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.

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.

Development and implementation of procedures for outpatient naloxone prescribing at a large academic medical center.

PURPOSE: An interprofessional initiative to operationalize outpatient naloxone prescribing at a large academic medical center is described. SUMMARY: The initiative was carried out by a work group of clinical pharmacists and pharmacy administrators in collaboration with physicians and nursing staff leaders from multiple practice settings. An opioid overdose risk-assessment guide was developed on the basis of literature review and expert opinion. An institutional policy to guide identification of high-risk patient populations and facilitate naloxone prescribing and dispensing was developed and vetted by multiple expert committees. Patient education materials were created, and patients at high risk for opioid overdose were educated about overdose risk factors and naloxone use by a pharmacist and/or nurse before discharge or, in some cases, by outpatient pharmacists; when feasible, patients' friends, family members, and/or caregivers were included in education sessions. Interventions included distribution of a pamphlet emphasizing the importance of contacting emergency medical services personnel immediately in the event of an overdose, depicting the process for administration of injectable and nasal spray formulations of naloxone, and providing information on other first-response steps. Collaboration with outpatient pharmacies allowed for successful dispensing of naloxone prescriptions. CONCLUSION: The implementation of an outpatient naloxone prescribing policy at a large academic medical center created a streamlined approach for the interprofessional healthcare team to use in providing naloxone education and improved naloxone access to patients at high risk for opioid overdose.

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.

Unit-Dose Packaging and Unintentional Buprenorphine-Naloxone Exposures.

BACKGROUND AND OBJECTIVES: Buprenorphine accounts for the most opioid-related pediatric hospital admissions when compared with other opioid analgesics. Since 2010, several manufacturers began distributing their buprenorphine products with unit-dose packaging (UDP). Our main objective in this study is to evaluate the impact of UDP on unintentional pediatric buprenorphine-naloxone poison center exposures. METHODS: This is an observational surveillance study in which the Researched Abuse, Diversion, and Addiction-Related Surveillance System Poison Center Program is used. The main outcome was cases of unintentional ingestions involving children <6 years old and buprenorphine-naloxone (combination) products. The study was split into 3 periods: pre-UDP (first quarter 2008 through fourth quarter 2010), transition to UDP (first quarter 2011 through fourth quarter 2012), and post-UDP (first quarter 2013 through fourth quarter 2016). RESULTS: Overall, there were 6217 exposures to combination products. In the pre-UDP period, there were 20.57 pediatric unintentional exposures per 100 000 prescriptions dispensed; in the transition to UDP period, there were 8.77 pediatric unintentional exposures per 100 000 prescriptions dispensed; and in the post-UDP period, there were 4.36 pediatric unintentional exposures per 100 000 prescriptions dispensed. This represents a 78.8% (95% confidence interval: 76.1%-81.3%; P < .001) relative decrease from the pre-UDP period. CONCLUSIONS: The shift from non-UDP to UDP in over 80% of buprenorphine-naloxone products was associated with a significant decrease in unintentional pediatric exposures reported to poison centers. Packaging controls should be a mainstay in the approach to the prevention of unintentional buprenorphine pediatric exposures as well as exposures to other prescription opioids.

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.

Parenteral buprenorphine-naloxone abuse is a major cause of fatal buprenorphine-related poisoning.

Buprenorphine (BPN) medication for opioid maintenance treatment in Finland consists predominantly of buprenorphine-naloxone (BNX). Both BPN and BNX are associated with diversion, abuse and non-medically supervised use worldwide. Our purpose was to estimate the proportion of BNX to all BPN-related fatalities. The material consisted of 225 deceased drug abusers in Finland from January 2010 to June 2011 with a positive BPN and/or norbuprenorphine (NOR) and/or naloxone (NX) finding in urine. The data were divided into three groups based on the urine NX and BPN concentrations. The "Parenteral BNX" group (>100 µg/l NX) was presumed to consist of injecting or snorting BNX abusers and the "Parenteral BPN" group (>50 µg/l BPN, 0 µg/l NX) of injecting or snorting BPN abusers, while the "Other BNX or BPN" group (≤100 µg/l NX, or ≤50 µg/l BPN combined with 0 µg/l NX) was presumed to consist of mainly sublingual BNX or BPN users. In 12.4% of cases the NX urine concentration was higher than the threshold 100 µg/l. In fatal BPN poisonings, the proportion of parenteral BNX was 28.4%. In the "Parenteral BNX", "Parenteral BPN" and "Other BNX or BPN" groups, the proportion of fatal BPN poisonings was 67.9, 31.0 and 22.6%, respectively. BNX abuse can be fatal. Among the 225 BPN-related fatalities, parenteral abuse of BNX was shown to be common (12.4%) and BNX poisoning was the underlying cause of death in 8.4%. Parenteral BNX caused fatal BPN poisoning proportionally more often than parenteral BPN.

Medical outcomes associated with nonmedical use of methadone and buprenorphine.

BACKGROUND: There exists a significant amount of misinformation regarding methadone and buprenorphine, and a belief that toxicity associated with nonmedical use of methadone and nonmedical use of buprenorphine is similar in severity and outcomes. OBJECTIVE: The objective of this study is to compare outcomes associated with nonmedical use of methadone vs. nonmedical use of buprenorphine in patients presenting to the Emergency Department (ED) and reported to poison centers. METHODS: This was a retrospective cohort study using data from the American Association of Poison Control Centers from January 1, 2003 to December 31, 2009 (7 years). Inclusion criteria were nonmedical use of methadone or buprenorphine (or buprenorphine/naloxone) as a single substance by history, age 18 years or older, ingestions only, evaluated in an ED. Outcome measures were clinical effects, treatments, disposition, and final medical outcomes. RESULTS: Of 1,920 cases, 1,594 were in the methadone group and 326 were in the buprenorphine group. Frequently reported clinical effects were lethargy, 59.2% vs. 29.4%, and respiratory depression, 28.7% vs. 2.5%, for methadone and buprenorphine groups, respectively. Hospitalization rates were 67.4% in the methadone group and 32.2% in the buprenorphine group. Half of all patients in the methadone group were admitted to the intensive care unit (ICU) vs. only 15% of all the patients in the buprenorphine group. Twenty-six patients in the methadone group died vs. no deaths in the buprenorphine group. There were significant differences in the distribution of clinical effects, disposition, and medical outcomes (p < 0.001). CONCLUSIONS: Patients who use methadone nonmedically have higher hospitalization rates, greater ICU utilization rates, and considerably worse medical outcomes when compared with patients who use buprenorphine nonmedically.

Buprenorphine prescribing practices and exposures reported to a poison center--Utah, 2002-2011.

Buprenorphine is an effective medication for the treatment of opioid dependence. Its use has increased in the United States as a result of the Drug Addiction Treatment Act of 2000, which allowed physicians to prescribe certain medications as part of office-based treatment for opioid addiction. In France, widespread use of medication-assisted therapy, primarily buprenorphine treatment, was associated with an 80% decrease in overdose deaths from heroin or cocaine from 465 in 1996 to 89 in 2003. With the expanded use of buprenorphine, an increase in exposures among children and adults has been reported in the United States. These exposures (including unintentional and intentional, therapeutic and nontherapeutic) have resulted in adverse effects and, in a small number of cases, death. To assess statewide increases in buprenorphine use and the number of reported exposures, the Utah Department of Health analyzed data from the Utah Controlled Substance Database (CSD) and the Utah Poison Control Center (PCC). The results of that analysis indicated a statewide increase in the annual number of patients prescribed buprenorphine from 22 in 2002 to 9,793 in 2011, and a concurrent increase in the annual number of prescribers writing buprenorphine prescriptions from 16 to 1,088. Over the same period, the number of exposures to buprenorphine reported annually to the PCC increased from six to 81. However, comparison of the ratios of buprenorphine exposures to patients and prescribers in 2002 with data for 2011 indicated substantial decreases from 6/22 for patients and 6/16 for prescribers in 2002 to 81/9,793 for patients and 81/1,088 for prescribers in 2011. Three of the total 462 buprenorphine exposures reported during 2002-2011 in Utah, in a teen and two adults, were associated with fatal outcomes. Increased buprenorphine prescribing in Utah during 2002-2011 likely represents expanded access to critically needed opioid addiction treatment; however, safeguards should be in place to prevent adverse effects. Prescribers and pharmacists are encouraged to counsel patients carefully regarding the safe use, storage, and disposal of buprenorphine.

Buprenorphine may not be as safe as you think: a pediatric fatality from unintentional exposure.

Buprenorphine is a partial µ-opioid receptor agonist that is approved for the treatment of opioid dependency. It is generally believed to be safer than methadone because of its ceiling effect on respiratory depression. As more adults in US households use buprenorphine, an increasing number of children are being exposed. We report a fatal exposure to buprenorphine in a small child that occurred after ingestion of a caretaker's buprenorphine/naloxone. Postmortem toxicology analysis showed free serum concentrations of 52 ng/mL and 39 ng/mL for buprenorphine and norbuprenorphine, respectively. No other drugs were detected. Autopsy did not find signs of injury or trauma. The theoretical safety provided by the ceiling effect in respiratory depression from buprenorphine may not apply to children, and buprenorphine may cause dose-dependent respiratory depression.

Toddlers requiring pediatric intensive care unit admission following at-home exposure to buprenorphine/naloxone.

BACKGROUND: Sublingual buprenorphine is an alternative to methadone for office-based treatment of opioid dependence. Recent reports have examined a growing number of unintentional buprenorphine exposures in children resulting in significant toxicity, even after a single lick or taste of a sublingual tablet. Here, we report a series of unintentional buprenorphine exposures in toddlers over a 2.5-yr period that led to admission to the pediatric intensive care unit. OBJECTIVES: The goals of this study were to determine: 1) the prevalence of symptomatic buprenorphine exposure in children <3 yrs of age; 2) the severity of toxicity associated with such exposures; and 3) effective clinical interventions. METHODS AND MAIN RESULTS: A retrospective case review was performed on records from the pediatric intensive care unit at an academic medical center located in the northeastern United States. Unintentional buprenorphine/naloxone exposure (n = 9) accounted for the largest single fraction of toxic ingestions among patients younger than 3 yrs within the study period (9/33, 27%). All exposures occurred at the child's place of residence (n = 9, 100%). Clinical signs of opioid toxicity were evident in all nine cases, with the most common symptom being drowsiness or lethargy (n = 9, 100%), followed by miosis (n = 6, 67%) and respiratory depression (n = 5, 56%). Six patients were effectively treated with naloxone (n = 6, 67%). CONCLUSIONS: The increased use and similarity to candy of the current formulation of buprenorphine pose a special risk to children, especially toddlers. Buprenorphine exposure in children <3 yrs old can cause significant opioid toxidrome. Naloxone is an effective agent for reversal of symptoms; however, given buprenorphine's high affinity and long action, higher doses or continuous infusion may be required. Adults on buprenorphine should be educated on the risks posed to young children in their household and the appropriate storage of medication.

Were the changes to Sweden's maintenance treatment policy 2000-06 related to changes in opiate-related mortality and morbidity?

AIMS: To analyse whether changes in maintenance treatment of opiate-dependent subjects in Sweden were related to changes in opiate-related mortality and inpatient care from 1998 to 2006. DESIGN: We collected data from surveys of methadone maintenance treatment units, of buprenorphine and methadone sales, and of mortality and inpatient care in Sweden. SETTING: Sweden. PARTICIPANTS: Patients in maintenance treatment. MEASUREMENTS: Survey data of treatment policy to all units in 2003 and 2005. Trend tests and correlation analyses of data on sales, mortality, inpatient care and forensic investigations. FINDINGS: The surveys showed a marked change to a less restrictive policy, with increased use of 'take-away doses' and a reduction of discharges due to side misuse. The one-year retention rate stayed high. Sales of buprenorphine and methadone and the number of patients in treatment increased more than threefold from 2000 to 2006, with the greatest increase for buprenoprphine, introduced in year 2000. There was a significant 20-30% reduction in opiate-related mortality and inpatient care between 2000-2002 and 2004-2006 but not of other drug-related mortality and inpatient care. This decline was larger in Stockholm County, which had a less restricted treatment policy. However, a significant increase in buprenorphine- and methadone-related mortality occurred. For the study period 1998-2006, statistically significant declines occurred only in Stockholm County. CONCLUSIONS: The liberalization of Sweden's drug policy correlated with an increase in maintenance treatment, a decrease in opiate-related mortality and inpatient care and an increase in deaths with methadone and buprenorphine in the tissues.

[Mechanisms of opioid-induced overdose: experimental approach to clinical concerns]. / Etude du mécanisme des overdoses aux opioïdes : apport de l'expérimental à la clinique.

The widely used term "overdose" denotes a toxic effect: opioid-induced intoxication and a mechanism: the poisoning results only from an overdose. Surprisingly, our understanding of the pathophysiology of this deadly complication is limited. In drug users, we attempted to: (1) improve knowledge of drug-induced respiratory effects; (2) clarify the mechanisms of drug interactions; (3) identify factors of variability and vulnerability. A prospective study of opioid overdoses confirmed that poisonings involving buprenorphine do exist. However, the mechanisms of buprenorphine poisoning are more complex than only an overdose, particularly the severity is less than that induced by heroin. In contrast, methadone overdose is life-threatening. Experimental studies addressed several clinical questions and also showed limited discrepancies. At pharmacological doses, opioids decrease the ventilatory response to CO(2). However, this effect does not account for the morbimortality of opioid poisonings. The mechanisms of opioid-induced morbimortality are different. Buprenorphine at doses near its median lethal dose did not induce acute respiratory failure as defined by a decrease in the partial pressure of oxygen in arterial blood (PaO(2)). In contrast, the combination of buprenorphine with flunitrazepam results in a decrease in PaO(2). This harmful interaction does not exist with other benzodiazepines in the rat, except for very high doses of nordazepam. The interaction results from a pharmacokinetic process. In contrast, methadone causes a dose-dependent decrease in PaO(2,) even significant before hypercapnia. We are assessing the relationships between on one hand alterations of ventilatory pattern and of arterial blood gas and on the other hand the different types of opiate receptors in the rats.

Clinical and diagnostic features of delayed hypoxic leukoencephalopathy.

Delayed hypoxic leukoencephalopathy is an underrecognized syndrome of delayed demyelination, which is important to consider when delayed onset of neuropsychiatric symptoms follows a hypoxic event. The authors describe clinical and diagnostic features of three such cases, review the pathophysiology of delayed hypoxic leukoencephalopathy, and discuss features which may help distinguish it from toxic leukoencephalopathy.

Suboxone (buprenorphine/naloxone) toxicity in pediatric patients: a case report.

BACKGROUND: Suboxone, a combination of buprenorphine and naloxone in sublingual tablet form, was recently approved in the United States for management of opioid dependence. Little information exists regarding the potential for opioid toxicity after Suboxone exposure in the pediatric population. We report a case of opioid toxicity after exposure to Suboxone in a pediatric patient and a review of other cases of pediatric Suboxone ingestion in the literature. CASE: A previously healthy 2-year-old boy was found with 1 tablet of Suboxone (8 mg buprenorphine/2 mg naloxone) in his mouth. Remnants of the partly dissolved tablet were immediately removed from the child's oropharynx. The child experienced 1 episode of spontaneous emesis and became drowsy en route to the emergency department 30 minutes after the exposure. The patient was observed in the emergency department; no interventions were necessary, and the child was discharged asymptomatic and stable 6 hours post ingestion. CONCLUSION: Suboxone, a combination of buprenorphine and naloxone, may produce opioid toxicity via sublingual absorption or ingestion by children. We present the case of a child with mild central nervous system depression after exposure to Suboxone. Pediatric case reports that demonstrate more significant central nervous system and respiratory depressant effects from Suboxone ingestion are emerging.

Opioid overdose deaths can occur in patients with naltrexone implants.

From Australian coronial records, we identified five deaths involving implantable naltrexone between 2000 and 2004. One man died from acute narcotism with a naltrexone implant in place and a blood naltrexone level of 0.3 mg/L. A woman died of combined drug effect (including naltrexone) accompanied by severe pain from a naltrexone implant site. These cases indicate that patients can die from opioid overdose with a naltrexone implant and blood naltrexone levels higher than reported blockade levels.

A survey of buprenorphine related deaths in Singapore.

Buprenorphine is available in Singapore as substitution treatment for opioid dependence since 2002. This study surveys buprenorphine related deaths in Singapore between September 2003 and December 2004. The aims are to establish the autopsy prevalence of buprenorphine related deaths and the demographical and toxicological profile of the cases. Toxicological screening was performed for all unnatural deaths, deaths involving known drug addicts, as well as when autopsy revealed no obvious cause of death. Twenty-one cases had buprenorphine detected in post-mortem blood and/or urine samples. Eighteen were sudden deaths. There were two fatal falls from height and one death by hanging. All subjects were male. The age range was 24-48 years. Fourteen subjects were between 30 and 39 years of age. The mean age was 35 years. The majority (62%) were Chinese. Eleven (52%) were known drug abusers. For sudden deaths, two groups were identified. Six cases died from natural causes. Blood buprenorphine levels ranged from undetected (detected in urine) to 3.2 ng/mL (mean 1.4 ng/mL). Twelve cases were attributed directly and indirectly to mixed drug poisoning. Blood buprenorphine levels ranged from undetected (detected in urine) to 17 ng/mL (mean 3.2 ng/mL). Nineteen cases showed concurrent abuse of buprenorphine and benzodiazepine, diazepam being the most frequently detected, followed by nitrazepam and midazolam. The availability of buprenorphine as substitution therapy is associated with an increase in buprenorphine related deaths. The danger of co-abuse of buprenorphine and benzodiazepines is highlighted.