Chronic pain management remains a major challenge due to the risks associated with conventional treatments, such as opioids and NSAIDs, which carry significant risks, including addiction, tolerance, and adverse side effects, particularly with prolonged use. Combining opioid with nonopioid drugs offer a potential solution, as it may minimize opioid-related side effects by reducing the required opioid dose. We performed a study to compare the analgesic effects and safety of a pregabalin-morphine combination to each drug alone and placebo in healthy volunteers. A randomized, double-blind, placebo-controlled crossover design was used, with subjects receiving 300 mg of pregabalin combined with 3 and 7 mg of morphine, morphine only, pregabalin only, or a double placebo. Analgesic effects and CNS side effects were assessed up to 10 h postdose using nociceptive and neurocognitive test batteries. Results demonstrated that the pregabalin-morphine combination significantly increased pain tolerance compared to either drug alone on several pain tests (cold pressor, electrical burst, electrical stair, and pressure pain) with only minimal additional CNS side effects compared to monotherapy and placebo. This study indicates that validated nociceptive and CNS test batteries were suitable to assess the potential of opioid-sparing combination therapies in an experimental setting.