Unintentional buprenorphine and methadone poisoning in children: a matched observational study.

OBJECTIVE: To compare accidental pediatric poisoning from methadone vs. buprenorphine in terms of clinical indicators and in-hospital morbidity. METHODS: A matched observational study conducted on children aged ≤12 years admitted to our center between March 2018 and March 2019 with acute poisoning from methadone or buprenorphine. Data were extracted from the electronic patient files of the pediatric methadone poisoning cases, and buprenorphine poisoning cases were followed from ED, during the study period. Cases were compared regarding rates of bradypnea/apnea (primary outcome), the need for antidote therapy and intubation, duration of hospital stay, miosis, loss of consciousness, blood gas analyses, and mortality (secondary outcomes). RESULTS: A total of 90 methadone- and 30 buprenorphine-poisoned children were evaluated. Methadone cases had significantly higher rates of apnea (20/90 methadone vs. 0/30 buprenorphine; OR = 17.7, 95% CI 1.1, 302.8; p = 0.047), but there was no group difference in bradypnea (39/90 methadone vs. 10/30 buprenorphine; p = ns). 28 (31%) methadone and 3 buprenorphine (10%) cases had been referred to as fully awake (p = 0.013). Methadone cases required higher median naloxone doses for initial bolus (0.4 vs. 0.02 mg; p = 0.014) and maintenance infusion (14.4 vs. 2.4 mg; p < 0.001). 20 apnea cases (all from the methadone group) had miotic pupils, and miotic pupils were seen in 44 (90%) cases with bradypnea (OR = 3.2, 95% CI 1.1, 9.3; p = 0.026). Intubation was needed in only 5 methadone cases (5.5%; p = ns). All patients survived. CONCLUSION: Compared to children poisoned with methadone, buprenorphine cases had higher rates of loss of consciousness on admission but subsequently experienced fewer complications during hospital treatment, which is likely due to the buprenorphine partial antagonist effect. Our findings suggest that methadone exposure is more toxic than buprenorphine in pediatric populations.

Respiratory depression following medications for opioid use disorder (MOUD)-approved buprenorphine product oral exposures; National Poison Database System 2003-2019.

BACKGROUND: Medications for opioid use disorder (MOUD) including buprenorphine is recommended for patients with opioid use disorders. We sought to evaluate the frequencies of respiratory depression, intubation, and naloxone administration, and clinical outcomes among patients reported to the National Poison Database System (NPDS) following single-substance and multiple-substance buprenorphine oral exposures. METHODS: NPDS was queried for all MOUD-approved buprenorphine product exposures between 1 January 2003 and 31 December 2019. Data abstracted included year, route, gender, age, site of exposure, management site, medical outcome, recorded "related" respiratory depression ("respiratory rate <10 breaths/min and/or a SpO2 (pulse oximetry)≤90%), reported administration of naloxone and intubation in oral exposure cases followed to known outcome. Concomitant products were also recorded in multiple-substance buprenorphine cases. RESULTS: 27,275 (11,010 multiple and 16,265 single) buprenorphine oral exposures were identified and followed to known outcome. A 65-fold increase in reported cases was reported over the study interval. A steady increase in the frequency of more serious outcomes by year was also observed. Respiratory depression occurred at a frequency of 11.8% (pediatric single-substance), 11.2% (pediatric multiple-substance), 11.3% (adult single-substance), and 11.9% (adult multiple-substance). Among oral exposures of buprenorphine and only one other product, benzodiazepines, opioids, ethanol, and amphetamines were most common. CONCLUSIONS: Oral exposures have increased substantially between 2003 and 2019. More serious outcomes including deaths following oral exposures to buprenorphine have also increased over the same interval for both adult and pediatric patients. Clinically significant rates of respiratory depression in both adult and pediatric patients when taken alone and with additional substances were observed.

Buprenorphine exposures in adolescents and adults: a 10-year experience of a French Poison Control Center.

Buprenorphine has been used in pain and opioid addiction management for nearly 25 years. Compared to methadone, buprenorphine is thought to exhibit less side effects and respiratory depression in case of accidental or suicidal overdose. The aim was to describe the characteristics of exposures reported to a French Poison Control Center (PCC). We conducted a retrospective study including all buprenorphine exposures for which advice of our PCC was required between 2009 and 2018. After data extraction from the electronic medical files and anonymous transfer to an Access base, a statistical descriptive analysis was performed focusing on adolescents over 10 years old and adults. One hundred and ninety-nine cases were analyzed. The major circumstances of exposure were suicide attempts and overdoses in patients with previously identified substance abuse. Buprenorphine exposures have been reduced by 50% between 2009 and 2018. Coingestions, often with benzodiazepines or antidepressants, were almost systematic and 79% of all the series exhibited at least one symptom. Among the symptomatic cases, neurological effects were the most frequent (83%) and respiratory symptoms occurred in 13%. No deaths were registered. Severity did not exceed PSS1 in 80% of all the cases. Treatment was mainly symptomatic even though naloxone was required in at least 5% of the symptomatic cases. Within 24 h after exposure, 120 patients were discharged from the emergency department. Despite loss to follow-up, our results suggest that buprenorphine is relatively safe.

Concomitant drugs with buprenorphine user deaths.

BACKGROUND: Buprenorphine is abused in several countries notwithstanding its benefits as an analgesic and as an opioid agonist treatment medication. Benzodiazepines and alcohol have previously been associated with buprenorphine toxicity. This study elucidates the role of emerging concomitant drugs in different groups of buprenorphine user deaths. METHODS: All cases in the Finnish national post-mortem toxicology database from 2016-2019 in which buprenorphine or norbuprenorphine was a laboratory finding in any post-mortem specimen and age at death of 15-64 years were investigated for cause and manner of death, concurrent drug and alcohol findings, age, and gender. RESULTS: There were 792 deaths with a buprenorphine finding, of which buprenorphine was implicated in poisoning without other opioids in 271 cases (34 %). In this group of buprenorphine poisoning deaths, concomitant benzodiazepines were found in 94 % (clonazepam 53 %), illicit drugs in 63 %, gabapentinoids in 50 % (pregabalin 41 %), alcohol in 41 %, antidepressants in 32 %, and antipsychotics in 28 % of cases; only three deaths showed no benzodiazepines, alcohol, or gabapentinoids. Polydrug use was common regardless of the cause of death. In the age group 15 to 24 years, concomitant use of benzodiazepines and illicit drugs, and buprenorphine poisoning were more prevalent than in the age group 25-64 years. CONCLUSIONS: The unprecedentedly high concomitant use of benzodiazepines in buprenorphine user deaths obscures other possible pharmacological risk factors for buprenorphine poisoning that could be relevant for prevention. Higher mortality in the younger age group suggests particularly unsafe drug use patterns that should be addressed.

The impact of the prescription opioid epidemic on young children: Trends and mortality.

BACKGROUND: Our objective was to describe trends and deaths in young children associated with opioid analgesics. METHODS: Analysis of pediatric exposures using the RADARS System Poison Center Program from July 1, 2010 through December 31, 2018. Cases involving a child < 6 years, with an exposure to one or more opioids: buprenorphine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tramadol. Poisson regression was used to model the shape of the time response curve. RESULTS: 48,560 cases were identified, median age 2 years (IQR 1.4, 2.0), 52.4 % male. The most commonly involved opioid was hydrocodone (32.5 %); buprenorphine and methadone had the highest exposure rates when adjusted for dispensed prescriptions (0.84 and 0.73 per 10,000 prescriptions). There were 28 deaths, methadone being the most commonly involved opioid (16). Exposures decreased significantly accounting for population (from 8.39 to 4.19 exposures per 100,000 children) and per prescription (from 0.33 to 0.25 exposures per 10,000 prescriptions). After adjustment for prescriptions, the exposure rate for hydromorphone and fentanyl increased over the study period, while buprenorphine had the greatest decrease in exposure rate. Among 28 deaths, 11 (39 %) were known or suspected to have been exposed, but medical care was not sought or was delayed. CONCLUSION: Pediatric opioid exposure rates by prescription and population decreased from July 2010 through December 2018. However, with over 48,000 exposures and 28 deaths, the opioid epidemic continues to impact young children. Many exposures including deaths were preventable. Continued improvements in prevention require a multifaceted approach.

Epidemiology of pediatric buprenorphine and methadone exposures reported to the poison centers.

BACKGROUND: Buprenorphine prescriptions have increased dramatically within the United States, whereas methadone continues to be used widely. We investigated the trends and characteristics of buprenorphine and methadone exposures in the pediatric population. METHODS: We identified pediatric exposures to buprenorphine and methadone using the National Poison Data System from 2013 to 2016. We descriptively assessed characteristics of the exposures. Trends in exposures were evaluated using generalized linear mixed models. RESULTS: Pediatric buprenorphine exposures increased from 2013 (1097) to 2016 (1226) while methadone calls decreased (486 to 396). After adjusting for the random effects of the geographical region, the mean number of pediatric buprenorphine exposures (per 100,000 pediatric population) increased from 1.3 to 1.5 (P = .05). Conversely, the mean number of methadone exposures decreased from 0.6 to 0.4 (P = .03). Children aged ≤3 years constituted the highest percentage of both exposures. Unintentional exposures accounted for most of the buprenorphine (86.9%) and methadone (62.4%) exposures. Major clinical effects were demonstrated in 2.3% of buprenorphine exposures and were more frequent with methadone (13%). West Virginia and Maryland demonstrated the highest incidence of buprenorphine and methadone exposures, respectively. CONCLUSIONS: Pediatric buprenorphine exposures increased but demonstrated less severe effects compared to methadone exposures, which decreased during the study period.

Investigating opioid-related fatalities in southern Sweden: contact with care-providing authorities and comparison of substances.

BACKGROUND: Opioid-related deaths have increased in Western countries over recent decades. Despite numerous studies investigating opioid-related mortality, only a few have focused on the lives of the deceased individuals prior to their deaths, specifically regarding contact with care-providing authorities such as health, social and correctional services. Furthermore, a change has been noted in the last two decades as to which opioids cause most deaths, from heroin to prescription opioids. However, studies comparing fatalities caused by different substances are rare. The aim of this study was to investigate contact with care-providing authorities during the year prior to death among individuals who died as a result of opioid intoxication and to analyse differences relating to which opioids caused their deaths. METHODS: The study is based on retrospective register data and includes 180 individuals with a history of illicit drug use, who died from opioid intoxication in Skåne, Sweden, between 1 January 2012 to 31 December 2013 and 1 July 2014 to 30 June 2016. Intoxications caused by heroin, methadone, buprenorphine and fentanyl were included. Data were collected from the National Board of Forensic Medicine, regional health care services, municipal social services and the Prison and Probation Service. Statistical testing was performed using Pearson's chi-square test, Fisher's exact test and the Mann-Whitney U test to analyse group differences. RESULTS: A total of 89% of the deceased individuals had been in contact with one or more of the care-providing authorities during the year prior to death; 75% had been in contact with health care, 69% with the social services, 28% with the Prison and Probation Service, and 23% had been enrolled in opioid substitution treatment at some point during their final year of life. Few differences appeared between the substance groups with regard to which opioid contributed to the death. In addition to opioids, sedatives were present in more than 80% of the cases. Individuals whose deaths were buprenorphine-related had been in contact with the social services to a significantly lesser extent during the year prior to death. CONCLUSIONS: The studied population is characterised by extensive contact with care-providing authorities, thus providing numerous opportunities for authorities to reach this group with preventive and other interventions. Few differences emerged between groups with regard to which opioid had contributed to the death.

Veterinary-Prescribed Buprenorphine Ingestion in a 2-Year-Old Girl.

INTRODUCTION: Ingestion of buprenorphine by young children is on the rise and can lead to life-threatening consequences and death. Exposure most often occurs when a child acquires the medication intended for adult use. However, buprenorphine is also prescribed by veterinarians and may be sent home, typically in non-child-resistant packaging, to be administered to the family pet. CASE: A previously healthy 2-year-old girl weighing 11.36 kg was found with a 1-mL syringe containing 0.6 mg/mL of buprenorphine in her mouth. The syringe had been in a plastic bag provided to the family by their veterinarian for the family dog. She was hospitalized for 24 hours but remained asymptomatic and was discharged healthy. This type of exposure to buprenorphine has not previously been described in the literature. CONCLUSIONS: Having this unsecured medication in the home increases the potential risk of exposure for young children and associated health consequences. Pediatricians should be aware of the potential dangers that veterinary pharmaceuticals can pose and educate parents about proper storage of medications. In addition, veterinarians should take extra precautions when dispensing these medications to pet owners with children.

Buprenorphine poisoning in children: a 10-year-experience of Marseille Poison Center.

Buprenorphine is a µ-partial agonist and k-antagonist acting on central opioid receptors. Patented for analgesia in 1968, buprenorphine has been used as opioid substitutive therapy since the 1990s, as well as methadone. The aim was to document pediatric poisoning, to discover the severity, and to evaluate the treatment with naloxone. All pediatric poisonings reported to the poison control center Marseille (France)-from January 1, 2009 to December 31, 2018-were included. Analysis put value on gender, age, estimated quantity, symptoms and their delay, place of treatment, medical treatment, utilization of antidotes, severity of intoxications, and patients' outcome. Fifty-four infant poisonings with buprenorphine were recorded, doses varied between 1 and 36 mg, and children showed mainly neurological (somnolence, miosis…) and gastroenteric (vomiting) effects. Pulmonary effects were described for four children. According to the poisoning severity score, 8 intoxications were classified as 'no symptoms or signs', 37 as minor poisonings, 3 as moderate, none as severe or fatal and 6 were unknown. Medical care was required for 46 children, and four of them were treated with naloxone. Buprenorphine poisoning can cause neurological, gastroenteric, and respiratory symptoms. Even licking a tablet leads to intoxication because of maximal tablet's absorption while placing it under the tongue. Hospital admission is necessary even at small doses. Naloxone was efficient in the four described cases. Parents have to be aware of the poisoning risk with buprenorphine. Recently, commercialized instantly dissolving formulations could cause more severe intoxications.

Epidemiology of severe buprenorphine exposures reported to the U.S. Poison Centers.

OBJECTIVE: This study aims to evaluate the trends and risk factors of severe buprenorphine outcomes (SBO) reported to the U.S. Poison Centers (PCs). METHODS: We queried the National Poison Data System for exposures to buprenorphine from 2011 to 2016. SBO cases were defined as exposures that resulted in either a death or major clinical outcomes. Trends were tested using Poisson regression. Characteristics of the exposures were descriptively assessed. Logistic regression was used to evaluate the risk factors of SBO. RESULTS: SBO cases (967) reported to the PCs increased by 66.6% during this period (114-190, p < 0.001). While adults between 20 and 39 years were more frequent in the SBO group (50.4%) compared to the non-SBO group (38.7%), cases under 6 years (29.6% vs 13.8%) were more common among the non-SBO group. Intentional abuse (20.1% vs 24.9%) and suspected suicides (13.7% vs 37.5%) were significantly higher among the SBO group. Multisubstance exposures were more frequent among the SBO cases (36.4% vs 71.4%). SBO risk increased with age, with cases above 60 years (AOR: 1.66, 95% CI: 1.14-2.42) demonstrating significantly increased odds. Suspected suicide (AOR: 1.87, 95% CI: 1.53-2.28) and abuse (AOR: 1.40, 95% CI: 1.13-1.73) cases were more likely to result in a SBO. Multisubstance exposures significantly increased the risk of a SBO. CONCLUSIONS: This study reflected an increase in the cases of SBO paralleling the rise in the buprenorphine prescriptions. Age, reasons for exposure and multi-substance exposures significantly increased the risk of SBO.

Opioid Deaths in Milwaukee County, Wisconsin 2013-2017: The Primacy of Heroin and Fentanyl.

Heroin and fentanyl are the overwhelming and increasing cause of opioid deaths in Milwaukee County, Wisconsin. We reviewed all drug and opioid deaths from 2013 to 2017 to delineate the specific opioid drugs involved and changes in their incidence. From 2013 to 2017, 980 deaths were due to opioids, rising from 184 in 2013 to 337 in 2017. In 2017, opioid deaths exceeded combined non-natural deaths from homicide and suicide. Illicit heroin and fentanyl/analogs caused 84% of opioid deaths and 80% of drug deaths, with no increase in deaths due to oral prescription drugs such as oxycodone and hydrocodone. Any approach to decreasing this dramatic increase in opioid deaths should first focus on interdicting the supply and cheap availability of these illicit opioids. Fentanyl and its analogs represent the most deadly opioids and the greatest threat to human life in our population.

High buprenorphine-related mortality is persistent in Finland.

Sublingual buprenorphine is used in opioid maintenance treatment but buprenorphine is also widely abused and causes fatal poisonings. The aim of this study was to investigate buprenorphine-positive fatalities in order to gain novel information on the magnitude and nature of buprenorphine abuse. All post-mortem toxicology cases positive for urinary buprenorphine, including fatal poisonings caused by buprenorphine and fatalities in which the cause of death was unrelated to buprenorphine, in the five year period of 2010-2014 in Finland were characterized according to urine buprenorphine and naloxone concentrations (n=775). Urine concentrations were used to assess which buprenorphine preparation had been used; mono-buprenorphine or a buprenorphine-naloxone combination, and whether they had been administered parenterally. In at least 28.8% of the buprenorphine-positive cases the drug had been administered parenterally. The majority of the parenteral users (68.6%) had taken mono-buprenorphine. Fatal poisoning was significantly more common among the identified parenteral users (65.5%) than among other users of buprenorphine products (45.3%). The proportion of buprenorphine-related poisoning was similar in identified parenteral users of mono-buprenorphine (68.6%) and buprenorphine-naloxone (64.1%). In nearly all of the fatal poisoningss the deceased had used other drugs and/or alcohol along with buprenorphine (98.7%). The median age of the deceased increased significantly over the study period, from 32 to 38 years. Our results show that there is ongoing parenteral abuse of both mono-buprenorphine and buprenorphine-naloxone combination. Parenteral users of buprenorphine put themselves into a great risk of fatal poisoning or other accidental injury death which is further exacerbated by the frequent poly-drug use.

Buprenorphine Exposures Among Children and Adolescents Reported to US Poison Control Centers.

OBJECTIVE: To investigate buprenorphine exposures among children and adolescents ≤19 years old in the United States. METHODS: Data were analyzed from calls to US poison control centers for 2007-2016 from the National Poison Data System. RESULTS: From 2007 to 2016, there were 11 275 children and adolescents ≤19 years old exposed to buprenorphine reported to US poison control centers. Most exposures were among children <6 years old (86.1%), unintentional (89.2%), and to a single substance (97.3%). For single-substance exposures, children <6 years old had greater odds of hospital admission and of serious medical outcome than adolescents 13 to 19 years old. Adolescents accounted for 11.1% of exposures; 77.1% were intentional (including 12.0% suspected suicide), and 27.7% involved multiple substances. Among adolescents, the odds of hospital admission and a serious medical outcome were higher for multiple-substance exposures than single-substance exposures. CONCLUSIONS: Buprenorphine is important for the treatment of opioid use disorder, but pediatric exposure can result in serious adverse outcomes. Manufacturers should use unit-dose packaging for all buprenorphine products to help prevent unintentional exposure among young children. Health providers should inform caregivers of young children about the dangers of buprenorphine exposure and provide instructions on proper medication storage and disposal. Adolescents should receive information regarding the risks of substance abuse and misuse. Suspected suicide accounted for 12% of adolescent exposures, highlighting the need for access to mental health services for this age group.

Suicide by Medication Overdose in Prison: A Study of Three Cases.

Suicide is one of the principal causes of mortality in a prison environment. Although suicide by medication overdose is less frequent than suicide by hanging, self-strangulation, or vein cutting, it raises questions as to how the medications are obtained, particularly in view of the specific organization of the medication circuit in prisons. We present three cases of suicide by medication overdose involving different therapeutic classes with different distribution circuits and review the regulatory requirements and the measures that could be taken to prevent such suicides.

Unintentional methadone and buprenorphine exposures in children: Developing prevention messages.

OBJECTIVES: To develop key messages for methadone and buprenorphine safety education material based on an analysis of calls to the NYC Poison Control Center (NYC PCC) and designed for distribution to caregivers of young children. METHODS: Retrospective review of all calls for children 5 years of age and younger involving methadone or buprenorphine from January 1, 2000, to June 15, 2014. A data abstraction form was completed for each case to capture patient demographics, exposure and caller sites, caller relation to patient, qualitative information regarding the exposure scenario, the product information, if naloxone was given, and the medical outcome of the case. RESULTS: A total of 123 cases were identified. The ages of the children ranged from 4 days to 5 years; 55% were boys. All exposures occurred in a home environment. The majority of the calls were made to the NYC PCC by the doctor (74%) or nurse (2%) at a health care facility. Approximately one-fourth of the calls came from the home and were made by the parent (22%) or grandparent (2%). More than one-half of the exposures involved methadone (64%). Naloxone was administered in 28% of cases. Approximately one-fourth of the children did not experience any effect after the reported exposure, one-half (51%) experienced some effect (minor, moderate, or major), and there was 1 death (1%). More than one-half of the children were admitted to the hospital, with 40% admitted to critical care and 13% to noncritical care. Approximately 23% were treated and released from the hospital, and 20% were lost to follow-up or never arrived to the hospital. The remaining 4% were managed on site without a visit to the hospital. CONCLUSION: Exposures to methadone and buprenorphine are dangerous with some leading to serious health effects. Safe storage and disposal instructions are needed for homes where children may be present.

Clinical effects of unintentional pediatric buprenorphine exposures: experience at a single tertiary care center.

CONTEXT: Exploratory buprenorphine ingestions in young children have been associated with clinically significant toxicity. However, detailed data on the clinical presentation and management of these patients are lacking. In an attempt to obtain more comprehensive data, we sought to examine a single center cohort of patients with report of buprenorphine exposure and provide descriptive analysis of rates of respiratory depression, time to respiratory depression, interventions, disposition, and outcomes. STUDY DESIGN: We performed a retrospective cohort study at a single pediatric tertiary care center of children between the age of 6 months and 7 years of age hospitalized between 1 January 2006 and 1 September 2014 with report of buprenorphine or buprenorphine/naloxone exposure. Patients with possible exposure to more than one agent were excluded. We extracted clinical findings, including time to respiratory depression, interventions, and disposition from the medical record. RESULTS: Eighty-eight patients met the inclusion criteria. Seven patients were excluded. The median age was 24 months [IQR 18-30]. 20 patients (23%) received activated charcoal while 48 (55%) were treated with naloxone. 36 (41%) patients were admitted to the ICU. Observed clinical effects included respiratory depression (83%), oxygen saturation by pulse oximetry (SpO2) < 93% (28%), depressed mental status (80%), miosis (77%), and emesis (45%). Median time from exposure to respiratory depression was 263 min [IQR 105-486]. The median hospital length of stay was 22 h [IQR 20-26] and was positively associated with estimated exposure dose (p = 0.002). CONCLUSION: Pediatric patients exposed to buprenorphine are likely to exhibit signs and symptoms of opioid toxicity, including respiratory depression, altered mental status and miosis. Although the majority of patients developed signs of clinical toxicity within 8 h of reported exposure, the optimum duration of monitoring remains unclear.

The relative risk of fatal poisoning by methadone or buprenorphine within the wider population of England and Wales.

OBJECTIVE: To examine the population-wide overdose risk emerging from the prescription of methadone and buprenorphine for opioid substitution treatment in England and Wales. DESIGN: Retrospective administrative data study. SETTING: National databases for England and Wales. PARTICIPANTS/CASES: Drug-related mortality data were drawn from the Office for National Statistics, and prescription data for methadone and buprenorphine were obtained from the National Health Service for the years 2007-2012. During this 6-year period, a total of 2366 methadone-related deaths and 52 buprenorphine-related deaths were registered, corresponding to 17,333,163 methadone and 2,602,374 buprenorphine prescriptions issued. The analysis encompassed poisoning deaths among members of the wider population of England and Wales who consumed, but were not prescribed these medications, in addition to patients prescribed methadone or buprenorphine. MAIN OUTCOME MEASURES: Mortality risk: substance-specific overdose rate per 1000 prescriptions issued; relative risk ratio of methadone in relation to buprenorphine. RESULTS: During the years 2007-2012, the pooled overdose death rate was 0.137/1000 prescriptions of methadone, compared to 0.022/1000 prescriptions of buprenorphine (including buprenorphine-naloxone). The analysis generated a relative risk ratio of 6.23 (95% CI 4.79 to 8.10) of methadone in relation to buprenorphine. UK Borders Agency data were taken into consideration and revealed that only negligible amounts of methadone and buprenorphine were seized on entering UK territory between 2007 and 2012, suggesting domestic diversion. CONCLUSIONS: Our analysis of the relative safety of buprenorphine and methadone for opioid substitution treatment reveals that buprenorphine is six times safer than methadone with regard to overdose risk among the general population. Clinicians should be aware of the increased risk of prescribing methadone, and tighter regulations are needed to prevent its diversion.

Intravenous methadone application as a serious risk factor for an overdose death: methadone-related fatalities in Hamburg from 2007 to 2012.

Methadone plays an increasing role in drug-related deaths in Hamburg. To find out whether intravenous application of methadone plays a relevant role in methadone-related deaths, body fluids of all methadone-positive cases (n=130) and three buprenorphine-positive cases where a urine sample was available (n=58+3) were investigated for disaccharides (sucrose and lactose as markers for intravenous methadone abuse). Sixty-four percent of the urine samples of the methadone cases showed positive results for disaccharides (22 times sucrose alone, range 2 to >1,000 mg/L; 6 times lactose and sucrose; and 9 times lactose alone, range 22 to 382 mg/L). The three buprenorphine cases showed positive results for lactose in urine. In blood, it was not possible to detect any disaccharides. Of the 116 fatal methadone intoxications, 49 % were under opiate maintenance treatment (OMT) at the point of death (A-OMT), 30 % were never in OMT (N-OMT) and 21 % were formerly in an OMT, but not at the point of death (F-OMT). Of the deceased in the OMT group, 12 % (n=7) died within the first 2 weeks of treatment, six of them within the first week. Overall, intravenous abuse of methadone plays a relevant role in methadone-related fatal cases of substituted patients and of drug consumers not in therapy. Thus, it is necessary that therapists keep to the statutory regulations and give take-home doses only after at least 6 months of successful therapy and when there is no suspicion of intravenous abuse.