St John's wort greatly reduces the concentrations of oral oxycodone
Department of Anesthesiology, Intensive Care, Emergency Care and Pain Medicine, Turku University Hospital and University of Turku, Turku, Finland. European journal of pain (London, England)
(Impact Factor: 2.93).
09/2010; 14(8):854-9. DOI: 10.1016/j.ejpain.2009.12.007
Chronic pain is associated with depression. Self-treatment of depression with herbal over-the-counter medicine St John's wort makes pain patients prone to drug interactions.
The aim of this study was to assess the potential of St John's wort to alter the CYP3A-mediated metabolism of a mu-opioid receptor agonist, oxycodone.
The study design was placebo-controlled, randomized, cross-over with two phases at intervals of 4 weeks and was conducted with 12 healthy participants. St John's wort (Jarsin) or placebo was administered t.i.d. for 15 days and oral oxycodone hydrochloride 15 mg on day 14. Oxycodone pharmacokinetics and pharmacodynamics were compared after St John's wort or placebo. Behavioural and analgesic effects were assessed with subjective visual analogue scales and cold pressor test. Plasma drug concentrations were measured from 0 to 48 h, behavioural and analgesic effects from 0 to 12 h.
Following St John's wort administration the oxycodone AUC decreased 50% (p<0.001). Oxycodone elimination half-life shortened from a mean+/-SD 3.8+/-0.7 to 3.0+/-0.4h (p<0.001). The self-reported drug effect of oxycodone as measured by AUEC(0-12) decreased significantly (p=0.004). Differences between St John's wort and placebo phases in cold pain threshold and intensity AUEC(0-12) were not observed.
St John's wort greatly reduced the plasma concentrations of oral oxycodone. The self-reported drug effect of oxycodone decreased significantly. This interaction may potentially be of some clinical significance when treating patients with chronic pain.
Available from: Alan L Myers
- "The severity of oxycodone use/misuse was well documented by the Drug Abuse Warning Network, which reported a total of 1014 oxycodonerelated deaths in a 3-year period (Cone et al., 2003). Ninety percent of these oxycodone-related deaths were attributed to DDIs that can be transporters/DME mediated (Burrows et al., 2003; Cone et al., 2003, 2004; Lee et al., 2006; Nakazawa et al., 2010; Nieminen et al., 2010). We used microarrays to obtain a global profile of genes (including XRs, transporters, and DMEs) regulated in liver tissue of oxycodone treated rats. "
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ABSTRACT: Perturbations of the expression of transporters and drug-metabolizing enzymes (DMEs) by opioids can be the locus of deleterious drug-drug interactions (DDIs). Many transporters and DMEs are regulated by xenobiotic receptors (XRs) [e.g., Pregnane X receptor (PXR), Constitutive androstane receptor (CAR) and Aryl hydrocarbon receptor (AhR)]; however, there is a paucity of information regarding the influence of opioids on XRs. The objective of this study was to determine the influence of oxycodone administration (15 mg/kg i.p. b.i.d/8 days) on liver expression of XRs, transporters and DMEs in rats. Microarray, quantitative RT-PCR and immunoblotting analyses were used to identify significantly regulated genes. Three XRs (e.g. PXR, CAR and AhR), twenty-seven transporters (e.g., ABCB1, SLC22A8) and nineteen DMEs (e.g., CYP2B2, CYP3A1) were regulated (p<0.05) with fold changes ranging from -46.3 to 17.1. Using MetaCore(TM )(computational platform), we identified a unique gene-network of transporters and DMEs assembled around PXR, CAR, and AhR. Hence, a series of transactivation/translocation assays were conducted to determine if the observed changes of transporters/DMEs are mediated by direct activation of PXR, CAR or AhR by oxycodone or its major metabolites (noroxycodone and oxymorphone). Neither oxycodone nor its metabolites activated PXR, CAR or AhR. Taken together, these findings identify a signature hepatic gene-network associated with repeated oxycodone administration in rats. And demonstrate that oxycodone alters the expression of many transporters and DMEs (without direct activation of PXR, CAR and AhR) which could lead to undesirable DDIs upon co-administration of substrates of these transporters/DMEs with oxycodone.
Available from: Wojciech Leppert
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ABSTRACT: Oxycodone is a valued opioid analgesic, which may be administered either as the first strong opioid or when other strong opioids are ineffective. In case of insufficient analgesia and/or intense adverse effects such as sedation, hallucinations and nausea/vomiting a switch from another opioid to oxycodone might be beneficial. Oxycodone is administered to opioid-naive patients with severe pain and to patients who were unsuccessfully treated with weak opioids, namely tramadol, codeine and dihydrocodeine. Oxycodone effective analgesia may be attributed to its affinity to μ and possibly κ opioid receptors, rapid penetration through the blood-brain barrier and higher concentrations in brain than in plasma. Oxycodone displays high bioavailability after oral administration and may be better than morphine in patients with renal impairment due to the decreased production of active metabolites. Recently an oral controlled-release oxycodone formulation was introduced in Poland. Another new product that was launched recently is a combination of prolonged-release oxycodone with prolonged-release naloxone (oxycodone/naloxone tablets). The aim of this review is to outline the pharmacodynamic and pharmacokinetic properties, drug interactions, dosing rules, adverse effects, equianalgesic dose ratio with other opioids and clinical studies of oxycodone in patients with cancer pain. The potential role of oxycodone/naloxone in chronic pain management and its impact on the bowel function is also discussed.
Available from: Pius Fasinu
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