Learning Objectives/Outcomes: After participating in this CME/CNE activity, the provider should be better able to:
1. Explain the extent of opioid addiction in the United States.
2. Summarize the evidence on the effectiveness of agonist pharmacotherapy for opioid addiction compared with abstinence-focused psychotherapy.
3. Compare findings from studies that evaluated the pharmacotherapy route of administration (oral, subcutaneous, or parenteral therapies) on long-term outcomes.
This article is the first of a 2-part series describing the results of a systematic literature review investigating the efficacy of medication-assisted treatments (MATs) for opioid addiction.
Part 1 describes the epidemiology of opioid addiction in the United States and provides a summary of the aggregate research evidence concerning the efficacy of full (methadone) and partial (buprenorphine) opioid-agonist medications in comparison to traditional abstinence-focused psychotherapies. Part 2, which will appear in the next issue, describes and synthesizes the results of a systematic literature review of the research evidence comparing the efficacy of methadone and buprenorphine MAT on long-term patient outcomes (as measured by treatment retention and drug abstinence rates).
The review also describes evidence concerning the efficacy of opioid-antagonist pharmacotherapy, using either the oral or injectable formulation of the [micro]-opioid receptor antagonist naltrexone. By specifically addressing studies that measured long-term patient outcomes (defined as outcome measures greater than or equal to 24 weeks), the article is intended to inform treatment of opioid addiction as a chronic neuropsychiatric disease requiring ongoing treatment.
A Nationwide Public Health Crisis
Addiction is a significant public health crisis in contemporary America. Misuse of both prescription and illicit opioids affects American society at the individual, family, and community levels. The most current statistics show that, as of 2017, approximately 30.5 million Americans engaged in illicit drug use during the previous month (11.2% of the adult population over the age of 12 years). For young adults aged 18 to 25 years, the rate was more than doubled (25%).
Past-year illicit opioid use, defined as any use of illicit opioids (heroin), or any use of prescription opioids without a prescription or in larger amounts or for longer duration than prescribed, was reported by 11.4 million Americans, comprising 4.2% of all adults and 7.3% of all young adults in the US population.1
The overwhelming increase in opioid-related overdose deaths and hospitalizations over the past 20 years has been directly linked to the parallel increase in opioid prescriptions since the introduction of oxycodone in 1996.2 In 2017, 2.1 million adults met the criterion for opioid-use disorder1 (with 1.7 million having prescription opioid-use disorder and 700,000 having a heroin-use disorder). The rate of opioid-use disorders in the young adult population is now 1.3%.
Evidence-based treatments for addiction to opioids and other substances clearly are a vital public health need. However, of the estimated 21.7 million Americans (8.1% of the US adult population) who required addiction treatment in 2015, only 10.8% (2.1 million) received addiction treatment.3 Expanding access to evidence-based addiction therapies will necessarily require a great deal of resources. The selection of efficacious treatment paradigms is therefore of critical importance.
The author undertook a systematic literature review of the extant published biomedical literature to answer the following question: What evidence exists as to the relative efficacy of full opioid agonist (methadone), partial opioid agonist (buprenorphine/naloxone), and opioid antagonist (naltrexone) medically assisted pharmacotherapies for improving long-term outcomes (defined as opioid abstinence and/or treatment retention) in the treatment of illicit and prescription opioid addiction?
Methods
The systematic literature review of the extant biomedical literature focused on the topic of relative efficacy of agonist and antagonist medication-assisted pharmacotherapies in the treatment of opioid addiction. A comprehensive literature review of the published, peer-reviewed biomedical literature was undertaken according to the Matrix Method,4 as described in the following section. The PubMed database was searched using the Boolean search terms "medication assisted treatment" AND "opioid addiction" AND "buprenorphine" OR "methadone" OR "naltrexone."
The search was delimited to clinical trials (published between 1992 and 2017), with the a priori decision to include only primary research publications containing original data (omitting review articles, letters to the editor, or philosophy or policy papers).
The initial database search returned 2049 results. A brief review of the article titles and abstracts identified 194 articles that were potentially relevant to the literature review. A detailed review of these articles (review of the abstracts, and the body of the text, if necessary) was then conducted to select articles to be analyzed within the systematic literature review, according to the following inclusion criteria:
1. A primary research article that reported the results of a clinical trial using a randomized controlled trial or quasiexperimental design and involved human subjects or the secondary analysis of clinical trial data;
2. Research aims addressed the efficacy of an agonist (buprenorphine or methadone) or antagonist (naltrexone) therapy in a clinical population of opioid-dependent individuals;
3. Research design that included an objective physiologic measure that quantified abstinence outcomes (toxicologic testing of urine, hair, or blood samples for prescription or illicit opioids or their metabolites); and
4. Study design that included objective measures of long-term treatment outcomes, operationally defined as abstinence based on toxicologic assays or treatment retention rates for a period of at least 6 months.
Exclusion criteria included:
1. Clinical research that did not involve a clinical trial or did not focus on efficacy of an agonist or antagonist for treatment of opioid dependence for at least 6 months; and
2. Articles that were published in a language other than English.
The in-depth review uncovered multiple research designs, which met other inclusion criteria but measured outcome data for at least 24 weeks. For the purposes of improving the comprehensiveness of the literature review, these studies were included, as the author determined that 24 weeks represented a period of outcome data that was unlikely to be significantly different from the a priori inclusion criteria that specified a 6-month (26.08 weeks) study duration.
Utilization of the expanded inclusion criteria yielded a total of 57 research articles that addressed the primary question and were included within the systematic literature review for analysis.
The PsycINFO database was then searched using identical search parameters. The search yielded a total of 344 articles, of which 13 additional articles meeting the review criteria were uncovered. Details on each step of the literature search process and the application of inclusion and exclusion criteria are shown in Figure 1.
The next phase of the review involved comprehensively reading the included articles and abstracting information relevant to the research questions. The abstracted information was synthesized to create a review matrix that summarized the aggregate research findings extracted from the systematic literature review according to the matrix method. The review matrix provided a heuristic tool for condensing and comparing and contrasting the findings contained within the extant research literature on long-term efficacy outcomes for MATs in opioid addiction, to present a logical and parsimonious summary of the aggregate findings of the addiction research literature concerning relative efficacies of MAT therapies. The Results section contains a discussion of these findings that is stratified by treatment modality.
The initial systematic review identified a large ongoing clinical research trial comparing the effectiveness of agonist and antagonist treatment modalities (X-BOT Trial). To include these important data, a decision was made to update the systematic review after the publication of the results of the ongoing trial. A search of the PubMed database using identical search parameters conducted in February 2019 returned 9 additional research articles, which were incorporated into an updated review article.
Results
The systematic literature review identified 70 articles, which fulfilled inclusion criteria and were subsequently abstracted in a review matrix. These articles comprised 60 primary research articles reporting data from human subjects' clinical trials and 10 secondary analyses of data from a parent clinical trial. The matrix divided the articles heuristically into 3 categories to facilitate comparative analysis of the research data. Specifically, the articles were classified as agonist (n = 45), antagonist (n = 23), and comparative agonist/antagonist (n = 2) research. The updated review identified 9 additional research articles that were incorporated into the existing categories.
Within these overarching treatment categories, individual research articles in the first 2 categories (agonist or antagonist research) were generally divided into these subcategories:
* Research comparing the active MAT therapy (agonist or antagonist) with a placebo intervention (typically psychosocial/counseling interventions described as "standard medical management" or "treatment as usual");
* Articles comparing the relative efficacy of different MATs by pharmacotherapeutic agent, such as agonist (methadone) versus agonist (buprenorphine/naloxone) or by method of drug delivery (oral vs implant/depot agonist or antagonist medications); and
* Articles investigating the relative efficacy of MAT therapy plus adjunctive medications (antidepressants or [alpha]-2 adrenergic agonists) with standard MAT.
The final category contained research articles reporting on the comparative efficacy of agonist and antagonist MATs.
The review, as updated in 2019, added an additional 9 articles to the heuristic categories described earlier. The ensuing sections discuss the aggregate findings by category.
Agonist Research
After the initial demonstration of clinical efficacy for methadone therapy in the treatment of heroin dependence provided by Dole and Nyswander (1965), methadone maintenance therapy was broadly implemented within the treatment of illicit and prescription opioid addiction, becoming the "gold standard" of medication-assisted addiction pharmacotherapy for chronic heroin addiction.
Basic scientific research undertaken under the authority of the National Institute of Drug Abuse in the 1970s identified the partial [micro]-opioid receptor agonist buprenorphine and the [micro]-opioid receptor antagonist naltrexone (discussed in subsequent sections) as potential alternative pharmacotherapeutic treatments for opioid addiction.
Early research investigations evaluated the relative efficacy of sublingual buprenorphine in comparison to the standard (methadone maintenance) MAT for improving outcomes in the clinical population of individuals with opioid-addiction disease. Before discussing the results of research on the relative efficacy of full (methadone) and partial (buprenorphine/naloxone) agonist MATs, we summarize the research evidence pertaining to comparisons of agonist therapies with different psychosocial interventions, and the body of research comparing the relative efficacy of agonist (buprenorphine) treatment by different routes of administration.
Research concerning agonist pharmacotherapy and psychosocial interventions can broadly be divided into 2 types of studies. The first of these types of studies sought to compare the efficacy of a pharmacotherapeutic intervention (opioid agonist treatment) with the traditional standard of care, which involved abstinence-focused psychotherapy. After sufficient evidence had accumulated to demonstrate the superiority of MAT, a second line of research developed, which sought to evaluate the efficacy of different behavioral/psychosocial therapeutic adjuncts to medication-assisted therapy.
Agonists With Abstinence-Focused Psychotherapy
An early study by Sees et al,5 comparing methadone maintenance treatment (MMT 30-100 mg/day) (n = 91), with a methadone detoxification protocol followed by 180 days of psychosocial treatment (n = 88), over a 6-month treatment period, demonstrated a significantly greater duration of treatment retention for MMT [median = 438.5 (413-441) days] versus psychosocial treatment [median = 174 (161-181) days], although monthly heroin use rates exceeded 50% in both treatment conditions.
A similar study compared buprenorphine maintenance treatment (16 mg/day) plus cognitive behavioral therapy (CBT) with a 6-day buprenorphine taper followed by placebo and CBT over 12 months. The results demonstrated that 1-year retention rates were 75% on buprenorphine maintenance versus 0% on placebo6 (P = 0.001).
The study provided overwhelming support for the superiority of combined buprenorphine and CBT over psychosocial (CBT) treatment alone.
A 2005 study by Schottenfeld et al7 evaluated the efficacy of buprenorphine (12-16 mg) and methadone (65-85 mg), with either contingency management behavioral therapy, or treatment as usual (performance feedback) in opioid- and cocaine-dependent patients. This study demonstrated the superiority of methadone treatment conditions over buprenorphine treatment conditions in duration of treatment retention, duration of abstinence, and percentage of opioid and cocaine-negative urinalyses. Contingency management improved outcomes during the 12-week period of escalating incentivization, but had a nonsignificant effect on treatment outcomes over the full 24-week study.
Buprenorphine maintenance therapy (16-24 mg/day), delivered with either weekly or thrice-weekly brief counseling, or thrice-weekly extended counseling over 24 weeks, showed comparable efficacy as measured by percent opioid-negative urinalyses (P = 0.82) and proportion of treatment completers (P = 0.64) that were not significantly different between groups.8
An important finding showed that the number of days of treatment adherence was moderately positively correlated with the number of opioid-negative urinalyses (r = 0.30) and mean consecutive number of abstinent weeks (r = 0.35, P < 0.001).
Within the correctional setting, a study by Gordon et al9 compared 6-month outcomes for inmates randomized to inpatient counseling only (CO = 70), counseling plus transfer to MMT at discharge (CT = 70), and counseling plus inpatient and community methadone maintenance (CM = 71). The study results demonstrated that prerelease inmates receiving counseling plus methadone maintenance (CM) had significantly greater treatment retention (100.4 days) versus CT (57.5 days) and CO (13.8 days) (P = 0.0001), and were significantly less likely to have opioid-positive urinalyses (27.9%) compared with the CO group (65%) (P = 0.002).
A study comparing the relative efficacy of MMT and an HIV harm-reduction program (HHRP+) (n = 45), and MMT plus enhanced methadone maintenance counseling (n = 45), in HIV and injection-drug users over 6 months showed that HHRP+ patients were significantly less likely (28.8% vs 43.6%, P < 0.01) to have opioid-positive urinalyses at 6 months of treatment.10
Comparison of buprenorphine management (16 mg/day) provided within an HIV clinic with case management, versus referral to counseling services through a traditional opioid treatment program (OTP), for HIV-positive opioid addicts over 12 months, demonstrated superior outcomes in significantly lower percentages of opioid and cocaine-positive urinalyses in HIV clinic patients vs OTP patients (p = 0.15), although significant baseline demographic differences in IV drug use and comorbid hepatitis C infection rates (with lower rates in the buprenorphine treatment condition) were present.11
A prospective clinical trial in Malaysia of (n = 301) HIV-positive opioid-dependent individuals transitioning from incarceration (1 week to 6 months prerelease) into the community evaluated the efficacy of MMT in combination with a harm-reduction counseling program (HHRP-M), with patient follow-up for 12 months.12 The study did not demonstrate significant differences in treatment retention between patients receiving HHRP-M+ (n = 150) and not receiving HHRP-M- (n = 151) the adjunctive harm-reduction counseling intervention.
A 2-phase experimental design, conducted in 2011 by Weiss et al,13 consisted of brief (4-week) and extended (16-week) phases of buprenorphine/naloxone treatment (8-32 mg/day), with either adjunctive opioid drug counseling (n = 324), or standard medical management (SMM) (n = 329). The authors documented no significant differences in abstinence rates between behavioral treatment conditions at completion of phase 2 of treatment (49.2%), while follow-up at 8 weeks posttreatment showed abstinence rates had decreased precipitously (8.6%), with abstinence significantly more likely during active treatment (P < 0.001).13
These results underscore the chronic relapsing nature of addictive diseases, providing further evidence in support of improved long-term outcomes with sustained treatment engagement in medication-assisted maintenance therapies.
A comparison of the efficacy of buprenorphine treatment (maximum dose 24 mg/day) within 3 different counseling milieus (CBT, OTP, and SMM) provided evidence of improved treatment retention in the CBT counseling condition relative to OTP treatment or SMM (P = 0.05). Abstinence rates assessed by the treatment effectiveness score, or TES (negative urinalyses/total urinalyses) were not significantly different between sites (P = 0.08).
Interestingly, higher dosage was associated with a lower percentage of opioid-negative urine test results (r = -0.41, P = 0.00), and increased duration of treatment retention correlated positively with rates of opioid-negative urinalyses (r = 0.58, P < 0.00).14
Similar results were obtained in a study investigating 16 weeks of behavioral treatment after a 2-week buprenorphine induction/stabilization phase.15 Participants were randomized to behavioral treatment of CBT, contingency management (CM), CBT + CM, or SMM with follow-up assessments at weeks 40 and 52, demonstrating no significant between-group differences in urinalysis rates (P = 0.75) or mean number of consecutive opioid-negative urinalyses (P = 0.16). This study demonstrated no added benefit of CM to CBT for reducing opiate use.
A study by Schwartz et al16 that investigated efficacy outcomes for methadone maintenance with interim counseling (n = 99), standard counseling (n = 104), and restored counseling (decreased patient-to-counselor ratios) (n = 29) failed to demonstrate significant between-group differences in treatment retention rates or opioid and cocaine abstinence outcomes over a 12-month treatment period.
A later research investigation, comparing the efficacy of patient-centered methadone maintenance (with optional counseling and flexible clinic rules), and standard MMT, over 12 months, also failed to detect significant between-group differences in retention or abstinence outcomes.17 These results have generally held consistent in subsequent research investigations.
Mitchell et al18 did not find statistically significant differences in opioid and cocaine-positive urinalysis rates at 3 and 6 months, between African-American opioid-dependent individuals randomized to receive 6 months of buprenorphine maintenance treatment (8-24 mg/day), with either intensive outpatient (n = 145) or standard outpatient (n = 155) counseling services. Metzger et al19 showed that 1 year of standard buprenorphine maintenance treatment with 21 adjunctive psychosocial counseling sessions (n = 470) demonstrated clear superiority over 1 year of treatment consisting of two 15-day buprenorphine detoxification periods and 21 psychosocial counseling sessions, with significantly greater rates of opioid-negative urinalyses at week 26 (P < 0.001), week 48 (P <0.001), and week 52 (P < 0.001). However, these differences became nonsignificant at posttreatment time points, week 78 (P = 0.38) and week 104 (P = 0.43).19
In contrast, Brigham et al20 demonstrated a significant improvement in opioid and other drug use rates for patients receiving buprenorphine treatment and an adjunctive psychosocial intervention delivered to opioid-addicted patients and their concerned significant others (CSOs) (CRAFT-T therapy), relative to patient dyads that received buprenorphine plus treatment as usual, for 14 weeks, with follow-up assessments at 6 and 9 months. Improvements in treatment retention rate were also demonstrated in the subpopulation of patients whose CSO was a parent rather than a spouse/partner (P < 0.01).
The aggregate results of the reviewed literature on agonist MAT demonstrate a clear superiority for agonist maintenance therapies in improving long-term outcomes for individuals with opioid addiction, in comparison to the outcomes achieved with traditional psychosocial abstinence-focused counseling interventions. The evidence on the utility of psychosocial or behavioral interventions as adjuncts to MAT therapy is more equivocal, with most studies demonstrating that these interventions did not produce statistically significant improvements in long-term outcomes (>6 months). However, several studies have provided evidence of improved outcomes associated with psychosocial adjuncts.7,14,20
Specifically, it has been demonstrated that individuals requiring services for both HIV infection and opioid addiction showed significant improvements in long-term outcomes, as reflected in lower rates of opioid-positive urinalyses, when services were provided within an integrated treatment paradigm.10,11
Similarly, improved treatment retention rates, but not improved abstinence outcomes, were demonstrated for buprenorphine treatment in combination with CBT, versus OTPs or SMM.14 CRAFT-T dyadic treatment therapy that included a sober family member in the regimen of psychosocial counseling provided with buprenorphine treatment improved abstinence rates and retention outcomes, in comparison to an individual counseling regimen.20
These studies suggest that certain therapeutic modalities (specifically CBT and family-focused therapy) can improve outcomes in MAT, and also provide evidence for the importance of integrated HIV/addiction treatment services that incorporate a harm-reduction component. The evidence for the efficacy of other psychosocial treatments within the broader population of opioid-addicted individuals is not presently supported when examining long-term (>6 months) abstinence and retention outcomes.
It is worth noting that current guidelines for MATs in many states require patient referral to adjunctive counseling as a condition of continuing treatment. How psychosocial and behavioral interventions can best be integrated in maintenance pharmacotherapies for opioid addiction is a question requiring future research.
Agonist Route of Administration for Medication-Assisted Treatment
Research investigations of the relative efficacy of agonist pharmacotherapies administered by different routes has been undertaken in recent years, with the goal of discovering whether treatment efficacy and long-term clinical outcomes are improved by subcutaneous or parenteral therapies, which require less medication compliance and potentially deliver more stable therapeutic serum levels of agonists relative to oral medications. A 6-month placebo-controlled trial evaluated the long-term efficacy outcomes (percent opioid-negative urinalyses and treatment retention rates) for individuals receiving subcutaneous buprenorphine implants (80 mg/implant) (n = 55) compared with placebo (n = 53).21
Both treatment groups could receive rescue doses of oral buprenorphine as needed, and superior outcomes for implant buprenorphine relative to placebo were demonstrated by higher opioid-negative urinalysis rates [36.6 (30.5%-42.6%)] versus [22.4 (15.3%-29.5%) (P = 0.01)] and 6-month treatment retention rates (65.7%) versus (30.9%).21
During the course of the study, 59% of implant patients required adjunctive oral doses of buprenorphine for craving or withdrawal symptoms. In a 2013 study, Rosenthal et al22 subsequently demonstrated the noninferiority of s/c buprenorphine (80-mg implants x 4) (n = 174) to open-label oral buprenorphine/naloxone (12-16 mg/day) (n = 118) in a placebo-controlled clinical trial, in cumulative percentage of opioid-negative urinalyses and treatment completion rates.
These results were subsequently confirmed by Rosenthal et al23 in a 2016 study in a population of opioid-dependent individuals stabilized on buprenorphine maintenance who were randomized to receive a 6-month course of implant buprenorphine and oral placebo, or to continue on oral maintenance therapy and receive placebo implants.23
The evidence supported the noninferiority of implant buprenorphine to standard sublingual (s/l) buprenorphine/naloxone maintenance therapies, as the 6-month abstinence rate for implant buprenorphine was significantly higher (85.7%) compared with s/l buprenorphine (71.9%) (P = 0.03). This is a phenomenon of potential clinical significance that will require replication in further research.
The literature provided strong empirical support for the safety and efficacy of parenteral agonist treatments, which were reflected in improved long-term abstinence and retention rates relative to oral buprenorphine treatment.21-23
It is important to note that although parenteral buprenorphine was superior to oral buprenorphine dosing alone, a large percentage of individuals receiving both routes required "rescue" doses of oral buprenorphine for symptoms of craving and withdrawal during treatment.21 Optimal treatment outcomes would result from the maintenance of therapeutic serum drug levels throughout maintenance therapy, and the provision of supplemental oral medications to individuals receiving parenteral treatment should support such outcomes.
A body of research has investigated the optimal dosing levels and frequencies for agonist pharmacotherapies. A cohort study of individuals (n = 133) on MMT over a wide dosing range (5-100 mg/day) over 6 months showed that higher doses [mean 67 (2.1) mg/day, P < 0.05] were significantly associated with treatment completion.24
These results were corroborated by a randomized double-blinded clinical trial comparing efficacy of moderate- (40-50 mg) (n = 97) and high- dose (80-100 mg) (n = 95) MMT in opioid dependence over 40 weeks.25
Intention-to-treat analyses demonstrated that high-dose methadone patients had significantly lower rates of opioid-positive urinalyses relative to moderate-dose patients during both active treatment [53% (46.9%-59.2%) vs 61.9% (55.9%-68%) P = 0.047] and detox (weeks 31-40) high-methadone [46% (37.3%-55.5%)] versus medium-methadone [66.9% (57.9%-5.9%) P = 0.002] phases of treatment, with no significant differences in treatment retention (159 vs 157 days).25 A retrospective cohort study of opioid-dependent women (n = 189) treated with methadone maintenance during pregnancy [average daily dose 60.8 (22.9) mg/day] demonstrated treatment retention at delivery (90.1% vs 74.1%, P < 0.005) and 60 days postpartum (71.6% vs 37%, P < 0.0001) for patients receiving more than 60-mg/day methadone versus less than 60 mg/day.26 Additionally, the percentage of opioid-negative urinalyses was significantly greater for individuals receiving more than 60-mg/day methadone (71.5% vs 58%, P < 0.04) and a generalized linear model analyses showed a significant positive association between methadone dosage and treatment retention at delivery (P < 0.02) and at 60 days postpartum (P < 0.004).26
Several research studies provided information about the efficacy and safety of agonist treatments within specific subgroups of the larger population of individuals with opioid addiction. A study of HIV-positive opioid-dependent patients (n = 209) receiving MMT for 12 months in China [average methadone dose 67.5 (28.7) mL/day] showed that morphine-positive urinalyses decreased from 95.9% in month 1 to an average of 40.9% between months 2 and 12, with a total of 1580 of 3741 (45.5%) of monthly urinalyses tests positive for morphine.27
Within this population, decreased percentage of morphine-positive urinalyses was associated with younger age (<30 years) [odds ratio (OR) = 0.31, 95% confidence interval (CI) = 0.12-0.78], whereas increased heroin use was associated with unemployment (OR = 1.99, 95% CI = 1.13-3.49). A cohort study of individuals (n = 3743) initiating MMT in Ontario between 2012 and 2013 demonstrated that individuals (n = 2605) receiving onsite (clinic) methadone dosage had significantly higher 1-year retention rates (57.3%) versus individuals (n =1138) receiving offsite community pharmacy dosing (11.9%), although the median daily methadone dose was also higher for onsite (80 mg) versus offsite (65 mg) patients.28
A research investigation of heroin-dependent adolescents (<18.5 years) (n = 120) inducted onto MAT (methadone or buprenorphine) for 12 months measured treatment retention outcomes.
Among the 39 individuals completing 12 months of MAT, heroin abstinence rates increased significantly from baseline to month 3 (21%, 95% CI = 9%-36%, P < 0.001) and from month 3 to month 12 (46%, 95% CI = 30%-63%, P = 0.01). However, rates for other drugs did not significantly change and individuals using cocaine at month 12 were significantly more likely to continue substance use (P = 0.02).29
A longitudinal investigation of long-term outcomes of 21 stable methadone maintenance patients (>5 years sobriety) transitioned to monthly medical methadone maintenance dosing for 12 years showed a 57% retention rate in treatment at 12 years [mean methadone dose = 71.4 (13.5) mg/day], with an extremely low rate of opioid-positive urinalyses (0.5%).30 A cohort analysis of (n = 890) opioid-dependent patients receiving MMT at 11 Israeli methadone clinics investigated survival and retention outcomes between clinic admission (6/1993-6/2016) until death or termination of the study (6/2017).31 Among the 810 participants admitted (10,146.9 person years), mean length of treatment retention was 7.9 (95% CI = 7.4-8.5) years and all-cause mortality rates (n = 237) were not significantly different between individuals remaining in treatment (2.6 per 100 person years) versus those who left treatment (2.1 per 100 person years); however, the mortality rate was significantly lower among those patients remaining in treatment for 1 year or more during any admission period (2.1 per 100 person years vs 3.3 per 100 person years, P = 0.004).31
Conclusion
The aggregate results of these research studies suggest that higher doses of methadone can improve retention and abstinence rates and that high-dose methadone can provide a stable pharmacotherapeutic maintenance medication for opioid addiction over long periods with minimal adverse effects. Part 2 of this series will synthesize the results of the systematic literature review comparing the efficacy of methadone and buprenorphine MAT modalities on long-term patient outcomes.
References