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Objective: To evaluate a decade of reported paediatric opioid poisoning cases in the UK., Methods: The National Poisons Information Service (NPIS) telephone enquiries database (UK Poisons Information Database) was searched for calls regarding opioid poisoning in children under 18 years from 2012 to 2021. The NPIS online clinical guidance database TOXBASE was searched for accesses relating to opioids for both adults and children. The Office of National Statistics provided paediatric data for hospital admissions and deaths in those aged under 20 years old due to opioids., Results: The NPIS received 426 774 telephone enquiries from 2012 to 2021 from across the UK, 3600 in relation to opioid exposures regarding children under 18 years. Annual telephone enquiries regarding paediatric opiate poisoning reduced year on year, from around 450 to 300 calls/year. A rise in all age TOXBASE annual accesses relating to opioids from 71 642 in 2012 to 87 498 in 2021 was noted, a total of 838 455 during the study period. Hospital admissions from opioid poisoning remained consistent, with around 1500 admissions/year. Deaths were uncommon, but averaged 18 deaths annually. Co-codamol was the most reported substance to NPIS, with 1193 calls (36.5%), followed by codeine with 935 (26.1%)., Conclusions: Opioid poisoning in children is not uncommon. There is a general downward trend in telephone enquiries to NPIS, but many childhood exposures may have been dealt with through consultations via TOXBASE, where accesses relating to opioids have increased. Unfortunately, children still die from opioid exposure each year in the UK and this figure has changed little during 2012-2021., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Context: On October 6, 2014, the United States Drug Enforcement Administration (DEA) implemented a regulatory change for hydrocodone combination products (HCPs), moving them from Schedule III to II, in an effort to decrease drug overdoses. Existing research suggests this regulatory action reduced HCP prescribing and dispensing; however, there is limited research assessing its possible effects on overdoses and accidental exposures., Objective: To analyze the changes in opioid exposures reported to the California Poison Control System (CPCS) before and after DEA rescheduling of HCPs., Methods: We collected monthly exposure data reported to CPCS from 2012 to 2019 and conducted interrupted time series analyses to assess changes in exposures after rescheduling for HCPs, tramadol, oxycodone, morphine, codeine, fentanyl, and heroin. Additional analyses were done to assess any changes in exposures resulting in severe outcomes (moderate or major health effects). For HCPs, we also conducted logistic regressions to identify characteristics of exposures resulting in severe outcomes before and after rescheduling., Results: Overall monthly opioid exposures reported to CPCS decreased after DEA rescheduling of HCPs. These decreases were significant for HCP, tramadol, and morphine ( p  < 0.001). Exposures significantly increased for heroin and fentanyl ( p  < 0.001). There were no significant changes in the share of severe outcomes attributed to HCP exposures after rescheduling., Discussion: The DEA rescheduling of HCPs was associated with a significant decrease in HCP exposures and prescription opioid exposures overall, but was associated with increased fentanyl and heroin exposures. While other initiatives may have contributed to this decrease, our findings suggest that rescheduling may be a useful regulatory strategy to reduce drug exposures., Conclusion: DEA rescheduling of HCPs was associated with a significant reduction in prescription opioid exposures, suggesting that rescheduling high-risk drugs may be an effective strategy to improve public health.

Background and Aims: Despite increases in opioid prescribing and related morbidity and mortality, few studies have comprehensively documented harms across opioid types. We examined a population-wide indicator of extramedical pharmaceutical opioid-related harm to determine if the supply-adjusted rates of ambulance presentations, the severity of presentations or other attendance characteristics differed by opioid type., Design: Retrospective observational study of coded ambulance patient care records related to extramedical pharmaceutical opioid use, January 2013 to September 2018., Setting: Australia CASES: Primary analyses used Victorian data (n = 9823), with available data from other Australian jurisdictions (n = 4338) used to determine generalizability., Measurements: We calculated supply-adjusted rates of attendances using Poisson regression, and used multinomial logistic regression to compare demographic, presentation severity, mental health, substance use and other characteristics of attendances associated with seven pharmaceutical opioids., Findings: In Victoria, the highest rates of attendance [per 100 000 oral morphine equivalent mg (OME)] were for codeine (0.273/100 000) and oxycodone (0.113/100 000). The lowest rates were for fentanyl (0.019/100 000) and tapentadol (0.005/100 000). Oxycodone-naloxone rates (0.031/100 000) were lower than for oxycodone as a single ingredient (0.113/100 000). Fentanyl-related attendances were associated with the most severe characteristics, most likely to be an accidental overdose, most likely to have naloxone administered and least likely to be transferred to hospital. In contrast, codeine-related attendances were more likely to involve suicidal thoughts/behaviours, younger females and be transported to hospital. Supply-adjusted attendance rates for individual opioids were stable over time. Victorian states were broadly consistent with non-Victorian states., Conclusions: In Australia, rates and characteristics of opioid-related harm vary by opioid type. Supply-adjusted ambulance attendance rates appear to be both stable over time and unaffected by large changes in supply., (© 2019 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Background and Aims: Globally, codeine is the most-used opioid. In December 2016, Australia announced that low-strength codeine (≤ 15 mg) would be re-scheduled and no longer available for purchase over-the-counter; this was implemented in February 2018. We aimed to evaluate the effect of this scheduling change on codeine misuse and use and misuse of other opioids., Design and Setting: Interrupted time-series analysis of monthly opioid exposure calls to New South Wales Poisons Information Centre (NSWPIC, captures 50% of Australia's poisoning calls), January 2015- January 2019 and monthly national codeine sales, March 2015-March 2019. We incorporated a washout period (January 2017 - January 2018) between the announcement and implementation, when prescriber/consumer behaviour may have been influenced., Participants: Intentional opioid overdoses resulting in a call to NSWPIC., Measurements: We used linear segmented regression to identify abrupt changes in level and slope of fitted lines. Codeine poisonings and sales were stratified into high strength (> 15 mg per dose unit) and low strength (≤ 15 mg). Only low-strength formulations were re-scheduled., Findings: We observed an abrupt -50.8 percentage [95% confidence interval (CI) = -79.0 to -22.6%] level change in monthly codeine-related poisonings and no change in slope in the 12 months after February 2018. There was no increase in calls to the NSWPIC for high-strength products, level change: -37.2% (95% CI = -82.3 to 8%) or non-codeine opioids, level change: -4.4% (95% CI = -33.3 to 24.4%). Overall, the re-scheduling resulted in a level change in opioid calls of -35.8% calls/month (95% CI = -51.2 to -20.4%). Low-strength codeine sales decreased by 87.3% (95% CI = -88.5 to -85.9%), with no increase in high-strength codeine sales in the 14 months following re-scheduling, -4.0% (95% CI = -19.6 to 14.6%)., Conclusions: Codeine re-scheduling in Australia appears to have reduced codeine misuse and sales., (© 2019 Society for the Study of Addiction.)

Background: Analgesics are used most frequently in fatal and non-fatal medicinal self-poisonings. Knowledge about their relative toxicity in overdose is important for clinicians and regulatory agencies., Methods: Using data for 2005-2012 we investigated case fatality (number of suicides relative to number of non-fatal self-poisonings) of paracetamol, aspirin, codeine, dihydrocodeine, tramadol, paracetamol with codeine (co-codamol), paracetamol with dihydrocodeine (co-dydramol), ibuprofen and co-proxamol (paracetamol plus dextropropoxyphene; withdrawn in the UK in 2008 due to high toxicity). Data on suicides obtained from the Office for National Statistics and on non-fatal self-poisonings from the Multicentre Study of Self-harm in England. Case fatality was estimated for each drug, using paracetamol as the reference category., Results: Compared to paracetamol and based on single drug deaths the case fatality index of dihydrocodeine was considerably elevated (odds ratio (OR) 12.81, 95% Confidence Interval (CI) 10.19-16.12). Case fatality indices for tramadol (OR 4.05, 95% CI 3.38-4.85) and codeine (OR 2.21, 95% CI 1.81-2.70) were also significantly higher than for paracetamol. The results when multiple drug deaths were included produced similar results. The relative toxicity of co-proxamol far exceeded that of the other analgesics., Limitations: Data on fatal self-poisonings were based on national data, whereas those for non-fatal poisonings were based on local data., Conclusions: Dihydrocodeine and tramadol are particularly toxic in overdose and codeine is also relatively toxic. They should be prescribed with caution, particularly to individuals at risk of self-harm., (Copyright © 2019. Published by Elsevier B.V.)

Purpose: The aims of this study were to examine a national database to assess codeine poisonings before and after the new guidance for pharmacists while also evaluating rates of codeine prescriptions following the introduction of restrictions on supply., Methods: Anonymised enquiry data of reported poisoning cases were reviewed for a period from 2005 to 2016 inclusive. The rate of pharmacy claims for codeine containing products was also examined using the national pharmacy claims database. Segmented regression analysis was used to detect changes in poisonings and claims before and after the new guidance., Results: There were 1851 codeine-related poisonings reported over the study period. An annual decline was evident with a significant 33% reduction from 2010 to 2011 (β2 coefficient for level change, 42.1; 95% CI, -68.1 to -16.0; P = 0.006). Following 2011, the declining rate of codeine poisonings plateaued. Analysis of the national pharmacy claims data revealed no change in the reimbursement rate for co-codamol products restricted by the guidance in 2010 (Incidence rate ratio 1.04, 95% CI, 0.997-1.08; P = 0.07). There was no corresponding increase in the reimbursement of alternative opioid medications., Conclusions: New guidance on codeine supply coincided with an initial reduction in reported codeine poisoning cases. This reduction was in keeping with the previous trend. However, this was without an increase in the prevailing rate of prescription claims for these products or potential substitutes. Policymakers may consider further restriction of codeine products to improve public health outcomes., (© 2019 John Wiley & Sons, Ltd.)

Given the current opioid crisis in Canada, there is interest in the role of opioid toxicity in suicide deaths, particularly in whether any observed patterns are similar to those of unintentional deaths. The present analysis examined characteristics of opioid-toxicity suicide, and its role in relation to other suicide methods, from 2000 to 2016 in Alberta. It does not appear that the opioid crisis has resulted in a disproportionately higher number of suicides in Alberta. Individuals who die from unintentional opioid toxicity and those who die by opioid-toxicity suicide are likely distinct populations, requiring nuanced public health responses for prevention., Competing Interests: The authors have no conflicts of interest to report.

Background: Butalbital is a small molecule (approximately 220 Da), with 26% protein binding, a 0.8 L/kg volume of distribution, and is eliminated nearly 80% unchanged in the urine. Although hemodialysis has been used to treat overdoses of other barbiturates, the extracorporeal clearance of butalbital is unknown. The objective of this case is to describe the use of extracorporeal therapy to augment elimination of butalbital after an overdose of aspirin 325 mg-butalbital 50 mg-caffeine 40 mg with codeine 30 mg (Fiorinal with Codeine)., Methods: This is a case report of a single patient., Results: A 67-year-old female was admitted to the medical intensive care unit approximately 3 h after ingestion of 40 tablets of Fiorinal with Codeine. Her presentation was notable for a decline in mental status, preserved renal function and a relatively low peak salicylate concentration at 46.4 mg/dL (3.4 mmol/L). Approximately 8 h after ingestion of 2000 mg of butalbital, our patient's serum concentration was 26.9 mg/L (normal <10 mg/L). At the end of a four-hour hemodialysis session, the total body elimination of butalbital was approximately 60% which corresponded to an intradialytic clearance of 233-300 mL/min., Conclusions: The extracorporeal clearance of butalbital observed in this case demonstrates the utility of dialysis to augment drug elimination in a Fiorinal with Codeine overdose.

Aims: Codeine containing analgesics are commonly taken in overdose, but the frequency of respiratory depression is unknown. We investigated whether paracetamol-codeine combination overdoses caused respiratory depression more than paracetamol alone., Methods: We reviewed deliberate self-poisoning admissions with paracetamol (>2 g) and paracetamol-codeine combinations presenting to a tertiary toxicology unit (1987-2013). Demographic information, clinical effects, treatment (naloxone, length of stay [LOS], mechanical ventilation) were extracted from a prospective database. Primary outcome was naloxone requirement or ventilation for respiratory depression., Results: From 4488 presentations, 1376 admissions were included with paracetamol alone (929), paracetamol-codeine combinations (346) or paracetamol-codeine-doxylamine combinations (101) without co-ingestants. Median age was 23 years (12-89 years); 1002 (73%) were female. Median dose was 12 g (interquartile range [IQR]: 7.5-20 g). Median LOS was 16 h (IQR: 6.5-27 h) and 564 (41%) were given acetylcysteine. Significantly larger paracetamol doses were ingested and more acetylcysteine given in paracetamol alone versus paracetamol combination overdoses. Seven out of 1376 patients were intubated or received naloxone (0.5%; 95% CI: 0.2-1.1%), three intubated, three given naloxone and one both. Three out of 929 patients ingesting paracetamol alone (0.3%; 95% CI: 0.1-1%) required intubation or naloxone, compared to two out of 346 ingesting paracetamol-codeine combinations (0.6%; 95% CI: 0.1-2.3%; absolute difference, 0.26%; 95% CI: -0.7-1.2%; P = 0.62). Two out of 101 patients ingesting paracetamol-codeine-doxylamine combinations (2%; 95% CI: 0.3-8%) required intubation or naloxone. Four patients were intubated for reasons other than respiratory depression: hepatotoxicity (2), retrieval (1), no data (1). Two out of 929 (0.2%) paracetamol alone overdoses had a Glasgow coma score < 9 compared to three out of 346 (0.9%) in the paracetamol-codeine group., Conclusions: Paracetamol-codeine combination overdoses are rarely associated with severe respiratory depression, with only two given naloxone and none intubated for respiratory depression., (© 2016 The British Pharmacological Society.)

Objective: To investigate alterations of resting brain function in codeine-containing cough syrups (CCS) dependent individuals before and after ultra-rapid opioid detoxification under general anaesthesia (UROD) combined with naltrexone treatment (NMT)., Methods: Fourteen CCS-dependent individuals were scanned using resting-state fMRI. After UROD and 2 weeks of NMT, CCS-dependent individuals were rescanned. Fourteen matched controls were studied at baseline and compared. The amplitude of low frequency fluctuations (ALFF) and seed-based functional connectivity (FC) were used to characterize resting-state cerebral function., Results: After UROD and 2 weeks of NMT, CCS-dependent individuals had increased ALFF in the bilateral parahippocampal gyrus and right medial orbitofrontal cortex (mOFC), decreased ALFF in the left post-central gyrus (PoCG), left middle occipital cortex (MOC) and left dorsal lateral prefrontal cortex (DLPFC), and reduced FC between right mOFC and right DLPFC, and between left DLPFC and left inferior parietal lobe relative to pretreatment. Decreased ALFFs in the left PoCG and left MOC were associated with decreased withdrawal syndrome severity in CCS-dependent individuals., Conclusions: We offer the first report describing how regional and integral synchronous neural activity occurs after UROD and short-term NMT, accompanied by decreased withdrawal syndrome severity. These findings contribute to the understanding of complex systems involved in UROD-NMT effects., Key Points: • CCS-dependent individuals had reduced ALFF and increased FC at baseline. • UROD treatment can change the regional and integral brain function of CCS-dependent individuals. • Attenuated ALFFs are correlated with the withdrawal syndrome after treatment.

The krokodil use disorder is an addictive pathology with quite severe organic effects, especially at the skin level, that causes severe and degenerative necrosis of blood and muscle tissue. Though this disorder has a low prevalence in Spain, compared to the large number of consumers in other countries such as Ukraine or Russia, its consumption is slowly but gradually expanding in countries of the European Union and America. The simplicity of the process of obtaining the substance from desomorphine, together with its high availability and low cost, contribute toward consumers' self-sufficiency. This article presents the case of a user of krokodil and reviews the clinical symptoms of oral ingestion.

Context: In October 2014, the Drug Enforcement Administration reclassified hydrocodone to schedule II, increasing regulations on use. The impact of rescheduling hydrocodone on opioid exposures is unclear, especially in states with special restrictions required for prescribing schedule II agents., Objective: To assess whether changes in exposures to prescription opioid analgesics and heroin as reported to poison centers occurred in the 6 months after hydrocodone rescheduling. We hypothesized that hydrocodone exposures would decrease, while less tightly regulated opioids, such as codeine and tramadol, would increase., Materials and Methods: This study compares opioid analgesic exposures reported to Texas Poison Centers before and after this change in a state that requires special prescription pads for Schedule II agents. Cases included all opioid analgesic exposures reported to a statewide poison center network, comparing exposures from 6 months before to 6 months after heightened regulations. Specific opioids with large changes in reported exposures were further characterized by patient age and exposure intent., Results: Hydrocodone exposures decreased from 1567 to 1135 (28%, p = 0.00017), decreasing for all ages. Codeine exposures increased significantly from 189 to 522 (176%, p = 0.00014), including a 263% increase for age >20 years. Codeine misuse increased 443% and adverse drug events 327%. Oxycodone exposures increased from 134 to 189 (39%, p = 0.0143), increasing only among patients age >20 years. Reported heroin exposures increased from 156 to 179 (15%, p = 0.2286) and tramadol from 666 to 708 (6%, p = 0.0193). Other opioid exposures changed little or had limited reports., Discussion: The increased regulation of hydrocodone was followed temporally by a decrease in reported hydrocodone exposures, but also increases in codeine, oxycodone and tramadol exposures. This may reflect a shift in prescribing practices, changes in street availability of hydrocodone or decreased drug diversion., Conclusion: The increased regulation was temporally associated with decreased hydrocodone exposures reported to Texas Poison Centers.

The increasing drug consumption in Lithuania and all over the world makes us think about the negative consequences - the risk of toxicity. Fast and accurate identification of material that caused the poisoning reduces the probability in death cases and makes easier to determine the main cause of death. The results have shown that the most appropriate systems of solvents for qualitative analysis by TLC method of the mixture consisting of alprazolam, codeine and paracetanol are: system "D" (trichloromethane : acetone : conc. ammonia = 55 : 40 : 5 (v/v/v)) and system "F" (trichloromethane : diethyl ether: isobutanol : conc. ammonia = 50 : 30 : 15 : 5 (v/v/v/v)). For qualitative analysis of the mixture consisting of alprazolam, codeine and paracetamol by HPLC method the chromatographic column ACE C18 (25 cm x 4.6 mm x 5 µm), gradient elution mode (mixture of 3% acetic acid and methanol and the flow rate 1 mL/min have been used. The injection volume was 10 pL. Photodiode array detector (210 - 240 nm range) has been used. UV absorption spectra of materials measured using photodiode array detector have been identical to those presented in the scientific literature.

Objectives: To examine trends in codeine-related mortality rates in Australia, and the clinical and toxicological characteristics of codeine-related deaths., Design and Setting: Analysis of prospectively collected data from the National Coronial Information System on deaths where codeine toxicity was determined to be an underlying or contributory cause of death. The study period was 2000-2013., Main Outcome Measures: Population-adjusted numbers (per million persons) of (1) codeine-related deaths, classified by intent (accidental or intentional); and (2) heroin- and Schedule 8 opioid-related deaths (as a comparator)., Results: The overall rate of codeine-related deaths increased from 3.5 per million in 2000 to 8.7 per million in 2009. Deaths attributed to accidental overdoses were more common (48.8%) than intentional deaths (34.7%), and their proportion increased during the study period. High rates of prior comorbid mental health (53.6%), substance use (36.1%) and chronic pain (35.8%) problems were recorded for these deaths. For every two Schedule 8 opioid-related deaths in 2009, there was one codeine-related death. Most codeine-related deaths (83.7%) were the result of multiple drug toxicity., Conclusions: Codeine-related deaths (with and without other drug toxicity) are increasing as the consumption of codeine-based products increases. Educational messages are needed to better inform the public about the potential harms of chronic codeine use, especially in the context of polypharmacy.

A 61-year-old woman presented with a progressive perianal ulcer which had developed 4 months ago. Upon further examination, another ulcer of the rectum was detected. Anorectal malignancies, viral infections or primary inflammatory bowel disease were not found. It could be demonstrated that the ulcers were induced by paracetamol and codeine suppositories. After discontinuation of these suppositories, the perianal ulcers healed almost completely within 3 weeks. The pathogenesis of paracetamol-induced ulcers is unknown. However, dose-dependent vasoconstriction is a possible explanation.

Background: Immigrants may be at a higher risk of adverse drug reactions, in that poor language proficiency reduces individuals understanding of drug label instructions. Additionally, there are reports of severe or fatal toxicity due to CYP2D6 ultrarapid hepatic metabolism of codeine to morphine among some ethnic groups, especially those from Eastern Africa., Methods: Between 2002 and 2012 we conducted a population-based cohort study among residents of Ontario, Canada. We used administrative health databases that linked immigrants and Canadian-born individuals to both prescription medication use and emergency department visits and hospital admissions. The primary composite outcome was the risk of drug overdose or all-cause mortality within 30 days of codeine prescription, comparing patients from various world regions to Canadian-born individuals. A secondary analysis stratified by codeine dose and ability to speak English and/or French., Results: There were 553 504 individuals exclusively prescribed codeine. Relative to an incidence rate of 57.1/100 000 person-days among Canadian-born codeine recipients, those who migrated from various world regions were at a lower risk of drug overdose or death. For example, Eastern Africans had an adjusted HR of 0.60 (95% CI 0.31 to 1.17) on controlling for potential confounders such as age, sex, income and physician visits. Patients unable to speak English or French who were prescribed codeine were at a lower risk of the composite outcome relative to those proficient in either language (adjusted HR 0.63, 95% CI 0.54 to 0.74)., Interpretation: Overdose and death following the institution of codeine therapy are not more commonly observed among immigrants from world regions with a high prevalence of ultrarapid CYP2D6 status relative to those born in Canada. Lower proficiency in English or French also did not appear to heighten the risk., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

The objective of this study was to assess the relationship between genetic polymorphisms and drug interactions on codeine and morphine concentrations in codeine-related deaths (CRD). All CRD in Ontario, Canada between 2006 and 2008 were identified. Post-mortem blood was analyzed for 22 polymorphisms in 5 genes involved in codeine metabolism and response. Sixty-eight CRD were included in this study. The morphine-to-codeine ratio was significantly correlated with the presence of a CYP2D6 inhibitor at varying potencies (p=0.0011). The presence of other central nervous system (CNS) depressants (i.e. benzodiazepines, hypnotics, and/or alcohol) was significantly associated with lower codeine concentration as compared to CRD in which other CNS depressants were not detected (p=0.0002). Individuals who carried the ABCB1 1236T variant had significantly lower morphine concentrations (p=0.004). In this population of individuals whose cause of death was related to codeine, drug interactions and genetic polymorphisms were significantly associated with post-mortem codeine and morphine concentrations., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

This report describes the deaths of three children ages 4-10 years due to codeine toxicity at home. All three children were overweight or obese; however, the codeine doses were within recommended dose ranges for adjusted lean weight. Codeine's analgesic effect depends on its metabolic conversion to morphine in the liver via the drug-metabolizing enzyme CYP2D6. Genetic variation may result in poor analgesia, opioid toxicity, or oversedation. Caregivers must be warned about risks associated with comorbidities including obesity and polypharmacy. Codeine should no longer be prescribed to children due to its poor analgesic effect and risk of opioid toxicity and oversedation.

OBJECTIVES. Cough mixture is the third most commonly abused substance in patients attending the Prince of Wales Hospital Substance Abuse Clinic. The content of the local cough mixture is not well researched. Paranoid psychosis manifesting as persecutory delusions and derogatory hallucination, as well as mood symptoms, is common in these patients. The natural history and outcome of such psychoses associated with cough mixture abuse are not well known. This study aimed to address these questions. METHODS. This was a retrospective study of cough mixture abuse in Hong Kong. Case records of cough mixture abusers currently receiving treatment at the 3 substance abuse clinics at the Prince of Wales Hospital, Alice Ho Miu Ling Nethersole Hospital, and the North District Hospital were retrieved for data collection. The patients' demographic data, duration and intake pattern of cough mixture, and use of any other drugs were documented. The presenting psychopathology, first urine toxicology results, diagnosis, treatment, number of hospitalizations, and course of the illness were also recorded. RESULTS. A total of 63 patients with the diagnosis of cough mixture abuse were identified in the database; 89% were male. The mean +/- SD age of the patients was 34.4 +/- 6.2 years; 67% were single and 83% were unemployed. The mean +/- SD age of onset of cough mixture abuse was 20 +/- 5 years. Psychiatric symptoms developed a mean +/- SD of 7.6 +/- 6.0 years after onset of abuse. According to the ICD-10 Mental and Behavioural Disorders criteria, the top psychiatric diagnoses were substance-induced psychotic disorder (67%), schizophrenia (19%), depressive disorder (11%), and dysthymia (10%). The most common ingredients in the urine sample at first presentation were promethazine (75%), pseudoephedrine (67%), codeine (60%), ephedrine (57%), zopiclone (17%), and hydrocodone (16%). Additionally, 16% of patients were in the priority follow-up group. The mean +/- SD follow-up period was 6.2 +/- 7.1 years during which there were 3.2 +/- 3.7 episodes of hospitalizations, with a mean +/- SD length of stay in each admission of 25.0 +/- 40.9 days. CONCLUSIONS. Promethazine, ephedrine, pseudoephedrine, codeine, and hydrocodone are the most common ingredients of cough mixture abused in this locality. Psychotic disorders are the most frequent psychiatric diagnosis associated with cough mixture abuse.

There is a rising trend of fatal poisonings due to medicinal opioids in several countries. The present study evaluates the drug and alcohol findings as well as the cause and manner of death in opioid-related post-mortem cases in Finland from 2000 to 2008. During this period, fatal poisonings by prescription opioids (buprenorphine, codeine, dextropropoxyphene, fentanyl, methadone, oxycodone, tramadol) increased as a share of all drug poisonings from 9.5% to 32.4%, being 22.3% over the whole period. A detailed study including the most prevalent opioids was carried out for the age group of 14-44 years, which is the most susceptible age for drug abuse in Finland. Poisonings by the weak opioids, codeine and tramadol, were found to be associated with large, often suicidal overdoses resulting in high drug concentrations in blood. Methadone poisonings were associated with accidental overdoses with the drug concentration in blood remaining within a therapeutic range. The manner of death was accidental in 43%, 55% and 94% of cases in codeine, tramadol and methadone poisonings, respectively. The median concentration of codeine and the median codeine/morphine concentration ratio were higher in codeine poisonings (1.4 and 22.5 mg/l, respectively) than in other causes of death (0.09 and 5.9 mg/l, respectively). The median concentrations of tramadol and O-desmethyltramadol were higher in tramadol poisonings (5.3 and 0.8 mg/l, respectively) than in other causes of death (0.6 and 0.2 mg/l, respectively). In methadone poisonings, the median concentration of methadone (0.35 mg/l) was not different from that in other causes of death (0.30 mg/l). Sedative drugs and/or alcohol were very frequently found in fatal poisonings involving these prescription opioids., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Unlabelled: We describe here a fatal abused case of cough syrup, containing chlorpheniramine and dihydrocodeine. Postmortem blood concentration of chlorpheniramine was above fatal levels, but dihydrocodeine concentration was within a therapeutic ranges, and those drug levels in blood were discussed from the viewpoint of forensic pharmacokinetics. We concluded that the cause death was due to the chlorpheniramine poisoning., Keywords: cough syrup abuse - chlorpheniramine - dihydrocodeine.

Patient-controlled analgesia (PCA) is an established standard therapy for providing postoperative analgesia. To avoid possible abuse by patients each PCA pump is secured by a pin code that should be neither known nor accessible to patients. The two case reports described illustrate how manipulation of a PCA pump led to massive opioid abuse by the patients who decoded the pin code for unlimited additional doses. One patient developed withdrawal symptoms after switching the therapy and, as a consequence even had to be admitted to the intensive care unit (ICU). Easy access to the PCA pump codes on the internet for the patients and the impossibility of changing the pin codes by the medical staff played an important role in these two cases.

Compared to morphine and morphine-6-glucuronide (M6G), codeine and its other major metabolites codeine-6-glucuronide and norcodeine have weak affinity to opioid μ-receptors. Analgesic effects of codeine are thus largely dependent on metabolic conversion to morphine by the polymorphic cytochrome P450 isoenzyme 2D6 (CYP2D6). How this relates to toxicity and post-mortem whole blood levels is not known. This paper presents a case series of codeine-related deaths where concentrations of morphine, M6G and morphine-3-glucuronide (M3G), as well as CYP2D6 genotype, are taken into account. Post-mortem toxicological specimens from a total of 1444 consecutive forensic autopsy cases in Central Norway were analyzed. Among these, 111 cases with detectable amounts of codeine in femoral blood were identified, of which 34 had femoral blood concentrations exceeding the TIAFT toxicity threshold of 0.3mg/L. Autopsy records of these 34 cases were retrieved and reviewed. In the 34 reviewed cases, there was a large variability in individual morphine to codeine concentration ratios (M/C ratios), and morphine levels could not be predicted from codeine concentrations, even when CYP2D6 genotype was known. 13 cases had codeine concentrations exceeding the TIAFT threshold for possibly lethal serum concentrations (1.6 mg/L). Among these, 8 individuals had morphine concentrations below the toxic threshold according to TIAFT (0.15 mg/L). In one case, morphine as well as M6G and M3G concentrations were below the limit of detection. A comprehensive investigation of codeine-related fatalities should, in addition to a detailed case history, include quantification of morphine and morphine metabolites. CYP2D6 genotyping may be of interest in cases with unexpectedly high or low M/C ratios., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Aim: To describe the characteristics of clients addicted to over-the-counter (OTC) codeine analgesics presenting to an Auckland open-access clinic, and to compare them to clients admitted to a New Zealand detoxification unit, and in the Australian community., Method: Cross-sectional study of clients presenting to a regional, open-access detoxification clinic covering the Greater Auckland area between 1 January and 31 March 2010., Results: Fifteen clients were analysed, and compared to 77 similar clients identified in Victoria and five other Australian States, and 7 clients admitted to a New Zealand detoxification unit. Cases in each cohort were consistent with those in the published literature, and appear to be similar to each other both demographically and in terms of the high average tablets consumption (49-65 tablets per day), the serious non-steroidal anti-inflammatory drug (NSAID) adverse drug reactions identified, and the long duration of misuse. Many had a history of alcohol or other drug use and mental health disorder., Conclusions: This study has identified that controls on OTC codeine analgesics in both countries were not sufficient to limit non-medical use of these products. As a result, cases identified in these two countries escalated the number of self-administered tablets taken daily for misuse, resulting in codeine dependence and serious NSAID toxicity secondary to this dependence.

Objective: To explore pharmacists' beliefs, practices, and experiences regarding opioid dispensing., Design: Mailed survey., Setting: The province of Ontario., Participants: A total of 1011 pharmacists selected from the Ontario College of Pharmacists' registration list., Main Outcome Measures: Pharmacists' experiences with opioid-related adverse events (intoxication and aberrant drug-related behaviour) and their interactions with physicians., Results: A total of 652 pharmacists returned the survey, for a response rate of 64%. Most (86%) reported that they were concerned about several or many of their patients who were taking opioids; 36% reported that at least 1 patient was intoxicated from opioids while visiting their pharmacies within the past year. Reasons for opioid intoxication included the patient taking more than prescribed (84%), the patient using alcohol or sedating drugs along with the opioid (69.9%), or the prescribed dose being too high (34%). Participants' most common concerns in the 3 months before the survey were patients coming in early for prescription refills, suspected double-doctoring, and requests for replacement doses for lost medication (reported frequently by 39%, 12%, and 16% of respondents, respectively). Pharmacists were concerned about physician practices, such as prescribing benzodiazepines along with opioids. Pharmacists reported difficulty in reaching physicians directly by telephone (43%), and indicated that physicians frequently did not return their calls promptly (28%). The strategies rated as most helpful for improving opioid dispensing were a provincial prescription database and opioid prescribing guidelines., Conclusion: Pharmacists commonly observe opioid intoxication and aberrant drug-related behaviour in their patients but have difficulty communicating their concerns to physicians. System-wide strategies are urgently needed to improve the safety of opioid prescribing and to enhance communication between physicians and pharmacists.

What Is Already Known About This Subject: Dihydrocodeine (DHC) is an opioid analgesic sometimes prescribed as an alternative to other medications (e.g. methadone and buprenorphine) for opioid misuse. Its effectiveness is, however, still controversial. DHC prescription rates seem to be related to levels of DHC fatalities, possibly in relation to levels of disregard of the availability of supervised or interval dispensing of opioids, but no large-scale analysis of DHC fatalities has been carried out. We analysed here involvement of DHC in fatalities that occurred between 1997 and 2007 among individuals with a history of opiate/opioid misuse reported to the National Programme on Substance Abuse Deaths (np-SAD)., What This Study Adds: DHC, either alone or in combination, was identified in 584 fatalities. Typical cases identified were males in their early thirties. In accidental overdoses, DHC, which had been prescribed to 45% of the victims, was typically identified in combination with other drugs, such as heroin/morphine, methadone and hypnotics/sedatives. Both paracetamol and antidepressants were more typically identified in combination with DHC in suicides. Opiate/opioid misusers should be educated about risks associated with polydrug intake and prescribers should carefully consider a pharmacological intervention alternative to DHC (e.g. methadone, buprenorphine) when managing and treating opiate addiction., Aims: Although its effectiveness is somewhat controversial, it appears that dihydrocodeine (DHC) is still prescribed in the UK as an alternative to both methadone and buprenorphine for the treatment of opiate addiction., Methods: Data covering the period 1997-2007 voluntarily supplied by coroners were analysed. All cases pertaining to victims with a clear history of opiate/opioid misuse and in which DHC, either on its own or in combination, was identified at post-mortem toxicology and/or implicated in death, were extracted from the database., Results: Dihydrocodeine, either alone or in combination, was identified in 584 fatalities meeting the selection criteria. In 44% of cases it was directly implicated in the cause of death. These cases represented about 6.8% of all opiate/opioid-related deaths during this period. Typical DHC cases identified were White males in their early thirties. Accidental deaths (96%) were likely to involve DHC in combination with other psychoactives, mainly heroin/morphine, hypnotics/sedatives and methadone. Both paracetamol and antidepressants were found in proportionately more suicide cases than in accidental overdoses. DHC had been prescribed to the decedent in at least 45% of cases., Conclusions: Opiate/opioid misusers should be educated about risks associated with polydrug intake. More in particular, co-administration of DHC with heroin, methadone and benzodiazepines may increase the risk of accidental fatal overdose. Prescribers should carefully consider pharmacological intervention alternative to DHC (e.g. methadone, buprenorphine) when managing and treating opiate addiction. More resources are required to do prospective research in this area., (© 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.)

The focus of this study was to report the blood and urine concentrations of dihydrocodeine (DHC) and its metabolites, dihydrocodeine-6-glucuronide (DHC6G), dihydromorphine (DHM), dihydromorphine-3-glucuronide (DHM3G), and dihydromorphine-6-glucuronide (DHM6G) in deaths involving DHC, and to report the range of concentrations detected in real cases in order to understand their contribution to DHC intoxication. Twenty-six positive postmortem cases were involved in the current study. Five cases were attributed solely to DHC intoxication, 13 cases to polydrug intoxication, and the remainder of the cases were unrelated to DHC (DHC has been detected but is unrelated to the cause of death). DHC and its glucuronide were detected in all cases investigated in blood and urine matrices. Unchanged parent drug is the most abundant analyte detected in blood samples mean and median of DHC/total DHC (DHC plus DHC6G) percentages were 63% and 72%, and DHC6G is the most abundant DHC metabolite in urine with a mean and median DHC6G/TDHC of 69% and 70%, respectively. Blood DHC concentrations ranged from 40 to 166,000 ng/mL and 200 to 159,000 ng/mL in urine. DHC6G concentrations in these cases ranged from 20 to 62,180 ng/mL in blood and 40 to 500,000 ng/mL in urine. However, DHM and its glucuronide were present at lower concentrations than DHC and its glucuronide. In the current study, it can be concluded that concentrations of DHC that cause death may be lower in polydrug intoxication. Concentrations found at autopsy overlapped between toxic and therapeutic concentrations because of the presence of other harmful substances, and death can occur with concentrations below lethal concentrations as reported in Case 1 (500 ng/mL). It has been suggested that DHM and DHM6G may play a major role in assessing the cause of death in cases where DHC is not detected and when it is detected in low concentrations. The current study does not support this hypothesis, and it can be seen clearly from the data reported here that DHM and its glucuronide were not detected where DHC was not detected. Toxic concentrations of DHM and DHM6G were identified in some of these cases; however, the concentration of DHC was enough to cause death on its own. It seems that DHM and DHM6G have less influence in causing death than the parent drug itself.

Phenazepam is a benzodiazepine derivative that has been in clinical use in Russia since 1978 and is not available by prescription in the United States; however, it is attainable through various internet websites, sold either as tablets or as a reference grade crystalline powder. Presented here is the case of a 42-year old Caucasian male who died as the result of combined phenazepam, morphine, codeine, and thebaine intoxication. A vial of white powder labeled "Phenazepam, Purity 99%, CAS No. 51753-57-2, Research Sample", a short straw, and several poppy seed pods were found on the scene. Investigation revealed that the decedent had a history of ordering medications over the internet and that he had consumed poppy seed tea prior to his death. Phenazepam, morphine, codeine, and thebaine were present in the blood at 386, 116, 85, and 72 ng/mL, respectively.

Background: Adverse drug reactions (ADRs) rank as one of the top 10 leading causes of death in the developed world, and the direct medical costs of ADRs exceed $100 billion annually in the United States alone. Pharmacogenomics research seeks to identify genetic factors that are responsible for individual differences in drug efficacy and susceptibility to ADRs. This has led to several genetic tests that are currently being used to provide clinical recommendations. The Canadian Pharmacogenomics Network for Drug Safety is a nation-wide effort established in Canada to identify novel predictive genomic markers of severe ADRs in children and adults. A surveillance network has been established in 17 of Canada's major hospitals to identify patients experiencing specific ADRs and to collect biological samples and relevant clinical history for genetic association studies. To identify ADR-associated genetic markers that could be incorporated into predictive tests that will reduce the occurrence of serious ADRs, high-throughput genomic analyses are conducted with samples from patients that have suffered serious ADRs and matched control patients., Summary: ADRs represent a significant unmet medical problem with significant morbidity and mortality, and Canadian Pharmacogenomics Network for Drug Safety is a nation-wide network in Canada that seeks to identify genetic factors responsible for interindividual differences in susceptibility to serious ADRs., Conclusions: Active ADR surveillance is necessary to identify and recruit patients who suffer from serious ADRs. National and international collaborations are required to recruit sufficient patients for these studies. Several pharmacogenomics tests are currently in clinical use to provide dosing recommendations, and the number of pharmacogenomics tests is expected to significantly increase in the future.

We report an unusual and emerging cause of profound hypokalaemia associated with a severe myopathy, attributable to misuse of Nurofen Plus, a readily available over-the-counter medication containing ibuprofen and codeine, and excessive ingestion of the caffeine-containing energy drink, Red Bull. The mechanism of the hypokalaemia may be ascribed to ibuprofen-mediated type 2 renal tubular acidosis, and caffeine-mediated antagonism of adenosine receptors or intercompartmental shift of potassium into the intracellular space. Practitioners should be aware that patients with codeine addiction who misuse Nurofen Plus may present with severe hypokalaemia complicated by myopathy.

Administering codeine to breast-feeding mothers had been considered safe until the recent death of a breast-fed neonate whose mother had been prescribed codeine. We investigated the risk of opioid poisoning to breast-fed neonates using coupled physiologically based pharmacokinetic models for the mother and child. Neonatal morphine plasma concentrations were simulated for various combinations of cytochrome P450 2D6 (CYP2D6) genotype and morphine clearance, assuming typical breast-feeding schedules and maternal codeine doses of

This work presents two cases of codeine intoxication in 3-year-old monozygotic twin brothers while treated with a codeine slow-release formulation. One child had to be admitted to the hospital, whereas the other one died at home after aspiration of gastric content. The concentrations of codeine and major metabolites including morphine and corresponding glucuronide conjugates were measured by liquid chromatography-tandem mass spectrometry in serum, urine, cerebrospinal fluid, and brain tissue, respectively. A genetic polymorphism study was carried out in order to determine the ability of the children to metabolize codeine by O-demethylation. A pharmacokinetic calculation was also performed to estimate the administered dose of codeine in question. High concentrations of all substances were found in samples of both children. The pharmacokinetic estimate suggests an overdose of codeine, and the possible reasons for the high opiate concentrations are discussed. Furthermore, the postmortem distribution--during and after resuscitation--might play a major role in the interpretation of postmortem concentration levels.

Purpose: Adverse drug reactions (ADRs) rank as the fifth leading cause of death in the western world. The nature and scope of these ADRs in children are not predictable based on post market surveillance reports that rely heavily on adult drug experience. The genotype-specific approaches to therapy in childhood (GATC) national ADR network was established to identify specific ADRs and to improve drug safety through identification of predictive genomic biomarkers of drug risk., Methods: GATC set out to establish a national network of trained surveillance clinicians in pediatric hospitals across Canada. Surveillance clinicians identified, enrolled, and collected clinical data and biological samples from ADR cases and controls. Surveillance was targeted to three ADRs: anthracycline-induced cardiotoxicity, cisplatin-induced hearing impairment, and codeine-induced mortality in breastfed infants., Results: The initial surveillance site was established in September 2005, with 10 sites fully operational by 2008. In 3 years, GATC enrolled 1836 ADR cases and 13188 controls. Target numbers were achieved for anthracycline-induced cardiotoxicity. Modified target numbers were nearly attained for cisplatin-induced hearing impairment. Codeine-induced infant mortality in a breastfed infant was discovered by GATC investigators. A case-control study was subsequently conducted., Conclusion: GATC has demonstrated a model of active and targeted surveillance that builds an important step toward the goal of personalized medicine for children. Effective communication, site-specific solutions and long-term sustainability across the network are critical to maintain participation and productivity. GATC may provide a framework of ADR surveillance that can be adapted by other countries and healthcare systems., (Copyright 2009 John Wiley & Sons, Ltd.)