No Detectable Phenytoin Plasma Levels After Topical Phenytoin Cream Application in Chronic Pain: Inferences for Mechanisms of Action
Bibliographic record
Abstract
David J Kopsky,1,2 Jan M Keppel Hesselink,1 Alan L Russell,3 Alexander FJE Vrancken2 1Institute for Neuropathic Pain, Amsterdam, the Netherlands; 2Department of Neurology, Brain Centre University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; 3 Brampton, Ontario, CanadaCorrespondence: David J Kopsky, Vespuccistraat 64-III, Amsterdam, 1056 SN, the Netherlands, Tel +31-6-28671847, Email info@neuropathie.nuPurpose: Topical phenytoin can act as an analgesic in chronic pain, but it is unclear if topical phenytoin gives rise to systemic side effects. Therefore, the aim of this study is: 1) to evaluate safety in chronic pain patients who used topical phenytoin up to 30% applied daily on intact skin and mucous membrane, through determining phenytoin plasma levels; and 2) to elaborate on the analgesic mechanism of action.Patients and Methods: In this retrospective study, we collected demographic and clinical data from 33 chronic pain patients who used 10% to 30% phenytoin cream, and in whom blood samples were drawn for phenytoin concentration measurement between January 2017 until September 2020. The instruction was to withdraw blood 1 to 4 hours after the last topical phenytoin application. The primary outcome was the detectability of plasma phenytoin after daily use of topical phenytoin.Results: Blood withdrawal was carried out after on average 14 treatment days with topical phenytoin and on average 2.5 hours after topical phenytoin application. The median daily applied amount of phenytoin cream was 1.2 grams, resulting in a median daily amount of 120 mg phenytoin on the skin. Phenytoin levels were below the limit of detection in all patients and no side effects were reported.Conclusion: Plasma phenytoin levels were below the limit of detection after topical use of phenytoin cream formulations up to 30% on intact skin and mucous membrane for the treatment of chronic pain, without side effects emerging. This finding suggests that the mechanism of analgesic action resides in the skin.Keywords: phenytoin cream, pain, plasma concentration, neuropathy, skin
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".