Acúfenos, seción fármacos experimentales, Naltrexona

Naltrexone treatment for opioid dependence: Does its effectiveness depend on testing the blockade?

• Maria A. Sullivan^{a, ,} ,
• Adam Bisaga^a,
• John J. Mariani^a,
• Andrew Glass^a,
• Frances R. Levin^a,
• Sandra D. Comer^a,
• Edward V. Nunes^b

• ^a Columbia University and the New York State Psychiatric Institute, 1051 Riverside Drive, Unit 120, New York, NY 10032, USA
• ^b Columbia University and the New York State Psychiatric Institute, 1051 Riverside Drive, Unit 51, New York, NY 10032, USA

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Abstract

Background

FDA approval of long-acting injectable naltrexone (Vivitrol) for opioid dependence highlights the relevance of understanding mechanisms of antagonist treatment. Principles of learning suggest an antagonist works through extinguishing drug-seeking behavior, as episodes of drug use (“testing the blockade”) fail to produce reinforcement.

We hypothesized that opiate use would moderate the effect of naltrexone, specifically, that opiate-positive urines precede dropout in the placebo group, but not in the active-medication groups.

Methods

An 8-week, double-blind, placebo-controlled trial (N = 57), compared the efficacy of low (192 mg) and high (384 mg) doses of a long-acting injectable naltrexone (Depotrex) with placebo (Comer et al., 2006). A Cox proportional hazard model was fit, modeling time-to-dropout as a function of treatment assignment and urine toxicology during treatment.

Results

Interaction of opiate urines with treatment group was significant. Opiate-positive urines predicted dropout on placebo and low-dose, but less so on high-dose naltrexone, where positive urines were more likely followed by sustained abstinence. Among patients with no opiate-positive urines, retention was higher in both low- and high-dose naltrexone conditions, compared to placebo.

Conclusions

Findings confirm that injection naltrexone produces extinction of drug-seeking behavior after episodes of opiate use. Adequate dosage appears important, as low-dose naltrexone resembled the placebo group; opiate positive urines were likely to be followed by dropout from treatment. The observation of high treatment retention among naltrexone-treated patients who do not test the blockade, suggests naltrexone may also exert direct effects on opiate-taking behavior that do not depend on extinction, perhaps by attenuating craving or normalizing dysregulated hedonic or neuroendocrine systems.

Keywords

• Long-acting injectable naltrexone;
• Opiate dependence;
• Opioid antagonist;
• Treatment retention;
• Urine toxicology

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Figures and tables from this article:

Fig. 1. (A–C) Graphical display of the treatment course of opiate-dependent patients (N = 57) in an 8-week, double-blind, placebo-controlled trial of a long-acting injection of naltrexone, comparing placebo (Fig. 1A; N = 17), low dose-192 mg naltrexone injection (Fig. 1B; N = 19), and high dose-384 mg naltrexone injection (Fig. 1B; N = 21). Each row in the figures represents the data for a patient, and the columns represent each of the 16 twice-weekly clinic visits at which urine was collected across the 8-week trial, plus an initial visit at the time of hospital discharge post-injection (Visit 0) and an extra visit (“2nd^”) to receive the second depot naltrexone injection, for a total of 17 visits (Visits 1–8 and 9–16). Open circles represent visits where the patient was present and gave a urine sample negative for opiates. Filled (darkened) circles represent visits where the patient was present and gave an opiate-positive urine sample. Blanks (no circle) indicate that patient was not present at that visit or did not provide a urine sample.

Figure options

Fig. 2. (A–C) Treatment retention as a function of opiate status of urine toxicology throughout duration of trial: all opiate-negative (1) vs. any opiate-positive urine (0). Each figure represents the survival in twice weekly study visits over the 8-week trial for participants who tested the blockade (0) vs. those who did not test (1).

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Table 1. Cox proportional hazards regression model, modeling time to dropout from treatment, as a function of naltrexone treatment assignment.

Placebo (N = 17) is the reference group, against which the low dose-192 mg (N = 19), and high dose-384 mg (N = 21) conditions are contrasted. Urine toxicology, measured at twice-weekly clinic visits, was scored as a dichotomous covariate in this analysis as positive if one or more urines was positive for opioids during the trial, and negative otherwise (negative is the reference group). Values in the table are the regression coefficients for each term in the model, corresponding significance levels, and the point estimate of the hazard ration and its 95% confidence limits. The significant low-dose naltrexone-by-urine interaction term, indicates that the effect of low-dose naltrexone differs between patients with vs. without a positive urine; when urine is positive dropout is similar (and high) on low-dose naltrexone and placebo, while when urines are all negative, dropout rate is low on low-dose naltrexone (compared to high dropout on placebo) and approaches the low dropout rates for the high-dose naltrexone condition.

Corresponding author. Tel.: +1 212 543 6525; fax: +1 212 543 6018.

Fuente:  Drug and Alcohol Dependence