Introduction to SSN’s Research Articles on MAT
Though the United States has experienced several opioid misuse epidemics, it is now facing its most deadly opioid crisis. More than two decades ago, this latest opioid epidemic emerged in the U.S. due to increased misuse of prescription opioids, and recently has changed profoundly as heroin and fentanyl (primarily illicitly manufactured) have come to dominate the escalating crisis in terms of higher death rates. Yet, although there has been nearly a 1,000% increase in people with an opioid use disorder (OUD) seeking treatment, most persons addicted to opioids are not in treatment and, among those who are, most are not exposed to the modality with the strongest evidence-base: medication assisted treatment (MAT), also known as medication-based treatment for OUD.
Opioid addiction is a chronic and severe disorder characterized by relapse, especially if not adequately treated. There is substantial data that agonist medications (e.g., methadone and buprenorphine) are the most effective interventions for treating this disorder since maintenance on these medications can effectively reduce/eliminate drug craving, prevent withdrawal, and block the euphoric effects of opioids. In addition to preventing relapse, agonist medications are associated with reductions in criminal behavior, HIV risk behaviors, and overdose deaths. There is also evidence that the opioid antagonist naltrexone, in its extended-release formulation (XR-NTX) [e.g., Vivitrol®], can also effectively treat opioid addiction. There is far less evidence that psychosocial interventions (whether residential or outpatient), without the addition of MAT, can effectively treat opioid addiction. Methadone is a μ-opioid agonist that has been used for more than 50 years to treat opioid addiction. Federal regulations stipulate that methadone maintenance must be administered at a certified opioid treatment program. In 2002, buprenorphine, a partial opioid agonist (often co-formulated with naloxone, an opioid antagonist that precipitates withdrawal if injected) was approved by the FDA to be used in office-based settings to treat OUD. The opioid antagonist naltrexone diminishes the reinforcing effects of opioids by occupying the μ receptors in the brain and, unlike agonist medications, has no addictive potential. Buprenorphine, methadone and naltrexone are examples of MAT and the only medications that are currently approved by the FDA for the treatment OUD.
Unfortunately, there are a number of factors that have prevented the expansion of MAT. Among these factors, as enumerated in a March 2019 news release from the National Academies of Sciences, Engineering and Medicine (NASEM), are:
1) Misunderstanding and stigma toward drug addiction, individuals with OUD, and the medications to treat it.
2) Inadequate education and training of the professionals responsible for working with people with OUD, including treatment providers and law enforcement and other criminal justice personnel.
3) Current regulations around methadone and buprenorphine, such as waiver policies, patient limits, restrictions on treatment settings, and other policies that are not supported by evidence or employed for other medical disorders.
4) A fragmented system of care.
Recognition among professionals, patients, their families and the general population that medications are a first-line treatment for OUD and, as noted in 2019 NASEM consensus study report, “an integral part of a person’s long-term treatment plan” will go a long way to reducing the harm stemming from our current opioid epidemic.
In an effort to provide education about MAT and the barriers that have diminished its implementation, Stop Stigma Now has begun to identify articles and other documents that describe MAT (including separate articles on the three medications), and factors that have prevented its use among the large number of OUD patients who could benefit from it. The list of articles includes abstracts and (for most) a link to the full article. Articles listed in the following categories:
- Criminal Justice
- Stigma and other impediments to MOUD
Andrew Rosenblum, PhD
SSN, Advisory Board
Selected articles on Medication for opioid use disorder (MOUD); AKA, Medication Assisted Treatment (MAT).
Dole VP, Nyswander MA. JAMA. 1965;193(8).
Twenty-two male patients, addicted to heroin 9.5 years (median), were stabilized using oral methadone hydrochloride and then observed for approximately 1 to 15 months (median, 3 months). The medication had 2 main effects: (1) relief of narcotic hunger (craving); and (2) induction of sufficient tolerance to block the average illegal dose of heroin.
A combination of the methadone treatment and a comprehensive program of rehabilitation was associated with marked improvement in patient problems such as jobs, returning to school, and family reconciliation. No adverse effect other than constipation was found.
The authors note that “careful medical supervision and many social services” were necessary and stressed that “both the medication and supporting program were essential.” The small size of the group studied and short duration of the follow-up would best describe this as a promising and exciting but preliminary report. (For commentary of this groundbreaking Dole & Nyswander article see: Methadone Maintenance 4 Decades Later: Thousands of Lives Saved But Still Controversial. Kleber HD. JAMA. 2008; 300, No. 19, 2303-2305.)
Dole, VP. Alcohol Clin Exp Res. 1991 Oct;15(5):749-52.
This article is the Distinguished Science Lecture presented at the Annual Meeting of the American Society of Addiction Medicine, Boston, MA, April 19, 1991. In this presentation, Dr. Dole describes how he became involved in developing an ‘addiction’ medication (now, MOUD), methadone, as part of a public health approach to the heroin epidemic of late 1950s and 1960s. The second part of the article describes his (surprising to him) invitation from Bill W., a founder of Alcoholics Anonymous (AA), to join their board as a non-alcoholic trustee. Fully recognizing the key role of social (‘community disintegration”) and psychological factors in opioid use disorder, Dr. Dole said (with enviable modesty), ‘At least I could examine one detail of the problem, to see if an effective large-scale treatment could be developed.” (p. 750), a “normalizing” medication, to cope with the immediate public health crisis. Bill W., countering the notion that AA was inflexible about abstinence and group support in addressing alcohol use disorder, asked Dr. Dole to see if an analogue to methadone could be developed for alcoholism. Even though many who are helped by AA’s 12 steps, many are not reached, many enter and do not return, and many are ‘lost’. Essential reading on background of methadone’s development and a public health approach to opioid use disorder. (This abstract prepared by Phil Appel, Ph.D.)
McCarty, D, Priest, KC, Korthuis, PT. Annual Review of Public Health. 2018. 39:525–41.
Treatment for opioid use disorder in the United States evolved in response to changing federal policy and advances in science. Inpatient care began in 1935 with the US Public Health Service Hospitals in Lexington, Kentucky, and Fort Worth, Texas. Outpatient clinics emerged in the 1960s to provide aftercare. Research advances led to opioid agonist and opioid antagonist
therapies. When patients complete opioid withdrawal, return to use is often rapid and frequently deadly. US and international authorities recommend opioid agonist therapy (i.e., methadone or buprenorphine). Opioid antagonist therapy (i.e., extended-release naltrexone) may also inhibit
return to use. Prevention efforts emphasize public and prescriber education, use of prescription drug monitoring programs, and safe medication disposal options. Overdose education and naloxone distribution promote access to rescue medication and reduce opioid overdose fatalities. Opioid use disorder prevention and treatment must embrace evidence-based care and integrate with physical and mental health care.
Kleber HD. JAMA. 2008; 300(19):2303-5.
Shulman M, Wai JM, Nunes EV. CNS Drugs. 2019; 33(6):567-580.
Opioid use disorder affects over 26 million individuals worldwide. There are currently three World Health Organization-recommended and US Food and Drug Administration-approved medication treatments for opioid use disorder: the full opioid agonist methadone, the opioid partial agonist buprenorphine, and the opioid receptor antagonist naltrexone. We provide a review of the use of buprenorphine for the treatment of opioid use disorder and discuss the barriers, challenges, risks, and efficacy of buprenorphine treatment vs. other treatments. Although evidence from numerous studies has shown buprenorphine to be effective for the treatment of opioid use disorder, a majority of patients with opioid use disorder do not receive buprenorphine, or any other medical treatment. We review the different formulations of buprenorphine, including newer long-acting injectable formulations that may decrease the risk of diversion and improve adherence.
Lee, JD, Nunes, EV, Novo, P, et al., Lancet. 2018 Jan 27;391(10118):309-318.
Background: Extended-release naltrexone (XR-NTX), an opioid antagonist, and sublingual buprenorphine-naloxone (BUP-NX), a partial opioid agonist, are pharmacologically and conceptually distinct interventions to prevent opioid relapse. We aimed to estimate the difference in opioid relapse-free survival between XR-NTX and BUP-NX.
Methods: We initiated this 24 week, open-label, randomised controlled, comparative effectiveness trial at eight US community-based inpatient services and followed up participants as outpatients. Participants were 18 years or older, had Diagnostic and Statistical Manual of Mental Disorders-5 opioid use disorder, and had used non-prescribed opioids in the past 30 days. We stratified participants by treatment site and opioid use severity and used a web-based permuted block design with random equally weighted block sizes of four and six for randomisation (1:1) to receive XR-NTX or BUP-NX. XR-NTX was monthly intramuscular injections (Vivitrol; Alkermes) and BUP-NX was daily self-administered buprenorphine-naloxone sublingual film (Suboxone; Indivior). The primary outcome was opioid relapse-free survival during 24 weeks of outpatient treatment. Relapse was 4 consecutive weeks of any non-study opioid use by urine toxicology or self-report, or 7 consecutive days of self-reported use. This trial is registered with ClinicalTrials.gov, NCT02032433.
Findings: Between Jan 30, 2014, and May 25, 2016, we randomly assigned 570 participants to receive XR-NTX (n=283) or BUP-NX (n=287). The last follow-up visit was Jan 31, 2017. As expected, XR-NTX had a substantial induction hurdle: fewer participants successfully initiated XR-NTX (204 [72%] of 283) than BUP-NX (270 [94%] of 287; p<0·0001). Among all participants who were randomly assigned (intention-to-treat population, n=570) 24 week relapse events were greater for XR-NTX (185 [65%] of 283) than for BUP-NX (163 [57%] of 287; hazard ratio [HR] 1·36, 95% CI 1·10-1·68), most or all of this difference accounted for by early relapse in nearly all (70 [89%] of 79) XR-NTX induction failures. Among participants successfully inducted (per-protocol population, n=474), 24 week relapse events were similar across study groups (p=0·44). Opioid-negative urine samples (p<0·0001) and opioid-abstinent days (p<0·0001) favoured BUP-NX compared with XR-NTX among the intention-to-treat population, but were similar across study groups among the per-protocol population. Self-reported opioid craving was initially less with XR-NTX than with BUP-NX (p=0·0012), then converged by week 24 (p=0·20). With the exception of mild-to-moderate XR-NTX injection site reactions, treatment-emergent adverse events including overdose did not differ between treatment groups. Five fatal overdoses occurred (two in the XR-NTX group and three in the BUP-NX group).
Interpretation: In this population it is more difficult to initiate patients to XR-NTX than BUP-NX, and this negatively affected overall relapse. However, once initiated, both medications were equally safe and effective. Future work should focus on facilitating induction to XR-NTX and on improving treatment retention for both medications.
Jarvis BP, Holtyn AF, Subramaniam S, et al. Addiction. 2018 Jul;113(7):1188-1209.
AIMS: To review systematically the published literature on extended-release naltrexone (XR-NTX, Vivitrol® ), marketed as a once-per-month injection product to treat opioid use disorder. We addressed the following questions: (1) how successful is induction on XR-NTX; (2) what are adherence rates to XR-NTX; and (3) does XR-NTX decrease opioid use? Factors associated with these outcomes as well as overdose rates were examined.
METHODS: We searched PubMed and used Google Scholar for forward citation searches of peer-reviewed papers from January 2006 to June 2017. Studies that included individuals seeking treatment for opioid use disorder who were offered XR-NTX were included.
RESULTS: We identified and included 34 studies. Pooled estimates showed that XR-NTX induction success was lower in studies that included individuals that required opioid detoxification [62.6%, 95% confidence interval (CI) = 54.5-70.0%] compared with studies that included individuals already detoxified from opioids (85.0%, 95% CI = 78.0-90.1%); 44.2% (95% CI = 33.1-55.9%) of individuals took all scheduled injections of XR-NTX, which were usually six or fewer. Adherence was higher in prospective investigational studies (i.e. studies conducted in a research context according to a study protocol) compared to retrospective studies of medical records taken from routine care (6-month rates: 46.7%, 95% CI = 34.5-59.2% versus 10.5%, 95% CI = 4.6-22.4%, respectively). Compared with referral to treatment, XR-NTX reduced opioid use in adults under criminal justice supervision and when administered to inmates before release. XR-NTX reduced opioid use compared with placebo in Russian adults, but this effect was confounded by differential retention between study groups. XR-NTX showed similar efficacy to buprenorphine when randomization occurred after detoxification, but was inferior to buprenorphine when randomization occurred prior to detoxification.
CONCLUSIONS: Many individuals intending to start extended-release naltrexone (XR-NTX) do not and most who do start XR-NTX discontinue treatment prematurely, two factors that limit its clinical utility significantly. XR-NTX appears to decrease opioid use but there are few experimental demonstrations of this effect.
Bisaga, A, Mannelli, P, Sullivan, MA, et al., The American Journal on Addictions. 2018 27: 177-187.
Background and objectives: Opioid use disorder (OUD) is a chronic condition with potentially severe health and social consequences. Many who develop moderate to severe OUD will repeatedly seek treatment or interact with medical care via emergency department visits or hospitalizations. Thus, there is an urgent need to develop feasible and effective approaches to help persons with OUD achieve and maintain abstinence from opioids. Treatment that includes one of the three FDA-approved medications is an evidence-based strategy to manage OUD. The purpose of this review is to address practices for managing persons with moderate to severe OUD with a focus on opioid withdrawal and naltrexone-based relapse-prevention treatment.
Methods: Literature available on PubMed was used to review the evolution of treatment strategies from the 1960s onward to manage opioid withdrawal and initiate treatment with naltrexone.
Results: Emerging practices for extended-release naltrexone induction include the use of agonist tapers and adjuvant medications. Clinical challenges frequently encountered when initiating this therapy include managing withdrawal and ongoing opioid use during treatment. Clinical factors may inform decisions regarding patient selection and length of naltrexone treatment, such as recent opioid use and patient preferences.
Conclusions and scientific significance: Treatment strategies to manage opioid withdrawal have evolved, but many patients with OUD do not receive medication for the prevention of relapse. Clinical strategies for induction onto extended-release naltrexone are now available and can be safely and effectively implemented in specialty and select primary care settings.
Medications to Treat Opioid Use Disorder. National Institute on Drug Abuse, June 2018. Link to PDF copy: https://www.drugabuse.gov/node/pdf/21349/medications-to-treat-opioid-use-disorder
Bart G. J Addict Dis. 2012;31(3):207-25.
Illicit use of opiates is the fastest growing substance use problem in the United States, and the main reason for seeking addiction treatment services for illicit drug use throughout the world. It is associated with significant morbidity and mortality related to human immunodeficiency virus, hepatitis C, and overdose. Treatment for opiate addiction requires long-term management. Behavioral interventions alone have extremely poor outcomes, with more than 80% of patients returning to drug use. Similarly poor results are seen with medication-assisted detoxification. This article provides a topical review of the three medications approved by the Food and Drug Administration for long-term treatment of opiate dependence: the opioid-agonist methadone, the partial opioid-agonist buprenorphine, and the opioid-antagonist naltrexone. Basic mechanisms of action and treatment outcomes are described for each medication. Results indicate that maintenance medication provides the best opportunity for patients to achieve recovery from opiate addiction. Extensive literature and systematic reviews show that maintenance treatment with either methadone or buprenorphine is associated with retention in treatment, reduction in illicit opiate use, decreased craving, and improved social function. Oral naltrexone is ineffective in treating opiate addiction, but recent studies using extended-release naltrexone injections have shown promise. Although no direct comparisons between extended-release naltrexone injections and either methadone or buprenorphine exist, indirect comparison of retention shows inferior outcome compared with methadone and buprenorphine. Further work is needed to directly compare each medication and determine individual factors that can assist in medication selection. Until such time, selection of medication should be based on informed choice following a discussion of outcomes, risks, and benefits of each medication.
National Institute on Drug Abuse, April, 2019. This study reported:
· Prisoners who received methadone maintenance treatment (MMT) during incarceration were more likely than prisoners who did not receive MMT to engage in the treatment after being released.
· Those who received methadone during incarceration also reported less heroin use and had a lower risk of nonfatal overdose after being released.
SAMHSA. HHS Publication No. PEP19-MATUSECJS, 2019.
This guide focuses on using medication-assisted treatment for opioid use disorder in jails and prisons and during the reentry process when justice -involved persons return to the community. It provides an overview of policies and evidence-based practices that reduce the risk of overdose and relapse.
Stigma and other impediments to MOUD
Magura S & Rosenblum A. Mt Sinai J Med. 2001 Jan;68(1):62-74.
Despite the demonstrated benefits of methadone maintenance, there have been concerns about the ethics, necessity and expense of maintaining addicts on methadone indefinitely. The inability of many patients to achieve normative levels of psychosocial functioning with methadone, combined with widely held attitudes favoring drug abstinence over replacement medication, has led to attempts to promote time-limited methadone treatment. This paper reviews the published research literature on post-discharge outcomes of patients exiting from extended methadone detoxification, “abstinence-oriented” methadone programs, and regular methadone maintenance programs. Virtually all of these studies document high rates of relapse to opioid use after methadone treatment is discontinued. Most of the patients studied left treatment without meeting clinical criteria for detoxification, although high relapse rates were also reported for patients who completed this program. The detrimental consequences of leaving methadone treatment are dramatically indicated by greatly increased death rates following discharge. Until more is learned about how to improve post-detoxification outcomes for methadone patients, treatment providers and regulatory/funding agencies should be very cautious about imposing disincentives and structural barriers that discourage or impede long-term opiate replacement therapy.
Long-Acting Opioid-Agonists in the Treatment of Heroin Addiction: Why Should We Call Them “Substitution”?
Gerra G1, Maremmani I, Capovani B, Somaini L, Berterame S, Tomas-Rossello J, Saenz E, Busse A, Kleber H. Subst Use Misuse. 2009;44(5):663-71.
Many studies have documented the safety, efficacy, and effectiveness of long-acting opioids (L-AOs), such as methadone and buprenorphine, in the treatment of heroin addiction. This article reviews the pharmacological differences between L-AO medications and short-acting opioids (heroin) in terms of reinforcing properties, pharmacokinetics, effects on the endocrine and immune systems. Given their specific pharmacological profile, L-AOs contribute to control addictive behavior, reduce craving, and restore the balance of disrupted endocrine function. The use of the term “substitution,” referring to the fact that methadone or buprenorphine replace heroin in binding to brain opioid receptors, has been generalized to consider L-AOs as simple replacement of street drugs, thus contributing to the widespread misunderstanding of this treatment approach.
Messages about methadone and buprenorphine in reality television: a content analysis of celebrity rehab with Dr. Drew.
Roose R, Fuentes L, Cheema M. Subst Use Misuse. 2012 Aug; 47(10):1117-24.
Medication-assisted treatment for opioid dependence is safe and effective, yet negative perceptions about methadone and buprenorphine may discourage patients from entering treatment. One source of information that may influence viewers’ perceptions is television. We performed a content analysis of a popular reality television program on addiction treatment. Although many patients had histories of opioid use, there were no positive messages about methadone or buprenorphine. The two main messages were that they (1) are primarily drugs of abuse, and (2) not acceptable treatment options. These messages reinforce negative stereotypes and may perpetuate stigma. There were multiple missed opportunities to provide evidence-based information.
Despite repeated criticism, medications (methadone, suboxone) for opioid use disorder continue being called “substitution” treatments.
Appel, P. Heroin Addict Relat Clin Probl. 2020.
Even though its use has declined, “Opioid Substitution Treatment or Therapy” (OST) is still used to describe agonist therapies, viz methadone, suboxone, despite its stigmatizing effects and fundamental inaccuracy. ‘Medication Assisted Treatment (MAT) was an earlier, ca. 2000, response to the need to improve terminology, which, in turn, has been superseded by ‘medications for opioid use disorder’ (MOUD). Yet agonist therapies continue being called ‘substitution’ treatment at a significant rate: a 2019-2020 online ‘verbatim’ search yielded 289 ‘hits’ for OST vs 330 ‘hits’, for MOUD respectively, showing the disturbing persistence of a discredited term. This essay explores how the term ‘substitution’ fails to describe MMT on linguistic and psychopharmacological grounds, its sometimes intentional stigmatizing effects, indirect fatal consequences, underscoring the need to abandon the term. Federal and state government agencies, non-MOUD treatment systems and support groups, treatment accrediting agencies, academics, journals, health services training institutions, international health agencies, and the media, should screen for the term “substitution”, eliminate it if found, and use MOUD instead. The goal is to increase the willingness to welcome and implement programs employing agonist medications for OUD as essential to public health and individual recovery, and to view MOUD programs as a key support for the communities where patients are treated.
Does it Matter How We Refer to Individuals With Substance-Related Conditions? A Randomized Study of Two Commonly Used Terms.
Kelly JF, Westerhoff CM. Int J Drug Policy. 2010 May;21(3):202-7.
OBJECTIVE: Stigma is a frequently cited barrier to help-seeking for many with substance-related conditions. Common ways of describing individuals with such problems may perpetuate or diminish stigmatizing attitudes yet little research exists to inform this debate. We sought to determine whether referring to an individual as “a substance abuser” vs. “having a substance use disorder” evokes different judgments about behavioral self-regulation, social threat, and treatment vs. punishment.
METHOD: A randomized, between-subjects, cross-sectional design was utilized. Participants were asked to read a vignette containing one of the two terms and to rate their agreement with a number of related statements. Clinicians (N=516) attending two mental health conferences (63% female, 81% white, M age 51; 65% doctoral-level) completed the study (71% response rate). A Likert-scaled questionnaire with three subscales [“perpetrator-punishment” (alpha=.80); “social threat” (alpha=.86); “victim-treatment” (alpha=.64)] assessed the perceived causes of the problem, whether the character was a social threat, able to regulate substance use, and should receive therapeutic vs. punitive action.
RESULTS: No differences were detected between groups on the social threat or victim-treatment subscales. However, a difference was detected on the perpetrator-punishment scale. Compared to those in the “substance use disorder” condition, those in the “substance abuser” condition agreed more with the notion that the character was personally culpable and that punitive measures should be taken.
CONCLUSIONS: Even among highly trained mental health professionals, exposure to these two commonly used terms evokes systematically different judgments. The commonly used “substance abuser” term may perpetuate stigmatizing attitudes.
White WL. J Addict Dis. 2012;31(3):199-206.
Recovery is being used as a conceptual fulcrum for the redesign of addiction treatment and related support services in the United States. Efforts by policy, research, and clinical leaders to define recovery and calls for assertive models of long-term recovery management raise critical questions about how transformation efforts of recovery-focused systems will affect the pharmacotherapeutic treatment of opioid addiction and the status of patients participating in such treatment. This article highlights recent work advocating a recovery-oriented approach to medication-assisted treatment.
Volkow, ND & Blanco, C.
Mol Psychiatry. 2021 January ; 26(1): 218–233.
The current opioid epidemic is one of the most severe public health crisis in US history. Responding to it has been difficult due to its rapidly changing nature and the severity of its associated outcomes. This review examines the origin and evolution of the crisis, the pharmacological properties of opioids, the neurobiology of opioid use and opioid use disorder (OUD), medications for opioid use disorder (MOUD), and existing and promising approaches to prevention. The results of the review indicate that the opioid epidemic is a complex, evolving phenomenon that involves neurobiological vulnerabilities and social determinants of health. Successfully addressing the epidemic will require advances in basic science, development of more acceptable and effective treatments, and implementation of public health approaches, including prevention. The advances achieved in addressing the current crisis should also serve to advance the science and treatment of other substance use disorders.