codeine-6-glucuronide and Pain

Acute and chronic pain often requires a multimodal approach. Combination therapy reduces the number of individual daily administrations and improves patient's compliance with the prescribed analgesic treatment. Despite the association codeine/paracetamol is one of the most widely used central analgesic, the exact mechanism of action, particularly of paracetamol, is still object of pharmacological research. Recent findings showed that paracetamol may act through cerebral cyclo-oxygenase, descending opioidergic inhibitory pathways, serotonin pathway, and the endocannabinoid system; while codeine activity seems to related not only to its conversion to morphine, as previously known, but also by itself and through its metabolites, such as norcodeine (NORC) and codeine-6-glucuronide (C-6-G). The addition of codeine to paracetamol significantly improves the analgesic action and reduces the number needed to treat (NNT) from 5 to 2.3-3.1. Recent warnings about the risk of its metabolism related to CYP450 and its genetic variability in general population should be mainly considered when the association is used in paediatric patients undergoing tonsillectomy and/or adenoidectomy procedures for obstructive sleep apnoea syndrome (OSAS). In adults, the association codeine/paracetamol has been shown to be effective and safe in different settings: acute pain, trauma patients, and chronic nociceptive pain.

Topics: Acetaminophen; Analgesics; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Codeine; Drug Combinations; Drug Therapy, Combination; Humans; Morphine; Pain; Treatment Outcome

The purpose of this study was to determine the pharmacokinetic and antinociceptive effects of an acetaminophen/codeine combination administered orally to six healthy greyhounds. Antinociception was assessed using an electronic von Frey (vF) device as a mechanical/pressure model. Acetaminophen was administered at a dose of 600 mg (14.4-23.1 mg/kg) and codeine phosphate at 90 mg (2.1-3.3 mg/kg) equivalent to 67.5 mg codeine base (1.6-2.5 mg/kg). The geometric mean maximum plasma concentrations of acetaminophen, codeine, and codeine-6-glucuronide were 7.95 μg/mL, 11.0 ng/mL, and 3819 ng/mL, respectively. Morphine concentrations were <1 ng/mL. The terminal half-lives of acetaminophen, codeine, and codeine-6-glucuronide were 0.94, 1.71, and 3.12 h. There were no significant changes in vF thresholds, except at 12 h which decreased on average by 17% compared to baseline. The decrease in vF thresholds at 12 h could be due to aversion, hyperalgesia, or random variability. The lack of antinociception in this study could be due to a true lack of antinociception, lack of model sensitivity, or specificity. Further studies using different models (including clinical trials), different dog breeds, multiple dose regimens, and a range of dosages are needed prior to recommended use or concluding lack of efficacy for oral acetaminophen/codeine in dogs.

Topics: Acetaminophen; Administration, Oral; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Codeine; Dogs; Drug Combinations; Pain