The Partial 5-Hydroxytryptamine1A Receptor Agonist Buspirone does not Antagonize Morphine-induced Respiratory Depression in Humans

pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
Clinical Pharmacology &#38 Therapeutics (Impact Factor: 7.9). 01/2007; 81(1):59-68. DOI: 10.1038/sj.clpt.6100018
Source: PubMed


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.

Download full-text


Available from: Jörn Lötsch, Aug 18, 2015
  • [Show abstract] [Hide abstract]
    ABSTRACT: The most serious side effect of μ-opioid analgesics is the development of respiratory depression as this effect is potentially lethal. Recent genetic studies in mice revealed that opioid analgesia and respiratory depression are linked to one gene (Oprm) and consequently that the synthesis or discovery of a potent opioid analgesic without (respiratory) side effects is highly unlikely. Genetic studies in humans show that part of the variability in opioid analgesia and respiratory depression is related to one specific single nucleotide polymorphism (SNP): OPRM1:c.118A>G. However, the effect of this SNP is different for analgesia and respiration. Whereas homozygous carriers of the mutated allele (about 4% of the Caucasian population) display reduced analgesia and respiratory depression, heterozygous carriers (29%) display a reduction in analgesia only. Evidently, these latter individuals carry an increased risk for opioid respiratory depression. Due to the respiratory effects of opioids, some physicians underdose or abstain from using potent opioids in the treatment of pain. Currently, the best approach to reduce the chance of opioid-induced respiratory depression and reduce the fear of clinicians is education and applying the knowledge that we have on the pharmacokinetics and pharmacodynamics (and their link) of opioids and their antagonists (naloxone). The latter is important in case a patient needs to be treated for opioid overdose. Furthermore, application of data on the genetics of opioid effect and variability will allow individualization of opioid therapy, aimed at optimal analgesic efficacy and reduced toxicity. This will be possible in the near future.
    No preview · Article · Jun 2007 · Seminars in Anesthesia Perioperative Medicine and Pain
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Low doses of morphine, the most commonly used opioid analgesic, have been shown to significantly reduce the affective but not the sensory intensive dimension of pain. This suggests differential dose-response relationships of opioid analgesia on the sensory and affective components of pain. We investigated the effects of different alfentanil plasma concentration levels (0, 19.6+/-2.7, 47.2+/-7.6, and 76.6+/-11.3 ng/ml) on pain-related brain activation achieved by short pulses of gaseous CO(2) delivered to the nasal mucosa, using functional magnetic resonance imaging (fMRI) on a 3.0 T MRI scanner in 16 non-carriers and 9 homozygous carriers of the mu-opioid receptor gene variant OPRM1 118A>G. Increasing opioid concentrations had differential effects in brain regions processing the sensory and affective dimensions of pain. In brain regions associated with the processing of the sensory intensity of pain (primary and secondary somatosensory cortices, posterior insular cortex), activation decreased linearly in relation to alfentanil concentrations, which was significantly less pronounced in OPRM1 118G carriers. In contrast, in brain regions known to process the affective dimension of pain (parahippocampal gyrus, amygdala, anterior insula), pain-related activation disappeared at the lowest alfentanil dose, without genotype differences.
    Full-text · Article · Apr 2008 · Clinical Pharmacology &#38 Therapeutics
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: This paper is the thirtieth consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2007 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular–biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior, and the roles of these opioid peptides and receptors in pain and analgesia; stress and social status; tolerance and dependence; learning and memory; eating and drinking; alcohol and drugs of abuse; sexual activity and hormones, pregnancy, development and endocrinology; mental illness and mood; seizures and neurologic disorders; electrical-related activity and neurophysiology; general activity and locomotion; gastrointestinal, renal and hepatic functions; cardiovascular responses; respiration and thermoregulation; and immunological responses.
    Full-text · Article · Dec 2008 · Peptides
Show more