Codeine Use Research Articles

Opioid Use and the Risk of Respiratory Depression and Death in the Pediatric Population

Pediatric patients may be at an increased risk of adverse effects from various medications. Recently, there have been a number of serious adverse events, including several pediatric patients experiencing severe respiratory depression and death as a result of the use of codeine for pain control following tonsillectomy and adenoidectomy. To assess the safety of opioid agonists in pediatric patients undergoing operative procedures or have experienced trauma and to evaluate the risk of respiratory depression and death among this population. PubMed and Medline were searched to identify randomized controlled studies from 1994 to 2012 addressing postsurgery/trauma opioid use in pediatric patients. Relative risks and confidence intervals (CIs) were calculated using data available in clinical trials. A total of 16 clinical trials were evaluated for this review. Randomized controlled trials included studies comparing opioids versus non-opioids for a variety of painful conditions. The relative risk of respiratory depression associated with opioid use in 1 trial was 1.63 (95% CI: 0.64-6.13). The remaining 15 trials reviewed described no significant difference in respiratory depression or adverse effects associated with treatment. No deaths were attributed to opioid use in any of these studies. Opioid-associated respiratory depression was very rare and no deaths were reported in the reviewed studies. These findings under the well-defined conditions of controlled studies may not be the best means of determining overall opioid-associated side effects in pediatric patients.

The restrictions to the use of codeine and dilemmas about safe alternatives

Objective Few patients participate in cancer support groups despite their benefits. This study investigated the importance of Theory of Planned Behaviour variables in predicting group participation, relative to disease impact, existing support, coping and demographic variables. Methods Longitudinal study of patients with colorectal, lung or prostate cancer recruited from a specialist oncology centre. Patients self-completed surveys at baseline and six-month follow up. Baseline measures included Theory of Planned Behaviour (TPB) variables, distress and control over cancer (IPQ-R), coping (Brief COPE), social support (MSPSS), health related quality of life (EORTC QLQ-C30) and readiness to participate (PAPM). Group participation and recommendations to participate were measured at follow up. Univariable and Random Forest analyses investigated predictors of baseline readiness to participate and participation by six-month follow up. Results N = 192 patients completed baseline questionnaires. N = 13 participated in a group and N = 59 did not by six-month follow up. Baseline readiness to participate was associated with inadequate support and positive views of support groups. Lower cognitive functioning, recommendations and readiness to participate predicted group participation by six-month follow up. Conclusion and practice implications Practitioners may facilitate group participation by promoting positive views of groups, recommending participation and focusing on patients experiencing greater disease impact and less existing support.

The Balance Between Effective Opioid-Based Pain Management and Patient Safety: Can It Be Achieved?

The Balance Between Effective Opioid-Based Pain Management and Patient Safety: Can It Be Achieved?

Lack of impairment due to confirmed codeine use prior to a motor vehicle accident: Role of pharmacogenomics

BackgroundWe examined forensic serum toxicology and pharmacogenomics data from a woman on codeine shortly before she caused a motor vehicle accident. MethodsA woman driving erratically collided with a parked car of a highway seriously injuring 2 men working to repair the parked vehicle. The woman tested positive for codeine, acetaminophen and barbital. She had been taking these medications for 20 years due to migraine headache. Serum toxicology and genotype analysis for cytochrome P450, UDP glucuronosyltransferase, and other metabolizing enzymes were measured. ResultsThe woman was tried and convicted of driving under the influence resulting in bodily harm and was sentenced to 6 years. Toxicology results on peripheral blood showed a total and free codeine of 840 and 348 μg/L, respectively, and total morphine of 20 μg/L (17, 3, and 0 μg/L for morphine-3-glucuronide, morphine-6-glucuronide, and free morphine, respectively). She was heterozygous for CYP 2D6 *2/*4 (extensive/poor metabolism) and heterozygous for UGT 2B7 *1/*2 (extensive/ultra-rapid metabolism). The woman was also taking fluoxetine and bupropion which are strong inhibitors of CYP 2D6. ConclusionsBased on her genotype and phenotype and reports by the arresting officer, we suggest that the subject in question was not intoxicated by opiates at the time of her motor vehicle accident and may have been falsely incarcerated.

Pain Management after Tonsillectomy without Codeine

Program Description: Tonsillectomy is a painful procedure. Management of pain is more problematic with recent reports of deaths associated with codeine use and the potential for acetaminophen toxicity. We will discuss opiate sensitivity associated with childhood OSA, genetic variations in narcotic metabolism in children, and the use of non-steroidal anti-inflammatory drugs. We will present tonsillectomy techniques that may reduce the need for analgesics. Panelists will include general and pediatric otolaryngologists and a pediatric pain specialist, with short presentations and case discussions. Educational Objectives: 1) Describe relative effectiveness and potential morbidities associated with narcotic use in children after adenotonsillectomy. 2) Use a safe and effective approach for pain control in children after adenotonsillectomy, including the use of narcotics and nonsteroidal anti-inflammatory drugs. 3) Analyze surgical techniques and postoperative treatments that could help with management of pain after tonsillectomy.

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.

A Clinical Tool for Reducing Central Nervous System Depression among Neonates Exposed to Codeine through Breast Milk

BackgroundNeonates are commonly exposed to maternal codeine through breast milk. Central Nervous System (CNS) depression has been reported in up to 24% of nurslings following codeine exposure. In 2009, we developed guidelines to improve the safety of codeine use during breastfeeding based on previously established pharmacogenetic and clinical risk factors. The primary objective of this study was to prospectively evaluate the effectiveness of these guidelines in ensuring neonatal safety.Methods and FindingsWomen taking codeine for pain following caesarean section were given safety guidelines, including advice to use the lowest codeine dose for no longer than four days and to switch to a non-opioid when possible. Mothers provided a saliva sample for analysis of genes involved in opioid disposition, metabolism and response. A total of 238 consenting women participated. Neonatal sedation was reported in 2.1% (5/238) of breastfeeding women taking codeine according to our safety guidelines. This rate was eight fold lower than that reported in previous prospective studies. Women reporting sedated infants were taking codeine for a significantly longer period of time (4.80±2.59 days vs. 2.52±1.58 days, p = 0.0018). While following the codeine safety guidelines, mothers were less likely to supplement with formula, reported lower rates of sedation in themselves and breastfed more frequently throughout the day when compared to previously reported rates. Genotyping analysis of cytochrome p450 2D6 (CYP2D6), uridine-diphosphate glucuronosyltransferase (UGT) 2B7, p-glycoprotein (ABCB1), the mu-opioid receptor (OPRM1) and catechol-o-demethyltransferase (COMT) did not predict codeine response in breastfeeding mother/infant pairs when following the safety guidelines.ConclusionsThe only cases of CNS depression occurred when the length of codeine use exceeded the guideline recommendations. Neonatal safety of codeine can be improved using evidence-based guidelines, even in those deemed by genetics to be at high risk for toxicity.

A cross‐sectional analysis of over‐the‐counter codeine use among an Australian sample of people who regularly inject drugs

The study aims to examine the medical and non-medical use of over-the-counter (OTC) codeine combination drugs in a sample of people who inject drugs; and to examine risk factors associated with exceeding the recommended dose of OTC codeine, including the experience of pain. This study analysed annual survey data from a convenience sample of people who inject drugs in Australia who are interviewed for the Illicit Drug Reporting System. People who have injected drugs (n = 902) on at least a monthly basis in the preceding six months across Australia were interviewed. Participants were asked about their use of OTC codeine and their experience of pain. One third (35%) of participants had used OTC codeine in the preceding six months and 52% (95% confidence interval 48.7-55.3) of this group had exceeded the recommended dose on their last occasion of use. This clearly places them at increased risk of harms associated with toxicity from the accompanying analgesic found in combination codeine products. Multivariate analyses demonstrated that those exceeding the recommended codeine dose of OTC codeine were more likely to be experiencing moderate to very severe pain. There is a need to evaluate the approach to pain management in this population. Greater pharmacist involvement, real-time monitoring of sales, the development of screening tools to identify those at risk of harm and further education of primary care practitioners could be beneficial in reducing the risk of harm associated with these medications for all users of OTC codeine, including people who inject drugs.

PRAC recommends restricting codeine use in children

PRAC recommends restricting codeine use in children

Wither codeine?

Wither codeine?

Post-op codeine use in children, new Boxed Warning

Post-op codeine use in children, new Boxed Warning

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.

Ibuprofen-Induced Hypokalemia and Distal Renal Tubular Acidosis: A Patient's Perceptions of Over-the-Counter Medications and Their Adverse Effects.

We highlight a case of distal renal tubular acidosis secondary to ibuprofen and codeine use. Of particular interest in this case are the patient's perception of over-the-counter (OTC) medication use, her own OTC use prior to admission, and her knowledge of adverse reactions or side effects of these medications prior to taking them.

Pain Management in Children: Part 2 — A Transition from Codeine to Morphine for Moderate to Severe Pain in Children

Opioids remain the agent of choice for the treatment of moderate to severe pain in both adults and children. Codeine, an opioid analogue, is commonly used in the treatment of mild to moderate pain in both adults and children. However, there has been growing concern about the safety of codeine use in children. This second part of the article on pain management in children will focus on codeine's questionable efficacy and safety concerns about the use of codeine in children.

Erratum to: Effects of codeine on pregnancy outcome: results from a large population-based cohort study

We would like to bring your attention to an error in the article “The effects of codeine on pregnancy outcome: results from a large population-based cohort study” published in Eur J Clin Pharmacology volume 67, year 2011, pages 1253–1261. The error was purely technical and led to some double counting and misclassification. We found one new statistically significant pregnancy outcome (atonic uterus) related to codeine exposure as shown in the tables below. This relationship was borderline significant in the old analysis (lower limit of the confidence interval 1.0). The outcome is directly biologically linked to postpartum hemorrhage, which was found to be significantly associated with codeine both in the previous analysis and in the new one. Otherwise, the odds ratios remained virtually unaltered as did the maternal socio-demographic and medical characteristics. No significant differences were found in the survival rate [adjusted odds ratio (OR) 0.9, 95 % confidence interval (CI) 0.6–1.5] or the congenital malformation rate (adjusted OR 0.9, 95 % CI 0.7–1.2) between codeine-exposed and unexposed infants. Codeine use anytime during pregnancy was associated with planned Cesarean delivery (adjusted OR 1.6, 95 % CI 1.3–2.0; P<0.0001) and atonic uterus (adjusted OR 1.4, 95 % CI 1.1–1.8; P<0.0001). Third trimester use was associated with acute Cesarean delivery (adjusted OR 1.6, 95 % CI 1.2– 2.2; P<0.0001) and postpartum hemorrhage (adjusted OR 1.4, 95 % CI 1.1–1.7; P<0.0001). No significant associations with other adverse pregnancy outcomes were found. In conclusion, no effects of maternal codeine intake during pregnancy were observed on infant survival or congenital malformation rate. Our findings are reassuring; however, the association with acute Cesarean delivery, atonic uterus, and postpartum hemorrhage may justify a certain level of caution when administering codeine toward the end of pregnancy. We sincerely hope that our error can be rectified.

Pain Management in Children: Part 1 — Pain Assessment Tools and a Brief Review of Nonpharmacological and Pharmacological Treatment Options

If pain is not treated quickly and effectively in children, it can cause long-term physical and psychological sequelae. Therefore, it is important for all health care providers to understand the importance of effective pain control in children. This article is divided into 2 parts: Part 1 reviews the pharmacotherapy of pain management in children and Part 2 will review the problems relating to the use of codeine in children, and the rationale for recommending morphine as the opioid of choice in the treatment of moderate to severe pain. There has been growing concern about codeine's lack of efficacy and increased safety concerns in its use in children. Due to the variability of codeine metabolism and unpredictable effects on efficacy and safety, The Hospital for Sick Children in Toronto, Ontario, no longer includes codeine or codeine-containing products on the regular hospital formulary and now recommends oral morphine as the agent of choice for the treatment of moderate to severe pain in children. A knowledge translation (KT) strategy was developed and implemented by the hospital's Pain Task Force to support this practice change.

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.

Neonatal withdrawal syndrome due to maternal codeine use

Neonatal withdrawal from maternal drugs and medications is not uncommon. Codeine-containing analgesic preparations given to pregnant mothers for headache have been identified as a cause of neonatal withdrawal syndrome. The present case highlights the importance of obtaining a detailed maternal drug history including prescription and nonprescription drugs, and highlights the need for prenatal counselling for women who are taking narcotic-containing analgesics.

Postpartum maternal codeine therapy and the risk of adverse neonatal outcomes: A retrospective cohort study

Objectives. To examine whether postpartum maternal prescription of codeine was associated with an increased risk of harm to newborns. Design. Population-based retrospective cohort study. Setting. Ontario, Canada, from April 1, 1998 to March 1, 2008. Participants. A total of 7804 mothers with publically-funded prescription drug coverage. Women who received a prescription for a codeine-containing product within 7 days following hospital discharge and their neonates were matched to 7804 mothers who did not receive codeine following delivery. Main outcome measures. The primary outcome was readmission of the neonate to hospital for any reason within 30 days. Secondary outcomes included arrival to hospital by ambulance, hospitalization for dehydration, for injury, any hospitalization involving resuscitation or assisted ventilation, and all-cause mortality. Results. We studied 7804 infants whose mothers filled a prescription for codeine shortly after delivery and 7804 whose mothers did not. In the primary analysis, infants whose mothers received codeine were no more likely to be readmitted to hospital in the subsequent 30 days than children whose mothers did not (hazard ratio 0.95, 95% confidence interval (CI) 0.81–1.11). Moreover, we found no association between maternal codeine use and the other adverse neonatal outcomes studied. A stratified analysis revealed no differential risk among infants born by Caesarian section (hazard ratio 0.86; 95% CI 0.69–1.08). Conclusions. In this large population-based study, maternal prescription of codeine following delivery was not associated with death or hospitalization in the early neonatal period.

A Patient With Dysphagia Associated With Opioid Medication

A 40-year-old male visited Asan Medical Center complaining of dysphagia, which he had experienced for about six months. His medical history indicated that he had suffered from pulmonary tuberculosis with destructive lung, and took various medications to control his chronic cough. He denied any symptom of heartburn or acid regurgitation. Upper endoscopy findings were normal. The barium esophagogram showed no definite abnormalies. However, esophageal manometry revealed nutcracker esophagus with a mean distal esophageal amplitude of 213.0 mmHg (resting lower esophageal sphincter pressure was 22.9 mmHg). He was taking many medications as needed, including codeine 20 mg, to control his frequent cough (more than 10 times/day). He also complained of chronic constipation after taking too many codeine tablets. At his second visit, he was instructed to decrease the use of codeine to 3 times per day. After reducing the dosage of codeine, the dysphagia improved. Four months later, a follow-up esophageal manometry was performed and it showed normal peristalsis without evidence of nutcracker esophagus, with a mean distal esophageal amplitude of 161.6 mmHg (resting lower esophageal sphincter pressure was 27.1 mmHg). Experimental evidence of opioid-induced esophageal dysmotility has been provided in several papers.1,2 However, clinical manifestations of this condition were recently presented only in case reports from the Mayo clinic.3,4 The lower esophageal sphincter and distal esophageal body are known to be vulnerable to chronic use of opioid medications with mu type opioid agonist function.1,3 The reason for this is not perfectly clear, however, the nitric oxide pathway is thought to be involved.3,4