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Molecular mechanisms underlying the enhanced analgesic effect of oxycodone compared to morphine in chemotherapy-induced neuropathic pain.

ABSTRACT: Oxycodone is a ?-opioid receptor agonist, used for the treatment of a large variety of painful disorders. Several studies have reported that oxycodone is a more potent pain reliever than morphine, and that it improves the quality of life of patients. However, the neurobiological mechanisms underlying the therapeutic action of these two opioids are only partially understood. The aim of this study was to define the molecular changes underlying the long-lasting analgesic effects of oxycodone and morphine in an animal model of peripheral neuropathy induced by a chemotherapic agent, vincristine. Using a behavioural approach, we show that oxycodone maintains an optimal analgesic effect after chronic treatment, whereas the effect of morphine dies down. In addition, using DNA microarray technology on dorsal root ganglia, we provide evidence that the long-term analgesic effect of oxycodone is due to an up-regulation in GABAB receptor expression in sensory neurons. These receptors are transported to their central terminals within the dorsal horn, and subsequently reinforce a presynaptic inhibition, since only the long-lasting (and not acute) anti-hyperalgesic effect of oxycodone was abolished by intrathecal administration of a GABAB receptor antagonist; in contrast, the morphine effect was unaffected. Our study demonstrates that the GABAB receptor is functionally required for the alleviating effect of oxycodone in neuropathic pain condition, thus providing new insight into the molecular mechanisms underlying the sustained analgesic action of oxycodone.

SUBMITTER: Thibault K

PROVIDER: S-EPMC3949760 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Molecular mechanisms underlying the enhanced analgesic effect of oxycodone compared to morphine in chemotherapy-induced neuropathic pain.

Thibault Karine K Calvino Bernard B Rivals Isabelle I Marchand Fabien F Dubacq Sophie S McMahon Stephen B SB Pezet Sophie S

PloS one 20140311 3

Oxycodone is a μ-opioid receptor agonist, used for the treatment of a large variety of painful disorders. Several studies have reported that oxycodone is a more potent pain reliever than morphine, and that it improves the quality of life of patients. However, the neurobiological mechanisms underlying the therapeutic action of these two opioids are only partially understood. The aim of this study was to define the molecular changes underlying the long-lasting analgesic effects of oxycodone and mo ...[more]

PMID: 24618941

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Project description:IntroductionThis study compared adverse outcomes and resource use for patients with a diagnosis of pain treated with tapentadol prolonged-release (PR) versus those treated with morphine controlled-release (CR) and oxycodone CR.MethodsData were sourced from the Clinical Practice Research Datalink (CPRD), a database derived from UK primary care. Patients prescribed tapentadol PR between May 2011 and December 2016 were selected and matched to two groups of controls treated with either morphine CR or oxycodone CR on gender, age, pain duration, pain site, pain aetiology, Charlson index and prior analgesia. Times to first adverse event (constipation or nausea/vomiting) were compared within a Cox proportional hazards model. Rates of primary care contacts, accident and emergency contacts and, for a subset of patients linked to Hospital Episode Statistics (HES), inpatient admissions and outpatient contacts were compared using incidence rate ratios (IRRs) derived from Poisson regression.ResultsA total of 1907 patients prescribed tapentadol PR were identified and 1791 (93.9%) had a pain diagnosis. Of these 1246 (65.3%) were matched to morphine controls and 829 (43.4%) to oxycodone controls. Compared to controls, gastrointestinal adverse events with tapentadol PR treatment were reduced; aHR?=?0.532 (0.402-0.703; p?<?0.001) versus morphine CR and 0.517 (0.363-0.735; p?<?0.001) versus oxycodone CR. Compared with morphine CR, primary care contacts [IRR?=?0.831 (0.802-0.861)], accident and emergency attendance [0.739 (0.572-0.951)], outpatient contacts [0.917 (0.851-0.989)] and inpatients contacts [0.789 (0.664-0.938)] were reduced. For oxycodone, the respective figures were 0.735 (0.703-0.768), 0.971 (0.699-1.352), 0.877 (0.799-0.962) and 0.748 (0.601-0.932).ConclusionTapentadol PR was associated with significantly fewer adverse gastrointestinal events than morphine CR and oxycodone CR in patients with a diagnosis of pain. There was also significantly reduced primary and secondary care resource use. As with all observational studies, potential bias due to residual confounding and confounding by indication should be considered.FundingGrünenthal Ltd.

Dataset Information

Molecular mechanisms underlying the enhanced analgesic effect of oxycodone compared to morphine in chemotherapy-induced neuropathic pain.

Publications

Molecular mechanisms underlying the enhanced analgesic effect of oxycodone compared to morphine in chemotherapy-induced neuropathic pain.

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