Abstract Objective The aim of this study was to test whether a combination of sumatriptan with dual enkephalinase inhibitor PL37 would result in an additive or a synergistic effect. Background Combination treatment is frequently used to improve the therapeutic efficacy of drugs. The co‐administration of two drugs may result in efficacy at lower doses than those needed for either drug alone, thus minimizing side effects. Here, we tested the effect of the co‐administration of two drugs on cutaneous mechanical hypersensitivity (MH), a symptom often affecting cephalic regions in patients with migraine: dual enkephalinase inhibitor PL37, a small molecule that protects enkephalins from rapid degradation, and sumatriptan, a serotonin 5‐HT 1B/1D receptor agonist. Methods We investigated the effects of oral administrations of sumatriptan, PL37, or their combination on changes in cutaneous mechanical sensitivity induced by a single intraperitoneal administration of the nitric oxide donor, isosorbide dinitrate (ISDN) in male rats. Mechanical sensitivity was assessed using von Frey filaments applied to the face of animals to determine pain thresholds. Isobolographic analysis was performed to determine the nature of the interaction between sumatriptan and PL37. Results Sumatriptan as well as PL37 each produced a dose‐dependent inhibition of ISDN‐induced cephalic MH. Median effective dose (ED 50 ) values were 0.3 and 1.1 mg/kg for sumatriptan and PL37, respectively. An isobolographic analysis of the effect of combined doses of sumatriptan and PL37 based on their calculated ED 50 values demonstrated a synergistic effect of the combination on cephalic MH, with an interaction index of 0.14 ± 0.04. Conclusion These results suggest that PL37 acts synergistically with sumatriptan to produce an anti‐allodynic effect in a rat model of migraine. Thus, combining PL37 and sumatriptan may be a useful therapeutic strategy in the management of migraine. Plain Language Summary There have been many advances in migraine treatment, but we still need more options that are effective and have few side effects. Sumatriptan is one available drug for acute treatment of migraine, but it does not work for every patient and is not suitable for some people. We tested a new drug called PL37 (that blocks enkephalinases) together with sumatriptan and the combination minimized side effects and allowed lower doses of the drugs for effective migraine treatment in an animal model.