NMPMNP19 • Mandatory Pain Management for NM

Table of Contents

NMPMNP19 • Mandatory Pain Management for NM

How to Receive Credit

NetCE 1 Hour Course #91041 • Developing a Safe Opioid Treatment Plan for Managing Chronic Pain

91041 • Developing a Safe Opioid Treatment Plan for Managing Chronic Pain

1. INTRODUCTION

2. INFORMED CONSENT AND TREATMENT AGREEMENTS

3. INITIATING A TRIAL OF OPIOID THERAPY

4. PERIODIC REVIEW AND MONITORING

5. PATIENT AND CAREGIVER EDUCATION

6. CONSULTATION AND REFERRAL

7. MEDICAL RECORDS

8. DISCONTINUING OPIOID THERAPY

9. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 1 Hour Course #94092 • The Mechanism-Based Approach to Pain Management

94092 • The Mechanism-Based Approach to Pain Management

1. INTRODUCTION

2. PRIMARY PAIN TYPES

3. PRIMARY PAIN PATHWAYS AND MECHANISMS OF PAIN

4. PSYCHOLOGIC PAIN MECHANISMS

5. CENTRAL SENSITIZATION IN THE DEVELOPMENT AND MAINTENANCE OF CHRONIC PAIN

6. PAIN THERAPIES AND TARGET MECHANISMS

7. CONCLUSION

8. GLOSSARY

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 3 Hour Course #95151 • Responsible and Effective Opioid Prescribing

95151 • Responsible and Effective Opioid Prescribing

1. INTRODUCTION

2. SCOPE OF THE PROBLEM

3. PAIN MANAGEMENT APPROACHES

4. CREATING A TREATMENT PLAN AND ASSESSMENT OF ADDICTION RISK

5. IDENTIFICATION OF DRUG DIVERSION/SEEKING BEHAVIORS

6. INTERVENTIONS FOR SUSPECTED OR KNOWN ADDICTION OR DRUG DIVERSION

7. COMPLIANCE WITH STATE AND FEDERAL LAWS

8. MANAGEMENT OF OPIOID USE DISORDER

9. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NMPMNP19 • Mandatory Pain Management for NM

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2024 NetCE, All rights reserved.

NMPMNP19 • Mandatory Pain Management for NM

Expiration Date: 10/31/2021

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.

91041 • Developing a Safe Opioid Treatment Plan for Managing Chronic Pain

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2018 NetCE, All rights reserved.

Healthcare professionals should know best clinical practices in opioid prescribing, including the associated risks of opioids, approaches to the assessment of pain and function, and pain management modalities. Patients with moderate-to-severe chronic pain who have been assessed and treated, over a period of time, with non-opioid pharmacologic or nonpharmacologic pain therapy without adequate pain relief are considered to be candidates for a trial of opioid therapy. The treatment plan should always be individualized for the patient and begun as a trial before embarking on a definitive course of treatment.

Table of Contents

91041 • Developing a Safe Opioid Treatment Plan for Managing Chronic Pain

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. INFORMED CONSENT AND TREATMENT AGREEMENTS

CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

3. INITIATING A TRIAL OF OPIOID THERAPY

4. PERIODIC REVIEW AND MONITORING

ASSESSMENT DURING ONGOING OPIOID THERAPY

VIGIL

PSEUDOADDICTION

INVOLVEMENT OF FAMILY MEMBERS

URINE DRUG TESTING

5. PATIENT AND CAREGIVER EDUCATION

SAFE USE OF OPIOIDS

DISPOSAL OF OPIOIDS

6. CONSULTATION AND REFERRAL

7. MEDICAL RECORDS

8. DISCONTINUING OPIOID THERAPY

9. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

91041 • Developing a Safe Opioid Treatment Plan for Managing Chronic Pain

Education Category. Management

Release Date. 11/01/2018

Expiration Date. 10/31/2021

Course Overview

Healthcare professionals should know best clinical practices in opioid prescribing, including the associated risks of opioids, approaches to the assessment of pain and function, and pain management modalities. Patients with moderate-to-severe chronic pain who have been assessed and treated, over a period of time, with non-opioid pharmacologic or nonpharmacologic pain therapy without adequate pain relief are considered to be candidates for a trial of opioid therapy. The treatment plan should always be individualized for the patient and begun as a trial before embarking on a definitive course of treatment.

Audience

This course is designed for physicians, pharmacists, nurses, and physician assistants involved in the care of patients prescribed opioids to treat pain.

Course Objective

The purpose of this course is to provide the information necessary for clinicians to formulate a opioid treatment plan for chronic pain that takes into consideration the risks and benefits of these agents and minimizes the potential for abuse.

Learning Objectives

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

1. Discuss characteristics of appropriate and inappropriate opioid prescribing and contributory factors to both.

2. Compare opioid abuse risk assessment tools and the utility of risk stratification.

3. Outline the appropriate periodic review and monitoring of patients prescribed opioid analgesics, including the role of urine drug testing.

4. Describe necessary components of patient/caregiver education for prescribed opioid analgesics, including guidance on the safe use and disposal of medications.

Faculty

Mark Rose, BS, MA, LP, is a licensed psychologist in the State of Minnesota with a private consulting practice and a medical research analyst with a biomedical communications firm. Earlier healthcare technology assessment work led to medical device and pharmaceutical sector experience in new product development involving cancer ablative devices and pain therapeutics. Along with substantial experience in addiction research, Mr. Rose has contributed to the authorship of numerous papers on CNS, oncology, and other medical disorders. He is the lead author of papers published in peer-reviewed addiction, psychiatry, and pain medicine journals and has written books on prescription opioids and alcoholism published by the Hazelden Foundation. He also serves as an Expert Advisor and Expert Witness to law firms that represent disability claimants or criminal defendants on cases related to chronic pain, psychiatric/substance use disorders, and acute pharmacologic/toxicologic effects. Mr. Rose is on the Board of Directors of the Minneapolis-based International Institute of Anti-Aging Medicine and is a member of several professional organizations.

Faculty Disclosure

Contributing faculty, Mark Rose, BS, MA, LP, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

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

Abimbola Farinde, PharmD, PhD

Division Planners Disclosure

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

About the Sponsor

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

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

Disclosure Statement

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

1. INTRODUCTION

Opioid analgesics can be highly effective in relieving physical and psychologic pain, but some patients are highly susceptible to opioid reward effects. A minority of patients may experience an initial response to opioid therapy of euphoria, stimulation, or intense well-being, and this response is associated with an increased risk for the development of opioid use disorder [17,18].

Healthcare professionals should know best clinical practices in opioid prescribing, including the associated risks of opioids, approaches to the assessment of pain and function, and pain management modalities. The goals of pain treatment include reasonably attainable improvement in pain to decrease suffering and to increase function; improvement in pain-associated symptoms, such as sleep disturbance, depression, and anxiety; screening for side effects of treatment; and avoidance of unnecessary or excessive use of medications [1]. Pharmacologic and nonpharmacologic approaches should be used on the basis of current knowledge in the evidence base or best clinical practices. Patients with moderate-to-severe chronic pain who have been assessed and treated, over a period of time, with non-opioid pharmacologic or nonpharmacologic pain therapy without adequate pain relief are considered to be candidates for a trial of opioid therapy. The treatment plan should always be individualized for the patient and begun as a trial for a defined period of time (usually no more than 30 days) before embarking on a definitive course of treatment [1].

All patients with pain have a level of risk that can only be roughly estimated initially and modified over time as more information is obtained. There are ten essential steps of opioid prescribing for chronic pain to help mitigate any potential problems [2]:

- Diagnosis with an appropriate differential

- Psychologic assessment, including risk of substance use disorders

- Informed consent

- Treatment agreement

- Pre- and post-treatment assessments of pain level and function

- Appropriate trial of opioid therapy with or without adjunctive medication

- Reassessment of patient levels of pain and functioning

- Regular assessment with the 5 A's (i.e., analgesia, activity, adverse effects, aberrant behaviors, and affect)

- Periodically review pain diagnosis and comorbid conditions, including substance use disorders

- Documentation

2. INFORMED CONSENT AND TREATMENT AGREEMENTS

The initial opioid prescription is preceded by a written informed consent or "treatment agreement" [1]. This agreement should address potential side effects, tolerance and/or physical dependence, drug interactions, motor skill impairment, limited evidence of long-term benefit, misuse, dependence, addiction, and overdose. Informed consent documents should include information regarding the risk/benefit profile for the drug(s) being prescribed. The prescribing policies should be clearly delineated, including the number/frequency of refills, early refills, and procedures for lost or stolen medications.

The treatment agreement also outlines joint prescriber and patient responsibilities. The patient agrees to using medications safely, refraining from "doctor shopping," and consenting to routine urine drug tests (UDTs). The prescriber's responsibility is to address unforeseen problems and prescribe scheduled refills. Reasons for opioid therapy change or discontinuation should be listed. Agreements can also include sections related to follow-up visits, monitoring, and safe storage and disposal of unused drugs.

It is important to remember that treatment agreements are only one aspect of developing a safe opioid use plan. The evidence to support the use of such agreements to decrease the misuse of opioids is relatively weak, with little or no proof of improvements in adherence or patient care [19].

CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

For patients 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.

3. INITIATING A TRIAL OF OPIOID THERAPY

Opioid therapy should be presented as a trial for a pre-defined period (e.g., ≤30 days). As noted, the goals of treatment should be reasonable improvements in pain, function, depression, anxiety, and avoidance of unnecessary or excessive medication use [1]. The treatment plan should describe therapy selection, measures of progress, and other diagnostic evaluations, consultations, referrals, and therapies.

In opioid-naïve patients, start at the lowest possible dose and titrate to effect. Dosages for opioid-tolerant patients should always be individualized and titrated by efficacy and tolerability. The need for frequent progress and benefit/risk assessments during the trial should be included in patient education. Patients should also have full knowledge of the warning signs and symptoms of respiratory depression.

Prescribers should be knowledgeable of federal and state opioid prescribing regulations. Issues of equianalgesic dosing, close patient monitoring during all dose changes, and cross-tolerance with opioid conversion should be considered. If necessary, treatment may be augmented, with preference for nonopioid and immediate-release opioids over extended-release/long-acting (ER/LA) opioid formulations. Taper opioid dose when no longer needed [3].

4. PERIODIC REVIEW AND MONITORING

When implementing a chronic pain treatment plan that involves the use of opioids, the patient should be frequently reassessed for changes in pain origin, health, and function [1]. This can include input from family members and/or the state prescription drug monitoring program. Prescription drug monitoring programs are one of the most effective measures for reducing opioid analgesic diversion and abuse, but their efficacy is undermined by inconsistent use [19]. During the initiation phase and during any changes to the dosage or agent used, patient contact should be increased. Decisions regarding the continuation, modification, or termination of opioid therapy for pain should be based on evaluation of the patient's progress and the absence of substantial risks or adverse events [1]. At every visit, chronic opioid response may be monitored according to the 5 A's [4]:

- Analgesia

- Activities of daily living

- Adverse or side effects

- Aberrant drug-related behaviors

- Affect (i.e., patient mood)

ASSESSMENT DURING ONGOING OPIOID THERAPY

Signs and symptoms that, if present, may suggest a problematic response to the opioid and interference with the goal of functional improvement include [4]:

- Excessive sleeping or days and nights turned around

- Diminished appetite

- Inability to concentrate or short attention span

- Mood volatility, especially irritability

- Lack of involvement with others

- Impaired functioning due to drug effects

- Use of the opioid to regress instead of re-engaging in life

- Lack of attention to hygiene and appearance

- Escalation of pain and/or pain medication dose

- Increasing number of medications prescribed to treat the side effects of opioids

The decision to continue, change, or terminate opioid therapy is based on progress toward treatment objectives and absence of adverse effects and risks of overdose or diversion [1]. Satisfactory therapy is indicated by improvements in pain, function, and quality of life. Brief assessment tools to assess pain and function may be useful, as may UDTs. Treatment plans may include periodic pill counts to confirm adherence and minimize diversion.

VIGIL

VIGIL is the acronym for a five-step risk management strategy designed to empower clinicians to appropriately prescribe opioids for pain by reducing regulatory concerns and to give pharmacists a framework for resolving ambiguous opioid analgesic prescriptions in a manner that preserves legitimate patient need while potentially deterring diverters. The components of VIGIL are:

- Verification: Is this a responsible opioid user?

- Identification: Is the identity of this patient verifiable?

- Generalization: Do we agree on mutual responsibilities and expectations?

- Interpretation: Do I feel comfortable allowing this person to have controlled substances?

- Legalization: Am I acting legally and responsibly?

The foundation of VIGIL is a collaborative prescriber/pharmacist relationship [5,6].

Current Opioid Misuse Measure

The Current Opioid Misuse Measure (COMM) is a 17-item patient self-report assessment designed to help clinicians identify misuse or abuse in patients with chronic pain. Unlike the ORT and the SOAPP-R, the COMM identifies aberrant behaviors associated with opioid misuse in patients already receiving long-term opioid therapy [7]. Sample questions include: In the past 30 days, how often have you had to take more of your medication than prescribed? In the past 30 days, how much of your time was spent thinking about opioid medications (e.g., having enough, taking them, dosing schedule)?

Pain Assessment and Documentation Tool

Guidelines by the FSMB and the Joint Commission stress the importance of documentation from both a healthcare quality and medicolegal perspective. Research has found widespread deficits in chart notes and progress documentation with patients with chronic pain receiving opioid therapy, and the Pain Assessment and Documentation Tool (PADT) was designed to address these shortcomings [8]. The PADT is a clinician-directed interview, with most sections (e.g., analgesia, activities of daily living, adverse events) consisting of questions asked of the patient. However, the potential aberrant drug-related behavior section must be completed by the physician based on his or her observations of the patient.

The Brief Intervention Tool

The Brief Intervention Tool is a 26-item, "yes-no," patient-administered questionnaire used to identify early signs of opioid abuse or addiction. The items assess the extent of problems related to drug use in several areas, including drug use-related functional impairment [9].

PSEUDOADDICTION

Patients with inadequately treated pain can develop pseudoaddiction, characterized by aberrant drug-seeking behaviors that mimic opioid use disorder but are driven by desperation for pain relief. In these patients, aggressive complaints of needing higher dosing, openly obtaining opioid analgesics, deception, stockpiling unused medication, and unsanctioned dose escalations resolve with adequate pain control [20,21].

This phenomenon is essential to understand. Many risk mitigation measures fail to consider this as a possibility, and rigid adherence without closer assessment may lead to further withholding of pain treatment from patients already distressed by pain.

INVOLVEMENT OF FAMILY MEMBERS

Family members of the patient can provide valuable information that better informs decision making regarding continuing opioid therapy. Family members can observe whether a patient is losing control of his or her life or becoming less functional or more depressed during the course of opioid therapy. They can also provide input regarding positive or negative changes in patient function, attitude, and level of comfort. The following questions can be asked of family members or a spouse to help clarify whether the patient's response to opioid therapy is favorable or unfavorable [4]:

- Is the person's day centered around taking the opioid medication? Response can help clarify long-term risks and benefits of the medication and identify other treatment options.

- Does the person take pain medication only on occasion, perhaps three or four times per week? If yes, the likelihood of addiction is low.

- Have there been any other substance (alcohol, tobacco, or drug) abuse problems in the person's life? An affirmative response should be taken into consideration when prescribing.

- Does the person in pain spend most of the day resting, avoiding activity, or feeling depressed? If so, this suggests the pain medication is failing to promote rehabilitation. Daily activity is essential, and the patient may be considered for enrollment in a graduated exercise program

- Is the person in pain able to function (e.g., work, do household chores, play) with pain medication in a way that is clearly better than without? If yes, this suggests the pain medication is contributing to wellness.

- Does this patient smoke? Smoking increases pain and reduces the effectiveness of opioids.

URINE DRUG TESTING

UDTs may be used to monitor adherence to the prescribed treatment plan and to detect unsanctioned drug use [1]. They should be used more often in patients receiving addiction therapy, but clinical judgment is the ultimate guide to testing frequency (Table 1) [10]. Although there is a general consensus in pain management guidelines for the use of UDTs prior to initiating and during opioid therapy, evidence supporting the benefits of UDTs in improving patient care is weak [11].

Table 1: MONITORING FREQUENCY ACCORDING TO PATIENT RISK

Monitoring Tool

Patient Risk Level

Low

Medium

High

Urine drug test

Every 1 to 2 years

Every 6 to 12 months

Every 3 to 6 months

State prescription drug monitoring program

Twice per year

Three times per year

Four times per year

Source: [10]

Evidence Based Practice Recommendation

According to the American Society of Interventional Pain Physicians, urine drug testing should be implemented from initiation of treatment with opioids along with subsequent adherence monitoring, in an in-office setting with immunoassay and confirmation for accuracy with chromatography in select cases, to identify patients who are noncompliant or abusing prescription drugs or illicit drugs. Urine drug testing may decrease prescription drug abuse or illicit drug use when patients are in chronic pain management therapy.

http://www.painphysicianjournal.com/2013/april/2013;16;S49-S283.pdf

Last Accessed: October 18, 2018

Level of Evidence: Good (Evidence includes consistent results from well-designed, well-conducted studies in representative populations that directly assess effects on health outcomes.)

Initially, testing involves the use of class-specific immunoassay drug panels [1]. If necessary, this may be followed with gas chromatography/mass spectrometry for specific drug or metabolite detection. It is important that testing identifies the specific drug rather than the drug class, and the prescribed opioid should be included in the screen. Any abnormalities should be confirmed with a laboratory toxicologist or clinical pathologist. Immunoassay may be used point-of-care for "on-the-spot" therapy changes, but the high error rate prevents its use in major clinical decisions unless liquid chromatography is coupled with mass spectrometry confirmation.

Urine test results suggesting opioid misuse should be discussed with the patient using a positive, supportive approach. The test results and the patient discussion should be documented.

Ethical Concerns with UDTs

It is important to appreciate the limitations of UDTs. Healthcare providers are increasingly relying on UDTs as a means to reduce abuse and diversion of prescribed opioids. This has led to a proliferation in diagnostic laboratories that offer urine testing. With this increase have come questions of whether these business interests benefit or hinder patient care, what prescribers should do with the information they obtain, the accuracy of urine screens, and whether some companies and clinicians are financially exploiting the UDT boom [12]. Despite wide endorsement and making intuitive sense, there is little empirical confirmation that UDTs reduce prescription opioid abuse [19].

A random sample of UDT results from 800 patients with pain treated at a Veterans Affairs facility found that 25.2% were negative for the prescribed opioid and 19.5% were positive for an illicit drug/unreported opioid [13]. However, a negative UDT result for the prescribed opioid does not necessarily indicate diversion; it may indicate the patient halted its use due to side effects, lack of efficacy, or pain remission. The increasingly stringent climate surrounding clinical decision-making regarding aberrant UDTs is concerning. In many cases, a negative result for the prescribed opioid or a positive UDT serves as the pretense to terminate a patient rather than an impetus to guide him or her into addiction treatment or an alternative pain management program [12].

In principle, and ideally in practice, UDTs are a worthwhile element of effective pain management and pharmacovigilance when used to enhance the diagnostic and therapeutic objectives of pain therapy. However, immunoassay screens have high false-positive and false-negative rates and only provide qualitative information about a select number of drug classes [11].

As a side note, cannabis use by chronic pain patients receiving opioid therapy has traditionally been viewed as a treatment agreement violation that is grounds for termination of opioid therapy. However, some now argue against cannabis use as a rationale for termination or substantial treatment and monitoring changes, especially considering the increasing legalization of medical use at the state level [14]. In addition, there is a substantive and growing body of research confirming cannabis efficacy (and opioid-sparing effects) in chronic pain conditions, including neuropathic pain, cancer pain, fibromyalgia, and headache pain [22,23,24,25,26].

5. PATIENT AND CAREGIVER EDUCATION

SAFE USE OF OPIOIDS

Patients and caregivers should be counseled regarding the safe use and disposal of opioids. As part of its mandatory Risk Evaluation and Mitigation Strategy (REMS) for ER/LA opioids, the U.S. Food and Drug Administration (FDA) has developed a patient counseling document with information on the patient's specific medications, instructions for emergency situations and incomplete pain control, and warnings not to share medications or take them unless prescribed [3]. A copy of this form may be accessed online at https://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM361110.htm.

When prescribing opioids, clinicians should provide patients with the following information and instructions [3]:

- Product-specific information

- Taking the opioid as prescribed

- Importance of dosing regimen adherence, managing missed doses, and prescriber contact if pain is not controlled

- Warning and rationale to never break or chew/crush tablets or cut or tear patches prior to use

- Warning and rationale to avoid other central nervous system depressants, such as sedative-hypnotics, anxiolytics, alcohol, or illicit drugs

- Warning not to abruptly halt or reduce the opioid without physician oversight of safe tapering when discontinuing

- The potential of serious side effects or death

- Risk factors, signs, and symptoms of overdose and opioid-induced respiratory depression, gastrointestinal obstruction, and allergic reactions

- The risks of falls, using heavy machinery, and driving

- Warning and rationale to never share an opioid analgesic

- Rationale for secure opioid storage

- Warning to protect opioids from theft

- Instructions for disposal of unneeded opioids, based on product-specific disposal information

DISPOSAL OF OPIOIDS

There are no universal recommendations for the proper disposal of unused opioids, and patients are rarely advised of what to do with unused or expired medications. According to the Office of National Drug Control Policy, most medications that are no longer necessary or have expired should be removed from their containers, mixed with undesirable substances (e.g., cat litter, used coffee grounds), and put into an impermeable, nondescript container (e.g., disposable container with a lid or a sealed bag) before throwing in the trash [16]. The FDA recommends that most opioid medications, including oxycodone/acetaminophen (Percocet), oxycodone (OxyContin tablets), and transdermal fentanyl (Duragesic Transdermal System), be flushed down the toilet instead of thrown in the trash [16]. Disposal by flushing down the toilet provides immediate and definitive elimination of safety hazards from intentional use or accidental exposure involving opioid products. All transdermal patch opioid products should be flushed down the toilet after folding in half by adhesive side against adhesive side [27]. Patients should be advised to flush prescription drugs down the toilet only if the label or accompanying patient information specifically instructs doing so. Flushing unused medications has been the subject of controversy, with some state governments and boards recommending against the practice due to pollution concerns and effects on waterways and wildlife [28].

The American Medical Association recommends the following three steps to promote the safe storage and disposal of opioids [15]:

- Educate patients about the safe use of opioids, including not sharing prescriptions with others.

- Remind patients that medications should be stored out reach of children and in a safe place—preferably locked—to prevent other family members and visitors from taking them.

- Talk to patients about the most appropriate way to dispose of expired, unwanted, and unused medications. The preferred option is that unwanted or unused pills, liquids or other medications should be disposed of in a local "take-back" or mail-back program or medication drop box at a police station, pharmacy, or authorized collection site. Contact your state law enforcement agency or visit https://www.dea.gov to determine if a program is available in your area.

6. CONSULTATION AND REFERRAL

It is important to seek consultation or patient referral when input or care from a pain, psychiatry, addiction, or mental health specialist is necessary. Clinicians who prescribe opioids should become familiar with opioid addiction treatment options (including licensed opioid treatment programs for methadone and office-based opioid treatment for buprenorphine) if referral is needed [1].

Ideally, providers should be able to refer patients with active substance abuse who require pain treatment to an addiction professional or specialized program. In reality, these specialized resources are scarce or non-existent in many areas [1]. Therefore, each provider will need to decide whether the risks of continuing opioid treatment while a patient is using illicit drugs outweigh the benefits to the patient in terms of pain control and improved function [14].

7. MEDICAL RECORDS

Documentation is a necessary aspect of all patient care, but it is of particular importance when opioid prescribing is involved. All clinicians should maintain accurate, complete, and up-to-date medical records, including all written or telephoned prescription orders for opioid analgesics and other controlled substances, all written instructions to the patient for medication use, and the name, telephone number, and address of the patient's pharmacy [1]. Good medical records demonstrate that a service was provided to the patient and that the service was medically necessary. Regardless of the treatment outcome, thorough medical records protect the prescriber.

8. DISCONTINUING OPIOID THERAPY

The decision to continue or end opioid prescribing should be based on a joint discussion of the anticipated benefits and risks. An opioid should be discontinued with resolution of the pain condition, intolerable side effects, inadequate analgesia, lack of improvement in quality of life despite dose titration, deteriorating function, or significant aberrant medication use [1].

Clinicians should provide physically dependent patients with a safely structured tapering protocol. Withdrawal is managed by the prescribing physician or referral to an addiction specialist. Patients should be reassured that opioid discontinuation is not the end of treatment; continuation of pain management will be undertaken with other modalities through direct care or referral.

9. CONCLUSION

Opioid analgesic medications can bring substantial relief to patients suffering from pain. However, the inappropriate use, abuse, and diversion of prescription drugs in America, particularly prescription opioids, has increased dramatically and has been identified as a national public health epidemic. Whenever opioids are necessary to manage chronic pain, healthcare professionals should take steps to ensure that these agents are used safely and appropriately.

Works Cited

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13. Sekhon R, Aminjavahery N, Davis CN Jr, et al. Compliance with opioid treatment guidelines for chronic noncancer pain (CNCP) in primary care at a Veterans Affairs Medical Center (VAMC). Pain Med. 2013;14(10):1548-1556.

14. Baxter J. Minimizing the Misuse of Prescription Opioids in Patients with Chronic Nonmalignant Pain. Available at https://www.drugabuse.gov/nidamed/centers-excellence/resources/minimizing-misuse-prescription-opioids-in-patients-chronic-nonmalignant-pain. Last accessed October 10, 2018.

15. American Medical Association. Promote Safe Storage and Disposal of Opioids and All Medications. Available at https://www.aafp.org/dam/AAFP/documents/patient_care/pain_management/safe-storage.pdf. Last accessed October 10, 2018.

16. Office of National Drug Control Policy. Proper Disposal of Prescription Drugs. Available at https://www.ncjrs.gov/ondcppubs/publications/pdf/prescrip_disposal.pdf. Last accessed October 10, 2018.

17. Walwyn
WM, Miotto KA, Evans CJ. Opioid pharmaceuticals and addiction: the issues, and research directions seeking solutions. Drug Alcohol Depend. 2010;108:156-165.

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19. Kaye AD, Jones MR1, Kaye AM, et al. Prescription opioid abuse in chronic pain: an updated review of opioid abuse predictors and strategies to curb opioid abuse (part 2). Pain Physician. 2017;20(2S):S111-S133.

20. Oliver J, Coggins C, Compton P, et al. American Society for Pain Management Nursing position statement: pain management in patients with substance use disorders. Pain Management Nursing. 2012;13:169-183.

21. McPherson ML. Opioids: fears, myths, and misconceptions. PainView. 2011;7:16-18.

22. Aggarwal SK. Cannabinergic pain medicine: a concise clinical primer and survey of randomized-controlled trial results. Clin J Pain. 2013;29:162-171.

23. Marijuana Policy Project. Science, Studies, and Research. Available at https://www.mpp.org/issues/medical-marijuana. Last accessed October 10, 2018.

24. Lynch ME, Ware MA. Cannabinoids for the treatment of chronic non-cancer pain: an updated systematic review of randomized controlled trials. J Neuroimmune Pharmacol. 2015;10:293-301.

25. Lynch ME, Clark AJ. Cannabis reduces opioid dose in the treatment of chronic non-cancer pain. J Pain Symptom Manage. 2003;25:496-498.

26. Bushlin I, Rozenfeld R, Devi LA. Cannabinoid-opioid interactions during neuropathic pain and analgesia. Curr Opin Pharmacol. 2010;10:80-86.

27. U.S. Food and Drug Administration. Where and How to Dispose of Unused Medicines. Available at https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm101653.htm. Last accessed October 10, 2018.

28. California Board of Pharmacy. Don't Flush Your Medicines Down the Toilet! Available at https://www.pharmacy.ca.gov/publications/dont_flush_meds.pdf. Last accessed October 10, 2018.

Evidence-Based Practice Recommendations Citations

1. Manchikanti L, Abdi S, Atluri S, et al. American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: part 2—guidance. Pain Physician. 2012;15(3 Suppl):S67-S116. Available at http://www.painphysicianjournal.com/2013/april/2013;16;S49-S283.pdf. Last accessed October 18, 2018.

94092 • The Mechanism-Based Approach to Pain Management

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2019 NetCE, All rights reserved.

An emerging paradigm in chronic pain treatment is a mechanism-based approach (MBA). MBA involves targeting the pathological reorganization in nervous system structure and function that are now recognized as contributing to the onset and perpetuation of pain chronicity. The neuroscience that supports MBA is recently emergent and vastly complex. Clinician knowledge of this neuroscience and how it informs treatment selection will greatly broaden their therapeutic options, and understanding the theoretical and evidence basis of MBA is likely to provide primary care physicians and other pain practitioners with treatment solutions to many of the vexing problems traditionally encountered in the treatment of chronic pain.

Table of Contents

94092 • The Mechanism-Based Approach to Pain Management

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

1. INTRODUCTION

2. PRIMARY PAIN TYPES

3. PRIMARY PAIN PATHWAYS AND MECHANISMS OF PAIN

NOCICEPTIVE PAIN

INFLAMMATORY PAIN

ACUTE NEURAL INJURY AND NEUROPATHIC PAIN

CENTRALIZED PAIN SYNDROMES

4. PSYCHOLOGIC PAIN MECHANISMS

5. CENTRAL SENSITIZATION IN THE DEVELOPMENT AND MAINTENANCE OF CHRONIC PAIN

6. PAIN THERAPIES AND TARGET MECHANISMS

PHARMACOTHERAPIES

NONPHARMACOLOGIC THERAPIES AND A MULTIMODAL APPROACH

7. CONCLUSION

8. GLOSSARY

Works Cited

Evidence-Based Practice Recommendations Citations

94092 • The Mechanism-Based Approach to Pain Management

Education Category. Infection Control / Internal Medicine

Release Date. 11/01/2019

Expiration Date. 10/31/2022

Course Overview

An emerging paradigm in chronic pain treatment is a mechanism-based approach (MBA). MBA involves targeting the pathological reorganization in nervous system structure and function that are now recognized as contributing to the onset and perpetuation of pain chronicity. The neuroscience that supports MBA is recently emergent and vastly complex. Clinician knowledge of this neuroscience and how it informs treatment selection will greatly broaden their therapeutic options, and understanding the theoretical and evidence basis of MBA is likely to provide primary care physicians and other pain practitioners with treatment solutions to many of the vexing problems traditionally encountered in the treatment of chronic pain.

Audience

This course is designed for practitioners involved in the care of patients with pain.

Course Objective

The purpose of this course is to provide primary care clinicians and nurses with a brief review of current concepts of the pathogenesis and persistence of chronic pain, and the clinical utility of a mechanism-based approach to pain management. The goal is to promote a broader understanding of the underlying neuroscience, and thus a more effective strategy for alleviating the suffering imposed by chronic pain.

Learning Objectives

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

1. Outline the primary pain types.

2. Identify the underlying mechanisms of pain.

3. Evaluate the factors involved in the transformation of acute to chronic pain and the pathways that perpetuate chronic pain.

4. Describe the interaction of pain mechanisms and the importance of central sensitization to devising a strategy for chronic pain management.

Faculty

Mark Rose, BS, MA, LP, is a licensed psychologist in the State of Minnesota with a private consulting practice and a medical research analyst with a biomedical communications firm. Earlier healthcare technology assessment work led to medical device and pharmaceutical sector experience in new product development involving cancer ablative devices and pain therapeutics. Along with substantial experience in addiction research, Mr. Rose has contributed to the authorship of numerous papers on CNS, oncology, and other medical disorders. He is the lead author of papers published in peer-reviewed addiction, psychiatry, and pain medicine journals and has written books on prescription opioids and alcoholism published by the Hazelden Foundation. He also serves as an Expert Advisor and Expert Witness to law firms that represent disability claimants or criminal defendants on cases related to chronic pain, psychiatric/substance use disorders, and acute pharmacologic/toxicologic effects. Mr. Rose is on the Board of Directors of the Minneapolis-based International Institute of Anti-Aging Medicine and is a member of several professional organizations.

Faculty Disclosure

Contributing faculty, Mark Rose, BS, MA, LP, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Ronald Runciman, MD

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

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.

1. INTRODUCTION

According to the Institute of Medicine, more than 116 million persons in the United States suffer with pain that persists for weeks to years, at an annual cost estimated to exceed $560 million [1]. Clearly, chronic pain is among the most common of afflictions, and relief from pain is difficult to come by. Impediments to effective pain relief are multiple. These include limited access to practitioners with the requisite knowledge, experience, and patience required to effectively manage this difficult clinical issue; patients' misunderstanding of the complex nature of pain and the limitations of prescription analgesia; outmoded or poorly informed clinical practices by some who either overprescribe medication, including opioids, or underprescribe for fear of violating government regulations. The current climate of clinical care for the patient with pain is further challenged by the ongoing epidemic of opioid misuse and diversion. Then, there are differences in expectations and outcomes related to psychologic make-up, life experiences, age, education, and past medical history [1].

Chronic pain is now known to have a distinct pathologic basis, with functional and structural changes in multiple areas of the nervous system that can worsen over time [1,87]. These adaptive changes may have psychologic and cognitive correlates that add to the complexity of chronic pain and influence response to therapy. A mechanism-based approach (MBA) to the treatment of pain is an emerging strategy driven by discoveries in pain neuroscience. MBA involves therapeutic targeting of the pathologic reorganization in nervous system structure and function that underlies chronic pain. The objective of this approach is to more effectively treat chronic pain and to prevent or minimize the risk of developing chronic pain.

A key foundation of MBA involves the concept of acute versus chronic pain. Traditionally, chronic pain has been defined as acute pain that persists beyond an arbitrarily selected temporal cut-off point (typically three to six months) from onset, or persistent pain beyond expected resolution. However, this concept of chronic pain as a continuation of acute pain no longer appears to be valid. Most chronic pain syndromes, even those that persist following acute injury or inflammation, reflect an acquired, dynamic neurophysiologic condition having multiple, complex mechanisms. Chronic pain is now known to develop from abnormal sensory processing and neuronal plasticity in peripheral and central pain pathways [2,3,4]. Based on this understanding, acute pain may persist for extended periods without the underlying mechanism undergoing a "chronification" [5].

The first step in managing pain is to identify the disease, lesion, or injury origin of pain, which until recently comprised the entire diagnostic process [6]. Evidence now strongly supports the use of MBA to classify pain conditions by the type of maladaptive nervous system alteration. This approach provides a comprehensive dual therapeutic focus that targets the pathologic sustaining mechanism of the pain and the original disease, lesion, or tissue injury [6,7]. Such an approach is now believed to optimize pain diagnosis and treatment by avoiding the limitations associated with the traditional etiology-based approach [3,4,9,10,11,12].

Importantly, MBA is not meant to replace the traditional approach of targeting the original anatomic cause of pain, which remains essential when indicated. By addressing the underlying pain pathophysiology, MBA aims to prevent the development of maladaptive plasticity and peripheral and central sensitization that characterize chronic pain and to promote normalized function of pain mechanisms [4,13,14].

The neuroscience that supports MBA is emergent. Knowledge of this neuroscience and how it informs treatment selection holds great promise for broader and more effective therapeutic options. Understanding the theoretical and evidence basis of MBA may provide primary care providers with treatment solutions to many vexing problems traditionally encountered in treating chronic pain. These include patient complaints of severe pain in the absence of apparent physiologic or anatomic cause, the failure to achieve a satisfactory therapeutic response to conventional analgesics such as non-steroidal anti-inflammatory drugs (NSAIDs) and opioids, and the loss of analgesic effectiveness in patients who have progressed from acute stage to chronic pain syndromes. MBA also explains why some pain therapies are ineffective and informs the clinician regarding potentially effective augmentation strategies to enhance pain control and reduce opioid requirements [3,4,6].

Pain neuroscience is exceptionally complex. The material obtained from the scientific literature and presented in this course is greatly simplified and reduced, and effort has been made to highlight pain mechanisms for which known therapies have been identified as targeting.

2. PRIMARY PAIN TYPES

Most pain syndromes involve multiple, often overlapping, neurobiologic mechanisms determined by the stage of the disease process. Current concepts of pain classify these into four main categories: nociceptive, inflammatory, neuropathic, and centralized [15].

Nociceptive pain is a physiologic response to tissue injury, the perception that arises from intense stimulation of specialized peripheral sensory neurons (nociceptors) that respond only to noxious (pain) stimuli. Nociceptive pain is subgrouped by location of involved tissues into somatic pain (muscle or connective tissue) and visceral pain (visceral structures) [13]. Nociceptive pain is considered adaptive during tissue healing but maladaptive and pathologic when it persists after healing has occurred.

Inflammatory pain occurs in response to tissue injury or infection that activates peripheral nociceptors, and initiates the immune response. While the resultant production and recruitment of pro-inflammatory mediators to the injury site may serve to perpetuate discomfort, it also facilitates tissue repair; thus, this is considered an adaptive pain mechanism [15].

Neuropathic pain originates from peripheral or central nervous system injury. Unlike nociceptive and inflammatory pain, the mechanism of neuropathic pain has no adaptive function and is strictly pathologic [4,16]. Acute pain from somatosensory damage is termed "acute neural injury." The term "neuropathic pain" implies pain that persists beyond the period of expected or actual tissue healing, and the underlying mechanism involves a maladaptive alteration in somatosensory nervous system function [11].

Centralized pain results from heightened nociceptive sensitivity in the absence of detectable peripheral stimulus and with negligible peripheral inflammatory pathology. The mechanism is poorly understood and is regarded as strictly pathologic as it lacks any evident adaptive function. Centralized pain syndromes include conditions such as fibromyalgia, tension headache, and irritable bowel syndrome [4,13,14].

3. PRIMARY PAIN PATHWAYS AND MECHANISMS OF PAIN

Whether pain originates from tissue injury, tissue infection, or peripheral nerve injury, similar mechanistic processes relay the nociceptive, inflammatory, or neuropathic pain impulse from the site of peripheral origin to the brain. This involves transduction, signaling, transmission, modulation, and perception of the pain impulse. These processes occur along a similar series of interconnected pathways, initially in the peripheral nervous system and spinal cord and then the mid-brain and cerebral cortex of the central nervous system (CNS).

Understanding the anatomy and physiology of normal pain perception is important, because altered structure and function of these mechanisms and pathways characterize chronic pain and represent therapeutic targets for a mechanism-based approach to pain treatment. Intercellular, cellular, and molecular contributions to pain impulse generation and propagation are highly complex, and the material presented in the following section is simplified.

NOCICEPTIVE PAIN

There are five stages of pain processing and location in the broader pain pathway. The first is transduction. Acute injury or damage to peripheral tissue initiates transduction (translation) by nociceptors of the physical stimulus into an electrical signal [4,17]. This involves noxious or inflammatory stimuli activating peripheral terminals of nociceptors. The stimulus is transduced into an electrical impulse via voltage-gated sodium channels (NaVs) and transient receptor-potential channels (e.g., TRPV1, TRPA1). Nociceptive receptor activation initiates peripheral nerve depolarization that, if sufficient, activates NaVs to trigger a burst of action potentials. The frequency and duration of the action potentials are determined by the intensity of the noxious stimuli. Nociceptor transduction and depolarization are influenced by neurochemical contributions from tissues, inflammatory cells, and the neuron itself.

The second stage is signaling, during which the pain impulse is relayed along the neuron from peripheral nociceptor terminals to the dorsal horn of the spinal cord [4,18]. Specifically, signaling involves the relay of action potentials along the nerve fiber, and the type of fiber carrying the signal influences pain quality. Sodium ions enter during depolarization, and then potassium ions leave to restore baseline negative charge.

In nociceptor neurons, signaling involves three types of primary afferents [17]:

- A-Beta fibers: Myelinated, large-diameter fibers that respond primarily to non-noxious stimuli such as touch or vibration

- A-Delta fibers: Myelinated, small-diameter fibers that rapidly carry sharp, well-localized pain signals

- C-fibers: Transmit delayed, long-lasting, dull, poorly localized pain from the injury area. Because they are unmyelinated, C-fibers are more easily damaged and bear the brunt of injury in herpes zoster (shingles) and painful diabetic neuropathy. Not surprisingly, the quality of pain in these conditions is often a burning allodynia.

Following signal entry into the dorsal horn of the spinal cord, transmission begins. This involves movement of the pain signal across the synaptic cleft (juncture) between the primary afferent neuron and the second-order ascending neuron for relay to the brain [10,11]. To enhance movement across the synaptic cleft, transmitter chemicals are released from the presynaptic afferent neurons, including substance P, cholecystokinin, calcitonin gene-related peptide (CGRP), and glutamate, the most widespread excitatory amino acid in the CNS [16,17,19]. The signal is relayed postsynaptically by ascending spinal pathways to supra-spinal sites. Some ascending pathway axons synapse with thalamic nuclei, which project by relay neurons to various cortical regions. These cortical regions and their contribution to pain processing include [4,20,21]:

- Primary somatic sensory cortex (mediates perception of pain intensity and location)

- Insular cortex (perception and affective components of pain)

- Cingulate cortex (processes the emotional response to pain)

- Insular and anterior cortical regions (mediate behavioral, emotional, and autonomic response to pain)

Other axonal projections enter limbic system regions involved in emotional response to pain, including the insula, amygdala, and cingulate cortex.

Modulation is the process whereby the intensity of pain signaling is weakened or amplified [4,21,22,23,24]. Modulation can follow an ascending or descending pathway.

Within ascending pathways, modulation of sensory pain begins in the dorsal root ganglion and dorsal horn neurons of the spinal cord, and then subsequently occurs at numerous neuraxis levels through involvement of endorphins, neurokinins, prostaglandins, biogenic amines, gamma-aminobutyric acid (GABA), neurotensin, cannabinoids, and purines. Glutamate facilitates pain signaling in the spinal cord and throughout most of the CNS. Several receptors mediate the action of glutamate; these include the ionotropic receptors alpha-amino-3-hydroxy-5-methyl-4-izoxazolepropionic acid (AMPA), kainate, N-methyl-D-aspartate receptors (NMDA); and the metabotropic glutamate receptor.

Descending pathway modulation involves limbic, cortical, and thalamic structures projecting to excitatory glutamatergic neurons in the periaqueductal gray (PAG) matter [4,16]. The glutamate neurons activate other neurons in the descending inhibitory pathway, which inhibit nociceptive transmission in the spinal cord through chemical signaling. Endogenous opioids activate pre- and post-synaptic opioid receptors in dorsal horn neurons. Noradrenergic inhibition originates in the locus coeruleus/subcoeruleus and travels to the spinal cord via the ventromedial funiculus. Norepinephrine released from these inhibitory terminals acts via presynaptic alpha-2 adrenergic receptors.

The dorsal horn neurons weaken pain transmission by regulating serotonergic neurons in the raphe nuclei and noradrenergic neurons in the reticular formation. This is achieved through:

- Release of endogenous opioids, norepinephrine, and serotonin in the dorsal spinal cord

- Recruitment of inhibitory interneurons that release GABA

- Direct inhibition of pain projection neurons

Input from cortical structures and the amygdala partially accounts for the influence of cognitive and emotional processes on pain intensity and experience [25].

In the non-pathologic state, only a small proportion of pain signals relayed to the spinal cord reach the thalamus, due to modulatory influences on synaptic transmission of sensory inputs in the dorsal horn, ascending, and descending pathway sites [4].

The final stage of pain processing is perception, the subjective pain experience resulting from interaction between transduction, transmission, and modulation with the psychologic state or traits of the individual [3,26,27,28,29,30]. These states/traits include attention, anticipation, fear/anxiety, empathy, reward, placebo, and direct control. Brain regions that mediate cognitive and emotional pain processing include the prefrontal cortex and primary and secondary somatosensory cortices; limbic system structures; and the hypothalamus. This diverse brain region involvement in pain response is termed the "distributed network." Most importantly, these same brain regions can undergo neuroplastic change and functional alteration as the result of intense or prolonged nociceptive signal barrage.

INFLAMMATORY PAIN

The process of inflammatory pain generation and relay is similar to that described for nociceptive pain, but it also involves inflammatory mediators released at the injury site that trigger nociceptor activation [4,11,31,32,33,34]. Peripheral tissue injury or infection releases the pro-inflammatory factors ATPase, potassium ions, chemokines, cytokines, prostaglandins, and nerve growth factors. The inflammatory mediators interleukin-1β and tumor necrosis factor (TNF)-α activate the release of cyclooxygenase (COX)-2, which generates prostaglandin PGE2, a vasodilator that produces pain and edema [18,35]. TRPV1 and TRPA1 in peripheral nociceptor terminals are stimulated by signaling from pro-inflammatory molecules and activate nociceptors. Bradykinin, prostaglandins, and nerve growth factor activate C-fibers, normally unresponsive to non-inflammatory stimuli. C-fiber and nociceptor activation then facilitates afferent signal transmission to the spinal cord and initiates the changes that lead to peripheral sensitization.

ACUTE NEURAL INJURY AND NEUROPATHIC PAIN

Neuropathic pain has been defined as pain originating from a lesion or disease affecting the somatosensory system [36]. This definition emphasizes the sensory pathway as the pathophysiologic locus and reflects the progress made in elucidating neuropathic pain mechanisms [37].

Neuropathic pain conditions are diverse in etiology and mechanism and may originate from infection, metabolic disorders, surgery, nerve entrapment or compression, chemotherapy or radiation, and ischemic injury [38,39]. Distinct mechanisms account for neuropathic pain but are nonspecific as to type of syndrome. Neuropathic pain may arise concurrently with nociceptive pain [40]. Neural damage is necessary but not sufficient for neuropathic pain to develop; the initiating condition must interact with the genotype, diet, and lifestyle of the individual [6].

Acute neural pain and neuropathic pain develop following neural damage that induces a neuroma (a regenerative nerve sprout) at the proximal nerve stump [6,11,38,39,40,41]. Dysregulated voltage-gated sodium channel and non-selective cation channel TRPV1 expression at the damage site and in dorsal root ganglion A-Beta fibers lead to primary afferent hyperexcitability (e.g., lowered threshold and higher firing rate) and ectopic firing, respectively. Peripheral immune cells and microglia in the dorsal root ganglia of both injured and uninjured ipsilateral adjacent afferents release interleukin-1β, TNF, bradykinin, and nerve growth factor, which contribute to neuropathic pain by activating nociceptive neurons.

CENTRALIZED PAIN SYNDROMES

Patients with chronic, diffuse hyperalgesic pain in the absence of obvious peripheral origin have traditionally received diagnostic labels of idiopathic or functional pain, functional somatic syndrome, and somatization. A number of prevalent disorders, about which the general public is increasingly aware, fall into this category, including irritable bowel syndrome, fibromyalgia, chronic fatigue syndrome, temporomandibular joint disorder, and myofascial pain syndrome [42]. Common underlying mechanisms in these conditions, now termed centralized pain syndromes or central sensitivity syndromes, have been identified and include heritable pain sensitivity combined with neuroplastic CNS alteration. This sensitivity and CNS alteration results in augmented pain transmission and amplified sensory inputs [42]. Although pain can be localized (as with temporomandibular joint disorder or generalized (as with fibromyalgia), differences in clinical presentation are now thought to reflect the manifestation of a shared disease state [4,43]. This construct of a centralized pain sensitivity condition has moved beyond the narrow consideration in functional pain syndromes to broader recognition of its essential contribution to pain in many chronic peripheral pain conditions. Therapeutic targeting of central pain is necessary for pain control in these patients [42,44,45].

Overlapping or shared characteristics in centralized pain syndromes include [42,43,44,45,46,47,48,49,50,51,52]:

- Multifocal pain, fatigue, insomnia, cognitive or memory problems, and, in many cases, psychologic distress

- Broad variation in symptom presence and severity

- Strong familial predisposition and unambiguous evidence that these syndromes are separable from depression and other psychiatric conditions

- Initiation or exacerbation by a broad range of biologic and psychologic stressors

- Presence of diffuse hyperalgesia and/or allodynia and often hypersensitivity to non-pain sensory input

- Neurogenic inflammation, especially of mucosal surfaces, resulting in increased mast cells and the appearance of a mild inflammatory process, autonomic nervous system dysfunction, and hypothalamic pituitary dysfunction

- Lack of response to traditional pain treatments for nociceptive or inflammatory pain

- Effectiveness of the same drug and non-drug therapies among these conditions

In centralized pain syndromes, widespread musculoskeletal pain and hyperalgesia are induced by pH-dependent (acidity-sensing) ion channel-3 activation and suppressed by neurotrophin-3 inhibition [53]. Pain sensitivity and response is inhibited by the action of serotonin-norepinephrine and opioidergic descending pathway projections to the dorsal horn of the spinal cord. Alteration in descending inhibitory pathway function diminishes analgesia and promotes hyperalgesia and allodynia in patients with centralized pain syndromes. Central sensitization results from glutamate action on NMDA receptors, which increases intracellular calcium levels and kinase activation to initiate hyperalgesia and allodynia [54].

4. PSYCHOLOGIC PAIN MECHANISMS

Although the concept of central sensitization as a mechanism of chronic pain was first described in reference to the dorsal horn of the spinal cord, similar synaptic plasticity with functional and structural alteration has been found in regions of the brain that mediate pain-related emotion and memory, including sensorimotor, limbic, and pre-frontal systems [55,56,57]. These may represent a substrate for chronic cognitive, emotional, and memory changes that are learned and retained—for example, conditioned fear and memory [11]. Pain is perceived via ascending nociceptive pain fibers that activate a complex system of pathways within diverse regions of the brain. Once activated, this system encodes nociceptive pain for location, intensity, quality, duration, and emotional association. The level of attention, distraction, and manipulation of mood also impact the degree of perceived pain, a reflection of the importance of psychologic factors in the chronic pain experience [15].

A 2019 narrative review, based on a neuroscience literature review to identify processes affecting pain chronification, examined the association between memory and the development of chronic pain, showing that chronic pain and memory interact closely on several levels [86]. Anatomically, the regions of the brain central to encoding and consolidation of memory are also implicated in experimental aspects of pain. Encoding of chronic pain and of memory is mediated by common neurotransmitters and involves similar mechanisms of neural plasticity, such as central sensitization. Serial imaging studies show that the transition to chronic pain is accompanied by spatiotemporal reorganization of brain activity, during which the representation of pain gradually shifts to emotional and limbic structures. The authors conclude that chronic pain can be seen, at least in part, as the persistence of the memory of pain and/or the inability to extinguish painful memories [86].

The relationship between emotion and pain perception is complex, and potentially reinforcing and potentiating. Pain involves active CNS regulation through excitatory and inhibitory modulation, primarily involving brainstem nuclei projections to the dorsal horn [15]. Forebrain centers and their products, including cognition, emotion, attention, and motivation, substantially influence brainstem nuclei and subjective pain experience. Specific cognitive styles and personality traits, such as somatization, catastrophizing, and hypervigilance, can amplify pain, sensitize dorsal horn spinal cord neurons and second-order pain pathway neurons, and prolong the development, amplification, and maintenance of persistent pain. Behavioral and cognitive therapies likely affect synaptic transmission in the spinal cord via descending pathways, and thus may prevent or reverse the long-term changes of synaptic strength in pain pathways [19,58,59,60].

5. CENTRAL SENSITIZATION IN THE DEVELOPMENT AND MAINTENANCE OF CHRONIC PAIN

In recent decades, neuroscience has advanced understanding of the pathogenesis of chronic pain, specifically in relation the process of central sensitization within the neocortex of the brain, a process that has important implications for patient education and pain management [87]. The transformation of acute into chronic pain occurs with the development of central sensitization that is usually, but not always (as with centralized pain syndromes), preceded by peripheral sensitization. The persistence of pain beyond the period of tissue healing, whether from nociceptive, inflammatory, or neural injury, indicates that ongoing nociceptive activity has become dissociated from peripheral input and that a pathologic alteration in pain processing and perception has developed involving peripheral and central pain pathways. The pain feels as if the origin involves peripheral tissue, but it is actually a manifestation of abnormal sensory processing within the CNS [10].

Central sensitization is often preceded by peripheral sensitization, the result of alteration in the transduction proteins and ion channels that determine nociceptor terminal excitability. With peripheral sensitization, inflammatory mediators such as adenosine triphosphate (ATP) are released by tissue damage to activate peripheral nociceptor terminals, producing the sensation of pain. Inflammatory cells such as neutrophils become activated and produce other chemical mediators that generate COX-2, which generates prostaglandin PGE2. PGE2 alters pain sensitivity by amplifying response and dropping response threshold to stimuli in peripheral nociceptors.

In general, the development of central sensitization follows several overlapping neurologic events. Peripheral tissue damage generates intense or protracted nociceptive signaling to the dorsal spinal cord. Signaling and molecular barrage from pre-synaptic afferents across the synaptic juncture stresses post-synaptic terminals of second-order ascending neurons. This causes receptor membranes to depolarize and excitatory receptors to activate. A cascade of events is initiated that alters synaptic receptor density, threshold, kinetics, and activation and dramatically increases pain transmission [4,25]. The resultant state of CNS stimulation and dysfunction is characterized by amplified pain signaling, nociceptor excitation, substantial drop in pain response threshold, pathologic loss of anti-nociceptive pain inhibition, and augmented descending pathway facilitation [11,61]. This activity is enhanced by cognitive-emotional factors such as stress, anger, and catastrophic beliefs and fear concerning the future. These factors are known to facilitate pain, in part by inducing a state of cognitive-emotional sensitization within the CNS that results in more severe pain [87]. Pain hypersensitivity, allodynia, hyperalgesia, and enhanced temporal summation of pain perception with central sensitization underlie many chronic pain conditions.

There is growing evidence that neuroinflammation in the peripheral and central nervous systems plays an important role in promoting central sensitization and the perpetuation of chronic pain [88]. Central to this process is the activation of glial cells (microglia and astrocytes) within the spinal cord and brain that stimulates the release of proinflammatory cytokines and chemokines. Glial cells are part of the non-neuronal matrix within the nervous system that provides supportive physiologic functions. Peripheral nerve injury stimulates the local production of prostanoids, causing widespread induction of COX-2 and macrophage activation. The macrophages activate lymphocytes, which in turn release cytokines and chemokines. These activate microglia and astrocytes, which augment the inflammatory response via the signaling molecules ATP, fractalkine, monocyte chemotactic protein-1, proinflammatory cytokines, nitric oxide and glutamate. Studies show that cytokines and chemokines are powerful neuromodulators that play a role in inducing allodynia and hyperalgesia; their sustained release within the CNS also promotes chronic widespread pain affecting multiple body sites [62,64,88].

Activation of microglia is associated with several mechanisms that underlie central sensitization within the CNS. These include synthesis and release of neurotrophic factors that increase neuronal excitability, enhanced synaptic efficacy in patients with chronic pain, and activation of astrocytes, which is important in maintaining neural circuit and mediating inflammation via release of cytokines [87]. Increased glial activation and astrocyte-mediated neuroinflammatory markers have been demonstrated in patients with chronic non-specific low back pain, fibromyalgia, and lumbar radiculopathy [87]. Neuroinflammation is now recognized as possibly mediating the persistence and chronification of many human pain conditions [88].

Neuroplasticity is the cellular-level process whereby neuronal cytoarchitecture is physically remodeled. It accounts for the development of central sensitization and represents the core process by which acute pain transitions to a chronic pain syndrome. Intense or persistent acute pain generates peripheral nociceptive signal transmission to the dorsal root ganglia and thence to the relay neurons within the dorsal horn of the spinal cord. This input stimulates the release of glutamate and the neuropeptides substance P and CGRP from afferent neurons into the synaptic cleft between afferents and second-order dorsal horn neurons. With sufficient signaling barrage, post-synaptic NMDA receptor membranes depolarize, removing the Mg2+ ion that blocks the NMDA receptor channel. The NMDA channel complex is now primed and readily activated by the surge in presynaptic glutamate release, which induces cellular Ca2+ influx and initiates protein kinase C activity. Protein kinase C then activates nitric oxide synthase and production. From this second-order dorsal horn neuron, nitric oxide diffuses through the membrane and synaptic cleft into the nociceptor to close K+ channels by stimulating guanyl synthase. This enhancement in channel conductance and receptor membrane trafficking contributes to prolonged membrane depolarization [23,61,62].

Post-synaptic NMDA receptor activation in the spinal cord (and eventually in the thalamus, limbic system, and cerebral cortex) is the greatest contributor to the development of central sensitization. A far-reaching cascade is generated, resulting in altered balance between pro- and anti-nociceptive neurotransmitters [25,54,62,63].

6. PAIN THERAPIES AND TARGET MECHANISMS

Strategies for managing chronic pain will increasingly rely on identification and targeting of the specific neurophysiologic mechanism(s) and molecular components responsible for pain generation and/or maintenance.

Peripheral tissue injury, damage, or inflammation initiates prostaglandin release at the injury site, where its precursor action helps propel the pain impulse from peripheral nociceptor terminals to the spinal cord. Prostaglandin PGE2 produces pain and edema and is highly active in arthritis and musculoskeletal injuries. NSAIDs inhibit the synthesis of PGE2 [18,35].

Action potentials, produced by the exchange of ions along the inner and outer neuron membrane, relay the pain signal from peripheral injury site to the spinal level. Action potentials can be suppressed with local anesthetics and anticonvulsants by blocking membrane ion influx and efflux [18,35].

Within the dorsal horn of the spinal cord, primary afferent neurons release transmitter molecules across the synaptic cleft to facilitate pain signal transmission to ascending neurons for relay to the brain. These neurotransmitters include substance P, cholecystokinin, CGRP, and glutamate. The presynaptic terminal is a major activity site of opioids and cannabinoids, and gabapentin and pregabalin act on the alpha-2-delta subunit of voltage-gated calcium channels to inhibit pain transmitter release here [18,35].

The pain signal is transmitted by ascending spinal neurons and enters the brain via the PAG, the reticular formation, and thalamus. It is then distributed to the limbic system and cortical structures. The PAG contains a high density of opioid receptors and is a site of opioid binding to induce analgesia [35].

The descending pain pathway originates in higher brain centers and descends to the spinal cord, inhibiting pain signaling through the release of endogenous opiates, serotonin, and norepinephrine. At this site, TCAs and SNRIs reduce pain by blocking serotonin and norepinephrine reuptake [18,35].

PHARMACOTHERAPIES

Topical Agents

Local Anesthetics

The local anesthetics lidocaine and bupivacaine block Na+ influx of voltage-gated ion channels in afferent neuron terminals, inhibiting depolarization and generation of action potentials, resulting in the transmission of fewer nociceptive impulses to the spinal cord. In clinical application, topical lidocaine is used for neuropathic pain to block hyperactive sodium ions in damaged peripheral nerves and inhibit transmission of ectopic impulses to the dorsal horn. This action interferes with peripheral and central sensitization and maladaptive neuroplasticity [66,67].

Capsaicin

Capsaicin defunctionalizes nerve fiber terminals through multiple mechanisms to produce analgesia. The initial reduction in neuronal excitability and responsiveness result from inactivation of voltage-gated sodium channels and direct desensitization of plasma membrane TRPV1 receptors. This is followed by extracellular Ca2+ entry of TRPV1 and release from intracellular stores to overwhelm the TRPV1 receptor intracellular Ca2+ buffering capacity, subsequent activation of calcium-dependent proteases, and cytoskeleton breakdown [37,61]. The persistent effect involves extracellular Ca2+ entry of TRPV1 and release from intracellular stores to overwhelm TRPV1 receptor intracellular Ca2+ buffering capacity, subsequent activation of calcium-dependent proteases, and cytoskeleton breakdown [37,61]. Capsaicin is available as a high-potency (8%) patch and as a lower-concentration cream. A single 60-minute application may provide up to 12 weeks of analgesia [66]. Capsaicin may initially cause pain because substance P is released from nociceptive terminals to initiate nociceptive firing. The analgesic response follows as nociceptive terminals desensitize to elevate pain threshold [68].

NSAIDs and Acetaminophen

NSAIDs alleviate pain by inhibiting the conversion of arachidonic acid to prostaglandins catalyzed by COX isozymes. Nonselective NSAIDs inhibit COX-1 and COX-2 and include ibuprofen, aspirin, and naproxen. The nonselective action inhibits the formation of both gastroprotective-mediating prostaglandins and pain-promoting prostaglandins, increasing the risk of serious toxicities such as gastrointestinal (GI) ulceration and bleeding. This prompted the development of selective COX-2 inhibitors, which produce fewer GI side effects but are linked with an increased risk of cardio-renal morbidities [67]. To mitigate risk of GI adverse events, proton pump inhibitors are recommended for use in some patients using NSAIDs [69].

Acetaminophen is available over the counter and is also included in combination with many prescription opioids. Analgesia is achieved through central but not peripheral inhibition of prostaglandin. Although effective in mild pain, acetaminophen is not anti-inflammatory. The side-effect profile is relatively benign with intermittent use at recommended labeled dosing, but long-term or high-dose use can be hepatotoxic, and the daily dose should never exceed 4 g. Acetaminophen is recommended over NSAIDs as an analgesic in patients with GI, renal, or cardiovascular comorbidity [70].

Anticonvulsant Drugs

Gabapentinoids

Gabapentin and pregabalin are effective in a wide range of neuropathic pain conditions. Their mechanism of action involves selective binding to and blockade of the α2δ1 subunit of voltage-gated calcium channel in various brain regions and the superficial dorsal spine. This inhibits the release of glutamate, norepinephrine, and substance P to decrease spinal cord levels of neurotransmitters and neuropeptides [23,66,71]. The binding affinity of pregabalin for the calcium channel α2δ1 subunit is six times greater than gabapentin, which is reflected in the greater efficacy of pregabalin at lower doses. Because gabapentin possesses a shorter half-life and nonlinear absorption, pregabalin is easier to titrate and better tolerated [71].

Lacosamide

Lacosamide can produce antinociceptive effects through the modulation of collapsin-response mediator protein 2, which inhibits the NMDA receptor subunit NR2B. Several clinical trials have confirmed its efficacy in painful diabetic neuropathy, and a 2.5-year follow-up study confirmed its long-term safety profile and sustained efficacy [71].

Topiramate

Topiramate is used clinically in neuropathic pain syndromes and migraine headache prophylaxis. It is characterized by a complex mechanism of action involving suppression of action potentials with sodium-channel and calcium-channel blockade; GABA receptor; and AMPA receptor antagonism and kainate inhibition. Topiramate is also a glutamate antagonist, the only anticonvulsant drug for which this action is prominent [72].

Antidepressants

Tricyclic Antidepressants

Tricyclic antidepressants (TCAs) are widely used in neuropathic pain. A TCA's mechanism involves blocking pre-synaptic reuptake of norepinephrine and serotonin; inhibition of neuronal membrane ion channels by reducing neuronal influx of calcium or sodium ions; and activity with adenosine and NMDA receptors [68]. A primary site of analgesic action is the descending modulatory pathway, where monoamine reuptake inhibition elevates norepinephrine and serotonin levels to enhance endogenous nociceptive inhibition. The secondary amines nortriptyline and desipramine are favored over the tertiary amines amitriptyline and imipramine due to more benign side effect profiles [11,73]. Amitriptyline is often the treatment of choice for neuropathic pain [68].

Serotonin-Norepinephrine Reuptake Inhibitors

The dual serotonergic and noradrenergic re-uptake inhibitors (SNRIs) duloxetine, venlafaxine, and milnacipran are widely used in the treatment of neuropathic pain conditions. Duloxetine is used in painful diabetic neuropathy, with demonstrated efficacy at 60 to 120 mg/day. Venlafaxine behaves like a serotonin-specific re-uptake inhibitor (SSRI) at doses of ≤150 mg/day and like an SNRI at doses >150 mg/day. A dose ≥150 mg/day is often necessary to achieve pain control [66]. Of the three available SNRIs, milnacipran has the greatest affinity for norepinephrine, duloxetine has the greatest potency in blocking serotonin, and venlafaxine selectively binds to the serotonin but not the norepinephrine transporter [74]. SNRIs are better tolerated than TCAs because they lack affinity for cholinergic, histaminic, and adrenergic receptors [71]. The anti-nociceptive effect of the SNRIs duloxetine and milnacipran primarily involves increasing serotonin and norepinephrine concentrations in descending inhibitory pain pathways, which enhances the suppression of afferent spinal inputs and reduce pain [11].

Mirtazapine

Mirtazapine is an atypical tetracyclic antidepressant that acts through inhibition of 5HT-2, 5HT3, H1-a2-hetero, and alpha-2-adrenergic receptors. This accounts for its beneficial effect in the adjuvant treatment of migraine headache, anxiety, agitation, depression, insomnia, and low appetite. H1-receptor antagonism is most prominent at low doses (≤30 mg) [72].

Glutamate Antagonists

Dextromethorphan

Dextromethorphan is a commonly used oral cough suppressant and acts as an NMDA receptor antagonist, a sigma-1 receptor agonist, an N-type calcium channel antagonist, and a serotonin reuptake transporter antagonist. Rapid hepatic cytochrome P450-2D6 (CYP2D6) metabolism interferes with maintaining plasma concentrations sufficient for analgesia, reflected in poor clinical trial outcomes. Co-administration of the potent CYP2D6 inhibitor quinidine has been found to maintain therapeutic levels. The U.S. Food and Drug Administration (FDA) approved dextromethorphan for use in the treatment of pseudobulbar palsy. One trial found efficacy in using dextromethorphan for painful diabetic polyneuropathy [37].

Ketamine

Ketamine is a phencyclidine anesthetic given parenterally, neuraxially, nasally, transdermally or orally in subanesthetic doses to alleviate a variety of pain conditions, including severe acute pain, chronic or neuropathic pain, and opioid tolerance [68]. The mechanism of analgesic effect primarily involves NMDA receptor inhibition. Thus, patients with NMDA-mediated central sensitization are likely to realize significant benefit from treatment with ketamine. Ketamine also has activity on nicotinic, muscarinic, and opioid receptors and exerts both anti-nociceptive and anti-hyperalgesic effects, with the latter produced at lower dose ranges [75].

Ketamine is one of very few therapies demonstrating substantial and durable pain reduction of treatment-refractory chronic regional pain syndrome [65]. Potentially distressing adverse reactions (e.g., hallucinations, disturbing dreams, out-of-body experiences) and unwanted changes in mood, perception, and intellectual performance have limited its clinical use in pain control. However, trials have effectively controlled these side effects with high-dose co-administration of midazolam or lorazepam combined with either clonidine or ondansetron [76,77].

Opioids

Morphine and Other Mu Opioid Receptor Agonists

The endorphinergic pathway is comprised of endogenous ligands and the mu, kappa, and delta opioid receptors. Endorphins, enkephalins, dynorphins, and their receptors are expressed in multiple CNS regions in peripheral nerves and the skin. Opioid analgesics bind to opioid receptors (primarily the mu opioid receptor), mimicking the action of endogenous ligands. In general, opioid drugs produce analgesia through opioid receptor binding on cell membranes, producing simultaneous activity at multiple presynaptic, postsynaptic, and nervous system sites. Presynaptic opioid receptor activation inhibits the release of nociceptive neurotransmitters such as substance P and glutamate. Postsynaptic activation inhibits pain transition by opening potassium or chloride channels to hyperpolarize and inhibit neuronal firing [78]. These actions inhibit pain signal transmission from peripheral afferents to ascending spinal cord neurons; activate descending pathway inhibition; and alter limbic activity, decreasing pain awareness [66].

Depending on receptor affinity, pharmacokinetics, mechanism of action, and other factors, each opioid produces a unique spectrum of pharmacologic effects. This includes analgesia, dysphoria, euphoria, somnolence, respiratory depression, diminished GI motility, altered circulatory dynamics, histamine release, physical dependence, and disease-specific utility [72]. As noted, the classical opioids, including morphine, codeine, hydrocodone, and oxymorphone, have greatest affinity for the mu opioid receptor and weak activity at kappa and delta opioid receptors [66].

Buprenorphine

Although opioids in general are less effective in reducing neuropathic pain than nociceptive pain, specific drugs vary in affinity for sodium channel types and thus in neuropathic pain efficacy. Buprenorphine is a partial mu opioid receptor agonist and a weak kappa and delta opioid receptor antagonist with efficacy in neuropathic pain due to its potent local anesthetic action and voltage-gated sodium channel blockade via the local anesthetic binding site. Buprenorphine efficacy in blocking sodium channels is superior to meperidine, lidocaine, tramadol, morphine, and bupivacaine [66].

Methadone

Methadone exerts modest NMDA antagonism and inhibition of 5-HT and norepinephrine reuptake. With nerve injury pain, it induces greater anti-allodynia action than morphine or oxycodone. Thus, methadone may be useful in neuropathic pain due to its cooperative actions as an NMDA receptor antagonist and mu-opioid receptor agonist [66].

Tramadol

Tramadol is a centrally acting, weak mu opioid receptor agonist and inhibits norepinephrine and serotonin reuptake to promote serotonin release [16]. About 30% of its analgesic effect is attributable to mu opioid receptor binding. Tramadol has shown some efficacy in fibromyalgia and neuropathic pain. Although tramadol is centrally acting, it has been associated with increased blood and intracranial pressure and should be used with caution [66].

Tapentadol

Tapentadol is a new opioid therapeutic for moderate-to-severe pain with a novel mechanism as a mu opioid receptor partial agonist and norepinephrine reuptake inhibitor [79]. Its potency is two to three times lower than morphine, and tolerance develops significantly slower than with morphine. Tapentadol has been approved by the FDA for relief of moderate-to-severe acute pain [37].

Cannabinoids

Cannabinoid receptors CB1 and CB2 are expressed in all peripheral and CNS nociceptive pathways, including spinal cord, dorsal root ganglion neurons, and peripheral nociceptors. Endogenous endocannabinoid ligands are derived from arachidonic acid, bind to cannabinoid receptors to decrease presynaptic Ca2+ concentration, and activate inward-rectifying K+ channels to inhibit presynaptic glutamate release and modulate neuronal excitability [61]. The cannabinoid receptor ligand mechanism involves retrograde synaptic inhibition and signaling that directly upregulates or downregulates presynaptic release of GABA, dopamine, norepinephrine, glutamate, and other neurotransmitters [80]. Numerous studies have found cannabinoid utility in pain management, demonstrated by reduced nociceptive pain and muscle spasticity; hyperalgesia and allodynia suppression in neuropathic pain; inflammatory modulation; and analgesic synergy between cannabinoid and opioid systems [61]. Cannabinoids have also displayed neuroprotection in ischemia and hypoxia [80]. Agonists include delta9-tetrahydrocannabinol (delta9-THC), cannabinol, and cannabidiol, all of which are found in the cannabis plant.

Alpha-2 Adrenoceptor Agonists

Antinociceptive activity of the α-2 adrenoceptor agonists clonidine and tizanidine includes modulating dorsal horn neuron function and norepinephrine and 5-HT release, potentiating mu-opioid receptors, and decreasing neuron excitability through calcium channel modulation [72]. Clonidine is available as a transdermal patch for use in neuropathic pain states. Local use enhances release of endogenous enkephalin-like substances. Intrathecal or epidural administration with opioids and/or local anesthetics is favored in treating neuropathic pain because the synergistic effect improves pain control. Tizanidine is used as a muscle relaxant and antispasticity agent [66,68].

Other Agents

Baclofen

Baclofen is a muscle relaxant that induces analgesia through agonist action on inhibitory GABA-B receptors. Baclofen is efficacious in patients with trigeminal neuralgia. Although efficacy has not been found in other neuropathic pain conditions, the anti-spasticity properties of baclofen may induce analgesia by relieving co-occurring muscle spasms [68].

Botulinum Toxin

Botulinum toxin is a neurotoxic protein synthesized by the bacterium Clostridium botulinum with broad clinical application. Botulinum toxin produces analgesia through blocking neurotransmitter release and TRPV1 receptor signaling in C-fibers, which inhibits substance P and CGRP release to reduce neurogenic inflammation and increase heat pain threshold. Trials have shown efficacy in focal painful neuropathies and mechanical allodynia and superior reduction in pain and opioid use versus lidocaine and placebo [37,71]. A 2013 single-dose randomized controlled trial resulted in substantial improvements in pain and sleep outcomes in patients with postherpetic neuralgia [81].

Sulfasalazine

Tetrahydrobiopterin is an essential co-factor in producing nitric oxide and monoamines. Following peripheral nerve injury, tetrahydrobiopterin levels dramatically elevate and contribute to pain through excess production of neurotransmitters or signaling molecules. Sepiapterin reductase contributes to tetrahydrobiopterin biosynthesis and is upregulated in nerve injury; reducing tetrahydrobiopterin levels inhibits sepiapterin reductase, producing analgesia. Sulfasalazine is an FDA-approved anti-inflammatory agent that inhibits sepiapterin reductase. This mechanism in sulfasalazine may represent an effective, novel therapy for neuropathic pain [82].

Ondansetron

Ondansetron, a 5-HT3 receptor antagonist, has shown anti-nociceptive effects by blocking descending serotonergic facilitatory drive to the dorsal horn laminae. By this action, it may prevent neuroplastic changes in the dorsal horn [83]. Although gabapentin interacts with the auxiliary α2δ1 subunit of voltage-gated calcium channels, evidence suggests the actions of gabapentin also involve 5-HT3 receptors [61].

NONPHARMACOLOGIC THERAPIES AND A MULTIMODAL APPROACH

Centrally acting drugs, such as TCAs, SNRIs, and others, each target a particular mechanism that may be at play in a patient with chronic pain and may provide some degree of benefit. However, general practice and clinical trials over the years have not demonstrated satisfactory outcomes for most patients [87]. This is not surprising given that chronic pain and central sensitization consists of complex neuro-immunologic and psychologic interactions by multiple mechanisms. A 2019 review recommends a pain management strategy that takes into account central sensitization, and that clinicians design an individually tailored multimodal plan comprised of the following elements: pain neuroscience education of the patient, cognition-targeted exercise therapy, sleep management, stress management, and possibly dietary intervention [87].

Evidence Based Practice Recommendation

According to the Institute for Clinical Systems Improvement, psychotherapy (e.g., cognitive-behavioral therapy, mindfulness-based stress reduction) is recommended for patients with a chronic pain diagnosis.

https://www.icsi.org/wp-content/uploads/2019/10/Pain-Interactive-7th-V2-Ed-8.17.pdf

Last Accessed: October 30, 2019

Strength of Recommendation: Expert Opinion/Consensus Statement

Many patients with chronic pain receive multimodality treatment that includes pharmacology, cognitive-behavioral or other coping skills therapy, and a progressive strengthening or functional restoration modality. In addition to the greater benefit observed with this combined approach comes validation from neuroscience research showing that chronic pain is mediated by cortical structures.

Researchers have observed that patients with chronic low back pain achieve greater overall improvement with therapies addressing coping skills, functional ability, and activity tolerance (e.g., cognitive-behavioral therapy, progressive relaxation, yoga, meditation combined with progressive activity or exercise therapy) compared with therapies strictly targeting the lumbar spine (e.g., decompressive laminectomy) [84]. The latter approach can reduce pain but seldom improves physical function, a serious concern given the substantial correlation between physical performance and future disability [8,85]. Diverse physiotherapies in chronic low back pain have been found effective in improving overall function unrelated to the original biomechanical focus [85]. The correlation between changes in brain structure and function suggests that structural and functional changes underlie or contribute to chronic low back pain and disability [8].

Learning- and memory-related neuroplastic changes that develop with chronic pain require therapies that facilitate extinction of aversive memories and restore body image and normal brain function. Successful approaches include brain stimulation, mirror training, therapeutic virtual reality, and behavioral extinction training [55].

7. CONCLUSION

The mechanism-based approach to pain management finds its greatest utility in the understanding and treatment of chronic pain. It is intended to augment, not replace, the traditional approach to the treatment of acute pain, which emphasizes the diagnosis and alleviation of the inciting injury or disease combined with the empiric application of analgesic medication. The aim of MBA is to identify and target the (potentially) multiple contributory mechanisms usually involved in any chronic pain syndrome. The strategy is to devise a therapeutic plan that addresses these mechanisms, often combining specific pharmacotherapies with psychotherapeutic approaches, physical rehabilitation, and behavior modification. Thus, MBA is consistent with the recommendations of numerous practice guidelines that suggest multidisciplinary modality treatment for many chronic pain conditions. It is also consistent with tailored treatment planning that considers the needs of the individual patient. The mechanism-based approach to pain management is now endorsed in a number of practice guidelines by leading organizations of pain professionals. The purpose of this course is to promote, among primary care clinicians and nurses, a broader understanding of the underlying neuroscience, pathophysiology, and treatment principles.

8. GLOSSARY

Terms associated with pain mechanisms and chronic pain [1,39]:

Allodynia: Pain produced by a normally innocuous stimulus, such as light touch to the skin.

Central sensitization: Sustained pathologic excitability of neurons within the CNS that mediate pain perception, such that normal stimuli inputs produce abnormal responses.

Hyperalgesia: Exaggerated and prolonged pain response to noxious stimuli.

Nociceptive neuron: A central or peripheral neuron of the somatosensory nervous system capable of encoding noxious stimuli.

Nociceptive pain: Pain arising from damage to non-neural tissue, the result of nociceptor activation.

Nociceptive stimulus: A tissue-damaging event transduced and encoded by nociceptors.

Nociceptor: A high-threshold sensory receptor of the peripheral somatosensory nervous system capable of transducing and encoding noxious stimuli.

Noxious stimulus: A stimulus that is damaging or threatens damage to normal tissues.

Peripheral sensitization: Reduction in threshold and increase in responsiveness to stimuli of peripheral nociceptors.

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77. Schwartzman RJ, Alexander GM, Grothusen JR, Paylor T, Reichenberger E, Perreault M. Outpatient intravenous ketamine for the treatment of complex regional pain syndrome: a double-blind placebo controlled study. Pain. 2009;147(1-3):107-115.

78. Dinakar P. Principles of pain management. In: Daroff RB, Jankovic J, Mazziotta JC, Pomeroy SL (eds). Bradley's Neurology in Clinical Practice. 7th ed. Philadelphia, PA: Saunders; 2016.

79. Afilalo M, Morlion B. Efficacy of tapentadol ER for managing moderate to severe chronic pain. Pain Physician. 2013;16(1):27-40.

80. Aggarwal SK. Cannabinergic pain medicine: a concise clinical primer and survey of randomized-controlled trial results. Clin J Pain. 2013;29(2):162-171.

81. Apalla Z, Sotiriou E, Lallas A, Lazaridou E, Ioannides D. Botulinum toxin A in postherpetic neuralgia: a parallel, randomized, double-blind, single-dose, placebo-controlled trial. Clin J Pain. 2013;29(10):857-864.

82. Costigan M, Latremoliere A, Woolf CJ. Analgesia by inhibiting tetrahydrobiopterin synthesis. Curr Opin Pharmacol. 2012;12(1): 92-99.

83. McCleane GJ, Suzuki R, Dickenson AH. Does a single intravenous injection of the 5HT3 receptor antagonist ondansetron have an analgesic effect in neuropathic pain? A double-blinded, placebo-controlled cross-over study. Anesth Analg. 2003;97(5): 1474-1478.

84. Stevans JM, Saper RB. Chronic low back pain. In: Rakel D (ed). Integrative Medicine. 3rd ed. Philadelphia, PA: Saunders; 2012.

85. Balagué F, Mannion AF, Pellisé F, Cedraschi C. Nonspecific low back pain. Lancet. 2012;379(9814):482-491.

86. McCarberg B, Peppin J. Pain pathways and nervous system plasticity: learning and memory in pain. Pain Med. 2019;[Epub ahead of print].

87. Nijs J, Leysen L, Vanlauwe, J, et al. Treatment of central sensitization in patients with chronic pain: time for change? Expert Opin Pharmacother. 2019;20(16):1961-1970.

88. Ji RR, Nackley A, Huh Y, et al. Neuroinflammation and central sensitization in chronic and widespread pain. Anesthesiology. 2018;129(2):343-366.

Evidence-Based Practice Recommendations Citations

1. Hooten WM, Thorson D, Hora J, et al. Pain: Assessment, Non-Opioid Treatment Approaches and Opioid Management. Bloomington, MN: Institute for Clinical Systems Improvement; 2017. Available at https://www.icsi.org/wp-content/uploads/2019/10/Pain-Interactive-7th-V2-Ed-8.17.pdf. Last accessed October 30, 2019.

95151 • Responsible and Effective Opioid Prescribing

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2021 NetCE, All rights reserved.

Opioid analgesic medications can bring substantial relief to patients suffering from pain. However, the inappropriate use, abuse, and diversion of prescription drugs in America, particularly prescription opioids, has increased dramatically in recent years and has been identified as a national public health epidemic. A set of clinical tools, guidelines, and recommendations are now available for prescribers who treat pain patients with opioids. By implementing these tools, clinicians can effectively address issues related to the clinical management of opioid prescribing, opioid risk management, regulations surrounding the prescribing of opioids, and problematic opioid use by patients. In doing so, healthcare professionals are more likely to achieve a balance between the benefits and risks of opioid prescribing, optimize patient attainment of therapeutic goals, and avoid the risk to patient outcome, public health, and viability of their own practice imposed by deficits in knowledge.

Table of Contents

95151 • Responsible and Effective Opioid Prescribing

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. SCOPE OF THE PROBLEM

3. PAIN MANAGEMENT APPROACHES

ACUTE PAIN

CHRONIC PAIN

PALLIATIVE CARE AND PAIN AT THE END OF LIFE

4. CREATING A TREATMENT PLAN AND ASSESSMENT OF ADDICTION RISK

RISK ASSESSMENT TOOLS

INFORMED CONSENT AND TREATMENT AGREEMENTS

PERIODIC REVIEW AND MONITORING

CONCURRENT USE OF BENZODIAZEPINES

CONSULTATION AND REFERRAL

MEDICAL RECORDS

PATIENT EDUCATION ON THE USE AND DISPOSAL OF OPIOIDS

DISCONTINUING OPIOID THERAPY

CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

5. IDENTIFICATION OF DRUG DIVERSION/SEEKING BEHAVIORS

6. INTERVENTIONS FOR SUSPECTED OR KNOWN ADDICTION OR DRUG DIVERSION

7. COMPLIANCE WITH STATE AND FEDERAL LAWS

CONTROLLED SUBSTANCES LAWS/RULES

STATE-SPECIFIC LAWS AND RULES

8. MANAGEMENT OF OPIOID USE DISORDER

CRISIS INTERVENTION

HARM REDUCTION

DETOXIFICATION AND WITHDRAWAL

AGONIST REPLACEMENT OR ABSTINENCE THERAPY

STIGMA OF ADDICTION

PROGNOSIS OF TREATMENT FOR OPIOID USE DISORDER

9. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

95151 • Responsible and Effective Opioid Prescribing

Education Category. Pharmacology

Release Date. 05/01/2021

Expiration Date. 04/30/2024

Course Overview

Opioid analgesic medications can bring substantial relief to patients suffering from pain. However, the inappropriate use, abuse, and diversion of prescription drugs in America, particularly prescription opioids, has increased dramatically in recent years and has been identified as a national public health epidemic. A set of clinical tools, guidelines, and recommendations are now available for prescribers who treat pain patients with opioids. By implementing these tools, clinicians can effectively address issues related to the clinical management of opioid prescribing, opioid risk management, regulations surrounding the prescribing of opioids, and problematic opioid use by patients. In doing so, healthcare professionals are more likely to achieve a balance between the benefits and risks of opioid prescribing, optimize patient attainment of therapeutic goals, and avoid the risk to patient outcome, public health, and viability of their own practice imposed by deficits in knowledge.

Audience

This course is designed for all physicians, osteopaths, physician assistants, pharmacy professionals, and nurses who may alter prescribing practices or intervene to prevent drug diversion and inappropriate opioid use.

Course Objective

The purpose of this course is to provide clinicians who prescribe or distribute opioids with an appreciation for the complexities of opioid prescribing and the dual risks of litigation due to inadequate pain control and drug diversion or misuse in order to provide the best possible patient care and to prevent a growing social problem.

Learning Objectives

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

1. Apply epidemiologic trends in opioid use and misuse to current practice so at-risk patient populations can be more easily identified, assessed, and treated.

2. Create comprehensive treatment plans for patients with pain that address patient needs as well as drug diversion prevention.

3. Evaluate behaviors that may indicate drug seeking or diverting as well as approaches for patients suspected of misusing opioids.

4. Identify state and federal laws governing the proper prescription and monitoring of controlled substances.

5. Describe the available treatment modalities for opioid use disorder.

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

Ronald Runciman, MD

Jane C. Norman, RN, MSN, CNE, 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

Pain is the leading reason for seeking medical care, and pain management is a large part of many healthcare professionals' practice. Opioid analgesics are approved by the U.S. Food and Drug Administration (FDA) for moderate and severe pain and are broadly accepted in acute pain, cancer pain, and end-of-life care, but are controversial in chronic noncancer pain. In response to the long-standing neglect of severe pain, indications for opioid analgesic prescribing were expanded in the 1990s, followed by inappropriate prescribing and increasing abuse, addiction, diversion, and overdose through the 2000s. In tandem with the continued under-treatment of pain, these practice patterns led to needless suffering from uncontrolled pain, opioid analgesic addiction, and overdose. Opioid analgesic prescribing and associated overdose peaked in 2011 with both now in multi-year decline.

Patients show substantial opioid response variations in analgesia and tolerability and may exhibit a range of psychologic, emotional, and behavioral responses that reflect inadequate pain control, an emerging opioid use problem, or both. Clinician delivery of best possible care to patients with pain requires appreciation of the complexities of opioid prescribing and the dual risks of inadequate pain control and inappropriate use, drug diversion, or overdose. A foundation for appropriate opioid prescribing is the understanding of factual data that clarify the prevalence, causality, and prevention of serious safety concerns with opioid prescribing.

2. SCOPE OF THE PROBLEM

Inappropriate opioid analgesic prescribing for pain is defined as the non-prescribing, inadequate prescribing, excessive prescribing, or continued prescribing despite evidence of ineffectiveness of opioids [1]. Appropriate opioid prescribing is essential to achieve pain control; to minimize patient risk of abuse, addiction, and fatal toxicity; and to minimize societal harms from diversion. The foundation of appropriate opioid prescribing is thorough patient assessment, treatment planning, and follow-up and monitoring. Essential for proper patient assessment and treatment planning is comprehension of the clinical concepts of opioid abuse and addiction, their behavioral manifestations in patients with pain, and how these potentially problematic behavioral responses to opioids both resemble and differ from physical dependence and pseudo-dependence. 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 [2].

The extent of opioid analgesic use in the United States in the 2000s was unprecedented in the country's history and unparalleled anywhere in the world. Before 1990, physicians in the United States were skeptical of prescribing opioids for chronic noncancer pain. In 2017, 20% of adults are prescribed an opioid such as oxycodone and hydrocodone for chronic pain, and sales of opioid analgesics totaled approximately $7 billion in 2016 [10,33].

Worldwide consumption of opioid analgesics has increased dramatically in the past few decades, with the United States driving a substantial proportion of this increase. For example, the 1990 global consumption of hydrocodone was 4 tons (3,628 kg), compared with the 2009 consumption of 39 tons (35,380 kg); 99% of this was consumed in the United States. Similarly, 3 tons (2,722 kg) of oxycodone were consumed globally in 1990, versus 77 tons (69,853 kg) in 2009, of which 62 tons (56,245 kg or 81%) were consumed in the United States [3]. With only 4.5% of the world's population, the United States annually consumes more than 80% of all opioid supplies, including [4]:

- 99% of all hydrocodone

- 80% of all oxycodone

- 58% of all methadone

- 54% of all hydromorphone

- 49% of all fentanyl

- 43% of all meperidine

This disproportionate rate of opioid consumption reflects sociocultural and economic factors and standards of clinical medicine.

Between 1992 and 2003, the U.S. population increased 14%, while persons abusing opioid analgesics increased 94% and first-time non-medical opioid analgesic users 12 to 17 years of age increased 542% [4]. It is interesting to note that while opioid prescribing has increased precipitously among adults in the United States, the rate remained low and steady for children between 1996 and 2012 [5]. A study using data from 2005 to 2015 showed opioid prescribing in 57 million visits from adolescents and young adults, representing a prescribing rate of nearly 15% in emergency departments and nearly 3% in outpatient clinical settings [36]. During the course of the study, emergency department prescribing decreased slightly while outpatient clinical setting prescribing remained the same [36]. To assist in monitoring the public health problem associated with prescribed opioids, numerous governmental, non-profit, and private sector agencies and organizations are involved in collecting, reporting, and analyzing data on the abuse, addiction, fatal overdose, and treatment admissions related to opioid analgesics.

Before it was halted in 2011, the Drug Abuse Warning Network (DAWN) provided estimates of the health consequences of nonmedical use of individual drugs, including opioid medications [6]. DAWN indicates that opioid abuse is a growing problem in the United States. In 2005 and 2011, hydrocodone and its combinations accounted for 51,225 and 97,183 emergency department visits, respectively. Oxycodone and its combinations resulted in 42,810 visits to the emergency department in 2005; this number increased to 175,229 visits in 2011 [7,8]. Visits for nonmedical use of all opioids increased from 217,594 to 420,040 during the six-year period. In 2016–2017, there were 127,101 nonmedical opioid emergency department visits [39]. While this number is an improvement from previous years, nonmedical use accounts for 47.6% of all emergency department visits related to opioids [39].

3. PAIN MANAGEMENT APPROACHES

Healthcare professionals should know the best clinical practices in opioid prescribing, including the associated risks of opioids, approaches to the assessment of pain and function, and pain management modalities. Pharmacologic and nonpharmacologic approaches should be used on the basis of current knowledge in the evidence base or best clinical practices. Patients with moderate-to-severe chronic pain who have been assessed and treated, over a period of time, with non-opioid therapy or nonpharmacologic pain therapy without adequate pain relief, are considered to be candidates for a trial of opioid therapy [9,10]. Initial treatment should always be considered individually determined and as a trial of therapy, not a definitive course of treatment [11].

In 2016, the CDC issued updated guidance on the prescription of opioids for chronic pain [10]. The guideline addresses when to initiate or continue opioids for chronic pain; opioid selection, dosage, duration, follow-up, and discontinuation; and assessing risk and addressing harms of opioid use. In addition, the CDC further updated guidance against the misapplication of this guideline in 2019, noting that some policies and practices attributed to the guideline were inconsistent with the recommendations [40].

While these guidelines were based on the best available evidence at the time, there was some criticism that they were too focused on limiting opioid prescriptions—to the point of patients and prescribers complaining of stigma and reduced access to needed opioid analgesics. In response to this and to the availability of new evidence, the CDC published an updated guideline in 2022 [88]. The updated clinical practice guideline is intended to achieve improved communication between clinicians and patients about the risks and benefits of pain treatment, including opioid therapy for pain; improved safety and effectiveness for pain treatment, resulting in improved function and quality of life for patients experiencing pain; and a reduction in the risks associated with long-term opioid therapy, including opioid use disorder, overdose, and death [88]. It is important to remember that inappropriately limiting necessary opioid medications to address patients' pain can be damaging and should be avoided.

ACUTE PAIN

Long-term opioid use often begins with treatment of acute pain. When opioids are used for acute pain, clinicians should prescribe the lowest effective dose of immediate-release opioids in a quantity no greater than that needed for the expected duration of severe pain. In most cases, three days or less will be sufficient; more than seven days will rarely be needed [10]. However, it is important to note that this guideline is based on emergency department prescribing guidelines for non-traumatic non-surgical pain [12]. It may be necessary to prescribe for longer periods in patients with acute severe pain.

With postoperative, acute, or intermittent pain, analgesia often requires frequent titration, and the two- to four-hour analgesic duration with short-acting hydrocodone, morphine, and oxycodone is more effective than extended-release formulations. Short-acting opioids are also recommended in patients who are medically unstable or with highly variable pain intensity [13,14,15].

CHRONIC PAIN

Nonpharmacologic therapy and non-opioid pharmacologic therapy are the preferred first-line therapies for chronic pain. Several nonpharmacologic approaches are therapeutic complements to pain-relieving medication, lessening the need for higher doses and perhaps minimizing side effects. These interventions can help decrease pain or distress that may be contributing to the pain sensation. Approaches include palliative radiotherapy, complementary/alternative methods, manipulative and body-based methods, and cognitive/behavioral techniques. The choice of a specific nonpharmacologic intervention is based on the patient's preference, which, in turn, is usually based on a successful experience in the past.

Implantable intrathecal opioid infusion and/or spinal cord stimulation may be options for severe, intractable pain. Both options require that devices or ports be implanted, with associated risks. With intrathecal opioid infusion, the ability to deliver the drug directly into the spine provides pain relief with significantly smaller opioid doses, which can help to minimize side effects (e.g., drowsiness, dizziness, dry mouth, nausea, vomiting, and constipation) that can accompany systemic pain medications that might be delivered orally, transdermally, or through an IV [43]. However, use of opioid infusion has traditionally been limited to cancer pain. With spinal cord stimulation therapy, the most challenging aspect is patient selection. In order for patients to be considered for spinal cord stimulation, other options should have been ineffective or be contraindicated. Spinal cord stimulation is indicated for severe neuropathic pain persisting at least six months.

If opioids are used, they should be combined with nonpharmacologic therapy and non-opioid pharmacologic therapy, as appropriate. Clinicians should consider opioid therapy only if expected benefits for pain and function are anticipated to outweigh risks to the patient [10].

Opioid therapy for chronic pain should be presented as a trial for a pre-defined period (e.g., ≤30 days). The goals of treatment should be established with all patients prior to the initiation of opioid therapy, including reasonable improvements in pain, function, depression, anxiety, and avoidance of unnecessary or excessive medication use [1,10]. The treatment plan should describe therapy selection, measures of progress, and other diagnostic evaluations, consultations, referrals, and therapies.

In patients who are opioid-naïve, start at the lowest possible dose and titrate to effect. Dosages for patients who are opioid-tolerant should always be individualized and titrated by efficacy and tolerability [1,10]. When starting opioid therapy for chronic pain, clinicians should prescribe short-acting instead of extended-release/long-acting opioid formulations [10].

The need for frequent progress and benefit/risk assessments during the trial should be included in patient education. Patients should also have full knowledge of the warning signs and symptoms of respiratory depression. Prescribers should carefully reassess evidence of benefits and risks when increasing the dosage to ≥50 mg morphine equivalent dose (MED) per day. Decisions to titrate dose to ≥90 mg MED/day should be avoided or carefully justified [10,40].

Prescribers should be knowledgeable of federal and state opioid prescribing regulations. Issues of equianalgesic dosing, close patient monitoring during all dose changes, and cross-tolerance with opioid conversion should be considered. If necessary, treatment may be augmented, with preference for nonopioids and immediate-release opioids over long-acting/extended-release opioids. Taper opioid dose when no longer needed [16].

PALLIATIVE CARE AND PAIN AT THE END OF LIFE

Unrelieved pain is the greatest fear among people with a life-limiting disease, and the need for an increased understanding of effective pain management is well-documented [27]. Although experts have noted that 75% to 90% of end-of-life pain can be managed effectively, rates of pain are high, even among people receiving palliative care [27,30,34,35].

The inadequate management of pain is the result of several factors related to both patients and clinicians. In a survey of oncologists, patient reluctance to take opioids or to report pain were two of the most important barriers to effective pain relief [37]. This reluctance is related to a variety of attitudes and beliefs [27,37]:

- Fear of addiction to opioids

- Worry that if pain is treated early, there will be no options for treatment of future pain

- Anxiety about unpleasant side effects from pain medications

- Fear that increasing pain means that the disease is getting worse

- Desire to be a "good" patient

- Concern about the high cost of medications

Education and open communication are the keys to overcoming these barriers. Every member of the healthcare team should reinforce accurate information about pain management with patients and families. The clinician should initiate conversations about pain management, especially regarding the use of opioids, as few patients will raise the issue themselves or even express their concerns unless they are specifically asked [38]. It is important to acknowledge patients' fears individually and provide information to help them differentiate fact from fiction. For example, when discussing opioids with a patient who fears addiction, the clinician should explain that the risk of addiction is low [27]. It is also helpful to note the difference between addiction and physical dependence.

There are several other ways clinicians can allay patients' fears about pain medication:

- Assure patients that the availability of pain relievers cannot be exhausted; there will always be medications if pain becomes more severe.

- Acknowledge that side effects may occur but emphasize that they can be managed promptly and safely and that some side effects will abate over time.

- Explain that pain and severity of disease are not necessarily related.

Encouraging patients to be honest about pain and other symptoms is also vital. Clinicians should ensure that patients understand that pain is multidimensional and emphasize the importance of talking to a member of the healthcare team about possible causes of pain, such as emotional or spiritual distress. The healthcare team and patient should explore psychosocial and cultural factors that may affect self-reporting of pain, such as concern about the cost of medication.

Clinicians' attitudes, beliefs, and experiences also influence pain management, with addiction, tolerance, side effects, and regulations being the most important concerns [27,34,37,42]. A lack of appropriate education and training in the assessment and management of pain has been noted to be a substantial contributor to ineffective pain management [37,42]. As a result, many clinicians, especially primary care physicians, do not feel confident about their ability to manage pain in their patients [37,42].

Clinicians require a clear understanding of available medications to relieve pain, including appropriate dosing, safety profiles, and side effects. If necessary, clinicians should consult with pain specialists to develop an effective approach.

Strong opioids are used for severe pain at the end of life [30,34]. Morphine, buprenorphine, oxycodone, hydromorphone, fentanyl, and methadone are the most widely used in the United States [45]. Unlike nonopioids, opioids do not have a ceiling effect, and the dose can be titrated until pain is relieved or side effects become unmanageable. Patients who are opioid-naïve or who have been receiving low doses of a weak opioid, the initial dose should be low, and, if pain persists, the dose may be titrated up daily until pain is controlled.

More than one route of opioid administration will be needed by many patients during end-of-life care, but in general, opioids should be given orally, as this route is the most convenient and least expensive. The transdermal route is preferred to the parenteral route, although dosing with a transdermal patch is less flexible and so may not be appropriate for patients with unstable pain [34]. Intramuscular injections should be avoided because injections are painful, drug absorption is unreliable, and the time to peak concentration is long [34].

4. CREATING A TREATMENT PLAN AND ASSESSMENT OF ADDICTION RISK

Information obtained by patient history, physical examination, and interview, from family members, a spouse, or state prescription drug monitoring program (PDMP), and from the use of screening and assessment tools can help the clinician to stratify the patient according to level of risk for developing problematic opioid behavioral responses (Table 1) [17,28]. Low-risk patients receive the standard level of monitoring, vigilance, and care. Moderate-risk patients should be considered for an additional level of monitoring and provider contact, and high-risk patients are likely to require intensive and structured monitoring and follow-up contact, additional consultation with psychiatric and addiction medicine specialists, and limited supplies of short-acting opioid formulations [10,26].

Table 1: RISK STRATIFICATION FOR PATIENTS PRESCRIBED OPIOIDS

Low Risk

Definable physical pathology with objective signs and reliable symptoms

Clinical correlation with diagnostic testing, including MRI, physical examination, and interventional diagnostic techniques

With or without mild psychologic comorbidity

With or without minor medical comorbidity

No or well-defined and controlled personal or family history of alcoholism or substance abuse

Age 45 years or older

High levels of pain acceptance and active coping strategies

High motivation and willingness to participate in multimodal therapy and attempting to function at normal levels

Medium Risk

Significant pain problems with objective signs and symptoms confirmed by radiologic evaluation, physical examination, or diagnostic interventions

Moderate psychologic problems, well controlled by therapy

Moderate coexisting medical disorders that are well controlled by medical therapy and are not affected by chronic opioid therapy (e.g., central sleep apnea)

Develops mild tolerance but not hyperalgesia without physical dependence or addiction

History of personal or family history of alcoholism or substance abuse

Pain involving more than three regions of the body

Defined pathology with moderate levels of pain acceptance and coping strategies

Willing to participate in multimodal therapy, attempting to function in normal daily life

High Risk

Widespread pain without objective signs and symptoms

Pain involving more than three regions of the body

Aberrant drug-related behavior

History of alcoholism or drug misuse, abuse, addiction, diversion, dependency, tolerance, or hyperalgesia

Major psychologic disorders

Age younger than 45 years

HIV-related pain

High levels of pain exacerbation and low levels of coping strategies

Unwilling to participate in multimodal therapy, not functioning close to a near normal lifestyle

HIV = human immunodeficiency syndrome, MRI = magnetic resonance imaging.

Source: [17,28]

Evidence Based Practice Recommendation

Despite limited evidence for reliability and accuracy, screening for opioid use is recommended by the American Society of Interventional Pain Physicians, as it will identify opioid abusers and reduce opioid abuse.

https://painphysicianjournal.com/2012/july/2012;%2015;S67-S116.pdf

Last Accessed: April 28, 2021

Level of Evidence: Limited (Evidence is insufficient to assess effects on health outcomes because of limited number or power of studies, large and unexplained inconsistency between higher-quality trials, important flaws in trial design or conduct, gaps in the chain of evidence, or lack of information on important health outcomes.)

Before deciding to prescribe an opioid analgesic, clinicians should perform and document a detailed patient assessment that includes [1]:

- Pain indications for opioid therapy

- Nature and intensity of pain

- Past and current pain treatments and patient response

- Comorbid conditions

- Pain impact on physical and psychologic function

- Social support, housing, and employment

- Home environment (i.e., stressful or supportive)

- Pain impact on sleep, mood, work, relationships, leisure, and substance use

- Patient history of physical, emotional, or sexual abuse

If substance abuse is active, in remission, or in the patient's history, consult an addiction specialist before starting opioids [1]. In active substance abuse, do not prescribe opioids until the patient is engaged in treatment/recovery program or other arrangement made, such as addiction professional co-management and additional monitoring. When considering an opioid analgesic (particularly those that are extended-release or long-acting), one must always weigh the benefits against the risks of overdose, abuse, addiction, physical dependence and tolerance, adverse drug interactions, and accidental exposure by children [10,16].

Screening and assessment tools can help guide patient stratification according to risk level and inform the appropriate degree of structure and monitoring in the treatment plan. It should be noted that despite widespread endorsement of screening tools used to help determine patient risk level, most tools have not been extensively evaluated, validated, or compared to each other, and evidence of their reliability is poor [17,28].

RISK ASSESSMENT TOOLS

Opioid Risk Tool (ORT)

The Opioid Risk Tool (ORT) is a five-item, patient-administered assessment to help predict aberrant drug-related behavior. The ORT is also used to establish patient risk level through categorization into low, medium, or high levels of risk for aberrant drug-related behaviors based on responses to questions of previous alcohol/drug abuse, psychologic disorders, and other risk factors [18].

Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R)

The Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R) is a patient-administered, 24-item screen with questions addressing history of alcohol/substance use, psychologic status, mood, cravings, and stress. Like the ORT, the SOAPP-R helps assess risk level of aberrant drug-related behaviors and the appropriate extent of monitoring [18,19].

Screening Instrument or Substance Abuse Potential (SISAP)

The Screening Instrument or Substance Abuse Potential (SISAP) tool is a self-administered, five-item questionnaire addressing history developed used to predict the risk of opioid misuse. The SISAP is used to identify patients with a history of alcohol/substance abuse and improve pain management by facilitating focus on the appropriate use of opioid analgesics and therapeutic outcomes in the majority of patients who are not at risk of opioid abuse, while carefully monitoring those who may be at greater risk [18].

CAGE and CAGE-AID

The original CAGE (Cut down, Annoyed, Guilty, and Eye-opener) Questionnaire consisted of four questions designed to help clinicians determine the likelihood that a patient was misusing or abusing alcohol. These same four questions were modified to create the CAGE-AID (adapted to include drugs), revised to assess the likelihood of current substance abuse [20].

Diagnosis, Intractability, Risk, and Efficacy (DIRE) Score

The Diagnosis, Intractability, Risk, and Efficacy (DIRE) risk assessment score is a clinician-rated questionnaire that is used to predict patient compliance with long-term opioid therapy [18,21]. Patients scoring lower on the DIRE tool are poor candidates for long-term opioid analgesia.

INFORMED CONSENT AND TREATMENT AGREEMENTS

The initial opioid prescription is preceded by a written informed consent or "treatment agreement" [1]. This agreement should address potential side effects, tolerance and/or physical dependence, drug interactions, motor skill impairment, limited evidence of long-term benefit, misuse, dependence, addiction, and overdose. Informed consent documents should include information regarding the risk/benefit profile for the drug(s) being prescribed. The prescribing policies should be clearly delineated, including the number/frequency of refills, early refills, and procedures for lost or stolen medications.

The treatment agreement also outlines joint physician and patient responsibilities. The patient agrees to using medications safely, refraining from "doctor shopping," and consenting to routine urine drug testing (UDT). The prescriber's responsibility is to address unforeseen problems and prescribe scheduled refills. Reasons for opioid therapy change or discontinuation should be listed. Agreements can also include sections related to follow-up visits, monitoring, and safe storage and disposal of unused drugs.

PERIODIC REVIEW AND MONITORING

When implementing a chronic pain treatment plan that involves the use of opioids, the patient should be frequently reassessed for changes in pain origin, health, and function [1]. This can include input from family members and/or the state PDMP. During the initiation phase and during any changes to the dosage or agent used, patient contact should be increased. At every visit, chronic opioid response may be monitored according to the "5 A's" [1,23]:

- Analgesia

- Activities of daily living

- Adverse or side effects

- Aberrant drug-related behaviors

- Affect (i.e., patient mood)

Signs and symptoms that, if present, may suggest a problematic response to the opioid and interference with the goal of functional improvement include [24,29]:

- Excessive sleeping or days and nights turned around

- Diminished appetite

- Short attention span or inability to concentrate

- Mood volatility, especially irritability

- Lack of involvement with others

- Impaired functioning due to drug effects

- Use of the opioid to regress instead of re-engaging in life

- Lack of attention to hygiene and appearance

The decision to continue, change, or terminate opioid therapy is based on progress toward treatment objectives and absence of adverse effects and risks of overdose or diversion [1]. Satisfactory therapy is indicated by improvements in pain, function, and quality of life. Brief assessment tools to assess pain and function may be useful, as may UDTs. Treatment plans may include periodic pill counts to confirm adherence and minimize diversion.

Involvement of Family

Family members of the patient can provide the clinician with valuable information that better informs decision making regarding continuing opioid therapy. Family members can observe whether a patient is losing control of his or her life or becoming less functional or more depressed during the course of opioid therapy. They can also provide input regarding positive or negative changes in patient function, attitude, and level of comfort. The following questions can be asked of family members or a spouse to help clarify whether the patient's response to opioid therapy is favorable or unfavorable [24,29]:

- Is the person's day centered around taking the opioid medication? Response can help clarify long-term risks and benefits of the medication and identify other treatment options.

- Does the person take pain medication only on occasion, perhaps three or four times per week? If yes, the likelihood of addiction is low.

- Have there been any other substance (alcohol or drug) abuse problems in the person's life? An affirmative response should be taken into consideration when prescribing.

- Does the person in pain spend most of the day resting, avoiding activity, or feeling depressed? If so, this suggests the pain medication is failing to promote rehabilitation. Daily activity is essential, and the patient may be considered for enrollment in a graduated exercise program

- Is the person in pain able to function (e.g., work, do household chores, play) with pain medication in a way that is clearly better than without? If yes, this suggests the pain medication is contributing to wellness.

Assessment Tools

VIGIL

VIGIL is the acronym for a five-step risk management strategy designed to empower clinicians to appropriately prescribe opioids for pain by reducing regulatory concerns and to give pharmacists a framework for resolving ambiguous opioid analgesic prescriptions in a manner that preserves legitimate patient need while potentially deterring diverters. The components of VIGIL are:

- Verification: Is this a responsible opioid user?

- Identification: Is the identity of this patient verifiable?

- Generalization: Do we agree on mutual responsibilities and expectations?

- Interpretation: Do I feel comfortable allowing this person to have controlled substances?

- Legalization: Am I acting legally and responsibly?

The foundation of VIGIL is a collaborative physician/pharmacist relationship [25].

Current Opioid Misuse Measure (COMM)

The Current Opioid Misuse Measure (COMM) is a 17-item patient self-report assessment designed to help clinicians identify misuse or abuse in patients being treated for chronic pain. Unlike the ORT and the SOAPP-R, the COMM identifies aberrant behaviors associated with opioid misuse in patients already receiving long-term opioid therapy [26]. Sample questions include: In the past 30 days, how often have you had to take more of your medication than prescribed? In the past 30 days, how much of your time was spent thinking about opioid medications (e.g., having enough, taking them, dosing schedule)?

Pain Assessment and Documentation Tool (PADT)

Guidelines by the CDC, the Federation of State Medical Boards (FSMB), and the Joint Commission stress the importance of documentation from both a healthcare quality and medicolegal perspective. Research has found widespread deficits in chart notes and progress documentation with patients with chronic pain receiving opioid therapy, and the Pain Assessment and Documentation Tool (PADT) was designed to address these shortcomings [46]. The PADT is a clinician-directed interview, with most sections (e.g., analgesia, activities of daily living, adverse events) consisting of questions asked of the patient. However, the potential aberrant drug-related behavior section must be completed by the physician based on his or her observations of the patient.

The Brief Intervention Tool

The Brief Intervention Tool is a 26-item, "yes-no," patient-administered questionnaire used to identify early signs of opioid abuse or addiction. The items assess the extent of problems related to drug use in several areas, including drug use-related functional impairment [22].

Urine Drug Tests

UDTs may be used to monitor adherence to the prescribed treatment plan and to detect unsanctioned drug use. They should be used more often in patients receiving addiction therapy, but clinical judgment is the ultimate guide to testing frequency (Table 2) [47]. The CDC recommends clinicians should use UDT before starting opioid therapy and consider UDT at least annually to assess for prescribed medications as well as other controlled prescription drugs and illicit drugs [10]. However, this recommendation was based on low-quality evidence that indicates little confidence in the effect estimate.

Table 2: PATIENT RISK LEVEL AND FREQUENCY OF MONITORING

Monitoring Tool

Patient Risk Level

Low

Medium

High

Urine drug test

Every 1 to 2 years

Every 6 to 12 months

Every 3 to 6 months

State prescription drug monitoring program

Twice per year

Three times per year

Four times per year

Source: [47]

Initially, testing involves the use of class-specific immunoassay drug panels [1]. If necessary, this may be followed with gas chromatography/mass spectrometry for specific drug or metabolite detection. It is important that testing identifies the specific drug rather than the drug class, and the prescribed opioid should be included in the screen. Any abnormalities should be confirmed with a laboratory toxicologist or clinical pathologist. Immunoassay may be used point-of-care for "on-the-spot" therapy changes, but the high error rate prevents its use in major clinical decisions except with liquid chromatography coupled to tandem mass spectrometry confirmation.

Urine test results suggesting opioid misuse should be discussed with the patient using a positive, supportive approach. The test results and the patient discussion should be documented.

CONCURRENT USE OF BENZODIAZEPINES

In 2019, 16% of persons who died of an opioid overdose also tested positive for benzodiazepines, a class of sedative medication commonly prescribed for anxiety, insomnia, panic attack, and muscle spasm [44]. Benzodiazepines work by raising the level of the neurotransmitter gamma-aminobutyric acid (GABA) in the brain. Common formulations include diazepam, alprazolam, and clonazepam. Combining benzodiazepines with opioids is unsafe because both classes of drug cause central nervous system depression and sedation and can decrease respiratory drive—the usual cause of overdose fatality. Both classes have the potential for drug dependence and addiction.

The CDC recommends that healthcare providers avoid prescribing benzodiazepines concurrently with opioids whenever possible [10]. If a benzodiazepine is to be discontinued, the clinician should taper the medication gradually, because abrupt withdrawal can lead to rebound anxiety and complications such as hallucinations, seizures, delirium tremens, and, in rare instances, death. A commonly used tapering schedule is a reduction of the benzodiazepine dose by 25% every one to two weeks [10].

CONSULTATION AND REFERRAL

It is important to seek consultation or patient referral when input or care from a pain, psychiatry, addiction, or mental health specialist is necessary. Clinicians who prescribe opioids should become familiar with opioid addiction treatment options (including licensed opioid treatment programs for methadone and office-based opioid treatment for buprenorphine) if referral is needed [1].

Ideally, providers should be able to refer patients with active substance abuse who require pain treatment to an addiction professional or specialized program. In reality, these specialized resources are scarce or non-existent in many areas [1]. Therefore, each provider will need to decide whether the risks of continuing opioid treatment while a patient is using illicit drugs outweigh the benefits to the patient in terms of pain control and improved function [48].

MEDICAL RECORDS

As noted, documentation is a necessary aspect of all patient care, but it is of particular importance when opioid prescribing is involved. All clinicians should maintain accurate, complete, and up-to-date medical records, including all written or telephoned prescription orders for opioid analgesics and other controlled substances, all written instructions to the patient for medication use, and the name, telephone number, and address of the patient's pharmacy [1]. Good medical records demonstrate that a service was provided to the patient and that the service was medically necessary. Regardless of the treatment outcome, thorough medical records protect the prescriber.

PATIENT EDUCATION ON THE USE AND DISPOSAL OF OPIOIDS

Patients and caregivers should be counseled regarding the safe use and disposal of opioids. As part of its mandatory Risk Evaluation and Mitigation Strategy (REMS) for extended-release/long-acting opioids, the U.S. Food and Drug Administration (FDA) has developed a patient counseling document with information on the patient's specific medications, instructions for emergency situations and incomplete pain control, and warnings not to share medications or take them unprescribed [16]. A copy of this form may be accessed online at https://www.fda.gov/media/114694/download.

When prescribing opioids, clinicians should provide patients with the following information [16]:

- Product-specific information

- Taking the opioid as prescribed

- Importance of dosing regimen adherence, managing missed doses, and prescriber contact if pain is not controlled

- Warning and rationale to never break or chew/crush tablets or cut or tear patches prior to use

- Warning and rationale to avoid other central nervous system depressants, such as sedative-hypnotics, anxiolytics, alcohol, or illicit drugs

- Warning not to abruptly halt or reduce the opioid without physician oversight of safe tapering when discontinuing

- The potential of serious side effects or death

- Risk factors, signs, and symptoms of overdose and opioid-induced respiratory depression, gastrointestinal obstruction, and allergic reactions

- The risks of falls, using heavy machinery, and driving

- Warning and rationale to never share an opioid analgesic

- Rationale for secure opioid storage

- Warning to protect opioids from theft

- Instructions for disposal of unneeded opioids, based on product-specific disposal information

There are no universal recommendations for the proper disposal of unused opioids, and patients are rarely advised of what to do with unused or expired medications [49]. According to the FDA, most medications that are no longer necessary or have expired should be removed from their containers, mixed with undesirable substances (e.g., cat litter, used coffee grounds), and put into an impermeable, nondescript container (e.g., disposable container with a lid or a sealed bag) before throwing in the trash [50]. Any personal information should be obscured or destroyed. The FDA recommends that certain medications, including oxycodone/acetaminophen (Percocet), oxycodone (OxyContin tablets), and transdermal fentanyl (Duragesic Transdermal System), be flushed down the toilet instead of thrown in the trash [31,50]. The FDA provides a free toolkit of materials (e.g., social media images, fact sheets, posters) to raise awareness of the serious dangers of keeping unused opioid pain medicines in the home and with information about safe disposal of these medicines. The Remove the Risk Outreach toolkit is updated regularly and can be found at https://www.fda.gov/drugs/ensuring-safe-use-medicine/safe-opioid-disposal-remove-risk-outreach-toolkit [31]. Patients should be advised to flush prescription drugs down the toilet only if the label or accompanying patient information specifically instructs doing so.

The American College of Preventive Medicine has established best practices to avoid diversion of unused drugs and educate patients regarding drug disposal [49]:

- Consider writing prescriptions in smaller amounts.

- Educate patients about safe storing and disposal practices.

- Give drug-specific information to patients about the temperature at which they should store their medications. Generally, the bathroom is not the best storage place. It is damp and moist, potentially resulting in potency decrements, and accessible to many people, including children and teens, resulting in potential theft or safety issues.

- Ask patients not to advertise that they are taking these types of medications and to keep their medications secure.

- Refer patients to community "take back" services overseen by law enforcement that collect controlled substances, seal them in plastic bags, and store them in a secure location until they can be incinerated. Contact your state law enforcement agency or visit https://www.dea.gov to determine if a program is available in your area.

DISCONTINUING OPIOID THERAPY

The decision to continue or end opioid prescribing should be based on a physician-patient discussion of the anticipated benefits and risks. An opioid should be discontinued with resolution of the pain condition, intolerable side effects, inadequate analgesia, lack of improvement in quality of life despite dose titration, deteriorating function, or significant aberrant medication use [1,10].

Clinicians should provide patients physically dependent on opioids with a safely structured tapering protocol. Withdrawal is managed by the prescribing physician or referral to an addiction specialist. Patients should be reassured that opioid discontinuation is not the end of treatment; continuation of pain management will be undertaken with other modalities through direct care or referral.

As a side note, cannabis use by patients with chronic pain receiving opioid therapy has traditionally been viewed as a treatment agreement violation that is grounds for termination of opioid therapy. However, some now argue against cannabis use as a rationale for termination or substantial treatment and monitoring changes, especially considering the increasing legalization of medical use at the state level [48].

CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

For patients 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.

5. IDENTIFICATION OF DRUG DIVERSION/SEEKING BEHAVIORS

Research has more closely defined the location of prescribed opioid diversion into illicit use in the supply chain from the manufacturer to the distributor, retailer, and the end user (the pain patient). This information carries with it substantial public policy and regulatory implications. The 2019 National Survey on Drug Use and Health asked non-medical users of prescription opioids how they obtained their most recently used drugs [51]. Among persons 12 years of age or older, 38.6% obtained their prescription opioids from a friend or relative for free, 34.7% got them through a prescription from one doctor (vs. 17.3% in 2009–2010), 9.5% bought them from a friend or relative, and 3.2% took them from a friend or relative without asking [51]. Less frequent sources included a drug dealer or other stranger (6.5%); multiple doctors (2.0%); and theft from a doctor's office, clinic, hospital, or pharmacy (0.9%) (vs. 0.2% in 2009–2010) [51].

As discussed, UDTs can give insight into patients who are misusing opioids. A random sample of UDT results from 800 patients treated for pain at a Veterans Affairs facility found that 25.2% were negative for the prescribed opioid while 19.5% were positive for an illicit drug/unreported opioid [52]. Negative UDT results for the prescribed opioid do not necessarily indicate diversion, but may indicate the patient halted his/her use due to side effects, lack of efficacy, or pain remission. The concern arises over the increasingly stringent climate surrounding clinical decision-making regarding aberrant UDT results and that a negative result for the prescribed opioid or a positive UDT may serve as the pretense to terminate a patient rather than guide him/her into addiction treatment or an alternative pain management program [53].

In addition to aberrant urine screens, there are certain behaviors that are suggestive of an emerging opioid use disorder. The most suggestive behaviors are [48,54,55]:

- Selling medications

- Prescription forgery or alteration

- Injecting medications meant for oral use

- Obtaining medications from nonmedical sources

- Resisting medication change despite worsening function or significant negative effects

- Loss of control over alcohol use

- Using illegal drugs or non-prescribed controlled substances

- Recurrent episodes of:

- Prescription loss or theft

- Obtaining opioids from other providers in violation of a treatment agreement

- Unsanctioned dose escalation

- Running out of medication and requesting early refills

Behaviors with a lower level of evidence for their association with opioid misuse include [48,54,55]:

- Aggressive demands for more drug

- Asking for specific medications

- Stockpiling medications during times when pain is less severe

- Using pain medications to treat other symptoms

- Reluctance to decrease opioid dosing once stable

- In the earlier stages of treatment:

- Increasing medication dosing without provider permission

- Obtaining prescriptions from sources other than the pain provider

- Sharing or borrowing similar medications from friends/family

6. INTERVENTIONS FOR SUSPECTED OR KNOWN ADDICTION OR DRUG DIVERSION

There are a number of actions that prescribers and dispensers can take to prevent or intervene in cases of drug diversion. These actions can be generally categorized based on the various mechanisms of drug diversion.

Prevention is the best approach to addressing drug diversion. As noted, the most common source of nonmedical use of prescribed opioids is from a family member or friend, through sharing, buying, or stealing. To avoid drug sharing among patients, healthcare professionals should educate patients on the dangers of sharing opioids and stress that "doing prescription drugs" is the same as "using street drugs" [49]. In addition, patients should be aware of the many options available to treat chronic pain aside from opioids. To prevent theft, patients should be advised to keep medications in a private place and to refrain from telling others about the medications being used.

Communication among providers and pharmacies can help to avoid inappropriate attainment of prescription drugs through "doctor shopping." Prescribers should keep complete and up-to-date records for all controlled substance prescribing. When possible, electronic medical records should be integrated between pharmacies, hospitals, and managed care organizations [49]. If available, it is also best practice to periodically request a report from the state's prescription reporting program to evaluate the prescribing of opioids to your patients by other providers [49].

When dealing with patients suspected of drug seeking/diversion, first inquire about prescription, over-the-counter, and illicit drug use and perform a thorough examination [49,56]. Pill counting and/or UDT may be necessary to investigate possible drug misuse. Photo identification or other form of identification and social security number may be required prior to dispensing the drug, with proof of identity documented fully. If a patient is displaying suspicious behaviors, consider prescribing for limited quantities [56].

If a patient is found to be abusing prescribed opioids, this is considered a violation of the treatment agreement and the clinician must make the decision whether or not to continue the therapeutic relationship. If the relationship is terminated, it must be done ethically and legally. The most significant issue is the risk of patient abandonment, which is defined as ending a relationship with a patient without consideration of continuity of care and without providing notice to the patient. The American Medical Association Code of Ethics states that physicians have an obligation to support continuity of care for their patients. While physicians have the option of withdrawing from a case, they should notify the patient (or authorized decision maker) long enough in advance to permit the patient to secure another physician and facilitate transfer of care when appropriate [57]. Patients may also be given resources and/or recommendations to help them locate a new clinician.

Patients with chronic pain found to have an ongoing substance abuse problem or addiction should be referred to a pain specialist for continued treatment. Theft or loss of controlled substances is reported to the DEA. If drug diversion has occurred, the activity should be documented and a report to law enforcement should be made [58].

7. COMPLIANCE WITH STATE AND FEDERAL LAWS

In response to the rising incidence in prescription opioid abuse, addiction, diversion, and overdose since the late 1990s, the FDA has mandated opioid-specific REMS to reduce the potential negative patient and societal effects of prescribed opioids. Other elements of opioid risk mitigation include FDA partnering with other governmental agencies, state professional licensing boards, and societies of healthcare professionals to help improve prescriber knowledge of appropriate and safe opioid prescribing and safe home storage and disposal of unused medication [24].

Several regulations and programs at the state level have been enacted in an effort to reduce prescription opioid abuse, diversion, and overdose, including [59]:

- Physical examination required prior to prescribing

- Tamper-resistant prescription forms

- Pain clinic regulatory oversight

- Prescription limits

- Prohibition from obtaining controlled substance prescriptions from multiple providers

- Patient identification required before dispensing

- Immunity from prosecution or mitigation at sentencing for individuals seeking assistance during an overdose

CONTROLLED SUBSTANCES LAWS/RULES

The U.S. Drug Enforcement Administration (DEA) is responsible for formulating federal standards for the handling of controlled substances. In 2011, the DEA began requiring every state to implement electronic databases that track prescribing habits, referred to as PDMPs. Specific policies regarding controlled substances are administered at the state level [60].

According to the DEA, drugs, substances, and certain chemicals used to make drugs are classified into five distinct categories or schedules depending upon the drug's acceptable medical use and the drug's abuse or dependency potential [61]. The abuse rate is a determinate factor in the scheduling of the drug; for example, Schedule I drugs are considered the most dangerous class of drugs with a high potential for abuse and potentially severe psychologic and/or physical dependence.

STATE-SPECIFIC LAWS AND RULES

Most states have established laws and rules governing the prescribing and dispensing of opioid analgesics. It is each prescriber's responsibility to have knowledge of and adhere to the laws and rules of the state in which he or she prescribes.

Arkansas Laws and Rules

An excerpt from the Arkansas Code rules and regulations relating to the regulation of controlled substances is available by clicking here.

Colorado Laws and Rules

An excerpt from the Colorado Revised Statutes relating to the electronic prescription drug monitoring program and the full Guidelines for the Safe Prescribing and Dispensing of Opioids are available by clicking here.

Michigan Laws and Rules

A summary of legislation enacted in Michigan to curb substance abuse and drug diversion is available by clicking here.

Nebraska Laws and Rules

An excerpt reprinted from the Nebraska Revised Statutes 71-2454 and 71-2455 is available by clicking here.

New Mexico Laws and Rules

An excerpt from the New Mexico Administrative Code Title 16, Chapter 10, Part 14: Management of Pain and Other Conditions with Controlled Substances is available by clicking here.

New York Laws and Rules

An excerpt from the New York Code, Rules, and Regulations relating to the regulation of controlled substances is available by clicking here.

Vermont Laws and Rules

Information on use of the Vermont Prescription Monitoring System (VPMS) is available by clicking here.

Washington Laws and Rules

Laws governing the prescribing of opioids in the state of Washington are available by clicking here.

Wisconsin Laws and Rules

The Wisconsin Medical Examining Board Opioid Prescribing Guideline is available by clicking here.

8. MANAGEMENT OF OPIOID USE DISORDER

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 [62]:

- 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 [62].

CRISIS INTERVENTION

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 patients who have overdosed. 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 2014, the FDA approved naloxone as an autoinjector dosage form for home use by family members or caregivers [63]. 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 [63]. In 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 central nervous system depression. It is available in a ready-to-use 2-mg, 4-mg, or 8-mg single-dose sprayer [64,65,87].

HARM REDUCTION

Harm reduction measures are primarily employed to minimize the morbidity and mortality from opioid abuse and to reduce public nuisance [20,66]. 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 [20,66].

DETOXIFICATION AND WITHDRAWAL

The process of tapering patients with opioid dependence from agonist therapy is often referred to as detoxification, or more accurately, medically supervised withdrawal [67,68]. 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 [68,69]. Detoxification alone should not be considered a treatment and should only be promoted in the context of a well-planned relapse-prevention program [62,68].

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 [67].

The three primary treatment modalities used for detoxification are opioid agonists, non-opioid medications, and rapid and ultra-rapid opioid detoxification [67]. 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 [70]. Methadone is the most frequently used opioid agonist due to the convenience of its once-a-day dosing [67]. 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 [70].

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 [70,71]. The first non-opioid treatment approved for the management of opioid withdrawal symptoms is lofexidine [86]. In studies, lofexidine resulted in less severe withdrawal symptoms and greater treatment retention than placebo.

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 [70].

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 [70]. 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 [70]. Psychosocial treatments offered in addition to pharmacologic detoxification treatments positively impact treatment retention and completion, results at follow-up, and compliance [72,73].

AGONIST REPLACEMENT OR ABSTINENCE THERAPY

Two principle treatment modalities are offered for patients with opioid dependence: 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 [74]. 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 [75].

At present, there are no direct interventions that are capable of reversing the effects of drugs of dependence on learning and motivation systems [76]. 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 [76]. Considering the high rate of relapse after detoxification, maintenance therapy with methadone or buprenorphine is currently considered to be the first-line treatment for patients with opioid dependence [62].

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 [62]. Patients who are dependent on opioids frequently suffer from physical and psychiatric disorders, and targeted interventions of psychiatric comorbidity are essential in improving treatment outcome for these patients [62]. 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 [62]. 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 [62].

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 [67]. 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 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 [67].

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 [77]. 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 [77].

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 [67]. 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 [67].

As of 2019, there were 1,691 treatment programs including opioid replacement therapy in the United States [78]. However, this represents only an estimated 19% of all patients with opioid use disorder. 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 [67]. 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%) [79].

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 [62].

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 [62].

12-Step/Self-Help Programs

Twelve-step programs for opioid abuse and dependence include Narcotics Anonymous (NA), Heroin Anonymous (HA), 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 has helped hundreds of thousands of alcoholics achieve sobriety [80]. 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 [80]. 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 [81].

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 [81].

Part of the effectiveness of NA, HA, 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 [82]. 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 [83].

STIGMA OF ADDICTION

Many terms used in discussions of opioid use and misuse may have ambiguous meanings, and the absence of consensus in the terminology and definitions of substance use, substance use disorders, and addiction has led to considerable confusion and misconceptions. These misconceptions may be harbored by clinicians, patients, family members, and the public and can negatively impact patient interaction, assessment, treatment, and outcomes. This, coupled with pervasive stereotypes about what an opioid addict "looks" like, can negatively impact willingness to receive treatment or seek help and impair the patient's self-worth and mental health. Correction of these erroneous beliefs and attitudes is important, as is the use of nonpejorative and nonstigmatizing language when describing opioid analgesics, the patients who need them, and patients who develop aberrant behaviors or addiction involving opioids [32,42]. It is important for all healthcare professionals to remember that addiction can affect any patients, regardless of age, sex, socioeconomic status, education, ability, or race.

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 [84]. Many cases of relapse are attributable to treatment noncompliance and lack of lifestyle modification [85].

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 [76].

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 [76].

9. CONCLUSION

Opioid analgesic medications can bring substantial relief to patients suffering from pain. However, the inappropriate use, abuse, and diversion of prescription drugs in America, particularly prescription opioids, has increased dramatically in recent years and has been identified as a national public health epidemic. A set of clinical tools, guidelines, and recommendations are now available for prescribers who treat patients with opioids. By implementing these tools, the clinician can effectively address issues related to the clinical management of opioid prescribing, opioid risk management, regulations surrounding the prescribing of opioids, and problematic opioid use by patients. In doing so, healthcare professionals are more likely to achieve a balance between the benefits and risks of opioid prescribing, optimize patient attainment of therapeutic goals, and avoid the risk to patient outcome, public health, and viability of their own practice imposed by deficits in knowledge.

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Evidence-Based Practice Recommendations Citations

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