The partial 5-Hydroxytryptamine(1A) receptor agonist buspirone does not antagonize morphine-induced respiratory depression in humans

Based on experiments in rats, serotonin receptor 5-hydroxytryptamine (5-HT)(1A) agonists have been proposed as a potential therapeutic strategy for the selective treatment of opioid-induced respiratory depression. We investigated the clinical applicability of this principle in healthy volunteers. Twelve subjects received 0.43 mg/kg morphine (30 mg for 70 kg body weight) administered intravenously (i.v.) over approximately 2 h. At the start of the morphine infusion, they received in a randomized, double-blind cross-over design 60 mg p.o. buspirone or placebo. Respiratory depression (hypercapnic challenge) and pain (electrical stimuli: 5 Hz sinus 0-20 mA; chemical stimuli: 200 ms gaseous CO2 pulses applied to the nasal mucosa) were assessed at baseline, at the end of the morphine infusion, and a third time after antagonizing the opioid effects by i.v. administration of 2 mg naloxone. The linear relationship between the minute ventilation and the CO2 concentration in the inspired air of 1.07 +/- 0.27 l/mm Hg CO2 at baseline conditions became shallower (0.45 +/- 0.23 l/mm Hg CO2) after morphine administration (P < 0.001), indicating respiratory depression, which was significantly reversed by naloxone (0.95 +/- 0.43 l/mm Hg CO2; P = 0.001). Co-administration of buspirone had no effect on morphine-induced respiratory depression (slope 0.45 +/- 0.23 l/mm Hg CO2 under morphine plus placebo versus 0.38 +/- 0.25 l/mm Hg CO2 under morphine plus buspirone; P = 0.7). Significant morphine-induced analgesia was observed in both pain models and was reversed by naloxone but unaffected by buspirone. Buspirone significantly increased the nausea induced by morphine (P = 0.011). Oral co-administration of a high dose of the clinically available 5-HT1A agonist buspirone cannot be advised as a remedy for opioid-induced respiratory depression. This is indicated by its lack of anti-respiratory depressive effects and by the buspirone-associated increase of morphine-induced nausea.