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.

Keywords: Calcium channel blocker; Drug discrimination; Humans; Naloxone; Opioid dependence; Opioid withdrawal.

Fig. 1

The effects of diltiazem alone (top left panel) or verapamil alone (top right panel) and diltiazem (bottom left panel) or verapamil (bottom right panel) in combination with the naloxone training dose on discrimination performance under the point distribution task. Abscissa: dose of drug in mg. Ordinate: Percentage naloxone- (filled circles) or ‘novel’-(open circles) appropriate responding. Each point in the diltiazem alone dose effect curve represents the mean across three participants. Each point in the diltiazem-naloxone dose effect curve represents the mean across four participants. Each point in the verapamil dose effect curves represents the mean across five participants. Each bar represents standard error of the mean. Points above “P” and “Nx” represent means of participants across placebo and naloxone training days, respectively, during the test phase.

Fig. 2

The effects of diltiazem alone (left panels) or verapamil alone (right panels) on selected self-report measures. Abscissa: dose of drug in mg. Ordinate: Mean change from predrug. Each point in the diltiazem dose effect curve represents the mean across three participants. Each point in the verapamil dose effect curve represents the mean across five participants. Each bar represents standard error of the mean. Points above “P” represent means of participants across placebo training days during the test phase. Data points significantly different from placebo are indicated by an asterisk (*).

Fig. 3

The effects of diltiazem alone (left panels) or verapamil alone (right panels) on selected self-report measures. Abscissa: dose of drug in mg. Ordinate: Mean score (top panels) or Mean change from predrug (middle and bottom panels). Each point in the diltiazem dose effect curve represents the mean across three participants. Each point in the verapamil dose effect curve represents the mean across five participants. Each bar represents standard error of the mean. Points above “P” represent means of participants across placebo training days during the test phase. Data points significantly different from placebo are indicated by an asterisk (*).

Fig. 4

The effects of naloxone alone and in combination with increasing doses of diltiazem (left panels) or verapamil (right panels) on selected self-report and physiological measures. Abscissa: dose of drug in mg. Ordinate: Change from predrug. Each point represents the mean across four participants for diltiazem and five participants for verapamil. Each bar represents standard error of the mean. Points above “Nx” represent means of participants across naloxone training days during the test phase.