Antinociceptive Effects of Morphine:Ketamine Mixtures in Rats

Chronic pain is a serious public health concern with an economic burden of $600 million annually and personal burden for approximately 100 million Americans. Prescription opioids (mu opioid receptor agonists) are the "gold standard" for treating moderate to severe pain despite their well-documented adverse effects (dependence, respiratory depression, constipation). Of all prescription medications, opioids are abused most widely, and fatal overdoses have reached epidemic levels. Thus, there is a dire need for safer, more effective treatments for pain. One strategy for improving the margin of safety of opioids is combining them with other analgesic drugs to decrease the opioid dose needed for pain relief, thereby avoiding adverse effects that occur with larger doses. The NMDA receptor antagonist ketamine has been used safely and effectively to treat pain, but only under a narrow range of conditions (in emergency departments, post-operative recovery, and combat casualty). The current studies used a model of acute pain (warm water tail withdrawal) and a model of chronic inflammatory pain (Von Frey paw withdrawal) to determine the antinociceptive effects of morphine and ketamine alone and in mixtures (in 3:1, 1:1, and 1:3 ratios) in 16 male Sprague Dawley rats. Given alone, both morphine (1-10 mg/kg) and ketamine (3.2-32 mg/kg) dose-dependently increased tail withdrawal latency, with morphine having greater potency and efficacy as compared to ketamine. Similarly, given alone, both morphine (0.56-5.6 mg/kg) and ketamine (3.2-32 mg/kg) dose-dependency increased force required to elicit a paw withdrawal response, with morphine having greater potency as compared to ketamine. ED values were used to determine the doses for mixtures. In mixtures, the potency of morphine or ketamine to produce antinociception was enhanced by 2-3 fold as compared to either drug given alone. Dose-equivalence and dose-additivity analyses showed that the effects of morphine:ketamine mixtures were additive. Furthermore, morphine:ketamine mixtures that relieved pain also were tested in an assay of constipation in a separate group of 8 rats. While both morphine (1-10 mg/kg) alone and ketamine (3.2-32 mg/kg) alone dose-dependently decreased fecal output, morphine:ketamine mixtures did not enhance constipation. Therefore, morphine:ketamine mixtures appear to selectively enhance antinociception. It remains unknown whether morphine:ketamine mixtures have other adverse effects (abuse, physical dependence, respiratory depression) and whether interactions between morphine and ketamine on these outcomes might be related to the ratio of each drug in mixtures. Morphine:ketamine mixtures might have greater therapeutic potential than mu opioids alone for treating moderate to severe pain, but only if adverse effects of each drug are not enhanced.