BACKGROUND: Neuropathic pain can be disabling, and is often difficult to treat. Within a year, over half of all patients stop taking their prescribed neuropathic pain medication, which is most probably due to side effects or disappointing analgesic results. Therefore, new therapies are needed to alleviate neuropathic pain. As such, topical analgesics could be a new inroad in the treatment of neuropathic pain. In 2014, we developed a new topical formulation containing either phenytoin or sodium phenytoin. After optimization of the formulation, we were able to reach a 10% concentration and combine phenytoin with other co-analgesics in the same base cream. OBJECTIVE: To describe a series of 70 neuropathic pain patients who were treated with phenytoin cream. MATERIAL AND METHODS: Cases treated with phenytoin 5% or 10% creams were gathered. The mean onset of pain relief, the duration of effect, and reduction in pain intensity measured on the 11-point numerical rating scale (NRS) were all studied. A single-blind response test with phenytoin 10% and placebo creams was conducted on 12 patients in order to select responders prior to prescribing the active cream. Plasma phenytoin concentrations were measured in 16 patients. RESULTS: Nine patients applied phenytoin 5% cream, and 61 patients used phenytoin 10% cream. After grouping the effects of all of the patients, the mean onset of pain relief was 16.3 min (SD: 14.8), the mean duration of analgesia was 8.1 h (SD: 9.1), and the mean pain reduction on the NRS was 61.2% (SD: 25.0). The mean pain reduction on the NRS while using phenytoin cream was statistically significant compared with the baseline, with a reduction of 4.5 (CI: 4.0 to 5.0, p < 0.01). The 12 patients on whom a single-blind response test was performed experienced a statistically significant reduction in pain in the area where the phenytoin 10% cream was applied in comparison to the area where the placebo cream was applied (p < 0.01). Thirty minutes after the test application, the mean pain reduction on the NRS in the areas where the phenytoin 10% cream and the placebo cream were applied was 3.3 (CI: 2.3 to 4.4, p < 0.01) and 1.1 (CI: 0.4 to 1.9, p < 0.05), respectively. In all 16 patients, the phenytoin plasma levels were below the limit of detection. So far, no systemic side effects were reported. Two patients only reported local side effects: a transient burning aggravation and skin rash. CONCLUSION: In this case series, the phenytoin cream had reduced neuropathic pain considerably, with a fast onset of analgesic effect. Full article