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Medication-Assisted Treatment for Opioid-Use Disorder

Published:September 19, 2019DOI:https://doi.org/10.1016/j.mayocp.2019.03.029

      Abstract

      The United States is in the midst of a national opioid epidemic. Physicians are encouraged both to prevent and treat opioid-use disorders (OUDs). Although there are 3 Food and Drug Administration-approved medications to treat OUD (methadone, buprenorphine, and naltrexone) and there is ample evidence of their efficacy, they are not used as often as they should. We provide a brief review of the 3 primary medications used in the treatment of OUD. Using data from available medical literature, we synthesize existing knowledge and provide a framework for how to determine the optimal approach for outpatient management of OUD with medication-assisted treatments.

      Abbreviations and Acronyms:

      CD (chemical dependency), FDA (Food and Drug Administration), IM (intramuscularly), IV (intravenously), MAT (medication-assisted treatment), NIDA (National Institute of Drug Abuse), OUD (opioid-use disorder), SBIRT (screening, brief intervention, and referral to treatment), SAMSHA (Substance Abuse and Mental Health Services Administration), X:BOT (extended-release naltrexone vs suboxone study), XR-NTX (extended-release naltrexone)
      In the early 1800s, the German chemist Friedrich Sertürner isolated the active ingredient of the opium poppy, calling it morphium after the Greek god of dreams. Although the opium poppy had been used medicinally and recreationally by humans for thousands of years, this event marked the beginning of the modern era of medicinal opioids.
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      The chemical history of morphine: an 8000-year journey, from resin to de-novo synthesis.
      By the 1850s, the full chemical formula was well established, and—in combination with the invention of the hypodermic needle—morphine became the medicinal choice for a host of ailments. However, its use became problematic when a lack of good surgical and medical options led to overuse. By the early 1900s, there was full-scale international recognition of the potential lethality and morbidity of opioid addiction. Subsequently, in 1912, the United States and many other countries signed the International Opium Convention, which controlled the import, manufacture, and sale of morphine, drastically reducing its consumption.
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      • Bennett J.
      • Desai S.P.
      The chemical history of morphine: an 8000-year journey, from resin to de-novo synthesis.
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      • Radbruch L.
      Pain treatment: a historical overview.
      Many believe that the modern opioid epidemic started in the 1990s,
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      • Burton M.C.
      • Dawson N.L.
      How good intentions contributed to bad outcomes: the opioid crisis.
      • Baker D.W.
      History of the Joint Commission's pain standards: lessons for today's prescription opioid epidemic.
      with a tenacious movement to improve the evaluation and treatment of non-cancer pain.
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      Improving outcomes of analgesic treatment: is education enough?.
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      • et al.
      The prescription opioid and heroin crisis: a public health approach to an epidemic of addiction.
      At the height of the movement, the Joint Commission revamped their pain-management standards requiring organizations to perform regular systematic assessments of pain (ie, pain on a 10-point scale).
      Shortly thereafter, Center for Medicare and Medicaid Services (CMS) began reimbursing physicians and hospitals directly or indirectly on pain control. These factors were compounded by the aggressive advertisement of new types of opioids, ultimately leading to a 4-fold increase in prescription opioid sales in the United States from 1999 to 2014.
      • Rummans T.A.
      • Burton M.C.
      • Dawson N.L.
      How good intentions contributed to bad outcomes: the opioid crisis.
      Centers for Disease Control and Prevention (CDC)
      Vital signs: overdoses of prescription opioid pain relievers–United States, 1999–2008.
      • Srivastava A.B.
      • Gold M.S.
      Beyond supply: how we must tackle the opioid epidemic.
      Consequently, overdose deaths involving prescription opioids rose by a factor of 5 during the same time period.
      • Seth P.
      • Scholl L.
      • Rudd R.A.
      • Bacon S.
      Overdose deaths involving opioids, cocaine, and psychostimulants–United States, 2015–2016.
      At present, the United Nations attributes 76% of addiction-related deaths worldwide to opioids, singly or in combination with other drugs.
      United Nations Office on Drugs and Crime
      World Drug Report 2018.
      The United States has long led the world in opioid consumption with 66.5 opioid prescriptions per 100 people.
      Centers for Disease Control and Prevention
      Annual Surveillance Report of Drug-Related Risks and Outcomes–United States, 2017.
      Opioid prescriptions are a dominant risk factor for developing substance-use disorders,
      • Morgan D.
      • Frost-Pineda K.
      • Gold M.S.
      Medical and nonmedical use of prescription opioids: epidemiology and prevalence.
      with almost 30% of patients prescribed opioids for chronic pain misusing them and up to 12% developing opioid-use disorders (OUDs).
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      • McEntee M.L.
      • Julnes P.S.
      • Frohe T.
      • Ney J.P.
      • van der Goes D.N.
      Rates of opioid misuse, abuse, and addiction in chronic pain: a systematic review and data synthesis.
      Almost 80% of people in the United States who went on to use heroin regularly (an injectable opioid associated with significant potency, comorbidity, and lethality) started their addictions with prescription opioids.
      • Muhuri P.K.
      • Gfroerer J.C.
      • Davies M.C.
      CBHSQ Data Review.
      An OUD is defined by 11 diagnostic criteria, occurring over a 12-month period. Symptoms include taking more of the opioid than intended; failed attempts to stop the opioid; excessive time spent obtaining the opioid; cravings for opioids; failure to fulfill obligations; repetitive interpersonal conflicts; giving up important things for the opioids; using opioids in hazardous situations; and using opioids despite knowing the substance is causing significant emotional or physical consequences, tolerance, and withdrawal. Relative severity (mild, moderate, and severe), is defined by the relative number of symptoms that an individual has.
      American Psychiatric Association DSM-5 Task Force
      Diagnostic and Statistical Manual of Mental Disorders.
      Certain factors increase the risk that an individual started on an opioid will develop an OUD.
      • Jones C.M.
      Heroin use and heroin use risk behaviors among nonmedical users of prescription opioid pain relievers–United States, 2002-2004 and 2008-2010.
      This can be difficult to predict, but prescribers can use tools such as the Opioid Risk Tool
      • Webster L.R.
      • Webster R.M.
      Predicting aberrant behaviors in opioid-treated patients: preliminary validation of the opioid risk tool.
      to help them identify a patient's risk level prior to and during opioid therapy. Opioid Assessment for Patients with Pain (SOAPP) (PainEDU, Inflexxion, Inc., Costa Mesa, CA) can also be used before initiation of long-term opioid therapy to predict which patients may exhibit aberrant medication behaviors. The Current Opioid Misuse Measure (COMM) (PainEDU, Inflexxion, Inc., Costa Mesa, CA) may serve as a useful tool to identify patients currently on long-term opioid therapy who may be exhibiting behaviors associated with misuse/abuse of opioid medications.
      • Butler S.F.
      • Budman S.H.
      • Fanciullo G.J.
      • Jamison R.N.
      Cross validation of the current opioid misuse measure to monitor chronic pain patients on opioid therapy.
      An OUD can be difficult to diagnose in general practice settings. Even when it is diagnosed, it can be unclear what the next best treatment option should be. Screening, Brief Intervention, and Referral to Treatment (SBIRT) training can be helpful in the referral process.
      • Babor T.F.
      • McRee B.G.
      • Kassebaum P.A.
      • Grimaldi P.L.
      • Ahmed K.
      • Bray J.
      Screening, Brief Intervention, and Referral to Treatment (SBIRT): toward a public health approach to the management of substance abuse.
      • Babor T.F.
      • Del Boca F.
      • Bray J.W.
      Screening, Brief Intervention and Referral to Treatment: implications of SAMHSA's SBIRT initiative for substance abuse policy and practice.
      Even without formal SBIRT training, it is recommended that a provider refer individuals suspected of having OUDs to addiction programs for a complete assessment. However, a medical provider's role should not end there. After a referral, Centers for Disease Control and Prevention (CDC), National Institute of Drug Abuse (NIDA), and Substance Abuse and Mental Health Services Administration (SAMSHA) have all indicated that providers have an important role in augmenting psychotherapeutic/psychosocial interventions by expanding medication-assisted treatment (MAT) for OUDs.
      • Volkow N.D.
      • Frieden T.R.
      • Hyde P.S.
      • Cha S.S.
      Medication-assisted therapies: tackling the opioid-overdose epidemic.
      Despite broad recognition of the importance of MAT, it is estimated that only 11% of patients with an opioid use disorder are prescribed Food and Drug Administration (FDA)-approved medications for the disorder. Three medications for treatment of OUDs are approved by the FDA.
      • Morgan J.R.
      • Schackman B.R.
      • Leff J.A.
      • Linas B.P.
      • Walley A.Y.
      Injectable naltrexone, oral naltrexone, and buprenorphine utilization and discontinuation among individuals treated for opioid use disorder in a United States commercially insured population.
      • Gold M.S.
      Opiate addiction and the locus coeruleus: the clinical utility of clonidine, naltrexone, methadone, and buprenorphine.
      Each of these medications has advantages and disadvantages compared with the others. This article will help providers better understand MAT options for OUDs and how to use these options most effectively.

      Naltrexone

       Background

      Naltrexone (N-cyclopropylmethylnoroxymorphone) was synthesized by Blumberg et al in 1965.
      • Blumberg H.
      • Dayton H.
      Naloxone, naltrexone, and related noroxymorphones.
      Synthetically derived from the opium poppy, it acts as a blocking (antagonist) agent rather than an activating (agonist) agent. Furthermore, it has a longer duration of action, greater potency, and more oral bioavailability than naloxone, the other clinically available opioid antagonist, which makes it ideal as an opioid blocking agent for the treatment of OUDs.
      • Willette R.
      • Barnett G.
      The clinical pharmacology of naltrexone: pharmacology and pharmacodynamics and sustained-release preparations.
      Naltrexone was unique in that it was brought to market through a public/private partnership as one of the first official actions of NIDA.
      • Ginzburg H.M.
      • Glass W.J.
      The role of the National Institute on Drug Abuse in the development of naltrexone.
      It is FDA approved for the treatment of opioid and alcohol dependence and for the blockade of the effects of exogenously administered opioids in adults.
      • Croop R.S.
      • Faulkner E.B.
      • Labriola D.F.
      The safety profile of naltrexone in the treatment of alcoholism: results from a multicenter usage study. The Naltrexone Usage Study Group.
      • Gold M.S.
      • Dackis C.A.
      • Pottash A.L.C.
      • et al.
      Naltrexone, opiate addiction, and endorphins.
      • Minozzi S.
      • Amato L.
      • Vecchi S.
      • Davoli M.
      • Kirchmayer U.
      • Verster A.
      Oral naltrexone maintenance treatment for opioid dependence.
      • Verebey K.
      The clinical pharmacology of naltrexone: pharmacology and pharmacodynamics.

       Benefits

      Some argue that because naltrexone blocks opioid receptors it works primarily as a deterrent to further use rather than as an anticraving medication. A study by Sullivan et al showed that some individuals maintained sobriety even better after “testing” the blockade.
      • Sullivan M.A.
      • Bisaga A.
      • Mariani J.J.
      • et al.
      Naltrexone treatment for opioid dependence: does its effectiveness depend on testing the blockade?.
      Medication-benefit studies have shown that, if taken as intended, it does increase the chance of sobriety and decreases risk of overdose.
      • Molero Y.
      • Zetterqvist J.
      • Binswanger I.A.
      • Hellner C.
      • Larsson H.
      • Fazel S.
      Medications for alcohol and opioid use disorders and risk of suicidal behavior, accidental overdoses, and crime.
      • Johansson B.A.
      • Berglund M.
      • Lindgren A.
      Efficacy of maintenance treatment with naltrexone for opioid dependence: a meta-analytical review.
      • Gold M.S.
      • Dackis C.A.
      • Washton A.M.
      The sequential use of clonidine and naltrexone in the treatment of opiate addicts.
      Therefore, motivation for abstinence appears to be a key component. This is further evidenced by improved rates of compliance in highly motivated upper middle-class individuals,
      • Washton A.M.
      • Gold M.S.
      • Pottash A.C.
      Naltrexone in addicted physicians and business executives.
      health care professionals,
      • Washton A.M.
      • Gold M.S.
      • Pottash A.C.
      Successful use of naltrexone in addicted physicians and business executives.
      • Ling W.
      • Wesson D.R.
      Naltrexone treatment for addicted health-care professionals: a collaborative private practice experience.
      and inmates on work release.
      • Brahen L.S.
      • Henderson R.K.
      • Capone T.
      • Kordal N.
      Naltrexone treatment in a jail work-release program.
      Naltrexone has no abuse potential, no street value, and neither tolerance nor dependence develops.
      • Navaratnam V.
      • Jamaludin A.
      • Raman N.
      • Mohamed M.
      • Mansor S.M.
      Determination of naltrexone dosage for narcotic agonist blockade in detoxified Asian addicts.
      Naltrexone is thought to be relatively safe for long-term treatment but can cause elevations in liver enzymes. However, it can still be used with close monitoring even with liver impairment.
      • Marrazzi M.A.
      • Wroblewski J.M.
      • Kinzie J.
      • Luby E.D.
      High-dose naltrexone and liver function safety.
      • Yen M.H.
      • Ko H.C.
      • Tang F.I.
      • Lu R.B.
      • Hong J.S.
      Study of hepatotoxicity of naltrexone in the treatment of alcoholism.
      • Ayanga D.
      • Shorter D.
      • Kosten T.R.
      Update on pharmacotherapy for treatment of opioid use disorder.

       Challenges

      One of the biggest challenges with naltrexone is getting patients to take it regularly enough to have it be effective.
      • Johansson B.A.
      • Berglund M.
      • Lindgren A.
      Efficacy of maintenance treatment with naltrexone for opioid dependence: a meta-analytical review.
      A Cochrane review in 2011 showed no significant improvements in opioid abstinence or reincarceration rates for individuals using oral naltrexone.
      • Minozzi S.
      • Amato L.
      • Vecchi S.
      • Davoli M.
      • Kirchmayer U.
      • Verster A.
      Oral naltrexone maintenance treatment for opioid dependence.
      This poor assessment was largely driven by poor compliance with the medication. Naltrexone study results have always been beleaguered by low adherence to the medication and poor retention in treatment. Some believe this to be related to the nonreinforcing nature of the medication and lack of incentives to continue a medication that primarily blocks the effects of opioids.
      • Adi Y.
      • Juarez-Garcia A.
      • Wang D.
      • et al.
      Oral naltrexone as a treatment for relapse prevention in formerly opioid-dependent drug users: a systematic review and economic evaluation.
      • Roozen H.G.
      • de Waart R.
      • van der Windt D.A.
      • van den Brink W.
      • de Jong C.A.
      • Kerkhof A.J.
      A systematic review of the effectiveness of naltrexone in the maintenance treatment of opioid and alcohol dependence.
      • Sullivan M.A.
      • Garawi F.
      • Bisaga A.
      • et al.
      Management of relapse in naltrexone maintenance for heroin dependence.
      • Ahmadi J.
      • Ahmadi K.
      • Ohaeri J.
      Controlled, randomized trial in maintenance treatment of intravenous buprenorphine dependence with naltrexone, methadone or buprenorphine: a novel study.
      This theory is supported by the fact that there are even lower naltrexone retention rates for patients who used re-enforcing medications, such as buprenorphine and methadone, before naltrexone.
      • Rothenberg J.L.
      • Sullivan M.A.
      • Church S.H.
      • et al.
      Behavioral naltrexone therapy: an integrated treatment for opiate dependence.

       Prescriptions/Administration

      Naltrexone has a high affinity to mu (μ)-opioid receptors. Common dosing strategies for opioid use disorder include 50 mg per day (can start with 25 mg daily for a few days to mitigate side effects).
      • Gold M.S.
      • Dackis C.A.
      • Pottash A.L.C.
      • et al.
      Naltrexone, opiate addiction, and endorphins.
      • Minozzi S.
      • Amato L.
      • Vecchi S.
      • Davoli M.
      • Kirchmayer U.
      • Verster A.
      Oral naltrexone maintenance treatment for opioid dependence.
      A typical daily dose (50 mg) will block the pharmacologic effects of 25 mg intravenous (IV) heroin up to 24 hours, with increasing doses extending the duration.
      • Kleber H.D.
      Naltrexone.
      Peak levels of naltrexone and its major metabolite 6 beta (β)-naltrexol are reached 1 hour after the first dose.
      • Verebey K.
      The clinical pharmacology of naltrexone: pharmacology and pharmacodynamics.
      In an effort to improve compliance, there has long been a push to develop long-acting “depo” formulations. Once-monthly–dosed injectable extended-release naltrexone (Vivitrol, Alkermes Corp., Dublin, Ireland) has been FDA approved for the treatment of OUDs.
      • Krupitsky E.
      • Nunes E.V.
      • Ling W.
      • Illeperuma A.
      • Gastfriend D.R.
      • Silverman B.L.
      Injectable extended-release naltrexone for opioid dependence: a double-blind, placebo-controlled, multicentre randomised trial.
      Initial studies were quite promising, showing superiority in patient sobriety over oral naltrexone.
      • Comer S.D.
      • Collins E.D.
      • Kleber H.D.
      • Nuwayser E.S.
      • Kerrigan J.H.
      • Fischman M.W.
      Depot naltrexone: long-lasting antagonism of the effects of heroin in humans.
      • Sullivan M.A.
      • Bisaga A.
      • Pavlicova M.
      • et al.
      A randomized trial comparing extended-release injectable suspension and oral naltrexone, both combined with behavioral therapy, for the treatment of opioid use disorder.
      • Brewer C.
      • Streel E.
      Long-acting naltrexone has long-acting benefits and 100% induction rates are not difficult to achieve.
      Its primary benefit over oral naltrexone is that it eliminates the need for daily compliance to a structured medication regimen. It is injected once a month (typically in a clinic) and provides a relatively constant level of bioavailable naltrexone to the patient.
      • Garbutt J.C.
      • Kranzler H.R.
      • O'Malley S.S.
      • et al.
      Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence.
      A recent study (Extended-Release Naltrexone vs Suboxone Trial [X:BOT]) directly compared long-acting injectable naltrexone with buprenorphine/naloxone (suboxone) and showed injectable naltrexone appears to be as efficacious at 6 months as buprenorphine after patients have been successfully detoxified. The study points out that early drop rates are much worse with naltrexone than buprenorphine/naloxone, but it appears that, once fully implemented, injectable naltrexone is beneficial. When both medications were taken as prescribed, days abstinent, negative urine tests, and time-to-relapse were comparable.
      • Lee J.D.
      • Nunes Jr., E.V.
      • Novo P.
      • et al.
      Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial.
      However, a recent meta-analysis of extended-release injectable naltrexone concluded that “Many individuals intending to start extended-release naltrexone (XR-NTX) do not and most that do start XR-NTX discontinue treatment prematurely, 2 factors that limit its clinical utility significantly. XR-NTX appears to decrease opioid use but there are few experimental demonstrations of this effect.”
      • Jarvis B.P.
      • Holtyn A.F.
      • Subramaniam S.
      • et al.
      Extended-release injectable naltrexone for opioid use disorder: a systematic review.
      Somewhat counter to this assessment, is a study comparing insurance data that showed, in a real-world clinical setting, injectable naltrexone, buprenorphine, and oral naltrexone had similar rates of discontinuation 30 days after starting treatment.
      • Morgan J.R.
      • Schackman B.R.
      • Leff J.A.
      • Linas B.P.
      • Walley A.Y.
      Injectable naltrexone, oral naltrexone, and buprenorphine utilization and discontinuation among individuals treated for opioid use disorder in a United States commercially insured population.
      Authors of the X:BOT study speculated that difficulties in extended-release naltrexone inductions could be driven by the need for complete detoxification off opioids before naltrexone use. This necessity is an inherent limitation related to the blocking effects of the medication.
      • Lee J.D.
      • Nunes Jr., E.V.
      • Novo P.
      • et al.
      Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial.
      Conversely, buprenorphine can be used to assist with opioid detoxification (alleviating withdrawal symptoms), allowing earlier inductions. However, there may also be a role in use of low-dose naltrexone to assist with the induction of long-acting naltrexone.
      • Mannelli P.
      • Wu L.-T.
      • Peindl K.S.
      • Swartz M.S.
      • Woody G.E.
      Extended release naltrexone injection is performed in the majority of opioid dependent patients receiving outpatient induction: a very low dose naltrexone and buprenorphine open label trial.
      Indeed, it appears that if buprenorphine induction and extended-release naltrexone induction are both implemented around the same time frame after complete detoxification, they have similar rates of implementation success.
      • Mannelli P.
      • Wu L.-T.
      • Peindl K.S.
      • Swartz M.S.
      • Woody G.E.
      Extended release naltrexone injection is performed in the majority of opioid dependent patients receiving outpatient induction: a very low dose naltrexone and buprenorphine open label trial.
      • Tanum L.
      • Solli K.K.
      • Latif Z.E.
      • et al.
      Effectiveness of injectable extended-release naltrexone vs daily buprenorphine-naloxone for opioid dependence: a randomized clinical noninferiority trial.
      • Baser O.
      • Chalk M.
      • Fiellin D.A.
      • Gastfriend D.R.
      Cost and utilization outcomes of opioid-dependence treatments.
      Naltrexone implants are a newer way of increasing compliance. Although not yet available in the United States, clinical trials have shown superior treatment retention with a naltrexone implant compared with oral naltrexone and a placebo implant,
      • Colquhoun R.
      • Tan D.Y.
      • Hull S.
      A comparison of oral and implant naltrexone outcomes at 12 months.
      • Larney S.
      • Gowing L.
      • Mattick R.P.
      • Farrell M.
      • Hall W.
      • Degenhardt L.
      A systematic review and meta-analysis of naltrexone implants for the treatment of opioid dependence.
      with reported abstinence rates of 74% to 79% after 12 weeks.
      • Foster J.
      • Brewer C.
      • Steele T.
      Naltrexone implants can completely prevent early (1-month) relapse after opiate detoxification: a pilot study of two cohorts totalling 101 patients with a note on naltrexone blood levels.

      Buprenorphine

       Background

      Buprenorphine hydrochloride (HCl), can be derived from thebaine. It is a semisynthetic opioid, characterized as a partial agonist at the μ receptor and a full antagonist at the kappa (κ) receptor. At the μ receptor, it has low activity but high affinity.
      • Walsh S.L.
      • Eissenberg T.
      The clinical pharmacology of buprenorphine: extrapolating from the laboratory to the clinic.
      • Lewis J.W.
      Buprenorphine.
      Buprenorphine was discovered in 1966, by John Lewis, a doctoral student of Sir Robert Robinson, Nobel Prize-winning discoverer of the structure of morphine.
      • Lewis J.W.
      Buprenorphine.
      • Campbell N.D.
      • Lovell A.M.
      The history of the development of buprenorphine as an addiction therapeutic.
      Because of its high receptor affinity, buprenorphine acts as both a stimulator and a blocker of the μ opioid receptor. This blockade appears to be dose dependent and can be overcome with increased doses of other opioids.
      • Weinstein Z.M.
      • Gryczynski G.
      • Cheng D.M.
      • et al.
      Tapering off and returning to buprenorphine maintenance in a primary care office based addiction treatment (OBAT) program.
      • Strain E.C.
      • Walsh S.L.
      • Bigelow G.E.
      Blockade of hydromorphone effects by buprenorphine/naloxone and buprenorphine.

       Benefits

      The clinical efficacy of buprenorphine for the treatment of OUD has been well established.
      • Li X.
      • Shorter D.
      • Kosten T.R.
      Buprenorphine in the treatment of opioid addiction: opportunities, challenges and strategies.
      • Kampman K.
      • Jarvis M.
      American Society of Addiction Medicine (ASAM) national practice guideline for the use of medications in the treatment of addiction involving opioid use.
      • Nielsen S.
      • Larance B.
      • Degenhardt L.
      • Gowing L.
      • Kehler C.
      • Lintzeris N.
      Opioid agonist treatment for pharmaceutical opioid dependent people.
      • Blum K.
      • Han D.
      • Modestino E.J.
      • et al.
      A systematic, intensive statistical investigation of data from the Comprehensive Analysis of Reported Drugs (CARD) for compliance and illicit opioid abstinence in substance addiction treatment with buprenorphine/naloxone.
      Buprenorphine compliance is quite high and is associated with improved rates of sobriety, decreased criminal activity outcomes, and reduction in accidental overdoses.
      • Molero Y.
      • Zetterqvist J.
      • Binswanger I.A.
      • Hellner C.
      • Larsson H.
      • Fazel S.
      Medications for alcohol and opioid use disorders and risk of suicidal behavior, accidental overdoses, and crime.
      • Blum K.
      • Han D.
      • Modestino E.J.
      • et al.
      A systematic, intensive statistical investigation of data from the Comprehensive Analysis of Reported Drugs (CARD) for compliance and illicit opioid abstinence in substance addiction treatment with buprenorphine/naloxone.

       Challenges

      Despite its relative safety and efficacy in the treatment of OUDs, its widespread use continues to be relatively modest. This may be due to some restrictions on administration. The induction process (getting started on buprenorphine) can sometimes be a hurdle for patients and primary care providers because induction typically requires office-based dosing and then monitoring with a same-day return appointment. However, home-based induction options have been explored with some success.
      • Lee J.D.
      • Grossman E.
      • DiRocco D.
      • Gourevitch M.N.
      Home buprenorphine/naloxone induction in primary care.
      • Cunningham C.O.
      • Giovanniello A.
      • Li X.
      • Kunins H.V.
      • Roose R.J.
      • Sohler N.L.
      A comparison of buprenorphine induction strategies: patient-centered home-based inductions versus standard-of-care office-based inductions.
      Another challenge with buprenorphine is the length of time needed for treatment. Indeed, there is no clear discontinuation time frame, and evidence suggests that individuals do not do well after tapers.
      • Fiellin D.A.
      • Schottenfeld R.S.
      • Cutter C.J.
      • Moore B.A.
      • Barry D.T.
      • O'Connor P.G.
      Primary care-based buprenorphine taper vs maintenance therapy for prescription opioid dependence: a randomized clinical trial.
      Another concern has been the potential for abuse of buprenorphine, which is increasing with the increasing use of buprenorphine. Research has demonstrated that buprenorphine does exhibit positive-reinforcement properties (which encourages compliance) similar to other opioids, and its reinforcing effects are especially prominent when injected.
      • Yokell M.A.
      • Zaller N.D.
      • Green T.C.
      • Rich J.D.
      Buprenorphine and buprenorphine/naloxone diversion, misuse, and illicit use: an international review.
      However, in countries where opioid addiction is more common, studies suggest the majority of diverted buprenorphine is used for “therapeutic” purposes such as alleviating withdrawal and reducing the use of other opioids.
      • Bazazi A.R.
      • Yokell M.
      • Fu J.J.
      • Rich J.D.
      • Zaller N.D.
      Illicit use of buprenorphine/naloxone among injecting and noninjecting opioid users.
      • Cicero T.J.
      • Ellis M.S.
      • Chilcoat H.D.
      Understanding the use of diverted buprenorphine.
      On the other hand, it appears that in countries with less access to opioids in general, buprenorphine can become the dominant opioid of abuse.
      • Aalto M.
      • Halme J.
      • Visapää J.P.
      • Salaspuro M.
      Buprenorphine misuse in Finland.
      In Australia, 32% of opioid addicts had injected buprenorphine in the past 3 months. In Finland, 68% of opioid addicts had injected buprenorphine; 73% were also using it to “treat” their addictions. In Sweden, 89% reported illicit use of buprenorphine, with 43% admitting IV use for intoxication and 87% for alleviation of opioid withdrawal (some using for both purposes). In the United States, 49% reported illicit use in the past; however, 97% of those who used illicitly reported that it was mainly to relieve opioid withdrawal.
      • Bazazi A.R.
      • Yokell M.
      • Fu J.J.
      • Rich J.D.
      • Zaller N.D.
      Illicit use of buprenorphine/naloxone among injecting and noninjecting opioid users.

       Preparation/Administration

      Buprenorphine's unique chemical properties increase its safety profile. For example, administration of 32 mg buprenorphine produces no greater respiratory depression than 16 mg buprenorphine.
      • Walsh S.L.
      • Eissenberg T.
      The clinical pharmacology of buprenorphine: extrapolating from the laboratory to the clinic.
      However, when combined with respiratory depressants, such as benzodiazepines and alcohol, there appears to be an increased risk of overdose and death.
      • Schuman-Olivier Z.
      • Hoeppner B.B.
      • Weiss R.D.
      • Borodovsky J.
      • Shaffer H.J.
      • Albanese M.J.
      Benzodiazepine use during buprenorphine treatment for opioid dependence: clinical and safety outcomes.
      • Reynaud M.
      • Tracqui A.
      • Petit G.
      • Potard D.
      • Courty P.
      Six deaths linked to misuse of buprenorphine-benzodiazepine combinations.
      The average dose of buprenorphine is 16 mg daily, with 24 mg per day as the most common maximum dose. It comes in several formulations (most commonly in films and dissolvable tablets). Buprenorphine has poor bioavailability when taken orally and must be dissolved sublingually. This allows coadministration with naloxone (not absorbed sublingually) to prevent the buprenorphine from being injected (an abuse deterrent).
      Center for Substance Abuse Treatment
      Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction.
      In 2000, Congress established the Drug Addiction Treatment Act of 2000 (DATA 2000), which established legal permission for physicians to prescribe buprenorphine for the treatment of OUDs (under certain conditions). The act dictated that prescribers must meet certain educational requirements and then must apply for a special designation on their Drug Enforcement Administration (DEA) license (known as an “X” number) to prescribe buprenorphine for addiction treatment. During the first year following the date of notification of this designation, physicians may treat up to 30 patients; during the second year, they may treat up to 100 patients. After prescribing buprenorphine for 100 patients over a year or longer, a physician may apply to the DEA for permission to increase the prescription limit to 275 (per recently amended guidelines). SAMHSA has laid out guidelines for the administration of the buprenorphine. Patients are typically provided a 1-week supply of medications for a designated period of time and then a 2-week supply. After demonstrating trustworthiness and sobriety, patients can receive monthly supplies of the medication. This process is much less restrictive than the daily administration required through methadone programs.
      • McNicholas L.
      Tip 40: Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction: Treatment Improvement Protocol (TIP) Series 40.
      Several new forms of buprenorphine are now available, including implantable and injectable formulations. Both have shown promise in improving compliance and efficacy comparable with sublingual dosing. Furthermore, they have the potential to eliminate diversion and abuse.
      • Rosenthal R.N.
      • Goradia V.V.
      Advances in the delivery of buprenorphine for opioid dependence.

      Methadone

       Background

      In 1964, Vincent Dole began a research program at Rockefeller University to pilot the use of methadone to treat opioid addicts.
      • Dole V.P.
      • Warner A.
      Selected bibliography on narcotic addiction treatment, 1960-1966: reports of treatment programs.
      • Dole V.P.
      • Nyswander M.
      A medical treatment for diacetylmorphine (heroin) addiction: a clinical trial with methadone hydrochloride.
      Fully aware of the addictive properties, they emphasized the “harm-reduction” effects of the medication describing it as “block[ing] the normal reactions of addicts to heroin and permit[ting] them to live as normal citizens in the community.”
      • Dole V.P.
      • Nyswander M.E.
      The use of methadone for narcotic blockade.
      In 1966, the university committee overseeing his work concluded that a “significant number of patients through methadone maintenance management have attained a reasonable degree of social rehabilitation. Their dependence has not been ameliorated nor has it been treated, but it may have been “controlled;” thus, the patient and society have gained.”
      • Eddy N.B.
      The National Research Council Involvement in the Opiate Problem, 1928-1971.
      This ultimately led to the Narcotic Addict Treatment Act of 1974, in which methadone was approved for opioid addiction treatment under the strict supervision of opioid treatment centers (methadone treatment clinics).
      • Stotts A.L.
      • Dodrill C.L.
      • Kosten T.R.
      Opioid dependence treatment: options in pharmacotherapy.
      • Farrell M.
      • Ward J.
      • Mattick R.
      • et al.
      Methadone maintenance treatment in opiate dependence: a review.

       Benefits

      Methadone administered in methadone maintenance programs reduces the use of illicit opioids, overdose death rates, criminality, and allows patients to improve their health and social productivity.
      • Ball J.C.
      • Ross A.
      The Effectiveness of Methadone Maintenance Treatment: Patients, Programs, Services, and Outcome.
      In addition, enrollment in methadone maintenance reduces the transmission of infectious diseases, such as hepatitis and HIV, associated with heroin injection.
      • Farrell M.
      • Ward J.
      • Mattick R.
      • et al.
      Methadone maintenance treatment in opiate dependence: a review.
      • Mattick R.P.
      • Breen C.
      • Kimber J.
      • Davoli M.
      Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence.
      The principal effects of methadone maintenance are to relieve narcotic craving, suppress the withdrawal syndrome, and block the euphoric effects associated with heroin.
      • Farrell M.
      • Ward J.
      • Mattick R.
      • et al.
      Methadone maintenance treatment in opiate dependence: a review.
      Since implementation, it has been shown to be the most successful long-term treatment option for severe OUD.
      • Stotts A.L.
      • Dodrill C.L.
      • Kosten T.R.
      Opioid dependence treatment: options in pharmacotherapy.
      Furthermore, supervised administration of methadone has been shown to improve retention in chemical dependency (CD) treatment programs and may even reduce suicidality in comorbidly depressed addicts.
      • Mattick R.P.
      • Breen C.
      • Kimber J.
      • Davoli M.
      Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence.
      • Hser Y.I.
      • Evans E.
      • Huang D.
      • et al.
      Long-term outcomes after randomization to buprenorphine/naloxone versus methadone in a multi-site trial.
      • Zhu Y.
      • Evans E.A.
      • Mooney L.J.
      • et al.
      Correlates of long-term opioid abstinence after randomization to methadone versus buprenorphine/naloxone in a multi-site trial.
      • Johansson B.A.
      • Berglund M.
      • Lindgren A.
      Efficacy of maintenance treatment with methadone for opioid dependence: a meta-analytical study.
      Methadone maintenance through formal methadone clinics has been found to be relatively safe (safer than illicit use).
      • Molero Y.
      • Zetterqvist J.
      • Binswanger I.A.
      • Hellner C.
      • Larsson H.
      • Fazel S.
      Medications for alcohol and opioid use disorders and risk of suicidal behavior, accidental overdoses, and crime.
      • Joseph H.
      • Stancliff S.
      • Langrod J.
      Methadone maintenance treatment (MMT): a review of historical and clinical issues.

       Challenges

      There is significant controversy around the idea of giving a potent long-acting opioid to an opioid addict.
      • Farrell M.
      • Ward J.
      • Mattick R.
      • et al.
      Methadone maintenance treatment in opiate dependence: a review.
      • Ball J.C.
      • Ross A.
      The Effectiveness of Methadone Maintenance Treatment: Patients, Programs, Services, and Outcome.
      Because of its full opioid agonist properties, abuse is possible, and with its long half-life, it carries a higher safety-risk profile than other MAT options. Individuals have been reported to take their methadone at their clinics and then add illicit opioids to the methadone throughout the day, which increases the risk of death.
      • Lev R.
      • Petro S.
      • Lee A.
      • et al.
      Methadone related deaths compared to all prescription related deaths.
      Methadone alone can be deadly with a lethal dose considered to be 70 mg to 75 mg for nontolerant individuals (average maintenance doses 80 mg to120 mg),
      • Gardner R.
      Methadone misuse and death by overdosage.
      and it has an increased risk for accidental overdoses compared with other medications that treat OUDs.
      • Molero Y.
      • Zetterqvist J.
      • Binswanger I.A.
      • Hellner C.
      • Larsson H.
      • Fazel S.
      Medications for alcohol and opioid use disorders and risk of suicidal behavior, accidental overdoses, and crime.
      Treatment length is for an “indefinite” period of time, as methadone maintenance is a “corrective but not a curative” intervention for opioid addiction.
      • Ball J.C.
      • Ross A.
      The Effectiveness of Methadone Maintenance Treatment: Patients, Programs, Services, and Outcome.
      Methadone continues to have a relatively high street value
      • Dasgupta N.
      • Freifeld C.
      • Brownstein J.S.
      • et al.
      Crowdsourcing black market prices for prescription opioids.
      and therefore may be diverted even when prescribed as a part of methadone clinic treatment.
      • Madden M.E.
      • Shapiro S.L.
      The methadone epidemic: methadone-related deaths on the rise in Vermont.

       Preparation/Administration

      Methadone is a synthetic μ-opioid receptor agonist, typically administered as a racemic mixture of (R)- and (S)-methadone, with the (R)- form primarily responsible for most biological effects. Methadone has a very slow onset of action and a long elimination half-life (24 to 36 hours).
      • Kristensen K.
      • Christensen C.B.
      • Christrup L.L.
      The mu1, mu2, delta, kappa opioid receptor binding profiles of methadone stereoisomers and morphine.
      At a given dose, methadone plasma levels can vary extensively among individuals.
      • Eap C.B.
      • Buclin T.
      • Baumann P.
      Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence.
      Methadone can activate the NMDA receptor and inhibit serotonin and norepinephrine reuptake (similar to antidepressants).
      • Eap C.B.
      • Buclin T.
      • Baumann P.
      Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence.
      Methadone comes in several preparations. It is most commonly prescribed as a tablet for pain but can be administered IV.
      • Haroutiunian S.
      • McNicol E.D.
      • Lipman A.G.
      Methadone for chronic non-cancer pain in adults.
      Liquid formulation is the most common and cheapest dose strategy for methadone clinics, and tablet formulations are the most common prescription formulations in pain clinics. A majority of patients require 80 mg per day to 120 mg per day of methadone or more to achieve the desired effects, with lower doses shown to be typically less effective.
      • Farrell M.
      • Ward J.
      • Mattick R.
      • et al.
      Methadone maintenance treatment in opiate dependence: a review.
      • Ball J.C.
      • Ross A.
      The Effectiveness of Methadone Maintenance Treatment: Patients, Programs, Services, and Outcome.
      Levomethadyl acetate (LAAM) is a longer-acting derivative of methadone, which allows 3-times-a-week dosing. It is no longer sold in the United States owing to cardiac concerns (prolonged QTC interval)
      • Clark N.
      • Lintzeris N.
      • Gijsbers A.
      • et al.
      LAAM maintenance vs methadone maintenance for heroin dependence.
      despite some direct comparison data indicating few differences in LAAM and methadone on safety outcomes.
      • Anglin M.D.
      • Conner B.T.
      • Annon J.
      • Longshore D.
      Levo-alpha-acetylmethadol (LAAM) versus methadone maintenance: 1-year treatment retention, outcomes and status.
      • Wieneke H.
      • Conrads H.
      • Wolstein J.
      • et al.
      Levo-alpha-acetylmethadol (LAAM) induced QTc-prolongation: results from a controlled clinical trial.
      Methadone clinics attempt to circumvent the abuse potential and safety risk through strict structure and regulation of administration. For the first 3 months of treatment, patients are typically required to present at the methadone treatment program 6 days a week (with 1 take-home dose). Once they have established their intent to participate in the program faithfully, they are eligible for 3-day-a-week clinic dosing and 4 take-home doses. After 1 year, patients can get 6 home doses, presenting to the clinic only 1 day a week. Throughout their treatment, these patients undergo supervised urine drug screenings and breathalyzer tests at each visit. It appears that these safety regulations are at least somewhat effective, as more methadone overdose deaths are associated with illicit methadone use than prescribed or methadone clinic use.
      • Weimer M.B.
      • Korthuis P.T.
      • Behonick G.S.
      • Wunsch M.J.
      The source of methadone in overdose deaths in Western Virginia in 2004.
      Programs may vary in their efficacy, depending on dosage of prescribed methadone. They can also vary in efficacy, based on use of support services, monitoring of the use of nonprescribed drugs, diversion of methadone, and opportunities for treatment of co-occurring disorders.
      • Farrell M.
      • Ward J.
      • Mattick R.
      • et al.
      Methadone maintenance treatment in opiate dependence: a review.
      • Ball J.C.
      • Ross A.
      The Effectiveness of Methadone Maintenance Treatment: Patients, Programs, Services, and Outcome.

      Comparison

      All 3 FDA-approved medications for the treatment of OUDs (naltrexone, buprenorphine and methadone) appear to offer some evidence of efficacy (Table).
      Substance Abuse and Mental Health Services Administration (SAMHSA)
      Medications for Opioid Use Disorder: Treatment Improvement Protocol (TIP) Series 63.
      Long-term data are somewhat limited for the 3 medications, but 1 study of individuals randomly assigned to either methadone or buprenorphine/naloxone showed that 33.2% had achieved 5-year abstinence from heroin. Unfortunately, only 20.7% had remained abstinent from both heroin and other opioids. The 2 treatment groups were compared, and it was shown that, after 5 years, opioid use at follow-up was higher among participants randomized to buprenorphine relative to methadone. This discrepancy was attributed largely to less CD treatment participation among participants randomized to buprenorphine than methadone. However, both were better than with the no-treatment group, and mortality was not different between the 2 groups.
      • Hser Y.I.
      • Evans E.
      • Huang D.
      • et al.
      Long-term outcomes after randomization to buprenorphine/naloxone versus methadone in a multi-site trial.
      • Zhu Y.
      • Evans E.A.
      • Mooney L.J.
      • et al.
      Correlates of long-term opioid abstinence after randomization to methadone versus buprenorphine/naloxone in a multi-site trial.
      Five-year outcome data for naltrexone are not available, with most studies focused on data over a 6-month period
      • Jarvis B.P.
      • Holtyn A.F.
      • Subramaniam S.
      • et al.
      Extended-release injectable naltrexone for opioid use disorder: a systematic review.
      • Zhu Y.
      • Evans E.A.
      • Mooney L.J.
      • et al.
      Correlates of long-term opioid abstinence after randomization to methadone versus buprenorphine/naloxone in a multi-site trial.
      • Saxon A.J.
      • Akerman S.C.
      • Liu C.C.
      • Sullivan M.A.
      • Silverman B.L.
      • Vocci F.J.
      Extended-release naltrexone (XR-NTX) for opioid use disorder in clinical practice: Vivitrol's Cost and Treatment Outcomes Registry.
      with a few studies looking up to a year showing some positive retention in the right populations with the right support.
      • Krupitsky E.
      • Nunes E.V.
      • Ling W.
      • Gastfriend D.R.
      • Memisoglu A.
      • Silverman B.L.
      Injectable extended-release naltrexone (XR-NTX) for opioid dependence: long-term safety and effectiveness.
      • Chang G.
      • Crawford M.
      • Pitts M.
      • Schein A.Z.
      • Goodwin K.
      • Enggasser J.L.
      Adherence to extended release naltrexone: patient and treatment characteristics.
      Research demonstrated an association of naltrexone injections with long-term recovery among nurses (2 years), but, again, this group was highly motivated, a generally higher socioeconomic status cohort, and heavily involved in a structured professional monitoring program.
      • Earley P.H.
      • Zummo J.
      • Memisoglu A.
      • Silverman B.L.
      • Gastfriend D.R.
      Open-label study of injectable extended-release naltrexone (XR-NTX) in healthcare professionals with opioid dependence.
      Given such robust response rates by this nursing cohort, it raises the question why this level of oversight and support is not more broadly used in the treatment community.
      • DuPont R.L.
      • McLellan A.T.
      • White W.L.
      • Merlo L.J.
      • Gold M.S.
      Setting the standard for recovery: Physicians' Health Programs.
      Generally speaking, all 3 medications offer some benefit in maintaining sobriety, and each offers some advantages over the others.
      TableComparison
      Parameter (characteristic)BuprenorphineMethadoneNaltrexone
      Pharmacologic actionPartial agonist at the μ-opioid receptors and an antagonist at κ-opioid receptorsFull opioid agonistFull opioid antagonist
      FDA-approved clinical indicationOpioid-use disorder, painOpioid-use disorder, painOpioid-use disorder, alcohol-use disorder
      Route of administrationBuccal film, subcutaneous extended-release injection, subdermal implant, transdermal patchOral, parenteralOral, intramuscular
      Therapeutic doseOrally: 8 to 16 (max 24) mg; subcutaneously monthly: 100 mg to 300 mg; subdermal implant: 74.2 mg every 6 months; transdermal patch: maximum 20 μg/h; replace every 7 days80 mg to 120 mg dailyOrally: 50 mg daily or 100 mg orally every other day; or 150 mg orally every third day
      Frequency of administrationOrally: daily, every other day, 3 times a week; subcutaneously: monthly; patch: weekly; implant: every 6 monthsDailyOrally: daily, every other day or every third day; intramuscularly: monthly
      Protein binding96%85% to 90%21%
      BioavailabilityBuccal film: 46% to 65%; transdermal: 15%Oral: 36% to 100%5% to 40%
      Half-life eliminationBuccal film, subdermal implant; transdermal patch: 24 to 48 hours; subcutaneous extended-release injection: 43 to 60 days8 to 59 hours4 to 13 hours
      Onset of action10 to 30 min30 to 60 minUp to 3 day; following 100-mg oral doses for 3 days (96% on day 1, 87% on day 2, 46% on day 3)
      Duration of action6 hours5 to 8 hours50 mg: 24 hours; 100 mg: 48 hours; 150 mg: 72 hours; intramuscularly: 4 weeks
      Adapted from Medications for Opioid Use Disorder. Treatment Improvement Protocol (TIP) Series 63.
      Substance Abuse and Mental Health Services Administration (SAMHSA)
      Medications for Opioid Use Disorder: Treatment Improvement Protocol (TIP) Series 63.
      Naltrexone, for example, has no discernible addiction potential. Therefore, it could be considered for individuals who have struggled with methadone and buprenorphine abuse in the past. It also could be considered an option for patients who have not tolerated the side effects of methadone and buprenorphine. Compliance with daily naltrexone is a challenge, which can be somewhat overcome by injectable formulations. As noted, it appears that naltrexone is most effective in highly motivated populations.
      Buprenorphine is associated with higher levels of compliance than naltrexone, leading to improved outcomes, and, if given at consistent dosing (greater than 16 mg per day), the compliance/retention rate is similar to methadone.
      • Nielsen S.
      • Larance B.
      • Degenhardt L.
      • Gowing L.
      • Kehler C.
      • Lintzeris N.
      Opioid agonist treatment for pharmaceutical opioid dependent people.
      • Mattick R.P.
      • Breen C.
      • Kimber J.
      • Davoli M.
      Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence.
      • Mattick R.P.
      • Kimber J.
      • Breen C.
      • Davoli M.
      Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence.
      This is likely because of its opioid receptor partial agonism, which is not only reinforcing while taking but leads to withdrawal symptoms if missed. Therefore, buprenorphine offers an advantage in a modestly motivated population. Unfortunately, this partial agonist property can also lead to potential for abuse. Furthermore, buprenorphine can only be prescribed through physicians with specific DEA registration numbers. Access to buprenorphine-waivered prescribers can be a challenge in some areas of the country, which could limit its accessibility. Buprenorphine will cause withdrawal symptoms if discontinued. Therefore, it can be more difficult to discontinue than naltrexone. However, it is thought to be easier to withdraw from than full agonists such as methadone.
      • Gowing L.
      • Ali R.
      • White J.M.
      • Mbewe D.
      Buprenorphine for managing opioid withdrawal.
      Although the office-based buprenorphine visits allow for autonomy over methadone clinics, risk associated with overdose in conjunction with other substances should be considered. American Society of Addiction Medicine (ASAM) recommendations indicate that buprenorphine may not be a good option for patients with active alcohol-, sedative-, hypnotic-, or anxiolytic-use disorders. They also recommend extreme caution when prescribing these substances to individuals taking buprenorphine.
      • Kampman K.
      • Jarvis M.
      American Society of Addiction Medicine (ASAM) national practice guideline for the use of medications in the treatment of addiction involving opioid use.
      Methadone has the greatest evidence for long-term sustained abstinence, as it has been available the longest. However, it requires the most structure such as daily administration; counseling; basic medical testing; and access to vocational, medical, and psychiatric resources; and is generally recommended for individuals who would benefit the most from that structure.
      • Kampman K.
      • Jarvis M.
      American Society of Addiction Medicine (ASAM) national practice guideline for the use of medications in the treatment of addiction involving opioid use.
      • Manhapra A.
      • Quinones L.
      • Rosenheck R.
      Characteristics of veterans receiving buprenorphine vs. methadone for opioid use disorder nationally in the Veterans Health Administration.
      As noted, daily administration can be a burden for individuals.
      • Saulle R.
      • Vecchi S.
      • Gowing L.
      Supervised dosing with a long-acting opioid medication in the management of opioid dependence.
      Despite the burden, methadone appears to have the best treatment retention of the 3 medications.
      CADTH Rapid Response Reports
      Buprenorphine/Naloxone Versus Methadone for the Treatment of Opioid Dependence: A Review of Comparative Clinical Effectiveness, Cost-Effectiveness and Guidelines.
      However, methadone's full agonist properties offer the greatest abuse potential of the three medications (which is only somewhat ameliorated by the structure of the methadone clinic program). Finally, methadone appears to be the most expensive to administer from a societal standpoint of the 3 options because of the amount of support required in its administration.
      • Baser O.
      • Chalk M.
      • Fiellin D.A.
      • Gastfriend D.R.
      Cost and utilization outcomes of opioid-dependence treatments.
      However, total health care costs (medication, inpatient, outpatient, and pharmacy costs) are significantly lower for patients who receive a medication for opioid dependence vs patients who do not.
      • Baser O.
      • Chalk M.
      • Fiellin D.A.
      • Gastfriend D.R.
      Cost and utilization outcomes of opioid-dependence treatments.

      Algorithmic Approach to Choosing the Optimal Therapy

      When choosing the right medication for your patient with OUD, special considerations should be given to availability of treatment options, safety and side effect profiles of each medication, and previous patient/provider experience. You should also consider the need for a close structured psychosocial support system; patients' preferences for treatment location, such as concerns about methadone clinics and associated stigma; patients’ detoxification needs; and pain control in patients with comorbid chronic pain. The accompanying Figure contains an algorithm with recommendations based on clinical experience and current evidence cited in this paper. First, a clear diagnosis of a moderate-to-severe OUD, based on DSM 5 criteria
      American Psychiatric Association DSM-5 Task Force
      Diagnostic and Statistical Manual of Mental Disorders.
      is important to establish. If there are any doubts about diagnoses, patients should be referred to more intensive evaluation (by addiction specialists) or CD treatment programs for multidisciplinary formal assessment. Once the diagnosis is made, we recommend an office visit focused on evaluating key comorbid conditions including, but not limited to, cardiovascular disease risk, head trauma, sexual-physical-emotional trauma, neuropsychiatric conditions, infectious disease, and comorbid substance use disorders. Developing a prescription opioid taper plan, if they are currently prescribed opioids, is also essential. If the patient needs opioid detoxification, developing a detoxification plan using local detoxification resources or office-based ambulatory detoxification through supportive medications is warranted. All patients on opioids, or with OUDs, should have, in their possession, naloxone to treat potential opioid overdoses. This prescription and recommendation should also be extended to their families, friends, and significant others. An appointment focused on the brief intervention and referral to treatment portions of SBIRT should be initiated. Ongoing use of motivational interviewing strategies should be implemented to encourage participation in treatment. If the patient is willing to participate in formal CD treatment, a referral to treatment should be made, and all medication options should be discussed. If the patient is willing to fully detoxify off opioids and is highly motivated or would prefer to avoid agonist therapy for personal/professional reasons, long-acting injectable naltrexone treatment should be considered. The decision between buprenorphine and methadone should be discussed thoroughly with the patient. If the patient has chronic pain and/or is pregnant, methadone or buprenorphine should be the first consideration. Both have advantages and disadvantages, as noted here, and good compliance with either option can often be predicated on patient preference. If the patient is unsuccessful with one or the other medication, the alternative medication should be tried. If the patient is initially unwilling to participate in an office-based or other CD treatment program, naltrexone (long-acting injectable) should be considered, along with ongoing motivational interviewing to encourage participation in CD formal treatment. If the patient is not successful on naltrexone or is pregnant, the patient should be referred to a methadone treatment program with ongoing visits to assess comorbidities and motivational interviewing to encourage formal treatment. If a patient returns to use after initial success (relapse), this algorithm can be repeated as often as necessary starting with referral for CD treatment and recommendation for reinitiation of previously successful medications or use of alternative medications. If a patient has struggled with buprenorphine side effects, dropped out or abused it, or continued to use opioids while on it, then methadone treatment through a methadone maintenance program should be strongly encouraged. If a patient has succeeded with MAT, the medication should be continued for as long as necessary. Successful use of sublingual buprenorphine is generally a good prognostic sign for injectable/implantable buprenorphine, and these formulations should be strongly considered given their decreased potential for abuse. Some patients, for myriad reasons, may prefer to try to detoxify off opioid agonists and continue with psychosocial treatment plus injectable naltrexone. Patients requesting to taper off their MAT should be closely monitored. Providers should assist with the safe and gradual taper off medications and be prepared to assist with reinitiation of medications, if necessary.
      Figure thumbnail gr1
      FigurePatient diagnosed with an opioid-use disorder through assessment.

      Special Considerations

       Pregnancy

      Naltrexone is typically not recommended during pregnancy because of detoxification concerns and an unknown safety profile in pregnancy. Opioid detoxification in pregnancy is not recommended because of associations of fetal exposure to fluctuating levels of opioids with repeated withdrawal that can harm placental function, with subsequent decreased neonatal birth weight, preterm labor, fetal convulsions, and even fetal death, as well opioid drug-use relapse and resumption of high-risk behaviors such as intravenous drug use and criminal activity.
      • Dashe J.S.
      • Jackson G.L.
      • Olscher D.A.
      • Zane E.H.
      • Wendel Jr., G.D.
      Opioid detoxification in pregnancy.
      • Stewart R.D.
      • Nelson D.B.
      • Adhikari E.H.
      • et al.
      The obstetrical and neonatal impact of maternal opioid detoxification in pregnancy.
      The standard of care for pregnant women with OUD is to initiate MAT with either methadone or buprenorphine.
      Committee Opinion No. 711: Opioid Use and Opioid Use Disorder in Pregnancy.
      Buprenorphine monoproduct was recommended over the buprenorphine/naloxone formulation because of risks of naloxone exposure and withdrawal from misuse, but these have not been supported by the available data.
      Committee Opinion No. 711: Opioid Use and Opioid Use Disorder in Pregnancy.
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      Buprenorphine treatment of opioid-dependent pregnant women: a comprehensive review.
      Buprenorphine as a single agent has been shown to have shorter treatment duration, less medication needed to treat neonatal abstinence syndrome (NAS) symptoms, and shorter hospitalizations for neonates compared with methadone.
      • Jones H.E.
      • Heil S.H.
      • Baewert A.
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      Buprenorphine treatment of opioid-dependent pregnant women: a comprehensive review.
      However, methadone remains the primary suggested treatment for severe OUD during pregnancy.
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      Methadone, buprenorphine, and naltrexone for the treatment of opioid use disorder in pregnant women.
      In 2013, the American Academy of Pediatrics cited well-established data confirming minimal transmission of methadone and buprenorphine in breast milk. Subsequently, they asserted that appropriate medically monitored use of methadone and buprenorphine should not impair breast feeding if the mother so desires.
      • Baser O.
      • Chalk M.
      • Fiellin D.A.
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      Cost and utilization outcomes of opioid-dependence treatments.
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      The transfer of drugs and therapeutics into human breast milk: an update on selected topics.
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      Neonatal abstinence syndrome.
      Despite good evidence of their efficacy, and no nefarious long-term fetal consequences,
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      Prenatal exposure to methadone or buprenorphine: early childhood developmental outcomes.
      both buprenorphine and methadone are, unfortunately, still underused during and after pregnancy.
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      • Stone R.H.
      • Vest K.M.
      • Todd T.J.
      Methadone, buprenorphine, and naltrexone for the treatment of opioid use disorder in pregnant women.

       Adolescence

      Adolescents with severe OUD are recommended to receive MAT by the American Academy of Pediatrics; however, research on these medications in adolescents is sparse.
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      The opioid epidemic is an historic opportunity to improve both prevention and treatment.
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      • Goodman R.
      Strengths and difficulties questionnaire as a dimensional measure of child mental health.
      • Minozzi S.
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      • Davoli M.
      Maintenance treatments for opiate-dependent adolescents.
      Owing to regulatory issues, most methadone treatment programs do not accept patients younger than 18 years of age. Naltrexone is certainly an option but is limited by compliance. Furthermore, there are very few data supporting its efficacy in this population.
      • Fishman M.J.
      • Winstanley E.L.
      • Curran E.
      • Garrett S.
      • Subramaniam G.
      Treatment of opioid dependence in adolescents and young adults with extended release naltrexone: preliminary case-series and feasibility.
      Buprenorphine is FDA approved for opioid addiction in persons 16 years and older. Several studies have shown benefit in adolescents with severe OUD.
      • Marsch L.A.
      • Bickel W.K.
      • Badger G.J.
      • et al.
      Comparison of pharmacological treatments for opioid-dependent adolescents: a randomized controlled trial.
      • Woody G.E.
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      • et al.
      Extended vs short-term buprenorphine-naloxone for treatment of opioid-addicted youth: a randomized trial.
      • Matson S.C.
      • Hobson G.
      • Abdel-Rasoul M.
      • Bonny A.E.
      A retrospective study of retention of opioid-dependent adolescents and young adults in an outpatient buprenorphine/naloxone clinic.

       Perioperative Use

      Recommendations related to surgery while on medications to address OUD typically suggest discontinuation of oral naltrexone use 72 hours before elective surgery and continuation of methadone with adjunctive opioids as needed. Treatment with buprenorphine tends to be a bit more complicated, given its agonist/antagonist properties. Options include continuing a home regimen, daily or in divided doses (3 or 4 times a day), with additional buprenorphine doses for breakthrough pain; stopping buprenorphine at 5 to 3 days preoperatively and converting to a traditional opioid; or continuing buprenorphine while using traditional opioids as needed, while maximizing nonopioid co-analgesics and regional anesthesia. A recent literature review suggests continuation of buprenorphine through surgery.
      • Harrison T.K.
      • Kornfeld H.
      • Aggarwal A.K.
      • Lembke A.
      Perioperative considerations for the patient with opioid use disorder on buprenorphine, methadone, or naltrexone maintenance therapy.

       Pain

      Naltrexone has no indication for pain. However, methadone and buprenorphine are both FDA approved for the treatment of pain. It is important to note that restrictions associated with buprenorphine and methadone prescriptions (ie, special DEA number and treatment in special clinics) are specific to use of these medications for treatment of OUDs, not pain. Both medications can be prescribed without restrictions for pain. Patients with opioid addiction who receive prescription opioids for treatment of chronic nonmalignant pain present a therapeutic challenge. In one study, 54 patients with chronic pain and opioid addiction were randomized to receive methadone or buprenorphine/naloxone. At the 6-month follow-up, both groups reported improvements in pain with methadone showing slightly better results.
      • Neumann A.M.
      • Blondell R.D.
      • Jaanimägi U.
      • et al.
      A preliminary study comparing methadone and buprenorphine in patients with chronic pain and co-existent opioid addiction.

      Conclusions

      We are currently in the midst of an opioid epidemic caused by many factors including overzealous use of medications, availability of potent opioids (both legal and illegal), and pervasive social expectations that all pain can be eliminated. We clearly cannot medicate our way out of the problem, but we have the opportunity to mediate the problem through more judicious use of prescription opioids. For those patients who develop OUDs, the research shows that MAT can help, but it is currently underused. Along with drug counseling, naltrexone, buprenorphine, and methadone all have a place in the treatment armamentarium for opioid addiction. The current opioid crisis is an opportunity to change the way we think and do things, moving beyond a medication-only approach to a future when we will establish a generalizable framework that uses the full repertoire of responses and resources we have at our disposal.

      Acknowledgements

      Dr Nuria Thusius died prior to publication of this article. Her co-authors would like to acknowledge her scholarship, compassion, and tireless efforts to treat individuals with substance use disorders. She will be greatly missed by her family, friends, colleagues, and patients.

      Supplemental Online Material

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