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Adapting methadone inductions to the fentanyl era

  • Megan Buresh
    Correspondence
    Corresponding author at: Division of Addiction Medicine, Johns Hopkins School of Medicine, 5200 Eastern Ave., MFL 2E, Baltimore, MD 21224, United States of America.
    Affiliations
    Division of Addiction Medicine, Johns Hopkins School of Medicine, Baltimore, MD, United States of America

    Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America
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  • Shadi Nahvi
    Affiliations
    Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, United States of America

    Department of Psychiatry and Behavioral Sciences, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, United States of America
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  • Scott Steiger
    Affiliations
    Department of Medicine, University of California San Francisco at Zuckerberg San Francisco General Hospital, United States of America

    Department of Psychiatry, University of California San Francisco at Zuckerberg San Francisco General Hospital, United States of America
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  • Zoe M. Weinstein
    Affiliations
    Grayken Center for Addiction, Boston Medical Center, Boston, MA, United States of America

    Clinical Addiction Research and Education (CARE) Unit, Section of General Internal Medicine, Department of Medicine, Boston University School of Medicine and Boston Medical Center, Boston, MA, United States of America
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      Highlights

      • Opioid treatment programs need to develop rapid methadone induction protocols for persons using fentanyl
      • Call for researchers to evaluate outcomes of rapid methadone induction protocols
      • Call for SAMHSA and professional organizations to draft updated guidelines for methadone inductions

      Abstract

      Since 2013, fentanyl and fentanyl analogs, which are significantly more potent than heroin, have been increasingly prevalent in the opioid drug supply. A need exists to adapt methadone dosing from opioid treatment programs (OTPs) in this era. Current methadone protocols at many clinics in the United States are based on expert consensus documents that were created prior to the introduction of fentanyl into the drug supply and are relatively conservative. To date, most OTP reform efforts have focused on relaxation of regulations for take-homes and have not addressed the need to adapt methadone induction schedules to be more rapid in the fentanyl era, as allowed by current regulations. Written by OTP and inpatient consult service addiction medicine physicians with expertise in OUD treatment from across the United States, the aims of the perspective piece are to: 1) highlight the need to improve OTP care by adapting methadone inductions to the fentanyl era, 2) cite emerging evidence for and examples of experiences of OTPs using more aggressive methadone inductions, and 3) call for research and updated guidelines on safety and best practices for methadone induction.

      Keywords

      1. Commentary

      Since 2013, fentanyl and fentanyl analogs have been increasingly prevalent in the U.S. drug supply and have contributed to escalating rates of overdose and mortality. The opioid agonist therapies methadone and buprenorphine reduce both all-cause and overdose mortality (
      • Santo T.
      • Clark B.
      • Hickman M.
      • Grebely J.
      • Campbell G.
      • Sordo L.
      • Chen A.
      • Tran L.T.
      • Bharat C.
      • Padmanathan P.
      • Cousins G.
      • Dupouy J.
      • Kelty E.
      • Muga R.
      • Nosyk B.
      • Min J.
      • Pavarin R.
      • Farrell M.
      • Degenhardt L.
      Association of opioid agonist treatment with all-cause mortality and specific causes of death among people with opioid dependence.
      ), and research has shown methadone to be protective even for persons who continue to use fentanyl (
      • Stone A.C.
      • Carroll J.J.
      • Rich J.D.
      • Green T.C.
      One year of methadone maintenance treatment in a fentanyl endemic area: Safety, repeated exposure, retention, and remission.
      ). Fentanyl is 50–100 times more potent than morphine, and our clinical observation is that prior to initiating treatment for opioid use disorder (OUD), many people use fentanyl nearly continuously to avoid withdrawal symptoms (
      • Comer S.D.
      • Cahill C.M.
      Fentanyl: Receptor pharmacology, abuse potential, and implications for treatment.
      ). For patients in treatment with methadone or buprenorphine, ongoing fentanyl use is common (
      • Krause D.
      • Plörer D.
      • Koller G.
      • Martin G.
      • Winter C.
      • Adam R.
      • Canolli M.
      • Al-Iassin J.
      • Musselmann R.
      • Walcher S.
      • Schafer F.
      • Pogarell O.
      High concomitant misuse of fentanyl in subjects on opioid maintenance treatment.
      ) and multiple observers have noted that higher doses of methadone may be required to suppress cravings and opioid use (
      • Bisaga A.
      • Mannelli P.
      • Sullivan M.A.
      • Vosburg S.K.
      • Compton P.
      • Woody G.E.
      • Kosten T.R.
      Antagonists in the medical management of opioid use disorders: Historical and existing treatment strategies.
      ;
      • Volkow N.D.
      The epidemic of fentanyl misuse and overdoses: challenges and strategies.
      ). Inability to reach a therapeutic dose quickly can lead to lack of perceived treatment efficacy by patients, contribute to medication-related stigma, and serve as an additional barrier to treatment access.
      Current methadone protocols at many opioid treatment programs (OTPs) in the United States are conservative and are focused on preventing methadone diversion and limiting risk of methadone overdose (
      • Baxter L.E.
      • Campbell A.
      • DeShields M.
      • Levounis P.
      • Martin J.A.
      • McNicholas L.
      • Payte J.T.
      • Salsitz E.A.
      • Taylor T.
      • Wilford B.B.
      Safe methadone induction and stabilization report of an expert panel.
      ;
      • Leavitt S.B.
      Methadone Dosing & Safety in the Treatment of Opioid Addiction. ATF Forum.
      ). The U.S. Substance Abuse and Mental Health Services Administration (SAMHSA) developed their methadone treatment guidelines prior to the introduction of fentanyl into the drug supply and suggest a starting dose of methadone of no more than 30 mg, with increases of 5–10 mg every 3–5 days (
      Substance Abuse and Mental Health Services Administration (SAMHSA)
      Medications for Opioid Use Disorder Treatment Improvement Protocol (TIP) Series 63.
      ). Risk of overdose is known to be highest in first 2 weeks of treatment (
      • Buster M.C.
      • van Brussel G.H.
      • van den Brink W.
      An increase in overdose mortality during the first 2 weeks after entering or re-entering methadone treatment in Amsterdam.
      ;
      • Santo T.
      • Clark B.
      • Hickman M.
      • Grebely J.
      • Campbell G.
      • Sordo L.
      • Chen A.
      • Tran L.T.
      • Bharat C.
      • Padmanathan P.
      • Cousins G.
      • Dupouy J.
      • Kelty E.
      • Muga R.
      • Nosyk B.
      • Min J.
      • Pavarin R.
      • Farrell M.
      • Degenhardt L.
      Association of opioid agonist treatment with all-cause mortality and specific causes of death among people with opioid dependence.
      ) when methadone may contribute to overdose risk from direct toxicity or combination with central nervous system depressants, including alcohol, benzodiazepines, or other opioids (
      • Baxter L.E.
      • Campbell A.
      • DeShields M.
      • Levounis P.
      • Martin J.A.
      • McNicholas L.
      • Payte J.T.
      • Salsitz E.A.
      • Taylor T.
      • Wilford B.B.
      Safe methadone induction and stabilization report of an expert panel.
      ). While appropriately highlighting these safety concerns, these guidelines fail to address the higher tolerance of persons using fentanyl and take weeks to months to achieve a minimum therapeutic dose of 60 to 120 mg daily (
      • Cousins G.
      • Boland F.
      • Barry J.
      • Lyons S.
      • Keenan E.
      • O’Driscoll D.
      • Bennett K.
      • Fahey T.
      J-shaped relationship between supervised methadone consumption and retention in methadone maintenance treatment (MMT) in primary care: National cohort study.
      ). Risks of methadone toxicity must be balanced with known increased mortality due to opioid overdose from ongoing fentanyl use (
      • Arfken C.L.
      • Suchanek J.
      • Greenwald M.K.
      Characterizing fentanyl use in methadone-maintained clients.
      ), as well as the 10-fold increase in mortality in the first four weeks after methadone treatment discontinuation (
      • Hickman M.
      • Steer C.
      • Tilling K.
      • Lim A.G.
      • Marsden J.
      • Millar T.
      • Strang J.
      • Telfer M.
      • Vickerman P.
      • Macleod J.
      The impact of buprenorphine and methadone on mortality: A primary care cohort study in the United Kingdom.
      ;
      • Santo T.
      • Clark B.
      • Hickman M.
      • Grebely J.
      • Campbell G.
      • Sordo L.
      • Chen A.
      • Tran L.T.
      • Bharat C.
      • Padmanathan P.
      • Cousins G.
      • Dupouy J.
      • Kelty E.
      • Muga R.
      • Nosyk B.
      • Min J.
      • Pavarin R.
      • Farrell M.
      • Degenhardt L.
      Association of opioid agonist treatment with all-cause mortality and specific causes of death among people with opioid dependence.
      ). OTPs need to adapt their methadone inductions to the fentanyl era to achieve a therapeutic dose more quickly, with the aim of increasing engagement and retention in treatment and decreasing opioid-related mortality.
      Though OTPs provide an ideal setting for rapid methadone dose induction under close clinical monitoring, data to support this approach are sparse. A case report documented safe induction to 70 mg within 48 h of admission to hospital (
      • Hemmons P.
      • Bach P.
      • Colizza K.
      • Nolan S.
      Initiation and rapid titration of methadone in an acute care setting for the treatment of opioid use disorder: A case report.
      ). Updated consensus guidelines from Ontario for persons with OUD who use fentanyl recommend starting methadone at 30 mg; increasing by 10–15 mg every 3–5 days for patients not at high risk of methadone toxicity (ex. concurrent using alcohol or high-dose benzodiazepines) until reaching a dose of 75–80 mg; then increasing by 10 mg every 5–7 days (
      • Bromley L.
      • Kahan M.
      • Regenstreif L.
      • Srivastava A.
      • Wyman J.
      Methadone treatment for people who use fentanyl: Recommendations.
      ). U.S. protocols focus on methadone dosing during the first 2–4 weeks of treatment, a time when patients at OTPs in the United States are generally limited to taking observed doses in clinic daily, allowing for close monitoring. A Rhode Island cohort of persons using fentanyl started methadone at 30 mg on day 1, then increased by 10 mg per day to 50 mg (day 3), then increased at a rate of up to 20 mg per week (
      • Stone A.C.
      • Carroll J.J.
      • Rich J.D.
      • Green T.C.
      One year of methadone maintenance treatment in a fentanyl endemic area: Safety, repeated exposure, retention, and remission.
      ). A similar protocol is used by one of our co-authors (SN), while the OTP where one co-author (SS) works utilizes a rapid induction protocol whose maximum dose of methadone on days 1, 2 and 3 is 40 mg, 60 mg, and 80 mg, respectively, followed by a dose increase of 10–20 mg every 4 days, up to 140 mg, for patients reporting fentanyl use amounting to 1 g or more daily. After this initial titration, doses may be increased beyond 140 mg following additional weekly evaluations by medical staff. While evaluation of these approaches is ongoing, the signal is clear: with current guidelines failing to meet patients' needs, providers are responding to patients with heterogeneous clinical approaches. This variation in clinical protocols highlights a need for more research on methadone inductions for persons who use fentanyl.
      Many alternatives to a rapid increase in methadone dose for getting patients to higher methadone doses may be of limited immediate utility. Adjunctive medications that treat symptoms of opioid withdrawal such as alpha-2-adrenergic receptor agonists have their own set of risks and research has not demonstrated that they are better than methadone in relieving withdrawal (
      • Gowing L.
      • Farrell M.
      • Ali R.
      • White J.M.
      Alpha2-adrenergic agonists for the management of opioid withdrawal.
      ). Clinical guidelines in British Columbia recommend supplementation with as needed short-acting opioids during initial methadone induction (
      British Columbia Centre on Substance Use (BCCSU)BC Ministry of HealthMinistry of Mental Health and Addictions
      Risk Mitigation in the Context of Dual Health Emergencies—Interim Clinical Guidance: Update.
      ), a strategy that would not be allowed in the outpatient setting in the United States under current controlled substances regulations.
      Though achievable without regulatory reform, rapid methadone induction does have limitations. The initial assessment of opioid tolerance in patients is challenging and is often reliant on patients' report of the amount and duration of fentanyl use. Individual cross-tolerance between fentanyl and methadone may vary widely enough that some patients do not need elevated methadone doses (
      • Eap C.B.
      • Buclin T.
      • Baumann P.
      Interindividual variability of the clinical pharmacokinetics of methadone: Implications for the treatment of opioid dependence.
      ). Not all patients who want a rapid induction will be eligible for it due to medical comorbidities, such as pulmonary disease, cirrhosis, end-stage renal disease, congestive heart failure, or ventricular arrhythmia. Other relative contraindications include concurrent use of alcohol or benzodiazepines, or medications that affect methadone metabolism (CYP inhibitors and inducers), older age, as well as factors such as transportation that may impact a patient's ability to come to clinic frequently. Some eligible patients may opt out of rapid inductions due to the requirement for daily observed dosing and closer monitoring. Careful weighing of risks and benefits for individual patients and the close monitoring of response to dose adjustment may require more involvement of medical professionals than many OTPs currently provide. On the other hand, increased involvement with clinic staff early in treatment may yield improvements in patients' satisfaction.
      To date, OTP clinical guidelines have not addressed the need to adapt methadone induction schedules to needs of persons with high opioid tolerance in the fentanyl era. The authors thus call for 3 urgent actions: 1) OTPs should provide patient-centered treatment to people who have high opioid tolerance from chronic nonmedical fentanyl use. Current regulations allow OTPs to provide a total of 40 mg on day 1 by documenting medical need, and leave the frequency and amount of subsequent dose adjustment to discretion of the medical provider (
      Federal Register
      ). 2) Investigators should evaluate outcomes of more rapid induction protocols to build a body of evidence around the risks and benefits, with focus on outcomes including mortality, methadone toxicity, overdose, and retention in treatment. 3) SAMHSA and addiction-focused professional organizations should convene expert panels to review the evidence and draft updated evidence-based methadone guidance for induction in the era of fentanyl. Without expert guidance from SAMHSA or professional organizations, OTPs may remain in a state of inertia; continue with outdated dosing protocols; and risk patients' treatment discontinuation, overdose, and death. While acknowledging that more rapid induction is not appropriate for all patients, the unprecedented number of overdose deaths in the setting of the poisonous drug supply is a call to immediate action for us all.

      Declaration of competing interest

      Pfizer provides varenicline to Albert Einstein College of Medicine for an NIH-funded randomized trial (PI: Nahvi). Pfizer had no role in the conceptualization, writing, or submission of this manuscript.

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