Miscellaneous

MAOIs can underlie the most serious and potentially fatal interaction of opioids with other drugs. Only meperidine is consistently implicated as capable of this severe interaction.^{[561] [562]} Opioid-MAOI interactions are either excitatory or depressive.^[562] The excitatory interaction results in agitation, headache, hemodynamic instability, fever, rigidity, convulsions, and coma. This interaction is thought to be due to excessive central serotoninergic activity. Meperidine, but not morphine, blocks neuronal uptake of serotonin. The depressive interaction consists of respiratory depression, hypotension, and coma as a result of MAOI inhibition of hepatic microsomal enzymes and meperidine accumulation.

Because opioids can inhibit voltage-dependent Ca²⁺ channel activity through the activation of G-proteins, it is possible that opioid action is potentiated by Ca²⁺ channel blockers. Numerous animal studies and a few clinical studies have documented that opioid-induced analgesia is potentiated by L-type Ca²⁺ channel blockers. Systemically administered nifedipine was shown to potentiate morphine analgesia in both rats and humans.^[563] Furthermore, intrathecal administration of verapamil, diltiazem, and nicardipine enhanced the antinociceptive effect of small doses of morphine in rats.^[564] However, there is also a report that L-type Ca²⁺ channel blockers do not potentiate morphine analgesia at clinically relevant doses.^[565] N-type Ca²⁺ channels are involved in the release

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Erythromycin can inhibit the metabolism of several compounds. It supposedly reduces the oxidizing activity of cytochrome P-450. Alfentanil, but not sufentanil, may have its action prolonged as a result of impaired metabolism in patients receiving erythromycin.^{[567] [568]} Cimetidine can prolong opioid effects by decreasing hepatic blood flow and/or diminishing hepatic metabolism. Other drugs that inhibit certain cytochrome systems can decrease endogenous morphine production from codeine.^[452]

Magnesium has been shown to have antinociceptive effects probably due to its antagonistic action on the NMDA receptor. Intravenous administration of magnesium sulfate preoperatively (50 mg/kg) and intraoperatively (8 mg/kg/hour) significantly reduced intra- and postoperative fentanyl requirements.^[569] However, passage of magnesium across the blood-brain barrier is limited. In patients requesting analgesia for labor, intrathecal administration of fentanyl (25 µg) plus magnesium sulfate (50 mg) provided significantly prolonged analgesia compared with fentanyl alone.^[570] It is likely that magnesium can potentiate opioid analgesia by both central and peripheral mechanisms.^[571]

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, diclofenac, and ketorolac, have been perioperatively administered to reduce opioid requirement. The preoperative administration of ibuprofen (2 × 800 mg) to patients scheduled for lower abdominal gynecologic surgery was shown to reduce postoperative morphine consumption without an increase in side effects. ^[572] It was also reported that the perioperative administration of diclofenac (75 mg twice daily) reduced morphine consumption and the incidence of adverse side effects such as sedation and nausea after total abdominal hysterectomy.^[573] In healthy volunteers, ketoprofen (1.5 mg/kg IV) reduced respiratory depression induced by morphine (0.1 mg/kg).^[574]

Diphenhydramine, a histamine H₁ receptor antagonist, is used as a sedative, antipruritic, and antiemetic agent. When administered alone, it modestly stimulates ventilation by augmenting the interaction of hypoxic and hypercarbic ventilatory drives. It was shown that diphenhydramine counteracts the alfentanil-induced decrease in the slope of the ventilatory response to carbon dioxide.^[575]