Rates of reported codeine-related poisonings and codeine prescribing following new national guidance in Ireland.

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 (ß2 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.

Lack of respiratory depression in paracetamol-codeine combination overdoses.

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.

Short-term UROD treatment on cerebral function in codeine-containing cough syrups dependent male individuals.

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.

INVESTIGATION OF A MIXTURE CONTAINING ALPRAZOLAM, CODEINE AND PARACETAMOL USING THIN-LAYER AND HIGH PERFORMANCE LIQUID CHROMATOGRAPHY METHODS.

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.

Orally ingestion of krokodil in Spain: report of a case. / Consumo de krokodil por vía oral en España: a propósito de un caso.

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.

El trastorno por uso de krokodil es una de las patologías adictivas con mayores repercusiones orgánicas, principalmente a nivel cutáneo, produciendo una grave y degenerativa necrosis del tejido sanguíneo y muscular. Se trata de un trastorno con escasa prevalencia en España, frente al elevado número de consumidores en otros países como Ucrania o Rusia, si bien se está produciendo una lenta aunque gradual expansión del consumo en países de la Unión Europea y del continente americano. El sencillo proceso de obtención de la sustancia desde la desomorfina, unido a la elevada disponibilidad y bajo coste, configura el proceso de autoabastecimiento de los consumidores. En este artículo revisamos un cuadro clínico, presentando el caso de un paciente que consume krokodil por vía oral.

Trends and characteristics of accidental and intentional codeine overdose deaths in Australia.

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.

[Perianal and rectal ulcers due to abuse of paracetamol-codeine suppositories]. / Perianale und rektale Ulzera nach Abusus von Paracetamol-Codein-Suppositorien.

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.

[Life-threatening opioid overdose. Decoding the physician pin code of a patient-controlled anesthesia pump by patients]. / Lebensbedrohliche Opioidüberdosierung. Entschlüsselung des Arztboluscodes einer Schmerzpumpe durch Patienten.

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.

A fatal case due to cough syrup abuse.

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.

Deaths of opiate/opioid misusers involving dihydrocodeine, UK, 1997-2007.

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.

Pharmacists' experiences with dispensing opioids: provincial survey.

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.

Toxicological detection of pholcodine in blood, urine and hair in three cases of fatal intoxication.

Pholcodine is an opioid antitussive reputed for its low toxicity and absence of addictive effect. We report three cases of pholcodine intoxication with fatal outcome. Large concentrations of pholcodine were quantified by gas chromatography coupled to mass spectrometry (GC/MS) in peripheral postmortem blood (respectively 2890 ng/mL, 979 ng/mL and 12,280 ng/mL). Segmental hair analyses by GC/MS and detected pholcodine in three 1.5-2 cm segments (38-161 ng/mg, 8.54-41.6 ng/mg, and 0.26-2.66 ng/mg, respectively). These findings underline that pholcodine can be involved in fatal poisoning and raise the question of misuse or abuse and of taking account of this drug in opioid overdose prevention policies.

Trends in hydrocodone combination product exposures reported to California Poison Control System (CPCS) following DEA rescheduling.

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.

Codeine use and harms in Australia: evaluating the effects of re-scheduling.

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.

Comparing rates and characteristics of ambulance attendances related to extramedical use of pharmaceutical opioids in Victoria, Australia from 2013 to 2018.

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.

Fatal and severe codeine intoxication in 3-year-old twins--interpretation of drug and metabolite concentrations.

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.