Nimodipine-enhanced opiate analgesia in cancer patients requiring morphine dose escalation: a double-blind, placebo-controlled study

Abstract

The ability of nimodipine, a dihydropyridine calcium antagonist, to reduce the daily dose of oral morphine in cancer patients who had developed dose escalation, was tested in 54 patients under randomized, double-blind, placebo-controlled conditions. We selected patients that required at least two successive increments of morphine to maintain pain relief. A possible pharmacokinetic interaction between nimodipine and morphine was also studied in 14 patients by assaying steady-state serum levels of morphine and its 3- and 6-glucuronides. A total of 30 patients completed the study, 14 and 16 in the nimodipine and placebo groups, respectively. Nimodipine controlled the escalation of the morphine dose in 9 patients (65%), and placebo in 4 (28%), the difference being statistically significant (P=0.03). The dose of morphine was reduced from 313+/-52 to 174+/-33 mg/day (P < 0.001) in the nimodipine group, and from 254+/-26 to 218+/-19 mg/day (not significant) in the placebo group. The percentages of reduction in the daily dose of morphine also showed significant differences between both groups (P=0.02). One week after introducing nimodipine or placebo, while the dose of morphine remained similar to that of the pre-test week, the serum levels of morphine and its glucuronides were not modified significantly. We conclude that the introduction of nimodipine in patients chronically treated with morphine may be a safe alternative to reduce the daily requirements of the opioid. It is suggested that interference with Ca2+-related events may attenuate the development and/or expression of tolerance to morphine in a clinically relevant way.

Autoradiographic mapping of µ-opioid receptors during opiate tolerance and supersensitivity in the rat central nervous system

“…It is interesting to note that the tractus solitarius nucleus is among the areas where µ-opioid receptor down-regulation was not prevented by the association of nimodipine to the chronic sufentanil treatment. In agreement with this finding, opioid-induced respiratory depression was not potentiated by simultaneous treatment with nimodipine in rats (Ruiz et al 1993) or in humans (Santillán et al 1998).…”

“…In clinical studies, we have previously demonstrated that the calcium channel blocker nimodipine reversed morphine dose escalation during chronic pain treatment in cancer patients (Santillán et al 1994(Santillán et al , 1998. In rats, chronic and simultaneous treatment with sufentanil and nimodipine not only prevented the development of tolerance, but induced supersensitivity to the analgesic effect of the opioid (Dierssen et al 1990;Díaz et al 1995a).…”

“…Ca 2+ antagonists increase the acute analgesic effects of opioids in humans (von Bormann et al 1985) and in rodents (Hoffmeister and Tettenborn 1986;Dierssen et al 1990;Díaz et al 1995a), whereas Ca 2+ channel activators, such as Bay K 8644, antagonised opioid antinociception (Dierssen et al 1990). Furthermore, Ca 2+ channel blockers have been shown to reduce the expression of opioid tolerance in humans (Santillán et al 1994(Santillán et al , 1998 and in rats (Dierssen et al 1990;Díaz et al 1995a;Michaluk et al 1998), and attenuate the withdrawal syndrome that is seen after chronic opioid administration (Bongianni et al 1986;Baeyens et al 1987; Barrios and Baeyens 1988;Pellegrini-Giampietro et al 1988;Alfaro et al 1990;Antkiewicz-Michaluk et al 1990, 1993Colado et al 1993;Zharkovsky et al 1993Zharkovsky et al , 1999Michaluk et al 1998).…”

Voltage‐Gated Ion Channels: 6.3 Calcium Channels

“…Total oral daily dose of morphine was significantly reduced by nimodipine (120 mg/day) from 283 to 159 mg. Intrathecal morphine was also reduced. This data was confirmed by a randomized, double-blind, placebo-controlled study which was published 4 years later (Santillan et al, 1998). The study started with 54 cancer patients.…”

Morphine in cancer pain management: a practical guide

“…The dose of morphine may be reduced with co-administration of dexamethasone or ketorolac or when it is combined intrathecally with bupivacaine or clonidine [9,14,134,195]. Nimodipine, a calcium channel blocker, enhances analgesia in cancer patients requiring regular dose increments of morphine to control pain [241]. These interactions are not pharmacokinetic but pharmacodynamic in nature [134,195].…”