Codeine Administration Research Articles

Detection of codeine, morphine, 6-monoacetylmorphine, and meconin in human umbilical cord tissue: method validation and evidence of in utero heroin exposure.

Background:Heroin abuse is a significant public health issue and is on the rise because of the unintended consequences of strengthening controls for nonmedical use of prescription pain killers. Included in this trend is an increase in opiate exposed newborns that are particularly vulnerable to a number of negative health outcomes.Methods:After presenting a fully validated liquid chromatography–tandem mass spectrometric method for codeine, morphine, 6-monoacetylmorphine, and meconin, a metabolite of the heroin contaminant noscapine, we compared the outcome of 46 authentic umbilical specimens with the results generated using a previous less sensitive method that did not include meconin. Additionally, we provided a summary of opiate finding from a year-long survey of specimens received into a commercial reference laboratory.Results:The limits of detection for all 4 compounds were 0.1 ng/g, the limit of quantitation was 0.2 ng/g, and the assay was linear from 0.2 to 10.0 ng/g. Of the 46 comparative specimens, this method improved the identification of heroin exposure from 2 to 5, and the year-long survey identified 86 heroin-exposed newborns with 11 of them identified by the sole identification of meconin.Conclusions:This study demonstrated that a more sensitive analytical platform and the inclusion of meconin in the opiates assay improved the ability to distinguish between in utero heroin exposure and maternal administration of codeine or morphine.

Codeine, alone and with paracetamol (acetaminophen), for cancer pain.

Pain is very common in patients with cancer. Opioid analgesics, including codeine, play a significant role in major guidelines on the management of cancer pain, particularly for mild to moderate pain. Codeine is widely available and inexpensive, which may make it a good choice, especially in low-resource settings. Its use is controversial, in part because codeine is not effective in a minority of patients who cannot convert it to its active metabolite (morphine), and also because of concerns about potential abuse, and safety in children. To determine the efficacy and safety of codeine used alone or in combination with paracetamol for relieving cancer pain. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2014, Issue 2), MEDLINE and EMBASE from inception to 5 March 2014, supplemented by searches of clinical trial registries and screening of the reference lists of the identified studies and reviews in the field. We sought randomised, double-blind, controlled trials using single or multiple doses of codeine, with or without paracetamol, for the treatment of cancer pain. Trials could have either parallel or cross-over design, with at least 10 participants per treatment group. Studies in children or adults reporting on any type, grade, and stage of cancer were eligible. We accepted any formulation, dosage regimen, and route of administration of codeine, and both placebo and active controls. Two review authors independently read the titles and abstracts of all studies identified by the searches and excluded those that clearly did not meet the inclusion criteria. For the remaining studies, two authors read the full manuscripts and assessed them for inclusion. We resolved discrepancies between review authors by discussion. Included studies were described qualitatively, since no meta-analysis was possible because of the small amount of data identified, and clinical and methodological between-study heterogeneity. We included 15 studies including 721 participants with cancer pain due to diverse types of malignancy. All studies were performed on adults; there were no studies on children. The included studies were of adequate methodological quality, but all except for one were judged to be at a high risk of bias because of small study size, and six because of methods used to deal with missing data or high withdrawal rates. Three studies used a parallel group design; the remainder were cross-over trials in which there was an adequate washout period, but only one reported results for treatment periods separately.Twelve studies used codeine as a single agent and three combined it with paracetamol. Ten studies included a placebo arm, and 14 included one or more of 16 different active drug comparators or compared different routes of administration. Most studies investigated the effect of a single dose of medication, while five used treatment periods of one, seven or 21 days. Most studies used codeine at doses of 30 mg to 120 mg.There were insufficient data for any pooled analysis. Only two studies reported our preferred responder outcome of 'participants with at least 50% reduction in pain' and two reported 'participants with no worse than mild pain'. Eleven studies reported treatment group mean measures of pain intensity or pain relief; overall for these outcome measures, codeine or codeine plus paracetamol was numerically superior to placebo and equivalent to the active comparators.Adverse event reporting was poor: only two studies reported the number of participants with any adverse event specified by treatment group and only one reported the number of participants with any serious adverse event. In multiple-dose studies nausea, vomiting and constipation were common, with somnolence and dizziness frequent in the 21-day study. Withdrawal from the studies, where reported, was less than 10% except in two studies. There were three deaths, in all cases due to the underlying cancer. We identified only a small amount of data in studies that were both randomised and double-blind. Studies were small, of short duration, and most had significant shortcomings in reporting. The available evidence indicates that codeine is more effective against cancer pain than placebo, but with increased risk of nausea, vomiting, and constipation. Uncertainty remains as to the magnitude and time-course of the analgesic effect and the safety and tolerability in longer-term use. There were no data for children.

Current Practices Regarding Codeine Administration Among Pediatricians and Pediatric Subspecialists

Pharmacogenomic studies have revealed a wide variation in the metabolism of codeine to its active metabolite, morphine. A particular subset of patients, known as ultrarapid metabolizers, possesses multiple copies of the CYP2D6 gene responsible for codeine metabolism. This has been linked to serious morbidity and mortality in pediatric patients leading to considerable debate regarding the use of codeine for analgesia in the pediatric population. The current study surveyed the current practice of codeine prescription in pediatric health care providers from a single tertiary care pediatric hospital. Of the 298 responders, 43.3% (129 of 298) continue to prescribe codeine for pain management in children. The vast majority of codeine prescribers were primary health care providers (89.1%). Most of the primary care practitioners were in office-based (42.6%) or hospital-based (45.7%) group practices. There was no significant difference in codeine use based on years of experience. Given the risks associated with this practice, increased education targeting this group appears warranted.

Morphine is a substrate of the organic cation transporter OCT1 and polymorphisms in OCT1 gene affect morphine pharmacokinetics after codeine administration

We investigated whether morphine and its pro-drug codeine are substrates of the highly genetically polymorphic organic cation transporter OCT1 and whether OCT1 polymorphisms may affect morphine and codeine pharmacokinetics in humans.Morphine showed low transporter-independent membrane permeability (0.5×10−6cm/s). Morphine uptake was increased up to 4-fold in HEK293 cells overexpressing human OCT1. The increase was concentration-dependent and followed Michaelis-Menten kinetics (KM=3.4μM, VMAX=27pmol/min/mg protein). OCT1-mediated morphine uptake was abolished by common loss-of-function polymorphisms in the OCT1 gene and was strongly inhibited by drug-drug interactions with irinotecan, verapamil and ondansetron. Morphine uptake in primary human hepatocytes was strongly reduced by MPP+, an inhibitor of organic cation transporters, and morphine was not a substrate of OCT3, the other organic cation transporter expressed in human hepatocytes. In concordance with the in vitro data, morphine plasma concentrations in healthy volunteers were significantly dependent on OCT1 polymorphisms. After codeine administration, the mean AUC of morphine was 56% higher in carriers of loss-of-function OCT1 polymorphisms compared to non-carriers (P=0.005). The difference remained significant after adjustment for CYP2D6 genotype (P=0.03). Codeine itself had high transporter-independent membrane permeability (8.2×10−6cm/s). Codeine uptake in HEK293 cells was not affected by OCT1 overexpression and OCT1 polymorphisms did not affect codeine AUCs.In conclusion, OCT1 plays an important role in the hepatocellular uptake of morphine. Carriers of loss-of-function OCT1 polymorphisms may be at higher risk of adverse effects after codeine administration, especially if they are also ultra-rapid CYP2D6 metabolizers.

Wither codeine?

Wither codeine?

First demonstration that brain CYP2D-mediated opiate metabolic activation alters analgesia in vivo

The response to centrally acting drugs is highly variable between individuals and does not always correlate with plasma drug levels. Drug-metabolizing CYP enzymes in the brain may contribute to this variability by affecting local drug and metabolite concentrations. CYP2D metabolizes codeine to the active morphine metabolite. We investigated the effect of inhibiting brain, and not liver, CYP2D activity on codeine-induced analgesia. Rats received intracerebroventricular injections of CYP2D inhibitors (20μg propranolol or 40μg propafenone) or vehicle controls. Compared to vehicle-pretreated rats, inhibitor-pretreated rats had: (a) lower analgesia in the tail-flick test (p<0.05) and lower areas under the analgesia-time curve (p<0.02) within the first hour after 30mg/kg subcutaneous codeine, (b) lower morphine concentrations and morphine to codeine ratios in the brain (p<0.02 and p<0.05, respectively), but not in plasma (p>0.6 and p>0.7, respectively), tested at 30min after 30mg/kg subcutaneous codeine, and (c) lower morphine formation from codeine ex vivo by brain membranes (p<0.04), but not by liver microsomes (p>0.9). Analgesia trended toward a correlation with brain morphine concentrations (p=0.07) and correlated with brain morphine to codeine ratios (p<0.005), but not with plasma morphine concentrations (p>0.8) or plasma morphine to codeine ratios (p>0.8). Our findings suggest that brain CYP2D affects brain morphine levels after peripheral codeine administration, and may thereby alter codeine's therapeutic efficacy, side-effect profile and abuse liability. Brain CYPs are highly variable due to genetics, environmental factors and age, and may therefore contribute to interindividual variation in the response to centrally acting drugs.

Simultaneous analysis of codeine and its active metabolites in human plasma using liquid chromatography–tandem mass spectrometry: Application to a pharmacokinetic study after oral administration of codeine

A rapid and sensitive bioassay based on liquid chromatography–tandem mass spectrometry (LC–MS/MS) has been developed and validated for the simultaneous determination of codeine and its active metabolites, including morphine, morphine 3β-glucuronide (M3G) and morphine 6β-glucuronide (M6G), in human plasma. Sample preparation of plasma after the addition of naloxone as internal standard (IS) involved solid-phase extraction (SPE) on C18 cartridges. Reversed-phase chromatography using a gradient elution with methanol and 0.04% formic acid solution (pH 3.5) was used for separation in a run time of 5min. The analytes were detected in the positive ion mode using multiple reaction monitoring (MRM) of the transitions at m/z 300.4→215.2 for codeine, 286.2→152.0 for morphine, and 462.2→286.2 for M3G and M6G. The method has the following performance characteristics: a reliable response range of 0.05–80ng/ml for codeine, M3G and M6G and a response range of 0.05–5.0ng/ml for morphine with correlation coefficients (r) of >0.997 for all analytes. The lower limit of quantitation (LLOQ) for all four analytes was 0.05ng/ml. The intra- and inter-day precision and accuracy of the quality control samples at low, medium and high concentration levels showed <12% relative standard deviation (RSD) and −6.9 to 8.1% relative error (RE) for all the analytes. The method was successfully applied to a pharmacokinetic study of codeine in healthy Mongolian Chinese volunteers after a 30mg oral dose.

Distinguishing Heroin Abuse from Codeine Administration in the Urine of Chinese People by UPLC-MS-MS

Heroin is a highly addictive drug, and heroin abuse is considered to be a serious criminal act. The major metabolite of heroin, morphine, can usually be detected as evidence of heroin abuse. However, it is difficult to determine heroin use when morphine and codeine are both detected, because codeine use will also result in the presence of morphine in urine. Therefore, it is important to distinguish heroin abuse from codeine administration. In this study, urine samples from 21 volunteers with various ingestion patterns of a compound codeine phosphate oral solution were used as negative controls, and urine samples from 89 alleged heroin users were used as positive controls. Urine from single and multiple doses of codeine administration were collected at different time points for a systematic comparison. After protein precipitation, the urine samples were analyzed for the presence of free morphine, free codeine and their metabolites by ultra-performance liquid chromatography-tandem mass spectrometry. The method of percentiles, with median and standard interquartile ranges, was used to describe and analyze the data based on the normality of the distribution. The ratios of concentration of morphine and morphine to codeine were found to be the possible criteria to distinguish heroin users from codeine users in Chinese people.

Pharmacogenomics of codeine, morphine, and morphine-6-glucuronide: model-based analysis of the influence of CYP2D6 activity, UGT2B7 activity, renal impairment, and CYP3A4 inhibition.

The analgesic effect of codeine depends on the formation of the opioid metabolites morphine and morphine-6-glucuronide. Different factors have been shown or suspected to affect the safety and efficacy of codeine treatment. The objective of the current study is to assess and quantify the impact of important pharmacokinetic factors, using a mechanistic modeling approach. By means of a generic modeling approach integrating prior physiologic knowledge, we systematically investigated the complex dependence of opioid exposure on cytochrome P450 2D6 and 3A4 (CYP2D6 and CYP3A4), and uridine diphosphate glucuronosyltransferase 2B7 (UGT2B7) activity, as well as renal function, by means of a virtual clinical trial. First, the known dominant role of CYP2D6 activity for morphine exposure was reproduced. Second, the model demonstrated that mild and moderate renal impairment and co-administration of CYP3A4 inhibitors have only minor influences on opioid exposure. Third, the model showed - in contrast to current opinion - that increased UGT2B7 activity is associated with a decrease in active opioid exposure. Overall, the model-based analysis predicts a wide range of morphine levels after codeine administration and supports recent doubts about safe and efficacious use of codeine for analgesia in non-genotyped individuals.

Pharmacogenetics of Opioids for the Treatment of Acute Maternal Pain During Pregnancy and Lactation

There have been an increasing number of clinical studies investigating the relationship between interindividual genetic variability and the safety and efficacy of opioid analgesics. Despite the widespread use of opioids in pregnant and lactating women for the treatment of acute pain, few studies have investigated the interplay of genetic factors and pregnancy-related physiological alterations in relation to opioid metabolism and response. Some interesting avenues of research require further pursuit- including evidence of cytochrome P450 2D6 (CYP2D6) induction during pregnancy and its effect on the generation of the active opioid metabolites morphine, oxymorphone, O-desmethyltramadol, and hydromorphone following the administration of codeine, oxycodone, tramadol, and hydrocodone respectively. Studies investigating the duration of maternal CYP2D6 induction after delivery are also needed to shed light on genotype to phenotype correlations in breastfeeding mothers using opioid analgesics in the postpartum period.

Pharmacogenomics of Codeine, Morphine, and Morphine-6-Glucuronide

Background and Objective: The analgesic effect of codeine depends on the formation of the opioid metabolites morphine and morphine-6-glucuronide. Different factors have been shown or suspected to affect the safety and efficacy of codeine treatment. The objective of the current study is to assess and quantify the impact of important pharmacokinetic factors, using a mechanistic modeling approach. Methods: By means of a generic modeling approach integrating prior physiologic knowledge, we systematically investigated the complex dependence of opioid exposure on cytochrome P450 2D6 and 3A4 (CYP2D6 and CYP3A4), and uridine diphosphate glucuronosyltransferase 2B7 (UGT2B7) activity, as well as renal function, by means of a virtual clinical trial. Results: First, the known dominant role of CYP2D6 activity for morphine exposure was reproduced. Second, the model demonstrated that mild and moderate renal impairment and co-administration of CYP3A4 inhibitors have only minor influences on opioid exposure. Third, the model showed — in contrast to current opinion — that increased UGT2B7 activity is associated with a decrease in active opioid exposure. Conclusion: Overall, the model-based analysis predicts a wide range of morphine levels after codeine administration and supports recent doubts about safe and efficacious use of codeine for analgesia in non-genotyped individuals.

Editors’ pick: codeine toxicity prediction in young infants – genotype the mothers

Codeine is a common analgesic used for postpartum pain in breastfeeding mothers. However, adverse reactions can happen even at low dosage, and evaluation of clinical risk factors for codeine toxicity, such as codeine dosage and administration time, are not sufficient alone to prevent such unfavorable events. A factor underlying this phenomenon is genetically determined variation in codeine response, which may range from poor analgesia to life-threatening central nervous system (CNS) depression. In 2006 an alarming case was published in The Lancet[1], describing a case of a barely two-week-old neonate who died from morphine poisoning by exposure to the drug through his mother’s milk. The high morphine concentration in the baby was found to be caused by the mother’s ultrarapid metabolizer (UM) phenotype due to a CYP2D6 gene duplication. This case led health officials in several countries to issue warnings of codeine use for nursing mothers. Meanwhile, the scientific community has made an effort to find predictive markers to increase the effectiveness and safety of codeine usage. In a new study, published in April 2012 in Clinical Pharmacology & Therapeutics, Sistonen et al.[2]. report new data. The authors addressed the codeine toxicity in infants by genotyping their nursing mothers for codeine and morphine metabolizing enzymes CYP2D6 and UGT2B7, respectively, as well as morphine transporting P-glycoproteine encoding ABCB1, opioid receptor OPRM1, and mu-receptor interacting COMT genes. They further collected comprehensive clinical information from 111 mothers belonging to a Motherisk program in Canada, of which 26 (23%) reported CNS depression in their babies and 37 (33%) indicated typical codeine adverse reactions in themselves. When clinical data from 26 infants with CNS depression were compared with 85 mothers with asymptomatic babies two parameters were significantly different: mothers with symptomatic babies were 2.8 years younger and they consumed 0.27 mg/kg more codeine per day. Interestingly, CYP2D6 genotype prediction of ultrarapid enzyme activity was significantly higher in the cases than controls (11.5% vs 2.4%), conferring an odds ratio (OR) of 16.5 when compared with the poor metabolizers. Similarly, three single nucleotide poilymorphisms (SNPs) in the ABCB1 gene had significantly higher allele and genotype frequencies in cases vs controls, conferring ORs ranging from 5.45 to 6.63. Furthermore, the authors showed additive value of genotyping. The predictive model for codeine-induced CNS depression improved for infants (P = 0.028), mothers (P = 0.029) and both (P = 0.008). It is noteworthy that most of the neonates were under two weeks old, whose UGTB27 enzyme capacity is still reduced at that age. The genetic pathway leading to CNS depression in these cases is thought to be as follows: increased CYP2D6 activity leads to abnormal conversion of codeine to morphine. The morphine is then accumulated in the absence of UGTB27 activity in these neonates, and the CNS depression is enhanced by decreased activity of ABCB1, which mediates the cellular efflux of morphine at the blood–brain barrier. Altogether, the major importance of the findings of Sistonen et al. is that they have designed a novel set of SNPs in two genes (CYP2D6 and ABCB1), which at least in the studied samples predicts over 80% of the codeine-induced CNS depression in nursing mothers and their infants. When combined with the known clinical risk factors, almost 90% of the risk cases can be predicted with a sensitivity of 80% and specificity of 87%. This study is the first to investigate the role of genetic variation in the morphine pathway related to codeine toxicity, and is clearly a promising step forwards in drug safety.

Dorsal penile nerve block for male pediatric circumcision – randomized comparison of ultrasound‐guided vs anatomical landmark technique

Dorsal penile nerve block (DPNB) is a commonly performed regional anesthetic technique for male circumcision. Traditionally, DPNB is based on an anatomical landmark technique. Recently, an ultrasound-guided technique for DPNB has been described. The aim of our study was to compare the anatomical landmark technique with this ultrasound-guided technique. The hypothesis to be tested was that ultrasound guidance of DPNB would lead to less administration of opioid when compared to the anatomical landmark technique. Boys of ASA status I/II scheduled for day case circumcision were prospectively recruited and randomized. DPNB was performed under general anesthesia using the anatomical landmark technique or ultrasound guidance. Fentanyl was administered intraoperatively and immediately postoperatively if patients demonstrated signs of pain. Similarly, oral codeine was given prior to discharge if required. The primary outcome measure was the number of patients requiring fentanyl. Secondary outcome measures included initial pain score on emergence from general anesthesia, requirement for codeine predischarge, and time to perform block. A total of 32 patients were recruited to the landmark group and 34 to the ultrasound group. There was no significant difference between the two groups in terms of fentanyl administration. The ultrasound technique took longer to perform but was associated with a reduction in codeine requirement prior to discharge. This study does not support the routine use of ultrasound for the performance of DPNB in male pediatric circumcision. Nonetheless, an associated reduction in codeine administration postoperatively suggests some benefit in terms of postoperative pain.

Central antitussive effect of codeine in the anesthetized rabbit

BackgroundCodeine represents a commonly used drug to suppress cough. Central antitussive effect of codeine has been confirmed in a number of animal studies. However, available data related to antitussive activity of codeine in rabbits are very limited.ObjectiveWe investigated the effects of codeine on cough, single expiratory responses (expiration-like reflex) induced by mechanical tracheo-bronchial stimulation, and on the sneeze reflex in the anesthetized rabbit.Materials and methodsTwenty pentobarbitone anesthetized spontaneously breathing rabbits were used for the study. Increasing doses of codeine (codeinum dihydrogenphosphate, Interpharm) were injected intravenously (iv); 0, 0.15, 0.76, and 3.78 mg/kg of codeine dissolved in saline, 0.25 ml/kg) or intracerebroventricularly (icv); 0, 0.015, 0.076, and 0.378 mg/kg of codeine dissolved in artificial cerebrospinal fluid, 0.033 ml/kg.ResultsBoth iv and icv injections of codeine led to a dose-dependent reduction of coughing provoked by tracheo-bronchial stimulation; however, the doses differed substantially. The effective cumulative dose for a 50% reduction in the number of coughs was 3.9 and 0.11 mg/kg after iv and icv administration of codeine, respectively; representing about 35-fold higher efficacy of the icv route. The numbers of expiration-like responses and sneeze reflex responses remained unchanged.ConclusionsThe study confirmed the central antitussive effect of codeine, but showed a low sensitivity of sneeze and expiration reflex to codeine. We validated the experimental model of an anesthetized rabbit for studies on central antitussive action.

Antihypernociceptive synergy between ibuprofen, paracetamol and codeine in rats

We investigated the effects of intraperitoneal injections of a combination of two cyclo-oxygenase inhibitors, ibuprofen and paracetamol, with a weak opiate, codeine, on nociception in Sprague Dawley rats. Administration of paracetamol (11, 44, and 88 mg/kg), ibuprofen (8.75, 35, and 140 mg/kg) or codeine (0.44, 1.75, and 3.5 mg/kg) alone caused a dose-dependent inhibition of reperfusion hypernociception. Administration of a combination of 0.44 mg/kg codeine + 8.75 mg/kg ibuprofen + 11 mg/kg paracetamol, drug doses that did not significantly reduce reperfusion hypernociception when administered individually or in pairs, abolished reperfusion hypernociception, such that the antihypernociceptive efficacy of the combination was ∼ 2.5-fold greater than that of the sum of the antihypernociceptive efficacy of the individual drugs. Coordinated motor function, tested using a rotarod, was not impaired at the doses we used. Thus, we have demonstrated that codeine, paracetamol and ibuprofen act synergistically to induce antihypernociception in rats at doses which do not affect motor function.

Pharmacokinetics of acetaminophen, codeine, and the codeine metabolites morphine and codeine-6-glucuronide in healthy Greyhound dogs

The purpose of this study was to determine the pharmacokinetics of codeine and the active metabolites morphine and codeine-6-glucuronide after i.v. codeine administration and the pharmacokinetics of acetaminophen (APAP), codeine, morphine, and codeine-6-glucuronide after oral administration of combination product containing acetaminophen and codeine to dogs. Six healthy Greyhound dogs were administered 0.734 mg/kg codeine i.v. and acetaminophen (10.46 mg/kg mean dose) with codeine (1.43 mg/kg mean dose) orally. Blood samples were collected at predetermined time points for the determination of codeine, morphine, and codeine-6-glucuronide plasma concentrations by LC/MS and acetaminophen by HPLC with UV detection. Codeine was rapidly eliminated after i.v. administration (T(1/2) = 1.22 h; clearance = 29.94 mL/min/kg; volume of distribution = 3.17 L/kg) with negligible amounts of morphine present, but large amounts of codeine-6-glucuronide (C(max) = 735.75 ng/mL) were detected. The oral bioavailability of codeine was 4%, morphine concentrations were negligible, but large amounts of codeine-6-glucuronide (C(max) = 1952.86 ng/mL) were detected suggesting substantial first pass metabolism. Acetaminophen was rapidly absorbed (C(max) = 6.74 microg/mL; T(max) = 0.85 h) and eliminated (T(1/2) = 0.96 h). In conclusion, the pharmacokinetics of codeine was similar to other opioids in dogs with a short half-life, rapid clearance, large volume of distribution, and poor oral bioavailability. High concentrations of codeine-6-glucuronide were detected after i.v. and oral administration.

Safety Issues of Maternal Drug Therapy During Breastfeeding

Two goals when counseling breastfeeding mothers taking medication are protecting the infant from adverse events and permitting necessary maternal therapy. Madadi et al. report a case-control study of neonatal and maternal opioid toxicity after codeine administration. Therapeutic considerations in counseling breastfeeding mothers include susceptibility to drug toxicity of the very young and/or premature infant, significant interindividual variations in drug response, the dose-response relationship with respect to drug toxicity, and the role of pharmacogenetics in both the mother and the infant. These host factors may combine in a particular patient to act synergistically to produce an adverse reaction.

Respiratory Depression with Tramadol in a Patient with Renal Impairment and CYP2D6 Gene Duplication

We observed opioid-related respiratory depression in a patient receiving tramadol via patient-controlled analgesia. Predisposing factors were the patient's genetic background and renal impairment. Complete recovery occurred after naloxone administration, thus confirming opioid intoxication. Analysis of the patient's genotype revealed a CYP2D6 gene duplication resulting in ultra-rapid metabolism of tramadol to its active metabolite (+)O-desmethyltramadol. Concomitant renal impairment resulting in decreased metabolite clearance enhanced opioid toxicity. This genetic CYP2D6 variant is particularly common in specific ethnic populations and should be a future diagnostic target whenever administration of tramadol or codeine is anticipated, as both drugs are subject to a comparable CYP2D6-dependent metabolism.

Central modulation of exercise‐induced muscle pain in humans

The purpose of the current study was to determine if exercise-induced muscle pain is modulated by central neural mechanisms (i.e. higher brain systems). Ratings of muscle pain perception (MPP) and perceived exertion (RPE), muscle sympathetic nerve activity (MSNA), arterial pressure, and heart rate were measured during fatiguing isometric handgrip (IHG) at 30% maximum voluntary contraction and postexercise muscle ischaemia (PEMI). The exercise trial was performed twice, before and after administration of naloxone (16 mg intravenous; n = 9) and codeine (60 mg oral; n = 7). All measured variables increased with exercise duration. During the control trial in all subjects (n = 16), MPP significantly increased during PEMI above ratings reported during IHG (6.6 +/- 0.8 to 9.5 +/- 1.0; P < 0.01). However, MSNA did not significantly change compared with IHG (7 +/- 1 to 7 +/- 1 bursts (15 s)(-1)), whereas mean arterial blood pressure was slightly reduced (104 +/- 4 to 100 +/- 3 mmHg; P < 0.05) and heart rate returned to baseline values during PEMI (83 +/- 3 to 67 +/- 2 beats min(-1); P < 0.01). These responses were not significantly altered by the administration of naloxone or codeine. There was no significant relation between arterial blood pressure and MSNA with MPP during either IHG or PEMI. A second study (n = 8) compared MPP during ischaemic IHG to MPP during PEMI. MPP was greater during PEMI as compared with ischaemic IHG. These findings suggest that central command modulates the perception of muscle pain during exercise. Furthermore, endogenous opioids, arterial blood pressure and MSNA do not appear to modulate acute exercise-induced muscle pain.

RETRACTED: Maternal Codeine is Not Safe for all Breast-Fed Infants

Answer When the mother is an ultra-rapid metabolizer of cytochrome 2D6, she produces much more morphine than most people. Considering limiting codeine administration to no more than a few days and staying aware of potential opioid toxicities are two management points discussed in this article. Codeine is commonly used in the postpartum period for pain associated with episiotomy and caesarean section. As most new mothers initiate breast-feeding, the safety of codeine itself, and its pharmacologically active metabolite, morphine, are of primary concern in breast-fed infants. The American Academy of Pediatrics and major authoritative texts list codeine as compatible with breast-feeding, despite the lack of sufficient published data to support this recommendation. To illustrate the need for further assessment of codeine/morphine transfer into breast milk, we use the case of a full-term, breast-fed infant who died with a picture consistent with morphine overdose. 3 The pharmacogenetic assessment of maternal drug biotransformation was consistent with an enhanced formation of the pharmacologically active opioid, morphine.