormone.org/diseases-and-conditions/cushings-disease. Last accessed May 19, 2021.

90. Laws ER, Pace L. Cushing's Disease: An Often Misdiagnosed and Not-So-Rare Disorder. 1st ed. London: Academic Press; 2016.

91. Natkaniec M, Pędziwiatr M, Wierdak M, et al. Laparoscopic adrenalectomy for pheochromocytoma is more difficult compared to other adrenal tumors. Wideochir Inne Tech Maloinwazyjne. 2015;10(3):466-471.

92. Beck-Peccoz P. Syndromes of Hormone Resistance on the Hypothalamic-Pituitary-Thyroid Axis. Boston, MA: Kluwer Academic; 2004.

93. Nelms M. Nutrition Therapy and Pathophysiology. 3rd ed. Boston, MA: Cengage Learning; 2015.

94. Johns Hopkins Medicine. Stereotactic Radiosurgery. Available at https://www.hopkinsmedicine.org/health/treatment-tests-and-therapies/stereotactic-radiosurgery. Last accessed May 19, 2021.

95. Gard PR. Human Endocrinology. 1st ed. New York, NY: Taylor and Francis: 2012.

96. Miles SK. Understanding the Thyroid and Endocrine System: More Healthy Choices 3. Online: CreateSpace Publishing; 2015.

97. Price SA, Wilson LM. Pathophysiology: Clinical Concepts of Disease Processes. 6th ed. St. Louis, MO: Mosby; 2003.

98. Bahnsali A, Gugate Y. Clinical Rounds in Endocrinology: Volume I, Adult Endocrinology. New Delhi: Springer; 2015.

99. DiPiro J, Talbert RL, Yee GC, Matzke GR, Wells BG. Pharmacotherapy: A Pathophysiologic Approach. 9th ed. New York, NY: McGraw-Hill Education; 2014.

100. Zerwekh JG, Claborn JC, Gaglione T. Mosby's Pharmacology Memory Note Cards: Visual, Mnemonic, and Memory Aids for Nurses. 4th ed. St. Louis, MO: Elsevier Mosby; 2015.

101. Kannan CR. Essential Endocrinology: A Primer for Nonspecialists. Heidelberg: Springer; 2013.

102. Ingbar SH. Contemporary Endocrinology. Amsterdam: Springer Verlag; 2013.

103. Ehrman Jk, Gordon PM, Visich PS, Keteyian SJ. Clinical Exercise Physiology. 3rd ed. Champaign IL: Human Kinetics; 2013.

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105. Sigmund CD, Carey RM, Appel LJ, et al. Report of the National Heart, Lung, and Blood Institute Working Group on Hypertension: barriers to translation. Hypertension. 2020;75(4):902-917.

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Evidence-Based Practice Recommendations Citations

1. Baldeweg SE, Ball S, Brooke A, et al. Society for Endocrinology clinical guidance: Inpatient management of cranial diabetes insipidus. Endocr Connect. 2018;7(7):G8-G11. Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013691. Last accessed August 5, 2021.

2. Spasovski G, Vanholder R, Allolio B, et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Intensive Care Med. 2014;40:320-331. Available at https://eje.bioscientifica.com/view/journals/eje/170/3/G1.xml. Last accessed August 5, 2021.

3. Molitch ME, Clemmons DR, Malozowski S, Merriam GR, Vance ML. Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(6):1587-1609. Available at https://academic.oup.com/jcem/article/96/6/1587/2833853

4. Katznelson L, Laws ER Jr, Melmed S, et al. Acromegaly: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(11):3933-3951. Available at https://academic.oup.com/jcem/article/99/11/3933/2836347. Last accessed August 5, 2021.

5. Nieman LK, Biller BMK, Findling JW, et al. Treatment of Cushing's syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015;100(8):2807-2831. Available at https://academic.oup.com/jcem/article/100/8/2807/2836065. Last accessed August 5, 2021.

6. Funder JW, Carey RM, Mantero F, et al. The management of primary aldosteronism: case detection, diagnosis, and treatment: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2016;101(5):1889-1916. Available at https://academic.oup.com/jcem/article/101/5/1889/2804729. Last accessed August 5, 2021.

7. Lenders JWM, Duh Q-Y, Eisenhofer G, et al. Pheochromocytoma and paraganglioma: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2014;99(6):1915-1942. Available at https://academic.oup.com/jcem/article/99/6/1915/2537399. Last accessed August 5, 2021.

96963 • Opioid Use Disorder

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2021 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 patients with opioid use disorder; 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 synthetic and prescription opioid use disorder will be addressed.

Table of Contents

96963 • Opioid Use Disorder

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

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 MISUSE 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

Works Cited

Evidence-Based Practice Recommendations Citations

96963 • Opioid Use Disorder

Education Category. Psychiatric / Mental Health

Release Date. 04/01/2021

Expiration Date. 03/31/2024

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 patients with opioid use disorder; 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 synthetic and prescription opioid use disorder will be addressed.

Audience

This course is designed for medical and mental healthcare providers, including physicians, nurses, pharmacy professionals, social workers, and counselors/therapists who may be involved in identifying or treating opioid use disorder.

Course Objective

Practice guidance for opioid use disorder in primary care has not kept pace with rapid, profound changes in this area, leaving healthcare professionals with outdated and incomplete information to guide the clinical management of opioid use disorder and related morbidity. The purpose of this course is to close this gap to allow healthcare professionals to provide the best, evidence-based care to patients with opioid use disorder.

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 V. Jurica, MD, MPH

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

Alice Yick Flanagan, PhD, MSW

James Trent, PhD

Randall L. Allen, PharmD

Division Planners Disclosure

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

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has 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.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

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

The definitions and terminology used to describe opioids, addiction, and pain vary in meaning to different stakeholders, and while periodically revised, previous iterations circulate. Some terminology perpetuates misinformation or myths. A few widely used updated definitions include [1,2,3,4,5,6]:

- Misuse, nonmedical use: Any use of a drug prescribed to someone else or of one's own prescription departing from the authorized directions.

- Abuse: This term from older DSMs has been largely replaced by misuse. 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 Agency (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 has been referred to as psychologic dependence, but this terminology is incorrect as persons with addiction have become psychologically dependent on the substance, but not all persons with psychologic dependence develop addiction.

- Dependence: Introduced by the APA to replace the term "addiction," opioid dependence described both psychologic dependence (a symptom of addiction) and physical dependence (a process of neurobiologic adaptation that can manifest as tolerance and withdrawal symptoms reflecting uninterrupted exposure to the opioid independent of addiction). This terminology is largely abandoned as imprecise and obsolete.

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. The diagnosis of OUD is made by meeting two or more criteria in a one-year period [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

- Excessive time spent to obtain, use, or recover from using the opioid

- Craving, an intense urge to use

- Opioid use interferes with obligations

- Continued use despite life disruption

- Reduction or elimination of important activities due to use

- Recurrent use in physically hazardous situations

- Continued use despite physical or psychologic problems

- Tolerance

- Need for increased doses of the opioid for the 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]. Despite replacement of "opioid dependence" with opioid use disorder in the DSM-5, use of this term persists, along with conflation of tolerance with opioid addiction and exposure to medically indicated opioid analgesics with opioid dependence with opioid addiction.

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 2018, the estimated worldwide prevalence of past-year opioid use was 58 million people [11]. In 2018, an estimated 10.3 million people in the United States had misused prescription opioids in the past year, and of those people, 9.9 million reported the non-medical use of prescription opioids while nearly 800,000 reported past-year use of heroin [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 European nations have reported a surge in prescription opioid abuse in the last decade, and there is growing evidence of the nonmedical use of opioids in India [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 ED 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, more than 81,000 drug overdose deaths occurred in the United States in the 12 months ending in May 2020, the highest number of overdose deaths ever recorded in a 12-month period, and the rise was mainly attributed to synthetic opioids [18]. From 2013 to 2019, the age-adjusted rate of deaths involving synthetic opioids other than methadone increased 1,040% [23].

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 948,000 by 2016 [19]. In addition, first-time past-year use increased significantly between 2006 (90,000) and 2016 (170,000), 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 50,000 new heroin users older than 12 years of age in 2019 [20]. Most new users are male and older than 18 years of age. In 2019, an estimated 438,000 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 declined slightly from 2017 to 2020 [21]. Lifetime heroin use (at least one use in an individual's lifetime) measured 0.5% among 8th-graders, 0.3% among 10th-graders, and 0.4% 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 0.9%, 1.0%, and 2.4%, 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 past-year nonmedical oxycodone use decreased from 9.6% in 2018 to 8.9% in 2019 [20]. During 2019 in the United States, an estimated 9.7 million (3.5%) individuals misused prescription pain relievers; 1.6 million (0.6%) initiated misuse of prescription pain relievers; and almost 1.4 million (0.5%) had a substance use disorder involving prescription pain relievers [20]. ED visits involving acute harm from prescription opioids were estimated to be 267,020 in 2017 [25].

Among high school seniors, 1.2% used hydrocodone/acetaminophen (Vicodin) nonmedically in 2020, while rates were 0.5% and 0.9% among 8th- and 10th-graders, respectively [21]. More than 40 million prescriptions were written for acetaminophen/hydrocodone in 2020, making it the twelfth 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 2018, 9.2 million young adults had used an prescription pain reliever for nonmedical purposes in the past year. This number dropped to 9.1 million in 2019 [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 between 2000 and 2010. In 2018, 735,000 people received past-year substance use treatment for prescription pain relievers. This number decreased slightly to 731,000 in 2019 [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 2019; the largest increase occurred with pain relievers. In 1990, there were 628,000 initiates compared with 1.6 million in 2019 [20]. As of 2019, it is conservatively estimated that 1.3 million individuals have a substance use disorder related to prescription pain medication [20]. The number of primary treatment admissions for pain medication use disorder was 731,000 in 2019 [20].

In 2019, 1.6 million individuals reported using prescription pain relievers nonmedically for the first time within the last year—nearly 4,400 per day [20]. Approximately 82.5 million individuals 12 years of age or older were past-year users of prescription pain relievers in 2019 [20].

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 2019, the percentages of past-year nonmedical use of pain relievers among the predominant racial and ethnic groups were [20]:

- White: 3.7%

- Hispanic or Latino: 3.7%

- Native Hawaiian or Pacific Islander: 2.1%

- American Indian/Alaska Native: 5.0%

- Black or African American: 3.2%

- Asian: 1.6%

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) [20]. 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) [20]. Past year oxycodone-only users are more likely to be 26 years of age or older (11.2%) [20]. As of 2019, individuals 18 to 34 years of age have the highest percentage of past year (5.2%) and past month (1.2%) illicit pain medication use [20].

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 (4.0%), large metro (3.4%), and urbanized nonmetro (3.4%) areas have the highest percentage of past-year illicit pain medication users; however, less urbanized (2.8%) and completely rural areas (2.9%) have significant rates as well [20]. Research data also suggest a problem with injecting among rural opioid users, a problem more typically associated with urban drug users [10]. The West (4.0%) and Midwest (3.6%) areas have the highest percentage of past-year users, followed by the South (3.5%) and Northeast (2.8%) [20].

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 misuse 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 toward 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 initiate 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.icsi.org/wp-content/uploads/2019/10/Pain-Interactive-7th-V2-Ed-8.17.pdf

Last Accessed: March 30, 2021

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 misuse [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. This is now clearly known to be the result of increases in illicitly manufactured formulations. 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]. As noted, the Centers for Disease Control and Prevention (CDC) reported the highest overdose rate in the year ending May 2020, primarily driven by rapid increases in overdose deaths involving synthetic opioids excluding methadone [18]. There were approximately 46,000 overdose fatalities attributable to synthetic opioids between May 2019 and May 2020. In 2018, men 25 to 44 years of age had the highest opioid death rate at 39.4 per 100,000, which was a decrease of 0.6% from 2017 [40]. While the overall opioid death rate decreased between 2017 and 2018, the rate increased for synthetic opioids.

Regional differences have been found in fatal drug overdose involving opioids. In 2018, the five states with the highest rates of death per 100,000 population due to overdose were West Virginia (51.5), Delaware (43.8), Maryland (37.2), Pennsylvania (36.1), Ohio (35.9), and New Hampshire (35.8) [41]. Significant increases from 2017 to 2018 were seen in the West. Only five states reported statistically significant increases in drug overdose death rates from 2017 to 2018 [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 1,293% [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 (40 mg) preparations 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 1/6,000th 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 [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 6.6% of new HIV infections in 2018 and 11.5% of those living with HIV in 2018 [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

As discussed, there were approximately 81,230 drug-overdose deaths in the United States in the 12-month period ending in May 2020 [18]. This was 18.2% higher than the rate in the year ending in June 2019, including approximately 46,000 deaths that involved synthetic opioid analgesics other than methadone, compared with 20,032 in 2015. Between 1999 and 2018, the age-adjusted death rate from drug overdose more than tripled (from 6.1 per 100,000 in 1999 to 20.7 in 2018) [95]. 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 9.9 in 2018. The heroin overdose death rate increased from 0.7 per 100,000 in 1999 to 4.7 per 100,000 in 2018, a slight decrease compared with 2017 [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 then decreased to 3.6 per 100,000 in 2018 [95]. Overdose deaths involving methadone increased from 0.3 per 100,000 in 1999 to a peak of 1.8 in 2006, then declined to 0.9 in 2018 [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 [24]. This agent may be incorporated into the treatment of adults with opioid withdrawal 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 MISUSE 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].

It is important to note that prescription opioid abuse has been tempered by improvements in opioid prescribing, community intervention, and improved awareness. Following a peak in opioid prescribing in 2011, numbers have consistently fallen. However, opioid use disorder rates and overdose fatalities continue to rise. This reinforces the need for appropriate opioid prescribing practices, patient assessment and referral, and optimal opioid use disorder treatment in patients with suspected addiction.

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 increased disproportionately to their availability between 2000 and 2011, 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 were linked to rising overdose death rates. Since 2011, misuse of prescription opioids has decreased; however, abuse of synthetic opioids (including illicitly manufactured fentanyl) has increased precipitously.

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.who.int/publications/i/item/9789241548816

Last Accessed: March 30, 2021

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 8-mg, 4-mg, or 2-mg single-dose sprayer [115,117,118,204].

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 [24]. 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 2019, 607,372 patients in the United States were enrolled in opioid replacement therapy in 1,691 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.jpain.org/article/S1526-5900(14)00522-7/fulltext

Last Accessed: March 30, 2021

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 $1,750 for a patient enrolled in a methadone maintenance program [141]. A 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 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.healthquality.va.gov/guidelines/MH/sud/VADoDSUDCPGRevised22216.pdf

Last Accessed: March 30, 2021

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 use disorder 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.who.int/publications/i/item/9789241548731

Last Accessed: March 30, 2021

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 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 [62]. 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.

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