Codeine intoxication associated with ultrarapid CYP2D6 metabolism
ABSTRACT Life-threatening opioid intoxication developed in a patient after he was given small doses of codeine for the treatment of a cough associated with bilateral pneumonia. Codeine is bioactivated by CYP2D6 into morphine, which then undergoes further glucuronidation. CYP2D6 genotyping showed that the patient had three or more functional alleles, a finding consistent with ultrarapid metabolism of codeine. We attribute the toxicity to this genotype, in combination with inhibition of CYP3A4 activity by other medications and a transient reduction in renal function.
Full-textDOI: · Available from: Jules Desmeules, May 30, 2015
Scandinavian Journal of Pain 04/2015; 7:25-27. DOI:10.1016/j.sjpain.2015.01.007
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ABSTRACT: Currently, the majority of the surgical procedures performed in paediatric hospitals are done on a day care basis, with post-operative pain being managed by caregivers at home. Pain after discharge of these post-operative children has historically been managed with oral codeine in combination with paracetamol (acetaminophen). Codeine is an opioid, which elicits its analgesic effects via metabolism to morphine and codeine-6-glucuronide. Oral morphine is a feasible alternative for outpatient analgesia; however, the pharmacokinetics of morphine after oral administration have been previously described only sparsely, and there is little information in healthy children. The clinical trial included 40 children from 2 to 6 years of age, with an American Society of Anaesthesiologists physical status classification of 1 or 2, who were undergoing surgical procedures requiring opioid analgesia. Morphine was orally administered prior to surgery in one of three doses: 0.1 mg/kg, 0.2 mg/kg and 0.3 mg/kg. Blood samples were collected for plasma morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) concentrations at 30, 60, 90, 120, 180 and 240 min after administration. All analyses were performed with the non-linear mixed-effect modelling software NONMEM version 7.2, using the first-order conditional estimation (FOCE) method. A pharmacokinetic model was developed to simultaneously describe the plasma profiles of morphine and its metabolites M3G and M6G after a single dose of oral morphine in young children (2-6 years of age). The disposition of morphine, M3G and M6G in plasma was best described by a one-compartment model. M3G and M6G metabolite formation was best described by a delay transit compartment, indicating a delay in the appearance of these two major metabolites. This model provides a foundation on which to further evaluate the use of oral morphine and its safety in young children. Longer follow-up time for morphine oral doses and incorporation of other important covariates, such as phenotype, will add value and will help overcome the limitations of the presented population pharmacokinetic analysis.Clinical Pharmacokinetics 03/2015; DOI:10.1007/s40262-015-0256-4 · 5.49 Impact Factor
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ABSTRACT: Dextromethorphan (DXM), a nonprescription psychoactive drug that may lead to spiritual or transpersonal altered states of consciousness, has legitimate therapeutic applications that are being investigated by clinical researchers. It is easily available in over-the-counter cough medicines, and due to its psychoactive properties, DXM is an increasingly popular drug of abuse. Nonmedical use of DXM can lead to dependence and death. Clinical research related to nonmedical DXM use is limited, but many theories and experience reports have been published on the Internet. Nonmedical DXM users may consist of two types: those who seek recreation and those who want to explore their mind (psychonauts). Given the potential importance of DXM-facilitated transpersonal experiences, this article suggests research be conducted on the chemical. The experiences of others must be taken into account before any adequate theory of DXM can be formulated. Dextromethorphan (DXM) was introduced over-the-counter (OTC) in 1958 (American Medical Association, 1988) as a nonprescription antitussive (cough suppressant). DXM is an opioid, ''the D-isomer of levorphanol, a semisynthetic morphine derivative'' (McFee, Mofenson, & Caraccio, 2000, p. 123). Several fields of medicine have used DXM therapeutically, which is a relatively safe drug when used for medical purposes (Bem & Peck, 1992; Steinberg, Bell, & Yenari, 1996). DXM is primarily of clinical and research interest because of its neuropharmacological properties. DXM binds to four distinct neuron receptor sites; these are most likely the sigma1, PCP2, sigma2, and NMDA receptor sites (Zhou & Musacchio, 1991). DXM also indirectly inhibits the reuptake of serotonin (International Programme on Chemical Safety [IPCS], 1996). Although DXM was derived from the opiate levorphanol, it does not bind to any of the opiate receptors. When individuals ingest doses five or more times the recommended dose, DXM becomes psychoactive and has been classified as a dissociative drug (National Institute on Drug Abuse [NIDA], 2001) and a club drug (Parks & Kennedy, 2004). Occasional clinical case reports appear of individuals ending up in the hospital related to negative side effects of their substance use. DXM, however, does not produce withdrawal symptoms characteristic of physically addictive substances, although tolerance does occur (Wolfe & Caravati, 1995).