Combined effects of quetiapine and opioids: A study of autopsy cases, drug users and sedation in rats

Abstract

Fatal opioid poisonings often involve methadone or morphine. This study aimed to elucidate if quetiapine, a widely used sedative antipsychotic medication, may increase the risk of fatal opioid poisoning by additive inhibitory effects on the central nervous system. We used data from 323 cases of fatal methadone or/and morphine poisonings autopsied from 2013 to 2020, a survey of 34 drug users, and performed blinded placebo-controlled studies in 75 Flinders Resistant Line rats receiving three cumulative intraperitoneal doses of vehicle, methadone (2.5, 10 and 15 mg/kg), morphine (3.75, 15 and 22.5 mg/kg), quetiapine (3, 10 and 30 mg/kg) or quetiapine combined with methadone or morphine. Quetiapine was detected in 20.4% of fatal opioid poisonings with a significantly increased frequency over time, primarily in low or therapeutic concentrations, and was not associated with methadone or morphine concentrations. Use of quetiapine, most commonly in low-to-moderate doses to obtain a sleep-inducing or tranquillizing effect, was reported by 67.6% of survey respondents. In the animal studies, a significant impairment of sedation score, performance on the rotarod and open field mobility was observed in all treatment groups compared with vehicle. However, the effect of quetiapine plus the opioid was not significantly different from that of the opioid alone. Thus, no additive sedative effects were observed in rats. Our results suggest that quetiapine is more often an innocent bystander than a contributor to fatal opioid poisoning. However, the combined effects on other parameters, including blood pressure, cardiac rhythm and respiratory rate, need investigation.

Combined effects of methadone and quetiapine on respiratory rate, haemodynamic variables, and temperature in conscious rats

“…Furthermore, a higher cumulative dose of methadone (30 mg/kg) was used in the previous study, 32 indicating that we might have seen an effect with higher doses. We did, however, observe severe sedation in Flinders Resistant Line rats treated with the same doses of methadone in a previous study 4 . Also in the present study, there was almost no movement of rats treated with methadone, indicating the used doses did have a pronounced effect on the central nervous system in rats.…”

“…We used doses of quetiapine that may correspond to therapeutic doses in human treatment. In the previous study of legal autopsy cases and persons using illegal narcotic drugs, 4 quetiapine seemed to be used mostly in low to moderate doses, rendering investigations of therapeutic quetiapine doses relevant. It is, though, important to note that additive effects with other doses and opioids than those used in the present study cannot be excluded.…”

“…Quetiapine induces sedation by antagonizing histamine (H1), alpha and beta‐adrenoceptors 9 . In a previous study, we found no evidence of additive effects of quetiapine and methadone in terms of sedation and locomotor activity in rats 4 . Quetiapine can cause respiratory depression in overdose, 10 induce hypotension through antagonizing alpha‐1 adrenoceptors, and cause prolonged QT‐interval 9 .…”

“…In Denmark, methadone has caused the most opioid‐related deaths in persons using illegal narcotic drugs since 2007 3 . Other concomitantly used drugs may lead to death in methadone poisonings as indicated by a recent study from Western Denmark, showing that other psychoactive substances were detected in post‐mortem blood in 98% of fatal poisonings involving methadone and/or morphine 4 . Benzodiazepines most commonly co‐occurred, and there is evidence that benzodiazepines increase the risk of fatal opioid overdose 5 by additive inhibitory effects on the central nervous system.…”

“…Quetiapine is a widely used second‐generation antipsychotic that can be abused 6 . Over time, quetiapine was detected in an increasing number of fatal poisonings involving methadone and/or morphine in Western Denmark, occurring in 28.9% of cases in 2019–2020 4 …”