Interactions between Opioids and Lorcaserin, a Serotonin 2C Receptor Agonist: Antinociceptive and Ventilatory‐depressant Effects

Abstract

Lorcaserin, a drug with agonist properties at serotonin (5-HT)2C receptors, was approved in the US for treating obesity and being investigated as a treatment for substance use disorders (SUD) including opioids. Although lorcaserin was withdrawn from the market over concerns of increased cancer risk, there remains significant interest in the potential utility of 5-HT2C receptor agonists for treating SUD. Therefore, it is important to explore interactions that might emerge when 5-HT2C receptor agonists, such as lorcaserin, are combined with other drugs. This study examined interactions between lorcaserin and opioids on antinociception (a primary therapeutic effect of opioids) and ventilatory depression (a primary cause of death from an opioid overdose) in rhesus monkeys. One group (4 females) was studied using the warm water tail withdrawal; tails were immersed in warm water and the latency to tail withdrawal was recorded. In another group (1 male and 3 females), minute volume (ml/min) was measured using head plethysmography. Effects morphine, fentanyl, and lorcaserin alone as well as for each opioid following pretreatment with lorcaserin were determined using cumulative dosing; all drugs were given s.c. When administered alone, morphine, fentanyl, and lorcaserin dose-dependently increased tail withdrawal latency from 48°C water; the doses that produced 50% of the maximum possible effect (ED50) were 0.06 mg/kg (morphine), 0.006 mg/kg (fentanyl), and 0.09 mg/kg (lorcaserin). Pretreatment with 0.1 mg/kg lorcaserin modestly increased latency when administered alone and produced a small (20-30% of the maximum possible effect) increase in effects of small doses of morphine and fentanyl. Morphine, fentanyl, and lorcaserin dose-dependently decreased minute volume; the doses that decreased ventilation to 80% of control (ED80) were 5.8 mg/kg (morphine), 0.05 mg/kg (fentanyl), and 0.75 mg/kg (lorcaserin). Pretreatment with 0.56 mg/kg lorcaserin alone did not alter ventilation but shifted the dose-effect curves for morphine and fentanyl leftward 10- and 5-fold, respectively. Lorcaserin exerted antinociceptive and ventilatory-depressant effects in the range of doses shown to attenuate the abuse-related (e.g., positive reinforcing) effects of opioids in rhesus monkeys. Although lorcaserin had modest antinociceptive effects alone, it did not markedly augment the antinociceptive effects of morphine or fentanyl; any interaction would likely not be more than simple additivity. In addition, lorcaserin potentiated the ventilatory-depressant effects morphine and fentanyl. Taken together, these data indicate that lorcaserin does not improve an important therapeutic effect of opioids (pain relief) and might enhance adverse effects. Whether these interactions extend to other 5-HT2C receptor agonists remains to be determined.