Effects of prototypic calcium channel blockers in methadone-maintained humans responding under a naloxone discrimination procedure

Abstract

Accumulating evidence suggests that L-type calcium channel blockers (CCBs) attenuate the expression of opioid withdrawal and the dihydropyridine L-type CCB isradipine has been shown to block the behavioral effects of naloxone in opioid-maintained humans. This study determined whether two prototypic L-type CCBs with differing chemical structures, the benzothiazepine diltiazem and the phenylalkamine verapamil, attenuate the behavioral effects of naloxone in methadone-maintained humans trained to distinguish between low-dose naloxone (0.15 mg/70 kg, i.m.) and placebo under an instructed novel-response drug discrimination procedure. Once discrimination was acquired, diltiazem (0, 30, 60, 120 mg) and verapamil (0, 30, 60, 120 mg), alone and combined with the training dose of naloxone, were tested. Diltiazem alone produced 33–50% naloxone- and novel-appropriate responding at 30 and 60 mg and essentially placebo-appropriate responding at 120 mg. Verapamil alone produced 20–40% naloxone- and 0% novel-appropriate responding. Diltiazem at 60 mg decreased several ratings associated with positive mood and increased VAS ratings of “Bad Drug Effects” relative to placebo, whereas verapamil increased ratings associated with euphoria. When administered with naloxone, diltiazem produced 94–100% naloxone-appropriate-responding with 6% novel-appropriate responding at 60 mg (n=3). When administered with naloxone, verapamil produced 60–80% naloxone- and 0% novel-appropriate responding (n=5). Diltiazem decreased diastolic blood pressure and heart rate whereas verapamil decreased ratings of arousal relative to placebo. These results suggest that CCBs with different chemical structures can be differentiated behaviorally, and that diltiazem and verapamil do not attenuate the discriminative stimulus effects of naloxone in humans at the doses tested.

Human drug discrimination: A primer and methodological review.

“…Most notably, the discriminative-stimulus effects of drugs may differ in participants that vary in their substance-use history and current abuse or dependence status. Although the discriminative-stimulus effects of various drugs have been assessed in normal healthy volunteers (e.g., Rush et al, 1995; Silverman & Griffiths, 1992), drug-dependent individuals (e.g., Lile et al, 2011; Oliveto et al, 2013), and individuals with a history of drug dependence who are currently abstinent/detoxified (e.g., Preston et al, 1989), there are no published studies in which the discriminative-stimulus effects of particular drugs have been prospectively compared between these populations. Several factors should be taken into consideration when selecting the most appropriate population of experimental participants given the specific research question(s) and the primary aim(s) of the study.…”

Randomized, placebo-controlled pilot trial of gabapentin during an outpatient, buprenorphine-assisted detoxification procedure.

“…Gabapentin at low doses (i.e., ≤400 mg) significantly attenuated naloxone-induced increases in ratings of “drug strength” in opioid-maintained humans responding under a naloxone discrimination procedure, although naloxone-induced discriminative stimulus effects were attenuated in a nonsignificant, dose-related manner (Oliveto et al, 2010). These findings suggest that higher doses of gabapentin may be necessary to attenuate naloxone-induced withdrawal in this population.…”

Human Drug Discrimination: Elucidating the Neuropharmacology of Commonly Abused Illicit Drugs

“…The discriminative-stimulus effects of various drugs have been assessed in normal healthy volunteers (e.g., Rush et al, 1995; Silverman & Griffiths, 1992), drug-dependent individuals (e.g., Lile et al, 2011a; Oliveto et al, 2013), and individuals with a history of drug dependence who are currently abstinent/detoxified (e.g., Preston et al, 1989). However, there are no published studies in which the discriminative-stimulus effects of particular drugs have been prospectively compared between these populations.…”