title: Toxicological and pathological findings in a series of buprenorphine related deaths. Possible risk factors for fatal outcome.
abstract: Buprenorphine is considered to have little respiratory side effects at therapeutic doses and the partial agonistic properties should produce a "ceiling effect" for respiratory depression at higher doses. Still, there are several reports on buprenorphine related deaths. Most deaths involve drug users and the co-administration of other CNS depressant drugs as well as reduced tolerance have been suggested to be risk factors. The primary aims were to investigate if lack of tolerance and/or co-ingestion of other psychotropic drugs are significant risk factors in buprenorphine fatalities. From July 2005 to September 2009, all autopsy cases where buprenorphine or norbuprenorphine had been detected in femoral blood and where analysis of buprenorphine had been performed in urine were selected. Results from the postmortem examination and toxicology were compiled. Postmortem toxicology was performed using the routine methodology at the laboratory. In total, 97 subjects were included in the study. These were divided into four groups; Intoxication with buprenorphine (N=41), Possible intoxication with buprenorphine (N=24), Control cases where buprenorphine was not the cause of death (N=14), and Unclear (N=18). The metabolite to parent compound ratios in both blood and urine in the Intoxication group were significantly different from those in the Control and Unclear groups. An extensive poly-drug use was seen in all groups with several additional opioids in the Possible group (54%) and in the Unclear group (78%) and hypnotics or sedatives in more than 75% of the Intoxication, Possible, and Unclear cases. Illicit drugs were present in all groups but not to a great extent with amphetamine and tetrahydrocannabinol as the main findings. Interestingly, 4 cases in the Intoxication group presented with no other significant drugs in blood other than buprenorphine. We conclude that a lethal concentration of buprenorphine in blood cannot be defined. Instead the analysis of blood as well as urine can be an important tool to show that the drug was taken shortly before death and to rule out a continuous use of buprenorphine supporting the notion that abstinence is an important risk factor. The presence of alprazolam in more than 40% of the Intoxications and the presence of hypnotics and sedatives in 75% of the Intoxications suggests that these drugs interact with buprenorphine producing toxic effects that buprenorphine alone would not have produced. Still, in 10% of the Intoxications no other drugs were found indicating that under certain circumstances buprenorphine alone may produce respiratory depression resulting in death.
authors.affiliation: Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden. tor.selden@rmv.se
authors.forename: Tor
authors.initials: T
authors.lastname: Seldén
authors.forename: Johan
authors.initials: J
authors.lastname: Ahlner
authors.forename: Henrik
authors.initials: H
authors.lastname: Druid
authors.forename: Robert
authors.initials: R
authors.lastname: Kronstrand
mesh_terms: D000328:Adult; D002047:Buprenorphine / Q000009:adverse effects* / Q000031:analogs & derivatives / Q000032:analysis* / Q000506:poisoning; D016022:Case-Control Studies; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D049429:Forensic Pathology; D053593:Forensic Toxicology; D006801:Humans; D006993:Hypnotics and Sedatives / Q000009:adverse effects / Q000032:analysis; D013287:Illicit Drugs / Q000009:adverse effects / Q000032:analysis; D008168:Lung / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009294:Narcotics / Q000009:adverse effects* / Q000032:analysis* / Q000506:poisoning; D004364:Pharmaceutical Preparations / Q000032:analysis; D063487:Prescription Drug Misuse; D011654:Pulmonary Edema / Q000473:pathology; D012119:Respiration / Q000187:drug effects; D012189:Retrospective Studies; D012307:Risk Factors; D019966:Substance-Related Disorders / Q000097:blood / Q000401:mortality* / Q000652:urine; D055815:Young Adult
chemical_list: D006993:Hypnotics and Sedatives; D013287:Illicit Drugs; D009294:Narcotics; D004364:Pharmaceutical Preparations; D002047:Buprenorphine; C043585:norbuprenorphine