Genetically deficient CYP2D6 metabolism provides protection against oral opiate dependence

Tyndale, Rachel F.; Droll, Kurt P.; Sellers, Edward M.

doi:10.1097/00008571-199710000-00006

Cited by 114 publications

(57 citation statements)

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“…The analgesic potency and abuse liability of opioid medications may, therefore, be influenced by variants in this gene (Sindrup et al, 1991(Sindrup et al, , 1993Kathiramalainathan et al, 2000). Tyndale et al (1997) reported that no subjects meeting DSM-IV criteria for oral opioid dependence had either of the defective mutant alleles CYP2D6*3 or CYP2D6*4 which reduce metabolism compared with control and multidrug-dependent individuals whose frequency for these alleles did not differ from that of previously reported Caucasian control populations. Pharmacological inhibition of CYP2D6 with fluoxetine or quinidine, which significantly reduces the formation OPIATE AND COCAINE ADDICTION: GENETICS AND PHARMACOGENOMICS of morphine following codeine administration (Kathiramalainathan et al, 2000;Romach et al, 2000), however, failed to reduce daily codeine intake in a small cohort of codeine addicts (Fernandes et al, 2002).…”

Section: A Metabolism/biotransformation Of Opiates and Other Opioidsmentioning

confidence: 99%

Pharmacogenetics and Human Molecular Genetics of Opiate and Cocaine Addictions and Their Treatments

et al. 2005

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Section: A Metabolism/biotransformation Of Opiates and Other Opioidsmentioning

confidence: 99%

Pharmacogenetics and Human Molecular Genetics of Opiate and Cocaine Addictions and Their Treatments

et al. 2005

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“…However, we have only begun to understand some of the patient factors that might predispose one individual to have a greater likelihood of experiencing an adverse effect from one opioid than from another. 33 Finally, as discussed previously (Methadone), cross-tolerance is not complete among the opioids so that the calculation of an equianalgesic dose is much more complicated in patients who have received increasing doses of an opioid.…”

Section: Opioid Rotationmentioning

confidence: 99%

Clinical Pharmacology of Opioids for Pain

Inturrisi¹

2002

The Clinical Journal of Pain

499

340

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Abstract:The pharmacological effects of the opioid analgesics are derived from their complex interactions with three opioid receptor types (, ␦, and ; morphine is an agonist at the opioid receptor). These receptors are found in the periphery, at presynaptic and postsynaptic sites in the spinal cord dorsal horn, and in the brain stem, thalamus, and cortex, in what constitutes the ascending pain transmission system, as well as structures that comprise a descending inhibitory system that modulates pain at the level of the spinal cord. The cellular effects of opioids include a decrease in presynaptic transmitter release, hyperpolarization of postsynaptic elements, and disinhibition. The endogenous opioid peptides are part of an endogenous pain modulatory system. A number of opioids are available for clinical use, including morphine, hydromorphone, levorphanol, oxymorphone, methadone, meperidine, oxycodone, and fentanyl, and their advantages and disadvantages for the management of pain are discussed. An understanding of the pharmacokinetic properties, as well as issues related to opioid rotation, tolerance, dependence, and addiction are essential aspects of the clinical pharmacology of opioids for pain.

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“…A reduced activity of CYP2D6 has been associated with protection against addictive behavior caused by oral opiate [288]. Interestingly, CYP2D6 is highly expressed in the brain of alcoholics [289].…”

Section: Cbd Enzyme Targets In Addictionmentioning

confidence: 99%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

449

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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Genetically deficient CYP2D6 metabolism provides protection against oral opiate dependence

Cited by 114 publications

References 0 publications

Pharmacogenetics and Human Molecular Genetics of Opiate and Cocaine Addictions and Their Treatments

Pharmacogenetics and Human Molecular Genetics of Opiate and Cocaine Addictions and Their Treatments

Clinical Pharmacology of Opioids for Pain

Molecular Targets of Cannabidiol in Neurological Disorders

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