The influence of three L-type calcium channel blockers on morphine effects in healthy volunteers

Numerous animal studies and several clinical studies have shown that calcium channel-blockers (CCBs) augment opioid analgesia. We sought to determine whether three CCBs from three L-type subgroups (i.e., L-CCBs) enhanced morphine analgesic effects in healthy volunteers, and whether other effects of morphine (e.g., mood-altering effects) were altered by the CCB pretreatment. We examined the effects of three L-CCBs-diltiazem (30 mg, per os [PO]), nimodipine (60 mg, PO), and verapamil (80 mg, PO)-on morphine (10 mg/70 kg, intravenously) effects in nine healthy volunteers. Subjects first ingested the oral drug or placebo and 120 min later were injected with morphine or saline. Dependent measures included pain ratings measured during a cold-pressor test and subjective, psychomotor, and physiological effects. The L-CCBs alone had no effect on any of the dependent measures. Morphine alone and in combination with the L-CCBs reduced pain ratings, but there were no statistically significant differences in the pain measures between the morphine alone and the L-CCB/morphine conditions. Pretreatment with the L-CCBs in most cases neither potentiated nor attenuated the other effects of morphine. L-CCBs as well as the N-type CCBs currently under drug development should continue to be investigated to determine their potential as analgesic adjuvants. Implications: This study is important because the results are at odds with numerous animal studies and several clinical studies, which indicate that calcium channel blockers of the L-type increase the amount of analgesia produced by morphine. Using clinically relevant doses of L-type blockers, we could find no potentiation of morphine analgesia.