Objective: The aim of this study was to compare the long-term outcomes of treatment-resistant heroin addicts with and without DSM-IV axis I psychiatric comorbidity (dual diagnosis). Method: 129 heroin addicts who also met criteria for treatment resistance, 66 with one or more DSM-IV axis I psychiatric diagnosis (DD patients), and 63 without DSM-IV axis I psychiatric comorbidity (NDD patients) were monitored prospectively (6 years on average, min. 1, max. 9) along a methadone maintenance treatment program (MMTP). Results: The rates for survival-in-treatment were about 50% for NDD patients and about 70% for DD patients. After 4 years of treatment onwards, such rates tended to become stable. DD patients showed better outcome measures than NDD patients. A significantly higher methadone dose was needed to have DD patients stabilized. Conclusions: Contrary to expectations, treatment-resistant patients with psychiatric comorbidity showed a better long-term outcome than treatment-resistant patients without psychiatric comorbidity.

We examined in vivo the influence of cytochrome P4503A4 (CYP3A4) activity, measured by the 30 min plasma 1′OH-midazolam/midazolam ratio after oral administration of 7.5 mg midazolam, on the methadone steady-state trough plasma concentrations in a group of 32 patients in methadone maintenance treatment. Patients were grouped as receiving ‘low’ (up to 99 mg/day, n=10), ‘high’ (100–199 mg/day, n=11) and ‘very high’ (>=200 mg/day, n=11) doses of methadone, and the CYP3A4 metabolic activity was compared between the three groups. (S)-methadone and (R,S)-methadone, but not (R)-methadone, concentrations to dose ratios significantly correlated with the midazolam ratios (r2=−0.17, P=0.018; r2=−0.14, P=0.032; r2=−0.10, P=0.083, respectively), with a 76% higher CYP3A4 activity in the very high-dose group as compared with the low-dose group. Significant differences in the CYP3A4 activity were calculated between the three groups (P=0.0036), and group-to-group comparisons, using the Bonferroni correction, showed a significant difference between the low-dose and the very high-dose group (P=0.0039), between the high-dose and the very high-dose group (P=0.0064), but not between the low-dose and the high-dose group (P=0.070). The higher CYP3A4 activity measured in patients receiving very high methadone doses could contribute to the need for higher doses in some patients, due to an increased metabolic clearance. This, however, must be confirmed by a prospective study.

Some methadone maintenance treatment (MMT) programs prescribe inadequate daily methadone doses. Patients complain of withdrawal symptoms and continue illicit opioid use, yet practitioners are reluctant to increase doses above certain arbitrary thresholds. Serum methadone levels (SMLs) may guide practitioners dosing decisions, especially for those patients who have low SMLs despite higher methadone doses. Such variation is due in part to the complexities of methadone metabolism. The medication itself is a racemic (50:50) mixture of 2 enantiomers: an active "R" form and an essentially inactive "S" form. Methadone is metabolized primarily in the liver, by up to five cytochrome P450 isoforms, and individual differences in enzyme activity help explain wide ranges of active R-enantiomer concentrations in patients given identical doses of racemic methadone. Most clinical research studies have used methadone doses of less than 100 mg/day [d] and have not reported corresponding SMLs. New research suggests that doses ranging from 120 mg/d to more than 700 mg/d, with correspondingly higher SMLs, may be optimal for many patients. Each patient presents a unique clinical challenge, and there is no way of prescribing a single best methadone dose to achieve a specific blood level as a "gold standard" for all patients. Clinical signs and patient-reported symptoms of abstinence syndrome, and continuing illicit opioid use, are effective indicators of dose inadequacy. There does not appear to be a maximum daily dose limit when determining what is adequately "enough" methadone in MMT.

We studied 90 opioid-dependent subjects, 38 with one or more additional Axis I diagnosis and 52 with no psychiatric comorbidity. There were significant differences between these two groups regarding the methadone dose required for clinical stabilization, but not in the rate of retention in treatment. Dual Diagnosis patients, those with psychiatric comorbidity, required an average stabilization dose of 154 +/- 84 of methadone compared to 99 +/- 49 mg/day for patients whose only Axis I diagnosis was Opioid Dependence. In the 990-day period considered there were no differences between the two groups of patients in terms of retention in treatment.

Using signs, symptoms and serum methadone levels to guide evaluation, the authors treated 164 patients in a methadone maintenance program with doses of methadone exceeding 100 mg/d. The mean dose of these higher dose (HD) patients was 211 mg/d (range 110-780 mg/d). A comparison group (C) of 101 patients was randomly selected from the general clinic population (mean dose 65 mg/d). At intake the HD group reported $153/day of heroin use versus $87/day in the C group. The HD group had more patients whose opiate of choice was an oral pharmaceutical (30% versus 2% of the C group). Sixty-three percent of the HD group had comorbid Axis I psychiatric diagnoses compared to 32% of the C group. Response to psychopharmacologic treatment was enhanced by increased methadone dose in HD patients with "refractory" psychiatric disorders. Urine toxicologies described as "before" were collected prior to increase over 100 mg/d in the HD group or at the first routine urine toxicology collection of the calendar year for the C group. These results were compared to the most recent urine toxicologies for both groups ("after"). The percentage of toxicologies positive for illicit drugs in the HD group dropped from 87% "before" to 3% "after". The C group were 54% positive "before" and 37% positive "after". We conclude that doses of methadone in excess of 100 mg/d (range 110-780 mg/d in our sample of 164 patients) are not only safe but necessary to prevent illicit opiate use, stabilize psychiatric symptoms, and diminish abuse of alcohol and benzodiazepines in many patients.

The authors, on the basis of their clinical experience, suggest that polydrug abuse in heroin addicts could be correlated with condition of opiate dependence improperly compensated by street heroin or by substitutive treatment dosages. Thus the search for an appropriate methadone dosage is crucial not only because it enhances patients' retention rate within the treatment group, so allowing an improvement in social rehabilitation, but also because it reduces the risk of polydrug abuse. Summary