Phenytoin Cream for the Treatment of Neuropathic Pain: Case Series

Abstract

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.

Single-Blind Placebo-Controlled Response Test with Phenytoin 10% Cream in Neuropathic Pain Patients

“…The McNemar’s test was used for the dichotomous variables MPR30 and MPR50 to determine statistically significant differences between the areas on which phenytoin 10% and the placebo were applied. As described earlier, the standard phenytoin plasma determination was measured with high-performance liquid chromatography of the plasma protein bound phenytoin concentration, which is approximately 90% of the total phenytoin in plasma [12,19]. The statistical analysis was performed using SPSS 22 (SPSS Inc., Chicago, IL, USA).…”

“…This SIBRET helps the patients and clinicians to rapidly identify the appropriate treatment and can be seen as one aspect in the domain of personalized medicine. Recently, in a cohort of 70 patients, SIBRET was performed in 12 patients [12]. In this article, we have also added patients who were lost to follow-up.…”

<p>Usefulness of a Double-Blind Placebo-Controlled Response Test to Demonstrate Rapid Onset Analgesia with Phenytoin 10% Cream in Polyneuropathy</p>

“…8,9 The latest developed topical analgesic is phenytoin, a broad-acting voltage-gated sodium blocker, with favourable qualities such as not entering the bloodstream and having an onset of action within 30 minutes in open and single-blind placebo-controlled response tests in our center. 10,11 Limitations of both the open and single-blind placebo-controlled tests are that patient and physicianrelated factors, expectations and their inter-relationship could influence the outcome of the tests, especially the placebo effect. [12][13][14] To minimize the placebo effect, we continued by performing a double-blind placebo-controlled response test (DOBRET) to compare the analgesic effect of phenytoin 10% cream to placebo cream and evaluate the usefulness of a DOBRET to identify responders.…”

Neuropathic pain due to chronic idiopathic axonal neuropathy: fast pain reduction after topical phenytoin cream application

“…Since our fi rst introduction of the cream, we have treated hundreds of patients, most of those successfully, and we reported a series of 12 and 21 patients recently, based on SIBRET. [3,7] In these patients, pain reduction on the phenytoin cream applied area was signifi cantly more pronounced than at the placebo cream applied area. [3 ,7] In order to further evaluate phenytoin cream in CIAP patients we started preparing a full powered cross-over RCT in CIAP patients, together with colleagues of the Medical Academic Centre in Utrecht.…”

“…The latest developed topical pain cream contains the old coanalgesic compound phenytoin. [3] Phenytoin cream can be used in combination with other therapies or as a stand-alone therapy.…”