Opioid Use Disorder (2024)

Continuing Education Activity

This activity focuses on the critical evaluation and management of opioid use disorder (OUD), a pervasive condition significantly diminishing patients' quality of life and contributing to a widespread epidemic in the United States. With over 16 million affected globally and 2.1 million in the United States, the course emphasizes the urgency of identifying and promptly treating persistent opioid use and misuse. Participants will review evidence-based treatment options, including methadone and buprenorphine, and examine their roles in both the acute phase for detoxification and long-term management. The program also discusses the Mainstreaming Addiction Treatment (MAT) Act, which empowers healthcare providers to prescribe buprenorphine without the previous X-Waiver limitations. Furthermore, the course explores the multidimensional approach to treatment, including behavioral therapy, peer support, and the integration of nonpharmacologic interventions, reinforcing the need for an interprofessional team in optimizing patient care. Overall, this activitywill equip healthcare professionals with the knowledge and skills necessary to navigate the intricate landscape of OUD, emphasizing a patient-centered, evidence-based, andinterdisciplinary approach to improve outcomes and address the ongoing opioid epidemic.

Objectives:

• Identify thesymptomsof opioid use disorder and opioid-related medical emergencies.

• Implement appropriate evaluation and diagnosis strategies for opioid use disorder.

• Differentiate the various treatment optionsfor opioid use disorder, including pharmacologic and nonpharmacologic strategies.

• Collaborate effectively with other healthcare professionals to diagnose, treat, and comprehensively manageopioid use disorder.

Earn FREE continuing education credits (CME/CE) on this topic.

Introduction

Opioid use disorder (OUD) is defined as the chronic use of opioids that causes clinically significant distress or impairment. Symptoms of this disease includean overpowering desire to use opioids, increased opioid tolerance, and withdrawal syndrome when opioids are discontinued. Thus, OUD can range from dependence on opioids to addiction.[1]OUD affects over 16 million people worldwide and over 2.1 million in the United States. Strikingly, there are as many patients using opioids regularly as there are patients diagnosed with obsessive-compulsive disorder, psoriatic arthritis, and epilepsy in the United States.More than 120,000 deaths worldwideevery yearare attributed to opioids.[2]Examples of opioids include heroin (diacetylmorphine), morphine, codeine, fentanyl, and oxycodone.

Arise in the prevalence ofOUDand opioid deaths lends to the importance of clinicians' appreciation for the complexity of OUD.OUDtypically involves periods of exacerbation and remission, but the vulnerability to relapse occurs throughout a patient's lifetime. Stressful events, loss of economic stability, and relationship issues can increase the risk of relapse.Opioid addiction is similar to other chronic relapsing conditions; signs and symptoms can be severe, and treatment adherence is often problematic.

Mainstreaming Addiction Treatment (MAT) Act

The Mainstreaming Addiction Treatment (MAT) Act provision updates federal guidelines to expand the availability of evidence-based treatment to address the opioid epidemic. The MAT Act empowers all health care providers with a controlled substance certificateto prescribe buprenorphine for OUD, just as they prescribe other essential medications. The MAT Act is intended to help destigmatize a standard of care for OUD and strives to integrate substance use disorder treatment across healthcare settings.

As of December 2022, the MAT Act eliminated the DATA-Waiver (X-Waiver) program that was previously required to prescribe medications for the treatment of OUD. All DEA-registered practitioners with Schedule III prescribing authority may now prescribe buprenorphine for OUD in their practice if permitted by applicable state law. Prescribers previously registered with a DATA Waiver will receive a new DEA registration certificate reflecting this change without further action. Additionally, there are no longer limits on the number of patients with OUD that a practitioner may treat with buprenorphine or tracking of patients treated with buprenorphinerequired. Pharmacists can now dispense buprenorphine prescriptions using the prescribing authority's DEA number. Of note,prescribers are still required to comply with any applicable state limits regarding the treatment of patients with OUD. Informationon State Opioid Treatment Authorities (SOTA) can be found at SAMHSA.gov.

Etiology

Opioid dependence andaddiction are products of many biological, environmental, genetic, and psychosocial factors.[3]Mostopioids in use are prescribed, but many are also obtained illegally. After a relatively brief period, many patients taking opioids demonstrate opioid dependence. Opioid dependencecan manifestasphysical dependence, psychological dependence, or both. Opioid-dependent patients will experience withdrawal ifopioids are stopped abruptly. Thus, many opioid-dependent patientswill seek continued access to opioids, by legal or illegal means, to prevent withdrawal. Ongoing opioid dependence may lead to addiction and uncontrolled opioid use.

OUDoccurs in individuals from all educational and socioeconomic backgrounds. Patients at particular risk for OUD include thosedeficient inneurotransmitters such as dopamine or with first-degree relatives who have a substance abuse disorder.[4] Patients who have been exposed to an environment that includes opioid use may also be more likely to develop OUD. Environmentalrisks for OUD include peer useof opioids or exposure to opioid analgesics due to aprevious injury. Patients with a history of untreated depression, post-traumatic stress disorder, anxiety, or childhood trauma are also at risk for OUD.[5]

Epidemiology

Over 16 million people worldwide and 3 million in the United States meet OUD criteria. Concerningly, OUDresults in over 120,000 and 47,000 deaths per year worldwide and in the United States, respectively.[6]In the United States, opioids have killed more people than any other drug in history. Recreational use of opioids was at its highest in 2010 and has gradually decreased as the opioid epidemic has gained attention in the United States. Up to 50% of patients on chronic opioid therapy meet the criteria for opioid use disorder.[7]

The prevalence of opioid use and dependency varies by age and gender. Men are more likely to use and become dependent on opioids. Thus, men account for the majority of opioid-related overdoses. Womenare prescribedopioidsfor analgesia more often than men. Opioid-related deaths are highest among individuals between the ages of 40 and 50 years, while heroin overdosesare most common among individualsbetween the ages of 20 and 30 years.

Pathophysiology

OUD develops along a continuum of opioid use. Physical dependence on opioids may develop rapidly and is likely the result of many changes in mu-opioid receptors, including receptor desensitization, internalization, and signaling abnormalities.[8][9] Physical dependence is also responsible for withdrawal symptoms when opioids are stopped abruptly. Thus,physical dependence on opioids creates both positive and negative reinforcement for continued opioid use. Patients meetOUD criteria if their continued opioid use creates clinically significant impairment or distress. Clinically significant impairment and distresscan manifest in several ways but are often the result ofimpairments in controlling opioid use and intense opioid cravings.[10]

History and Physical

To make the diagnosis of OUD, the patient must meet the diagnostic criteria per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).[11][12]Per the DSM-5,OUDis defined as repeatedopioid use within 12 months leading to problems or distress with2 or more ofthe following occurring:

1. Continued opioid use despite worsening physical or psychological health

2. Continued opioid usedespite social and interpersonal consequences

3. Decreased social or recreational activities

4. Difficulty fulfilling professional duties at school or work

5. Excessive time is taken to obtain or recover from taking opioids

6. More opioids are taken than intended

7. Opioid cravingsoccur

8. Inability to decrease the amount of opioids used

9. Tolerance to opioids develops

   See Also

   Medication-Assisted Treatment: Pros and Cons of MAT for Recovery - New Choices Treatment CentersMedication-Assisted Treatment Improves Outcomes for Patients With Opioid Use DisorderWhat is Psychotherapy?Medication-Assisted Treatment For Opioid Use Disorders

10. Opioid use continues despite the dangers it poses to the user

11. Withdrawal occurs, or the user continues to take opioids to avoid withdrawal

The presence of 6 or more of these diagnostic criteria indicates severe OUD.The signs and symptoms of opioid use disorder include drug-seeking behavior, the presence of legal or social ramifications due to opioid use, multiple opioid prescriptions from different prescribers, opioid cravings, increased opioid usage over time, and symptoms of opioid withdrawal when stopping opioid use. Physical findings and complaints consistent with opioid withdrawal include muscle aches, diarrhea, rhinorrhea, nerve excitability, and chills with cessation of use.

Evaluation

A full social and mental health history should be a part of an initial evaluation for OUD. History of injuries, trauma, previous surgeries, and hospitalizationmay be crucial to the evaluation to identify gateways for opioid use.If the patientuses intravenous drugs, testsshould be orderedto screen for HIV and hepatitis B and C.[13][14][15]Urine drugscreening for opioids should be performedbefore starting treatment for OUD and regularly with subsequent visits to evaluate the patient's compliance with treatmentand abstinence from illicit opioid use.[16]

Treatment / Management

The treatment ofOUD improves physical and psychological conditions, reduces risks of overdose, and helps with the avoidance of criminal behavior and subsequent penalties.[17][18]There are a variety of approaches to the rehabilitation and maintenance of patients with OUD. Rehabilitation begins with a cognitive behavioral approach similar to that used in the treatment of other chronic conditions. Maintenance programs include psychological support. Patients are encouraged and motivated to change through education, reward cooperation, and medications. The goal of cognitive behavioral therapy is to minimize drug relapses. Patients withOUD are encouraged to participate in self-help programs such as Narcotics Anonymous. The combination of education, motivational enhancement, and self-help assists patients to change how they think about the ways that opioids affect their lives.[19][20][19]Group therapy helps maintain self-control and restraint for patients with OUD.[21]Group therapy is also cost-effective compared to individualized therapy in treating OUD.[22]

Various forms of rehabilitation help patientsrecognize that change is possible. There is a need to decrease behaviors that perpetuate illicit drug use while developing new behaviors that diminish drug-related problems.[23] Nonopioid drugs and physical therapy can provide a long-term solution to pain managementinstead of relying on the use of opioids, for example. Additionally, education about dealing with pain syndromes and minimizing opioid use can help build rapport and create realistic treatment goals. Cognitive behavioral therapy is most effective if combined with medications; however, there are mixed results on its effectiveness.[12][24]

Opioid replacement, maintenance, or substitution therapy involves replacing the problematic opioid with a safer one. These alternative agents are prescribed under medical supervision. Medication-assisted treatment (MAT) and outpatient buprenorphine office therapy (OBOT) help the patient experience reduced symptoms of drug withdrawal and cravings and little or no euphoria. Opioid maintenance drugs help the patient experience reduced symptoms. Almost half of the patients can maintain abstinence from additional opioids while receiving replacement therapy.[25]

The selection of which agent or agents to use for treatment can be simple or very complex, depending on patient-specific factors. Methadone, an oral mu-receptor agonist, is commonly used in opioid replacement. It has been widely used worldwide. In the US, outpatient methadone is offered only for specially monitored clinics. Patients withOUD with physiologic features of opioid withdrawal or who are likely to relapseare eligible to receive methadone from a clinic. The advantages of methadone treatment includereduced euphoric effects, decreased narcotic cravings, and reduced transmission of infectious diseases through avoidance of intravenous drug use. Methadone maintenance is non-sedating and is medically safe, provided there is no concomitant use of other prescription or illicit drugs. The maintenance phasecan be attained with carefulramping of the dose upward. Consideration must be given to the long half-life of methadone, even if all of the symptoms of withdrawal, as well as the cravings, are not quickly abated. Other ancillary medications can be used to treat the symptoms as the dose of methadone is slowly increased. The length of the maintenance phase can last years to an entire lifetime. Tapering off methadone can take weeks or months, depending on the patient's level of opioid dependence.[26][27]

An alternative oral, long-acting opioidfor maintenance therapy is buprenorphine. Buprenorphine is a partial mu-receptor agonist. Similar to methadone, Buprenorphine is graduallyramped upwards to achieve an effectivedose, and not all the symptoms of withdrawal can be immediately abated. It is crucial toensure that the patientis in opioid withdrawalbefore the initiation of buprenorphine to avoid the occurrence of precipitated withdrawal.[28][29]Buprenorphine isavailable as a sublingual tablet, sublingual film, buccal film, subcutaneous solution, transdermal patch, and intradermal implant. Sublingual tablets and films may alsobecombined with naloxone, a mu-opioid receptor antagonist. Naloxone is not absorbed orally and onlyexerts its actionwhen injected into the bloodstream. Thus, the addition of naloxone to the buprenorphine formulation helps to deter abuse. Following induction and stabilization with sublingual tablets or the buccal film, subcutaneoussolutions and intradermal implants may be used for lasting maintenance therapy.

There is no consensus among experts on whether methadone or buprenorphine therapy is superior in a broad population of patients with OUD. Thus, the agent use should be based on patient-specific factors.[30]The use of methadone maintenance may increase patient retention over buprenorphine. Additionally, methadone may treat withdrawal symptoms and cravings better than buprenorphinefor patients who use fentanyl.

The length of treatment for OUD should also be individualized for each patient. Some clinicians attempt to discontinue medications for OUD after 1 year of treatment. Other clinicians suggest that treatment should be lifelong due to the risk of relapse and overdose death after patients stop treatment. If treatment is stopped,medications should be decreased slowly and adjusted if withdrawal symptoms are observed.[31][32][33].

Naltrexone may also be used in patients with OUD. Naltrexoneworks by blocking opioid effects and helps maintain abstinence from opioids by antagonizing the mu-opioid receptor. Naltrexone may only be initiated when the patient is free of physiological opioid dependence, and at least seven days without acute withdrawal symptoms are required before starting the medication. Both oral and intramuscular naltrexone are superior to placebo in maintaining abstinence from opioids, butthe intramuscular form may be more effective.[34]The intramuscular form may also offer better compliance due to monthly administrations. Intramuscular naltrexone is FDA-approved for opioid dependence, and naltrexone administration following completion of treatment withbuprenorphine has shown to be an effective treatment in OUD.[35][36]

Many other medications are used adjunctively to treat OUD. Clonidinemay abate withdrawal symptoms while the dose of methadone or buprenorphine is being adjusted. Tizanidine helps decrease anxiety as well as muscle pain associated with opioid withdrawal. Bupropion is used to combat the symptoms of anxiety. Diarrhea, nausea, and vomiting are treated with loperamideand ondansetron, respectively.

Differential Diagnosis

The differential diagnosis ofOUD includes malingering and other substance abuse disorders. Chronic pain disorders and untreated mental health issues may also appear similar to OUD. Evaluation andidentification of the underlying medical and mental health disorders are of the utmost importance in making a definitive diagnosis of OUD. Often,OUD is diagnosed in addition to other substance abuse and mental health disorders.

Prognosis

The diagnosis ofOUDhelps clinicians tomitigate risks for patients taking chronic opioids. Cliniciansshould offer naloxone to all patients with OUD.[37][38] Patients are at the highest risk for opioid-related death in the first 4 weeks ofOUDtreatment and for 4 weeks after treatment ends.[39]Thus, close contact with the patient should be maintained both during and after treatment.[40]

OUD treatment reduces the incidence of long-term opioid addiction while decreasing illegal opioid use and mortality. Crimes associated with drugs and the expense of dealing with HIV, sepsis, and other medical complications are also decreased. Specifically, methadone treatment is associated with a 50% reduction in all-cause mortality, as well as a 50% reduction in the incidence of hepatitis C. Methadone therapy has also been shown to decrease drug-related crimes and illicit drug use, improve social interactions, and increase rates of retention in rehabilitation programs.[41][42][43]

Complications

Addiction is the most severe complication of OUD. Addiction to opioids is the continued use of these drugs despite adverse consequences or events. Opioid addiction occurs by sensitizing the drug-reward system and amplifying compulsive drug-seeking. Specifically, chronic opioid use affects the orbitofrontal area, which is essential for regulating anxiety, emotional responses, and reward-related behaviors. Additionally,opioidaddiction affects every aspect of a person's life. Legal trouble, loss of personal relationships, and significant morbidity and mortality are all consequences of opioid addiction.[39]

Opioid withdrawal is also a significant complication of OUD. Opioid withdrawal onset varies with the type of opioid used. Heroin withdrawal begins in as little as five hours, whereas methadone withdrawal may occur 2 to 3 days following the last ingestion. The duration of opioid withdrawal symptoms varies greatly by patient. Thus, symptoms may last for a few days or persist for weeks.[44]

Finally, opioid overdose may occur as a result of OUD. The risk of overdose in untreated patients with OUD is high, but there is still a significant risk of overdose in patients who have received treatment. The time of highest risk for treated patients is the period between detoxification and the start of maintenance therapy. The use and acceptance of cognitive behavioral therapy may decrease this risk. Sadly, however, the mortality rate for patients on chronic opioids remains extremely high.[45]

Deterrence and Patient Education

Methadone and buprenorphine should be considered for patients with OUD to minimize the risk of death. Naloxone is used in the acute treatment of an opiate overdose and can be given subcutaneously, intramuscularly, intravenously, intranasally, or by inhalation. It is reasonable to prescribe naloxone to any patient with OUD. Naloxone prescriptions should also be considered for a more general population of patients taking chronic opioids.[46][47]Finally, the involvement of an addiction or pain medicine specialistin the care of patients with OUD is essential to the development of a comprehensive and effective treatment plan.

Enhancing Healthcare Team Outcomes

Appropriate treatment of OUD requires an interprofessional approach. Specifically, cognitive and behavioral therapies need to be supported by medical intervention to reduce the chance of withdrawal, relapse, and overdose. An interprofessional team, including physicians or advanced practice providers, nurses, pharmacists, therapists, and other addiction and substance use professionals, is responsible for coordinating OUD care. The tenets of comprehensive OUD care include:

1. Timely diagnosis of OUD

2. Discussion of the OUD diagnosis (focusing on the immediate and long-term effects of opioids on morbidity and mortality)

3. Treatment of the underlying conditions associated with OUD (ie, cognitive behavioral therapy and antidepressants for major depressive disorder)

4. Prescription of naloxone forthe treatment of overdose

5. Prescription of opioid replacement therapy or referral to an addiction medicine specialistto manage opioid replacement therapy

   See Also

   Opioids | National Institute on Drug Abuse

6. Referral to a rehabilitation program to promote cognitive and behavioral changes

Physicians, advanced practice providers, and pharmacists all play a role in recognizing and diagnosing OUD. While physicians and advanced practice providers may make the formal diagnosis of OUD, nurses and pharmacists maybe the first to notice opioid misuse. Nurses may detect opioid misuse through patient screening and interviews. Pharmacists may identify patterns of opioid misuse by noting the duration of use, the receipt of opioid prescriptions from multiple providers, and the number of early refill requests.

All team members playa vital role in the treatment of OUD. Physicians and advanced practice providers prescribe medications for OUD, including buprenorphine under the MAT Act, and make referrals for cognitive behavioral therapies. Nurses assist with coordinating OUD therapies and educating patients on the importance of therapy adherence. Pharmacists and addiction medicine specialists provide recommendations to optimize OUD medication therapies and promote adherence to cognitive behavioral therapies. Therapists and other addiction and substance abuse professionals carry out cognitive behavioral therapies and promote adherence to medical therapies.

Ultimately, a successful, interprofessional approach will optimize OUD therapy for patients. Effective communication and coordinationamong all healthcare team members are integral to a successful approach. Additionally, the healthcare team should empower family members and members of the lay public to support the tenets of OUD care. This may further improve a patient's chances of successful OUD management.

Review Questions

• Access free multiple choice questions on this topic.

• Access free CME on this topic.

• Comment on this article.

References

1.

Vallersnes OM, Jacobsen D, Ekeberg Ø, Brekke M. Mortality, morbidity and follow-up after acute poisoning by substances of abuse: A prospective observational cohort study. Scand J Public Health. 2019 Jun;47(4):452-461. [PubMed: 29886813]

2.

Chang HY, Kharrazi H, Bodycombe D, Weiner JP, Alexander GC. Healthcare costs and utilization associated with high-risk prescription opioid use: a retrospective cohort study. BMC Med. 2018 May 16;16(1):69. [PMC free article: PMC5954462] [PubMed: 29764482]

3.

Brat GA, Agniel D, Beam A, Yorkgitis B, Bicket M, Homer M, Fox KP, Knecht DB, McMahill-Walraven CN, Palmer N, Kohane I. Postsurgical prescriptions for opioid naive patients and association with overdose and misuse: retrospective cohort study. BMJ. 2018 Jan 17;360:j5790. [PMC free article: PMC5769574] [PubMed: 29343479]

4.

Dick DM, Agrawal A. The genetics of alcohol and other drug dependence. Alcohol Res Health. 2008;31(2):111-8. [PMC free article: PMC3860452] [PubMed: 23584813]

5.

Sharma B, Bruner A, Barnett G, Fishman M. Opioid Use Disorders. Child Adolesc Psychiatr Clin N Am. 2016 Jul;25(3):473-87. [PMC free article: PMC4920977] [PubMed: 27338968]

6.

Theisen K, Jacobs B, Macleod L, Davies B. The United States opioid epidemic: a review of the surgeon's contribution to it and health policy initiatives. BJU Int. 2018 Nov;122(5):754-759. [PubMed: 29896932]

7.

Højsted J, Sjøgren P. Addiction to opioids in chronic pain patients: a literature review. Eur J Pain. 2007 Jul;11(5):490-518. [PubMed: 17070082]

8.

Christie MJ. Cellular neuroadaptations to chronic opioids: tolerance, withdrawal and addiction. Br J Pharmacol. 2008 May;154(2):384-96. [PMC free article: PMC2442443] [PubMed: 18414400]

9.

Rich MM, Wenner P. Sensing and expressing homeostatic synaptic plasticity. Trends Neurosci. 2007 Mar;30(3):119-25. [PubMed: 17267052]

10.

Volkow ND, Blanco C. The changing opioid crisis: development, challenges and opportunities. Mol Psychiatry. 2021 Jan;26(1):218-233. [PMC free article: PMC7398847] [PubMed: 32020048]

11.

John WS, Zhu H, Mannelli P, Schwartz RP, Subramaniam GA, Wu LT. Prevalence, patterns, and correlates of multiple substance use disorders among adult primary care patients. Drug Alcohol Depend. 2018 Jun 01;187:79-87. [PMC free article: PMC5959766] [PubMed: 29635217]

12.

Ober AJ, Watkins KE, McCullough CM, Setodji CM, Osilla K, Hunter SB. Patient predictors of substance use disorder treatment initiation in primary care. J Subst Abuse Treat. 2018 Jul;90:64-72. [PMC free article: PMC6336395] [PubMed: 29866385]

13.

LeFevre ML., U.S. Preventive Services Task Force. Screening for hepatitis B virus infection in nonpregnant adolescents and adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2014 Jul 01;161(1):58-66. [PubMed: 24863637]

14.

Moyer VA., U.S. Preventive Services Task Force. Screening for hepatitis C virus infection in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2013 Sep 03;159(5):349-57. [PubMed: 23798026]

15.

Moyer VA., U.S. Preventive Services Task Force*. Screening for HIV: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2013 Jul 02;159(1):51-60. [PubMed: 23698354]

16.

Johnson RE, Strain EC, Amass L. Buprenorphine: how to use it right. Drug Alcohol Depend. 2003 May 21;70(2 Suppl):S59-77. [PubMed: 12738351]

17.

Moberg K. The role of managed care professionals and pharmacists in combating opioid abuse. Am J Manag Care. 2018 May;24(10 Suppl):S215-S223. [PubMed: 29851451]

18.

Szalavitz M, Rigg KK. The Curious (Dis)Connection between the Opioid Epidemic and Crime. Subst Use Misuse. 2017 Dec 06;52(14):1927-1931. [PubMed: 28952839]

19.

Fals-Stewart W, O'Farrell TJ. Behavioral family counseling and naltrexone for male opioid-dependent patients. J Consult Clin Psychol. 2003 Jun;71(3):432-42. [PubMed: 12795568]

20.

Gossop M, Stewart D, Marsden J. Attendance at Narcotics Anonymous and Alcoholics Anonymous meetings, frequency of attendance and substance use outcomes after residential treatment for drug dependence: a 5-year follow-up study. Addiction. 2008 Jan;103(1):119-25. [PubMed: 18028521]

21.

Galanter M. Combining medically assisted treatment and Twelve-Step programming: a perspective and review. Am J Drug Alcohol Abuse. 2018;44(2):151-159. [PubMed: 28387530]

22.

Fals-Stewart W, O'Farrell TJ, Birchler GR. Behavioral couples therapy for substance abuse: rationale, methods, and findings. Sci Pract Perspect. 2004 Aug;2(2):30-41. [PMC free article: PMC2851021] [PubMed: 18552731]

23.

Meyers RJ, Miller WR, Hill DE, Tonigan JS. Community reinforcement and family training (CRAFT): engaging unmotivated drug users in treatment. J Subst Abuse. 1998;10(3):291-308. [PubMed: 10689661]

24.

Fiellin DA, Barry DT, Sullivan LE, Cutter CJ, Moore BA, O'Connor PG, Schottenfeld RS. A randomized trial of cognitive behavioral therapy in primary care-based buprenorphine. Am J Med. 2013 Jan;126(1):74.e11-7. [PMC free article: PMC3621718] [PubMed: 23260506]

25.

Strain EC, Stitzer ML, Liebson IA, Bigelow GE. Dose-response effects of methadone in the treatment of opioid dependence. Ann Intern Med. 1993 Jul 01;119(1):23-7. [PubMed: 8498759]

26.

Gibson A, Degenhardt L, Mattick RP, Ali R, White J, O'Brien S. Exposure to opioid maintenance treatment reduces long-term mortality. Addiction. 2008 Mar;103(3):462-8. [PubMed: 18190664]

27.

fa*ggiano F, Vigna-Taglianti F, Versino E, Lemma P. Methadone maintenance at different dosages for opioid dependence. Cochrane Database Syst Rev. 2003;(3):CD002208. [PubMed: 12917925]

28.

Johnson RE, Chutuape MA, Strain EC, Walsh SL, Stitzer ML, Bigelow GE. A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence. N Engl J Med. 2000 Nov 02;343(18):1290-7. [PubMed: 11058673]

29.

Kakko J, Svanborg KD, Kreek MJ, Heilig M. 1-year retention and social function after buprenorphine-assisted relapse prevention treatment for heroin dependence in Sweden: a randomised, placebo-controlled trial. Lancet. 2003 Feb 22;361(9358):662-8. [PubMed: 12606177]

30.

Mattick RP, Breen C, Kimber J, Davoli M. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Syst Rev. 2014 Feb 06;2014(2):CD002207. [PMC free article: PMC10617756] [PubMed: 24500948]

31.

Ma J, Bao YP, Wang RJ, Su MF, Liu MX, Li JQ, Degenhardt L, Farrell M, Blow FC, Ilgen M, Shi J, Lu L. Effects of medication-assisted treatment on mortality among opioids users: a systematic review and meta-analysis. Mol Psychiatry. 2019 Dec;24(12):1868-1883. [PubMed: 29934549]

32.

Kakko J, Heilig M, Sarman I. Buprenorphine and methadone treatment of opiate dependence during pregnancy: comparison of fetal growth and neonatal outcomes in two consecutive case series. Drug Alcohol Depend. 2008 Jul 01;96(1-2):69-78. [PubMed: 18355989]

33.

Senay EC, Dorus W, Goldberg F, Thornton W. Withdrawal from methadone maintenance. Rate of withdrawal and expectation. Arch Gen Psychiatry. 1977 Mar;34(3):361-7. [PubMed: 843188]

34.

Minozzi S, Amato L, Vecchi S, Davoli M, Kirchmayer U, Verster A. Oral naltrexone maintenance treatment for opioid dependence. Cochrane Database Syst Rev. 2011 Apr 13;2011(4):CD001333. [PMC free article: PMC7045778] [PubMed: 21491383]

35.

Edelman EJ, Oldfield BJ, Tetrault JM. Office-Based Addiction Treatment in Primary Care: Approaches That Work. Med Clin North Am. 2018 Jul;102(4):635-652. [PubMed: 29933820]

36.

Fudala PJ, Bridge TP, Herbert S, Williford WO, Chiang CN, Jones K, Collins J, Raisch D, Casadonte P, Goldsmith RJ, Ling W, Malkerneker U, McNicholas L, Renner J, Stine S, Tusel D., Buprenorphine/Naloxone Collaborative Study Group. Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone. N Engl J Med. 2003 Sep 04;349(10):949-58. [PubMed: 12954743]

37.

Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain--United States, 2016. JAMA. 2016 Apr 19;315(15):1624-45. [PMC free article: PMC6390846] [PubMed: 26977696]

38.

Coffin PO, Behar E, Rowe C, Santos GM, Coffa D, Bald M, Vittinghoff E. Nonrandomized Intervention Study of Naloxone Coprescription for Primary Care Patients Receiving Long-Term Opioid Therapy for Pain. Ann Intern Med. 2016 Aug 16;165(4):245-52. [PMC free article: PMC5783639] [PubMed: 27366987]

39.

National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Health Sciences Policy; Committee on Pain Management and Regulatory Strategies to Address Prescription Opioid Abuse. Pain Management and the Opioid Epidemic: Balancing Societal and Individual Benefits and Risks of Prescription Opioid Use. Phillips JK, Ford MA, Bonnie RJ, editors. National Academies Press (US); Washington (DC): Jul 13, 2017. [PubMed: 29023083]

40.

Gandhi DH, Jaffe JH, McNary S, Kavanagh GJ, Hayes M, Currens M. Short-term outcomes after brief ambulatory opioid detoxification with buprenorphine in young heroin users. Addiction. 2003 Apr;98(4):453-62. [PubMed: 12653815]

41.

Sordo L, Barrio G, Bravo MJ, Indave BI, Degenhardt L, Wiessing L, Ferri M, Pastor-Barriuso R. Mortality risk during and after opioid substitution treatment: systematic review and meta-analysis of cohort studies. BMJ. 2017 Apr 26;357:j1550. [PMC free article: PMC5421454] [PubMed: 28446428]

42.

Fullerton CA, Kim M, Thomas CP, Lyman DR, Montejano LB, Dougherty RH, Daniels AS, Ghose SS, Delphin-Rittmon ME. Medication-assisted treatment with methadone: assessing the evidence. Psychiatr Serv. 2014 Feb 01;65(2):146-57. [PubMed: 24248468]

43.

Sorensen JL, Copeland AL. Drug abuse treatment as an HIV prevention strategy: a review. Drug Alcohol Depend. 2000 Apr 01;59(1):17-31. [PubMed: 10706972]

44.

Clinical Guidelines for Withdrawal Management and Treatment of Drug Dependence in Closed Settings. World Health Organization; Geneva: 2009. [PubMed: 26269862]

45.

Hser YI, Mooney LJ, Saxon AJ, Miotto K, Bell DS, Zhu Y, Liang D, Huang D. High Mortality Among Patients With Opioid Use Disorder in a Large Healthcare System. J Addict Med. 2017 Jul/Aug;11(4):315-319. [PMC free article: PMC5930020] [PubMed: 28426439]

46.

Zhang X, Marchand C, Sullivan B, Klass EM, Wagner KD. Naloxone access for Emergency Medical Technicians: An evaluation of a training program in rural communities. Addict Behav. 2018 Nov;86:79-85. [PubMed: 29572041]

47.

Kinsman JM, Robinson K. National Systematic Legal Review of State Policies on Emergency Medical Services Licensure Levels' Authority to Administer Opioid Antagonists. Prehosp Emerg Care. 2018 Sep-Oct;22(5):650-654. [PubMed: 29485328]

Disclosure: Alexander Dydyk declares no relevant financial relationships with ineligible companies.

Disclosure: Nitesh Jain declares no relevant financial relationships with ineligible companies.

Disclosure: Mohit Gupta declares no relevant financial relationships with ineligible companies.