Co‐administration of morphine and levamisole increases death risk, produces neutropenia and modifies antinociception in mice

Abstract Levamisole is a veterinary anthelmintic drug and a common adulterant of misused drugs. This study analyses the lethal, antinociceptive and haematological effects produced by acute or repeated levamisole administration by itself or combined with morphine. Independent groups of male Swiss Webster mice were i.p. injected with 100 mg/kg morphine, 31.6 mg/kg levamisole (lethal doses at 10%, LD 10 ) or the same doses combined. Naloxone pretreatment (10 mg/kg, i.p.) prevented morphine‐induced death, as did 2.5 mg/kg, i.p. mecamylamine with levamisole. Co‐administration of levamisole and morphine (Lvm + Mor) increased lethality from 10% to 80%. This augmented effect was prevented by 30 mg/kg, i.p. naloxone and reduced with 10 mg/kg naloxone plus 2.5 mg/kg, i.p. mecamylamine. In independent groups of mice, 17.7 mg/kg, i.p. levamisole antagonized the acute morphine's antinociceptive effect evaluated in the tail‐flick test. Repeated 17.7 mg/kg levamisole administration (2×/day/3 weeks) did not affect tolerance development to morphine (10 mg/kg, 3×/day/1 week). Blood samples obtained from mice repeatedly treated with levamisole showed leukopenia and neutropenia. Morphine also produced neutropenia, increased erythrocyte count and other related parameters (e.g. haemoglobin). Lvm + Mor had similar effects on leukocyte and neutrophil counts to those seen with levamisole only, but no erythrocyte‐related alterations were evident. Blood chemistry analysis did not indicate liver damage but suggested some degree of electrolyte balance impairment. In conclusion, Lvm + Mor increased death risk, altered morphine‐induced antinociceptive effects and produced haematologic abnormalities. The importance of studying combinations of drugs of abuse lies in the fact that drug users frequently combine drugs, which are commonly adulterated.