Objectives: The main objective is to evaluate the efficacy and safety of phenytoin cream in patients with neuropathic pain due to chronic idiopathic axonal polyneuropathy (CIAP). The second objective is to determine the predictive value of a double-blind placebo-controlled response test (DOBRET) to identify sustained responders.

Study design: This is a 6-week enrichment randomized double-blind, placebo-controlled cross-over trial evaluating phenytoin cream in 84 participants with painful CIAP, whereafter an open label extension phase is offered with phenytoin 20 percent cream for up to one year.

At baseline a DOBRET with phenytoin 10 percent and placebo cream will be performed in each study participant to stratify participants according to their response to the DOBRET before entering the double-blind cross-over phase. DOBRET positive participants are those who experience at least two points pain reduction on the 11-point numerical rating scale (NRS) on the phenytoin 10 percent cream applied area within 30 minutes and at least one-point difference in pain reduction on the NRS between phenytoin 10 percent and placebo cream applied area, in favour of the former.

Participants will receive three treatments in a double blind fashion and in a randomized order: phenytoin 10 percent, phenytoin 20 percent and placebo cream. The duration of each treatment period is two weeks. Participants will cross-over two times to each of the other treatments. The study does not have wash-out periods between treatments, because the mean duration of analgesic effect after an application is expected to be less than nine hours. A blood sample will be collected at the end of the second week of the first treatment period to test for phenytoin plasma levels.

Study population: The investigators aim to include 84 participants, age 40 years or older, who have been diagnoses with painful CIAP at the University Medical Center Utrecht and fulfil the inclusion criteria and have given written informed consent.

Interventions: Phenytoin cream in concentrations of 10 percent and 20 percent cream compared to placebo cream.

Primary endpoint: Change in pain intensity measured on the NRS between baseline and week 2 for phenytoin 20% cream versus placebo cream.

Inclusion Criteria:

• Patients have been diagnosed with CIAP defined as: presence of symmetrical distal sensory or sensorimotor symptoms such as numbness, pins and needles, tightness, coldness, unsteadiness, muscle cramps, and weakness with onset in the feet, compatible with polyneuropathy; presence of symmetrical distal sensory or sensorimotor signs with evidence of large nerve fiber involvement such as decreased sense of touch, vibration, and proprioception, usually in the presence of decreased pin prick/temperature sense, decreased/absent tendon reflexes, or slight muscle weakness on neurologic examination, compatible with polyneuropathy; an insidious onset and slow or no progression of the polyneuropathy over the course of at least 6 months; no identifiable cause for the polyneuropathy after thorough history-taking, clinical examination, and extensive laboratory testing; no suggestion of a hereditary polyneuropathy based on detailed kinship history (i.e., one or more affected family member), neurologic examination, or confirmation by genetic analysis; and nerve conduction studies excluding a demyelinating polyneuropathy and confirming large nerve fiber involvement if the findings on neurologic examination are equivocal considering the patient's age.
• Presence of chronic localized neuropathic pain due to CIAP
• Neuropathic pain localized in two anatomically symmetrical areas of feet/lower legs
• Duration of neuropathic pain ≥3 months
• Duration of ≥1 hour neuropathic pain per day
• Neuropathic pain characteristics defined by the Douleur Neuropathique 4 questions (DN4) score ≥4
• Mean pain score during daytime of ≥4 and <10 on the NRS at study entry (baseline)
• Difference of pain intensity between left and right foot and/or lower leg of not more than 1 point on the NRS
• No changes in neuropathic pain medication for at least 1 month
• Absence of any of the exclusion criteria outlined below

Exclusion Criteria:

• Painful (poly)neuropathy other than CIAP
• Presence of neuropathic pain due to any other condition than CIAP
• Neuropathic pain (distribution, duration, characteristics, intensity) not fulfilling the inclusion criteria
• Pregnancy or planned pregnancy in the study period (will only be asked)
• Use of oral phenytoin
• Open wounds in the neuropathic pain area
• Current use of topical analgesics
• Presence of other pain syndromes such as the widespread pain syndrome or pain in joints
• Presence of serious psychological/psychiatric morbidity
• Addiction to intoxicants
• Hypersensitivity to the study medication (active substance and excipients)
• Insufficient mastery of the Dutch language
• Cognitive impairment and insufficiently capable to understand the purpose of the study