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The Partial 5‐Hydroxytryptamine 1A Receptor Agonist Buspirone does not Antagonize Morphine‐induced Respiratory Depression in Humans
Author(s) -
Oertel BG,
Schneider A,
Rohrbacher M,
Schmidt H,
Tegeder I,
Geisslinger G,
Lötsch J
Publication year - 2007
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/sj.clpt.6100018
Subject(s) - morphine , buspirone , (+) naloxone , anesthesia , opioid , medicine , placebo , agonist , pharmacology , respiratory system , crossover study , receptor , alternative medicine , pathology
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 CO 2 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 CO 2 concentration in the inspired air of 1.07±0.27 l/mm Hg CO 2 at baseline conditions became shallower (0.45±0.23 l/mm Hg CO 2 ) after morphine administration ( P <0.001), indicating respiratory depression, which was significantly reversed by naloxone (0.95±0.43 l/mm Hg CO 2 ; P =0.001). Co‐administration of buspirone had no effect on morphine‐induced respiratory depression (slope 0.45±0.23 l/mm Hg CO 2 under morphine plus placebo versus 0.38±0.25 l/mm Hg CO 2 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‐HT 1A 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. Clinical Pharmacology & Therapeutics (2007) 81 , 59–68. doi: 10.1038/sj.clpt.6100018