Sex and opioid maintenance dose influence response to naloxone in opioid-dependent humans: a retrospective analysis

Abstract

Pooled self-report and physiological data from 32 male and 15 female methadone or levo-alpha-acetyl methadol (LAAM) maintained volunteers were retrospectively analyzed for individual differences in response to naloxone (0.15 mg/70 kg, IM) and placebo at 20 and 40 min post-injection. Males and females were each divided by the median splitmethadone maintenance dose (MMD, in mg/kg body weight) into high and low MMD groups and MMD was used as a factor in the analyses, along with sex, drug, and time post-drug. Females in the low but not high, MMD group showed naloxone-induced increases in ratings on the Antagonist and Mixed-Action sub-scales of the Adjective Rating Scale, and the Lysergic acid diethyl amine (LSD) sub-scale of the Addiction Research Center Inventory at 20 min post-injection. Males in the high MMD group showed significant naloxone-induced increases in scores of these measures at both post-injection time-points. In addition, low MMD subjects showed more short-lived naloxone-induced increases on Visual Analogue Scale (VAS) Bad and Any drug effects ratings than high MMD subjects. These results suggest that those on a lower MMD, especially women, experience a more intense, but short-lived, response to naloxone, whereas those on a higher MMD experience a more modest, but longer-lasting effect.

Figure 1

A, B, C, D: Effects of 0.15 mg/70 kg of naloxone (filled bars) and placebo (open bars) on self-reported ratings on the opioid Antagonist (first graph), opioid Agonist (second graph), Mixed action opioid (third graph) subscales of the Adjective Ratings Scale and the LSD subscale (fourth graph) of the Addiction Research Center Inventory in females (left half of each graph) and males (right half) maintained on high- or low-dose methadone. Ordinate: mean change from pre-drug score. Abscissa: 20 min and 40 min post-drug time points for the low- and high-dose methadone groups. Each bar represents the mean and standard error, + significant difference at p ≤ 0.05, and .* significant difference at p ≤ 0.005.

Figure 2

A, B: Effects of 0.15 mg/70 kg of naloxone (filled bars) and placebo (open bars) on self-reported ratings on the Any Drug Effects (first graph) and the Bad Drug Effects (second graph) subscales of the Visual Analogue Scales on subjects maintained on high- or low-dose methadone. Ordinate: mean log-transformed change from pre-drug score. Abscissa: 20 min and 40 min post-drug time points for the low- and high-dose methadone groups. Each bar represents the mean and standard error, + significant difference at p ≤ 0.05, and .* significant difference at p ≤ 0.005.