A Meta-Analysis of Retention in Methadone Maintenance by Dose and Dosing Strategy

Abstract

Objective

To estimate, via meta-analysis, the influence of different methadone dose ranges and dosing strategies on retention rates in methadone maintenance treatment (MMT).

Methods

A systematic literature search identified 18 randomized controlled trials (RCTs) evaluating methadone dose and retention. Retention was defined as the percentage of patients remaining in treatment at a specified time point. After initial univariate analyses of retention by Pearson chi-squares, we used multilevel logistic regression to calculate summary odds ratios (ORs) and 95% confidence intervals for the effects of methadone dose (above or below 60 mg/day), flexible vs. fixed dosing strategy, and duration of follow-up.

Results

The total number of opioid-dependent participants in the 18 studies was 2831, with 1797 in MMT and 1034 receiving alternative mediations or placebo. Each variable significantly predicted retention with the other variables controlled for. Retention was greater with methadone doses ≥ 60 than with doses <60 (OR: 1.74, 95% CI: 1.43–2.11). Similarly, retention was greater with flexible-dose strategies than with fixed-dose strategies (OR: 1.72, 95% CI: 1.41–2.11).

Conclusions

Higher doses of methadone and individualization of doses are each independently associated with better retention in MMT.

INTRODUCTION

Opioid addiction is generally characterized as a chronic, relapsing disorder (1). Abuse and dependence on opioid drugs are a major health and social burden in many countries. The μ-agonist opioid methadone is a first-line treatment for opioid addiction; methadone has good oral bioavailability, can be dosed once per day, suppresses opioid withdrawal, and provides crosstolerance to the effects of other opioids (2). Since the mid-1960s, when Dole and his colleagues introduced methadone maintenance treatment (MMT) to reduce the use of heroin (3, 4), MMT has been used successfully to reduce the morbidity and criminality associated with heroin abuse, permit improvements in social engagement and vocational productivity, and prevent the spread of blood borne diseases (5, 6). Since the 1980s, growing epidemics of HIV and hepatitis C have encouraged the expansion of MMT as an effective opioid treatment throughout the world (7–9).

Retention in MMT is comparatively good. This finding is borne out over the last 25 years and exemplified in a landmark study by Ball and Corty that also explored factors associated with success in methadone maintenance, including clinic policies and the extent of adjuvant psychosocial services (11). Other studies have found that patients in maintenance-oriented clinics are 30% more likely to remain in treatment than those in abstinence-oriented centers (10). Some systematic reviews have shown that retention is associated with on-site dosing and that higher rates of dropout are associated with lower doses of methadone (12–14). Gruber found that MMT, even with minimal counseling, reduced heroin and alcohol use more than methadone detoxification (15). It has been recommended that methadone doses be individualized and flexible because each patient presents a unique clinical challenge and there is no single best dose for all patients and dose induction and followed subsequent dose adjustments have usually been needed in practice (16, 17). Several algorithms exist for individualization of doses, such as dose adjustment based on urine toxicology and withdrawal symptoms (2, 18). A systematic review introduced the conception of flexible dosing strategy and summarized that the flexible dosing strategy in MMT was somewhat more effective than the fixed-dose maintenance therapy (19). Clinic-management issues, like methadone dose and dose-adjustment regimens, may also have a significant impact on treatment outcome.

To explore how these components of MMT influence retention, we undertook a meta-analysis. In particular, we assessed the respective influences of two related but not identical factors: the typical dose administered and the flexibility of dosing.

METHODS

Literature Search

Studies for the meta-analysis were selected from peer-reviewed published literature in the Medline database (1950-), Embase (1966-), and the Chinese literature database CNKI, up to August 2007. Key search terms were “Methadone/MMT,” “Randomized controlled trial (RCT),” and “human” (and the corresponding terms in Chinese). Additional studies were identified from the cited reference lists of articles, and studies in all languages were eligible for inclusion.

To be included in the meta-analysis, articles had to: (1) report randomized, controlled, double-blind clinical trials with MMT as at least one of the treatments, (2) report in detail the doses of methadone administered (quantity of methadone in fixed-dosage studies; average dose and dose-determination strategy in flexible-dosage studies), (3) report the sample size and follow-up period for each subgroup of participants, and (4) include retention rate as an outcome variable. Trials with opioid detoxification as the main objective and crossover trials were excluded. Studies in which MMT was supplemented with specialized adjuvant behavioral interventions (such as cognitive-behavioral therapy or contingency management) were also excluded, unless they included a control group in which those interventions were not given, in which case only the control group was included (20).

Data Abstraction

The following information was extracted for each study: first author’s name, year of publication, bibliographic reference, treatment medication, control treatment, dose of methadone (the mean dose used at the time of the final evaluation), dosage strategy (flexible or fixed dose), number of patients in each group, follow-up months, and retention at the end of follow-up period. For studies with two or more follow-up periods, the retention data were collected from the longer follow-up period separately (21).

According to a consensus statement from the National Institutes of Health (NIH), 60 mg of methadone per day is the minimum effective maintenance dose for most patients (7). Therefore, we dichotomized studies into two categories: <60 mg/day vs. ≥ 60 mg/day. The follow-up period was dichotomized as short-term (3–6 months) vs. long-term (6–12 months). Dosing strategy was dichotomized as flexible vs. fixed.

Statistical Analyses

In initial univariate analyses, treatment retention was compared by Pearson chi-square as a function of dose, dosing strategy, and duration of follow-up. To examine the effect of each predictor while controlling for the other two, summary odds ratios (ORs) were estimated in a multilevel logistic regression model (Genmod procedure, SAS version 8.0). Some studies included more than one dose group, but all studies except one (16) used a single duration of follow-up and a single dose strategy. Each study was treated as a block, with the characteristics of the intervention clustered within dose group. Dose was a within-subjects predictor; dosing strategy and follow-up period were between-subjects predictors. In all analyses, p values less than or equal to .05 were considered statistically significant.

RESULTS

Studies Included

A total of 18 studies, shown in Table 1, met the inclusion criteria (2, 10, 18, 20–34). Of the 2831 participants, 1797 (63.5%) received methadone, 236 (8.3%) received levo-acetylmethadol, 667 (23.6%) received buprenorphine, and 131 (4.6%) received only placebo. Of the 1797 participants who received methadone in any of the 18 included studies, 1028 (57.2%) received <60 mg/day and 769 (42.8%) received ≥ 60 mg/day; 634 (35.3%) underwent flexible dosing and 1163 (64.7%) underwent fixed dosing; and 957 (53.3%) were followed up at 3–6 months and 840 (46.7%) at 6–12 months. Table 2 shows the distribution of participants and retention rates in terms of dose, dosing strategy, and duration of follow-up.

TABLE 1.

Summary of the eligible studies included in this analysis

Author (Year)	Journal	Follow up (weeks)	Strategy	Drug	Dose	N	Retention	Rate (%)
Jaffe JH (1972)	JAMA	15	Fixed	Methadone	55	15	13	86.7
				LAAM	65	19	14	73.7
Goldstein A (1973)	Proc Natl Conf Methadone Treat	27	Fixed	Methadone	160	40	25	62.5
				Methadone	80	40	26	65.0
				Methadone	40	40	15	37.5
Ling W (1976)	Arch Gen Psychiatry	40	Fixed	Methadone	50	146	61	41.8
				Methadone	100	142	74	52.1
				LAAM	80	142	44	31.0
Panell J (1977)	Med J Aust	40	Fixed	Methadone	100	20	17	85.0
				Methadone	50	20	14	70.0
				LAAM	80	20	12	60.0
Newman RG (1979)	Lancet	32	Flexible	Methadone	97	50	38	76.0
				Placebo	—	50	5	10.0
Johnson RE (1992)	JAMA	17	Fixed	Buprenorphine	8	53	22	42.0
				Methadone	60	54	17	31.5
				Methadone	20	55	11	20.0
Kosten TR (1993)	J Nerv Ment Dis	24	Fixed	Methadone	35	34	23	67.7
				Methadone	65	35	21	60.0
				Buprenorphine	6	28	—	—
				Buprenorphine	2	28	—	—
Strain EC (1993)	Ann Intern Med	20	Fixed	Methadone	50	84	44	52.4
				Methadone	20	82	34	41.5
				Placebo	—	81	17	21.0
Strain EC (1994)	Psychopharmacology	16	Flexible	Methadone	66.6/20–90	24	13	54.2
				Buprenorphine	11.2/2–16	27	16	59.3
Strain EC (1994)	Am J Psychiatry	16	Flexible	Methadone	54/20–90	80	45	56.3
				Buprenorphine	8.9/2–16	84	47	56.0
Ling W (1996)	Arch Gen Psychiatry	52	Fixed	Methadone	30	75	16	21.3
				Methadone	80	75	26	34.7
				Buprenorphine	8	75	26	34.7
Schottenfeld RS (1997)	Arch Gen Psychiatry	24	Fixed	Methadone	65	28	18	64.3
				Methadone	20	30	14	46.7
				Buprenorphine	12	29	16	55.2
				Buprenorphine	4	29	10	34.5
Fisher G (1999)	Addiction	24	Flexible	Methadone	63/20–80	31	22	71.0
				Buprenorphine	7.5/2–8	29	11	37.9
Strain EC (1999)	JAMA	30	Flexible	Methadone	46/40–50	97	54	55.7
				Methadone	90/80–100	95	57	60.0
Johnson RE (2000)	N Engl J Med	17	Flexible	LAAM	75–115	55	29	52.7
				Buprenorphine	16–32	55	32	58.2
				Methadone	60–100	55	39	70.9
			Fixed	Methadone	20	55	11	20.0
Pani PP (2000)	Drug and alcohol dependence	24	Fixed	Methadone	60	34	22	64.7
				Buprenorphine	8	38	18	47.4
Preston KL (2000)	Arch Gen Psychiatry	13	Fixed	Methadone	70	31	27	87.1
				Methadone	50	28	27	96.4
Mattick RP (2003)	Addiction	13	Flexible	Methadone	52.1/20–150	202	120	59.4
				Buprenorphine	10.1/2–32	192	96	50.0

LAMA: levo-acetylmethadol. For flexible-dose studies, doses are shown as mean/range.

TABLE 2.

Unadjusted data showing MMT retention by dose and dosage strategy (N = 1797)

Dosage in MMT (mg/day)	3–6 M		6–12 M		All
	n	Retention rate (%)	n	Retention rate (%)	n	Retention rate (%)
< 60
Flexible dose	282	58.5	97	56.0	379	57.9
Fixed dose	368	44.6	281	37.8	649	41.6
Total	650	50.6	378	42.5	1028	47.6
≥ 60
Flexible dose	110	67.3	145	65.5	255	66.3
Fixed dose	197	59.9	317	53.1	514	55.7
Total	307	62.5	462	57.0	769	59.2
All
Flexible dose	392	61.0	242	61.7	634	61.3
Fixed dose	565	49.9	598	45.9	1163	47.8
Total	957	54.4	840	50.4	1797

Retention in MMT—Univariate Analyses

Table 2 shows treatment retention as a function of methadone dose and dosing strategy, at different lengths of follow-up. Across dosing strategies, doses ≥ 60 were associated with greater retention than doses < 60 at both 3–6 months (62.5% vs. 50.6%, chi-square = 11.96, p = .0005) and 6–12 months (57.0% vs. 42.5%, chi-square = 17.09, p < .0001). Across doses, flexible dosing strategies were associated with greater retention than fixed dosing strategies at both 3–6 months (61.0% vs. 49.9%, chi-square = 11.41, p = .0007) and 6–12 months (61.7% vs. 45.9%, chi-square = 17.10, p < .0001). Flexible dosing strategies were also associated with greater retention within individual dose categories and durations of follow-up (with the exception of the ≥ 60 category at 3–6 months).

Retention in MMT—Multilevel Model

Table 3 shows the summary odds ratios (ORs) for retention as a function of follow-up duration, dose, and dosing strategy, as estimated by multilevel logistic regression. Each variable significantly predicted retention with the other two variables controlled for. As expected, retention was lower at 6–12 months than at 3–6 months (OR: .80, 95% CI: .65–.87). Retention was greater with doses ≥ 60 than with doses < 60 (OR: 1.74, 95% CI: 1.43–2.11). Similarly, retention was greater with flexible-dose strategies then with fixed-dose strategies (OR: 1.72, 95% CI: 1.41–2.11).

TABLE 3.

Summary odds ratios (ORs) and adjusted retention rates from multilevel logistic regression (N = 1797)

Variable	Number	Adjusted retention rate	OR	95% CI
Follow-up period
3–6 M	957	54.4	1
6–12 M	840	50.4	.80	(.65–.97)
Flexible vs. Fixed
Fixed dose	1163	47.8	1
Flexible dose	634	61.3	1.72	(1.41–2.11)
Dose
< 60	1028	47.6	1
≥ 60	769	59.2	1.74	(1.43–2.11)

DISCUSSION

To our knowledge, this analysis is the first to assess the influence of both methadone dose (high/low) and dosage strategy (flexible/fixed) on retention in treatment.

As expected, retention was lower in studies with longer periods of follow up (6–12 months vs. 3–6 months). However, within each follow-up period, greater retention was associated with greater methadone dose, regardless of flexible or fixed dosing strategy. Greater retention was also associated with flexible dosing strategies, regardless of dose.

Prior randomized, controlled trials (RCTs) have shown that higher doses of methadone are associated with significantly greater retention (2, 18, 20–25). Caplehom et al. found that patients who received a maximum daily dose of less than 60 mg of methadone were 4.8 (95% CI: 2.6–8.3) times as likely to leave treatment as those who received a maximum dose of 80 mg (35). National Institutes of Health (NIH) Consensus Conference guidelines for methadone substitution therapy recommend a dose of at least 60 mg and note that higher doses are often required (7). In England, the Department of Health (DoH) recommends maintaining individuals on a daily dose of methadone between 60 and 120 mg (8). Based on these guidelines, we initially classified dose categories as ≥ 60 mg/day, 60–119 mg/day and > 120 mg/day. In that analysis, we found that patients maintained 60–119 mg/day had longer retention that those maintained on < 60 mg/day, but did not differ from those maintained on > 120 mg/day. However, only one study (with only 40 participants) fell into the highest dose category. Therefore, we dichotomized the doses in accordance with the minimum effective dose cited in the NIH consensus statement (7). Our findings with regard to dose are consistent with those of previous meta-analysis (12–14). However, more RCT data are needed to clarify the risk: benefit ratio of higher doses of methadone, especially in patients who abuse alcohol or benzodiazepines or who have risk factors for QT prolongation (37). More evidence about retention and other outcome measures at > 120 mg/day group are needed. In the United States, the percentage of patients receiving doses less than the recommended 60 mg/day decreased from 79.5% in 1988 to 35.5% in 2000, and the average methadone dose increased from 45 mg/day in 1988 to 59 mg/day in 1995 (38).

Our meta-analysis also showed that retention is greater with a flexible, individualized dosing strategy than with a fixed-dose strategy. Fortunately, flexible dosing is probably more reflective of real-world practice. Predictors of the appropriate dosage of methadone for a given individual include prior frequency and amount of drug use, diagnosis of posttraumatic stress disorder or depression, greater number of previous opioid detoxifications, and living in a region where street heroin is high in purity (16, 17, 39–41). In the studies included in our meta-analysis, different dosing strategies were used at different clinics, leaving the possibility that the observed effects of dosing strategy were confounded by unmeasured variables. A direct comparison at a single site would provide stronger confirmation of the superiority of flexible dosing.

Other factors playing a role in retention included age, stability of income, aboriginal ethnicity, availability of free treatment, clinic management policies, use of cognitive behavior therapy, and use of contingency management (42). The combination of adjuvant treatment strategies with better dosing practices has probably contributed to successful experiences with MMT in the United States, Europe, and other developed countries.

This meta-analysis had the strength of a large sample size, but was limited by the requirement for homogeneity, leading to exclusion of some studies. The eligible studies were conducted in the United States, Australia, and Europe. More well-designed RCTs and epidemiological studies are needed in developing countries, especially because policymakers in developing countries require persuasive evidence of MMT’s effectiveness in their own cultures.

In summary, our findings suggest that consideration of dose and dosage strategies will increase retention in MMT treatment even in a clinic whose policies impose a ceiling on the actual range of doses administered. It is likely that retention will be greatest when the dosing strategy is flexible and doses are relatively high.