Toxicological and pathological findings in a series of buprenorphine related deaths. Possible risk factors for fatal outcome Tor Selde ´n a,b, *, Johan Ahlner a,b , Henrik Druid c,d , Robert Kronstrand a,b a Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linko ¨ping, Sweden b Division of Drug Research, Linko ¨ping University, Linko ¨ping, Sweden c Department of Forensic Medicine, National Board of Forensic Medicine, Linko ¨ping, Sweden d Department of Oncology–Pathology, Karolinska Institutet, Stockholm, Sweden 1. Introduction Buprenorphine is a semi-synthetic opioid widely used in treatment of opioid addiction under the trade names Subutex 1 and Suboxone 1 . The doses range from 1 up to 32 mg/day but it is also used to treat moderate to severe chronic pain with therapeutic doses of 0.2–0.8 mg/day. Many of the opioids have severe adverse effects, respiratory depression being one of the more serious that can lead to coma and death. The respiratory depression is caused by a decreased sensitivity to carbon dioxide at chemoreceptors in the medulla oblongata and is thought to be mediated by the mu-receptor subtype [1]. There are three receptor subtypes, mu, kappa, and delta that all are G-protein coupled. Buprenorphine is a partial agonist at the mu- receptor and a weak antagonist at the kappa-receptor. At therapeutic doses buprenorphine is considered to have little respiratory side effects and the partial agonistic properties should Forensic Science International 220 (2012) 284–290 A R T I C L E I N F O Article history: Received 14 December 2011 Received in revised form 8 March 2012 Accepted 16 March 2012 Available online 6 May 2012 Keywords: Buprenorphine Respiratory depression Poly-drug use Postmortem toxicology Death A B S T R A C T 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. ß 2012 Elsevier Ireland Ltd. All rights reserved. * Corresponding author at: National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Artillerigatan 12, SE-587 58 Linko ¨ ping, Sweden. Tel.: +46 13252100. E-mail address: tor.selden@rmv.se (T. Selde ´ n). Contents lists available at SciVerse ScienceDirect Forensic Science International jou r nal h o mep age: w ww.els evier .co m/lo c ate/fo r sc iin t 0379-0738/$ – see front matter ß 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.forsciint.2012.03.016