Buprenorphine-Related Deaths in North Carolina from 2010 to 2018.

Buprenorphine (BUP) is a commonly prescribed medication for the treatment of opioid use disorder (OUD). As prescriptions increase in North Carolina, BUP is more frequently encountered statewide in routine postmortem casework. Between 2010 and 2018, there were 131 select cases investigated by the Office of the Chief Medical Examiner where BUP was detected in peripheral blood and considered a primary cause of death (COD), with no other opioids present and no other non-opioid substances found in the lethal range. The decedents ranged in age from 14 to 64 years, with 67% male. The mean/median peripheral blood concentrations were 4.1/2.1 ng/mL for BUP and 7.8/3.4 ng/mL for its metabolite, norbuprenorphine. These postmortem blood concentrations overlap antemortem therapeutic concentrations in plasma reported in the literature for opioid-dependent subjects receiving sublingual maintenance therapy. The pathologist considered scene findings, prescription history, autopsy findings, toxicological analysis and decedent behavior prior to death to conclude a drug-related COD. Many of the deaths were complicated by the presence of other central nervous system depressants along with contributory underlying cardiovascular and respiratory disease. The three most prevalent additive substances were alprazolam, ethanol and gabapentin, found in 67, 36 and 32 cases out of 131, respectively. Interpreting BUP involvement in a death is complex, and instances may be underestimated in epidemiological data because of the lack of a defined toxic or lethal range in postmortem blood along with its good safety profile. As expansion of access to OUD treatment becomes a priority, awareness of the challenges of postmortem interpretation is needed as increased use and diversion of BUP are inevitable.

Degradation of Bupropion: Implications for Interpretation of Postmortem Case Data.

The interpretation of postmortem bupropion is often a challenge to the forensic toxicology community because of the instability of the parent compound. At the North Carolina Office of the Chief Medical Examiner (NC OCME) toxicology laboratory, one of the active metabolites, threobupropion, is used as a complementary indicator for the extent of exposure to the parent compound. Metabolite data will address postmortem normal concentrations as well as when bupropion was attributed to the cause of death. For 55 natural cases where bupropion was unattributed to the cause of death, the blood and liver mean threobupropion concentrations were 1.8 mg/L and 12.1 mg/kg, respectively, with median concentrations of 1.5 mg/L and 10 mg/kg, respectively. For the 51 suicidal ingestion cases when bupropion was attributed to the cause of death, the blood and liver mean threobupropion concentrations were 15.8 mg/L and 131.5 mg/kg, respectively, with median concentrations of 13.5 mg/L and 110 mg/kg, respectively. The laboratory completed a stability study over the course of 50 days to evaluate how bupropion and threobupropion degrade in postmortem blood, liver and liver homogenate. The samples were subjected to forensically relevant conditions by storing them at room temperature (RT, 20°C), refrigerated (4°C) and frozen (-20°C). While the concentration of bupropion decreased in all specimens, the rate of degradation of the RT samples was the most dramatic. The threobupropion metabolite appeared to be relatively stable. The postmortem case data along with the evaluation of potential degradation products should provide an overall picture to assist the toxicological community with the interpretation of bupropion found in routine casework.

Loperamide-Related Deaths in North Carolina.

Loperamide (Imodium®) has been accepted as a safe, effective, over-the-counter anti-diarrheal drug with low potential for abuse. It is a synthetic opioid that lacks central nervous system activity at prescribed doses, rendering it ineffective for abuse. Since 2012, however, the North Carolina Office of the Chief Medical Examiner has seen cases involving loperamide at supratherapeutic levels that indicate abuse. The recommended dose associated with loperamide should not exceed 16 mg per day, although users seeking an opioid-like high reportedly take it in excess of 100 mg per dose. When taken as directed, the laboratory organic base extraction screening method with gas chromatography-mass spectrometry/nitrogen phosphorus detector lacks the sensitivity to detect loperamide. When taken in excess, the screening method identifies loperamide followed by a separate technique to confirm and quantify the drug by liquid chromatography-tandem mass spectrometry. Of the 21 cases involving loperamide, the pathologist implicated the drug as either additive or primary to the cause of death in 19 cases. The mean and median peripheral blood concentrations for the drug overdose cases were 0.27 and 0.23 mg/L, respectively. Furthermore, an extensive review of the pharmacology associated with loperamide and its interaction with P-glycoprotein will be examined as it relates to the mechanism of toxicity.