Influence of Cytochrome P450, Family 2, Subfamily D, Polypeptide 6 (CYP2D6) Polymorphisms on Pain Sensitivity and Clinical Response to Weak Opioid Analgesics

Zahari, Zalina; Ismail, Rusli

doi:10.2133/dmpk.dmpk-13-rv-032

Cited by 36 publications

(27 citation statements)

References 101 publications

(226 reference statements)

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“…In addition, it is possible that CBD affects the metabolism of opioid analgesics by inhibiting CYP2D6, because polymorphism of CYP2D6 has been linked to distinct pain sensitivity and difference of response to opioid analgesics [268].…”

Section: Cbd Enzyme Targets In Painmentioning

confidence: 99%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

462

323

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Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD's beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD's relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent withmodulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug's action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excludin...

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Section: Cbd Enzyme Targets In Painmentioning

confidence: 99%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

462

323

View full text Add to dashboard Cite

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“…These patients may, however, be at a greater risk of respiratory depression at standard doses compared to normal metabolizers 12,18. However, data demonstrating associations between CYP2D6 phenotype and poor pain control have been mixed 13,16. Several studies have indicated that persons with a poor metabolizer phenotype experience less pain relief from codeine and tramadol,19–25 but the effect of a poor metabolizer phenotype on pain relief from oxycodone and hydrocodone is less clear 26–30.…”

Section: Introductionmentioning

confidence: 99%

“…Several studies have indicated that persons with a poor metabolizer phenotype experience less pain relief from codeine and tramadol,19–25 but the effect of a poor metabolizer phenotype on pain relief from oxycodone and hydrocodone is less clear 26–30. In addition, the impact of CYP2D6 variants on mild, nonlife threatening, adverse reactions associated with opioids (e.g., nausea), and subsequent effects on pain control due to intolerance, has not been routinely studied 16. A larger study of cancer patients found no differences in pain control, nausea, or tiredness among poor, normal, and ultrarapid metabolizers taking oxycodone 30.…”

Section: Introductionmentioning

confidence: 99%

<em>CYP2D6</em> phenotypes are associated with adverse outcomes related to opioid medications

Sauver¹,

Olson²,

Roger³

et al. 2017

PGPM

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BackgroundVariation in the CYP2D6 gene may affect response to opioids in both poor and ultrarapid metabolizers, but data demonstrating such associations have been mixed, and the impact of variants on toxicity-related symptoms (e.g., nausea) is unclear. Therefore, we examined the association between CYP2D6 phenotype and poor pain control or other adverse symptoms related to the use of opioids in a sample of primary care patients.Materials and methodsWe identified all patients in the Mayo Clinic RIGHT Protocol who were prescribed an opioid medication between July 01, 2013 and June 30, 2015, and categorized patients into three phenotypes: poor, intermediate to extensive, or ultrarapid CYP2D6 metabolizers. We reviewed the electronic health record of these patients for indications of poor pain control or adverse symptoms related to medication use. Associations between phenotype and outcomes were assessed using Chi-square tests and logistic regression.ResultsOverall, 257 (25% of RIGHT Protocol participants) patients received at least one opioid prescription; of these, 40 (15%) were poor metabolizers, 146 (57%) were intermediate to extensive metabolizers, and 71 (28%) were ultrarapid metabolizers. We removed patients that were prescribed a CYP2D6 inhibitor medication (n=38). After adjusting for age and sex, patients with a poor or ultrarapid phenotype were 2.7 times more likely to experience either poor pain control or an adverse symptom related to the prescription compared to patients with an intermediate to extensive phenotype (odds ratio: 2.68; 95% CI: 1.39, 5.17; p=0.003).ConclusionOur results suggest that >30% of patients with a poor or ultrarapid CYP2D6 phenotype may experience an adverse outcome after being prescribed codeine, tramadol, oxycodone, or hydrocodone. These medications are frequently prescribed for pain relief, and ~39% of the US population is expected to carry one of these phenotypes, suggesting that the population-level impact of these gene–drug interactions could be substantial.

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“…4, 5 M1 has a higher affinity (Ki=3.4 nM) for the mu-opioid receptor compared to the parent compound (Ki=2.4 µM) 6 , highlighting the importance of M conversion by CYP2D6. The relevance of CYP2D6 genetics for M has been established in the adult population 4,7,8 and in neonates 9 , implicating decreased concentrations of the active metabolite and an absence of analgesia. However, the variation in disposition of M extends beyond this conversion in M1.…”

Section: Introductionmentioning

confidence: 99%