The hepatic and developmental toxicity of chronic morphine and disulfiram co-treatment for pain relief - a comprehensive in vitro and in vivo assessment.

Tolerance and opioid-induced hyperalgesia are clinically relevant side effects that may hinder prolonged opioid use. Recent studies report that disulfiram - a drug registered for alcohol use disorder, fully suppresses their onset. Unfortunately, morphine exacerbating the risk of disulfiram-induced acute liver injury has recently been reported. However, the single dose of disulfiram used, vastly exceeded that effective for pain relief. Hence, this study aimed to comprehensively reevaluate the interaction of disulfiram and morphine in terms of liver and developmental toxicity in various models. The antiproliferative effect was studied in the MTS test in human HepG2 cells, following a 5-day exposure to disulfiram and morphine. Cytotoxicity was determined in the lactate dehydrogenase (LDH) assay. Developmental toxicity was assessed in zebrafish larvae by studying hatching rate, morphology, and locomotor activity, following 24 h and 5-day exposure. Liver function markers were tested in rat serum following 19 days of morphine and disulfiram co-treatment. We determined that the combination of morphine and low-dose disulfiram exerted a synergistic antiproliferative effect in HepG2 cells, but was not cytotoxic. However, it delayed the zebrafish hatching rate by 21 % and impaired swim bladder inflation in a concentration-dependent manner. In clinically relevant doses, disulfiram decreased serum alkaline phosphatase levels in morphine-treated rats, but not outside the physiological range. The potential use of disulfiram as a co-analgesic in morphine therapy is not associated with significant liver toxicity, but could potentially be limited in subjects with impaired liver function. Morphine and disulfiram co-treatment may also have a potentially negative impact on lung organogenesis.