Deaths related to the combination of pregabalin and other drugs of abuse: About two cases

Abstract

The number of deaths involving pregabalin has dramatically increased in recent years. In the majority of the cases described in France, pregabalin is associated with opioids, mainly methadone, as well as benzodiazepines and other psychoactive drugs, notably antidepressants and antipsychotics. Association with alcohol, cannabis and psychostimulants is also mentioned in the literature (Evoy KE et al. Drugs 2021;81:125–56). In this context, pregabalin concentrations are usually high, above therapeutic concentrations, in order to achieve euphoric effects, to enhance the effects of other substances or to improve sociability (Hofmann M & Besson M. Psychiatry Res 2021;35:114193). The authors present two cases of unusual deaths, a few days apart, for which toxicological analyses, showing low concentrations of pregabalin, buprenorphine, clonazepam and psychostimulants, are in favor of new patterns of use. Case 1: a 30-year-old man with a known addiction to pregabalin and cocaine, was seen by a witness snorting buprenorphine. He was found dead two hours later. Case 2: A young homeless man is found dead in the street in the early hours of the morning. No information is available on his identity and medical history. In both cases, the autopsy performed within 48 hours only show diffuse polyvisceral congestion with major cerebral and pulmonary oedema and the pathological examination did not allow to determine the cause of death. The usual toxicological samples, including femoral blood, with sodium fluoride as preservative, were collected and complete toxicological analyses were requested. Analyses were performed in femoral blood. Alcohols were measured by HS-GC-FID. Non-targeted screening and simultaneous quantification was performed by LC-HRMS. Specific detection of drugs of abuse (DOA) was done by LC-MS/MS. In case 1, analyses showed the presence of pregabalin (4900 ng/mL), buprenorphine (2.5 ng/mL), norbuprenorphine (2.5 ng/mL), 7-aminoclonazepam (14 ng/mL), diazepam (51 ng/mL), nordiazepam (137 ng/mL), oxazepam (7 ng/mL), cocaine (4 ng/mL), benzoylecgonine (177 ng/mL), ecgonine methylester (33 ng/mL) and THC-COOH (4 ng/mL). In case 2, results showed the presence of pregabalin (5700 ng/mL), buprenorphine (4.5 ng/mL), norbuprenorphine (0.5 ng/mL), 7-aminoclonazepam (23 ng/mL), MDMA (1140 ng/mL) and MDA (54 ng/mL). Alcohol testing was negative in both cases. In both cases, the concentrations of pregabalin, benzodiazepines and buprenorphine are far below the toxic concentrations. While the risk of death when buprenorphine is combined with benzodiazepines at therapeutic doses, particularly when buprenorphine is injected or absorbed nasally (Sansone RA & Sansone LA. Innov clin NeuroSci 2015;12:32–6), is well described in the literature, the potential role of pregabalin remains to be determined. Indeed, if the combination of gabapentinoids/opioids/other depressants is known to favor the occurrence of respiratory depression, it seems that the favoring factors are a high dose, an advanced age and co-morbidities (chronic pulmonary disease, renal insufficiency in particular) (Gomes T. et al. PLoS Med 2017;14:e1002396). Finally, if the epidemiological profile of the two victims is compatible with the data found in the literature concerning pregabalin misuse (young man, history of addiction for case n o 1), these results are in favor of new patterns of use.