Lack of effect of ondansetron on the pharmacokinetics and analgesic effects of morphine and metabolites after single‐dose morphine administration in healthy volunteers

• Published in: British journal of clinical pharmacology Vol. 51; no. 4; pp. 309 - 316
• Main Authors: Crews, Kristine Radomski, Murthy, Bindu P., Hussey, Elizabeth K., Passannante, Anthony N., Palmer, Jonathan L., Maixner, William, Brouwer, Kim L. R.
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01-04-2001; Blackwell Science; Blackwell Science Inc
• Subjects: Adolescent; Adult; Analgesics, Opioid - administration & dosage; Analgesics, Opioid - pharmacokinetics; Analgesics, Opioid - pharmacology; Biological and medical sciences; Cross-Over Studies; Double-Blind Method; Drug Interactions; Female; Humans; Main Paper; Male; Medical sciences; Middle Aged; morphine; Morphine - administration & dosage; Morphine - pharmacokinetics; Morphine - pharmacology; Morphine Derivatives - pharmacokinetics; Morphine Derivatives - pharmacology; morphine‐3‐glucuronide; morphine‐6‐glucuronide; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; ondansetron; Ondansetron - adverse effects; Ondansetron - pharmacology; Pain Measurement; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; pharmacodynamics; pharmacokinetics; Pharmacology. Drug treatments; Placebos; Serotonin Antagonists - adverse effects; Serotonin Antagonists - pharmacology; Human; Drug combination; Intravenous administration; Bioequivalence; Serotonin antagonist; Single dose; Controlled therapeutic trial; Morphine; Opiates; Bioavailability; Narcotic analgesic; Metabolism; Normal; Randomization; Absorption; 5-HT3 Serotonine receptor; Distribution; Double blind study; Drug interaction; Pharmacokinetics; Antiemetic; Ondansetron
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1046/j.1365-2125.2001.01369.x

Aims  The purpose of this investigation was to study the influence of ondansetron on the single‐dose pharmacokinetics and the analgesic effects elicited by morphine and the 3‐ and 6‐glucuronide metabolites of morphine in healthy volunteers.
Methods
This was a randomized, double‐blind, placebo‐controlled, two‐way crossover study in which six male and six female subjects were administered a single 10 mg intravenous dose of morphine sulphate, followed 30 min later by a single 16 mg intravenous dose of ondansetron hydrochloride or placebo. Serum and urine concentrations of morphine, morphine‐3‐glucuronide (M3G) and morphine‐6‐glucuronide (M6G) samples were quantified over 48 h using high performance liquid chromatography with detection by mass spectrometry. Analgesia was assessed in the volunteers with a contact thermode device to provide a thermal pain stimulus. Four analgesic response variables were measured including thermal pain threshold, thermal pain tolerance, temporal summation of pain and mood state.
Results
The two treatments appeared to be equivalent based on the 90% confidence intervals (0.6, 1.67) of the least squares means ratio. All least squares means ratio confidence intervals for each parameter, for each analyte fell within the specified range, demonstrating a lack of an interaction.
Conclusions
The results of this study suggest that administration of ondansetron (16 mg i.v.) does not alter the pharmacokinetics of morphine and its 3‐ or 6‐glucuronide metabolites to a clinically significant extent, nor does it affect the overall analgesic response to morphine as measured by the contact thermode system.