Enriched enrollment randomized double-blind placebo-controlled cross-over trial with phenytoin cream in painful chronic idiopathic axonal polyneuropathy (EPHENE): a study protocol.

BACKGROUND: Patients with chronic idiopathic axonal polyneuropathy (CIAP) can have neuropathic pain that significantly impacts quality of life. Oral neuropathic pain medication often has insufficient pain relief and side effects. Topical phenytoin cream could circumvent these limitations. The primary objectives of this trial are to evaluate (1) efficacy in pain reduction and (2) safety of phenytoin cream in patients with painful CIAP. The main secondary objective is to explore the usefulness of a double-blind placebo-controlled response test (DOBRET) to identify responders to sustained pain relief with phenytoin cream. METHODS: This 6-week, enriched enrollment randomized double-blind, placebo-controlled triple cross-over trial compares phenytoin 20%, 10% and placebo cream in 48 participants with painful CIAP. Enriched enrollment is based on a positive DOBRET in 48 participants who experience within 30 minutes ≥2 points pain reduction on the 11-point numerical rating scale (NRS) in the phenytoin 10% cream applied area and ≥1 point difference in pain reduction on the NRS between phenytoin 10% and placebo cream applied area, in favour of the former. To explore whether DOBRET has predictive value for sustained pain relief, 24 DOBRET-negative participants will be included. An open-label extension phase is offered with phenytoin 20% cream for up to one year, to study long-term safety. The main inclusion criteria are a diagnosis of CIAP and symmetrical neuropathic pain with a mean weekly pain score of ≥4 and <10 on the NRS. The primary outcome is the mean difference between phenytoin 20% versus placebo cream in 7-day average pain intensity, as measured by the NRS, over week 2 in DOBRET positive participants. Key secondary outcomes include the mean difference in pain intensity between phenytoin 10% and phenytoin 20% cream, and between phenytoin 10% and placebo cream. Furthermore, differences between the 3 interventions will be evaluated on the Neuropathic Pain Symptom Inventory, EuroQol EQ5-5D-5L, and evaluation of adverse events. DISCUSSION: This study will provide evidence on the efficacy and safety of phenytoin cream in patients with painful CIAP and will give insight into the usefulness of DOBRET as a way of personalized medicine to identify responders to sustained pain relief with phenytoin cream. TRIAL REGISTRATION: ClinicalTrials.gov NCT04647877 . Registered on 1 December 2020.

Pulsed Radiofrequency Increases Nestin and Matrix Metalloproteinase-2 Expression in Porcine Lumbar Dorsal Root Ganglion.

Background: Pulsed radiofrequency (PRF) has been used for the treatment of chronic lumbar radicular pain and other chronic pain states. The dorsal root ganglion (DRG) consists of primary afferent somatic and visceral nerve cell bodies that transduce sensory signals from the periphery to the central part of the nervous system. It is a very important part of acute nociception, as well as the development and maintenance of chronic pain. Methods: A total of seven domestic pigs were investigated. All pigs underwent a PRF procedure while under general anesthesia and with X-ray imaging. Four lumbar DRGs were randomly treated. We used the opposite side of the DRGs as controls. The lumbar region of the spine was placed in 10% formaldehyde for one month. After this fixation, DRG samples were prepared for slide analysis. Results: Nestin (Nes, code-Nr. AB 5968, dilution 1:250, rabbit, Abcam, United Kingdom) and matrix metallopeptidase 2 (MMP-2, code-Nr. DUB 03, dilution 1:100, goat) expressions were detected by immunohistochemical staining. The cell numbers with Nes (28.4 ± 3.3 vs. 16.1 ± 3.4; P < 0.05) and MMP-2 (26.2 ± 3.2 vs. 14.1 ± 2.3; P < 0.05) expressions were larger on the PRF side compared to the control side. The glial cells in the spinal ganglia on both sides showed immunoreactivity. Conclusions: The increase of MMP-2-containing gangliocytes one month after PRF procedures highlights active neural cell proliferation. Increased Nes factor expression in spinal gangliocytes of the lumbar region indicates neural remodeling and regeneration.

Study Design Characteristics and Endpoints for Enriched Enrollment Randomized Withdrawal Trials for Chronic Pain Patients: A Systematic Review.

Enriched enrollment randomized withdrawal (EERW) pain trials are designed to include only responders with considerable pain relief without unacceptable side effects into the randomized phase. There are no recommendations for primary endpoints in such trials. Our objective was to propose recommendations based on assessment of trial characteristics, endpoints and effect sizes in EERW pain trials. We conducted a systematic review by searching electronic databases up to June 2020 for EERW trials comparing an analgesic with a placebo in adults suffering from chronic pain. A total of 28 trials met our criteria, involving 13662 patients in the open or single-blind phase and 7937 patients in the double-blind phase. As primary endpoint 18 trials used pain intensity measured with the visual analogue scale (VAS) or the 11-point numerical rating scale (NRS); 1 trial used a 4-point NRS. Loss of therapeutic response (LTR) was used in 1 trial and time to LTR was used in 8 trials as primary endpoint. Definitions of time to LTR differed considerably between trials. Only 2 out of 8 trials using time to LTR as primary endpoint reported the percentage of patients experiencing a minimum pain relief of 50%, compared to 14 out of 18 trials using NRS or VAS. Due to the complexity and diversity of time to LTR in EERW pain trials, we propose to use the NRS as primary endpoint with conservative imputation methods, and to use time to LTR as secondary endpoint.

No Detectable Phenytoin Plasma Levels After Topical Phenytoin Cream Application in Chronic Pain: Inferences for Mechanisms of Action.

PURPOSE: 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.

Topical Treatments and Their Molecular/Cellular Mechanisms in Patients with Peripheral Neuropathic Pain-Narrative Review.

Neuropathic pain in humans results from an injury or disease of the somatosensory nervous system at the peripheral or central level. Despite the considerable progress in pain management methods made to date, peripheral neuropathic pain significantly impacts patients' quality of life, as pharmacological and non-pharmacological methods often fail or induce side effects. Topical treatments are gaining popularity in the management of peripheral neuropathic pain, due to excellent safety profiles and preferences. Moreover, topical treatments applied locally may target the underlying mechanisms of peripheral sensitization and pain. Recent studies showed that peripheral sensitization results from interactions between neuronal and non-neuronal cells, with numerous signaling molecules and molecular/cellular targets involved. This narrative review discusses the molecular/cellular mechanisms of drugs available in topical formulations utilized in clinical practice and their effectiveness in clinical studies in patients with peripheral neuropathic pain. We searched PubMed for papers published from 1 January 1995 to 30 November 2020. The key search phrases for identifying potentially relevant articles were "topical AND pain", "topical AND neuropathic", "topical AND treatment", "topical AND mechanism", "peripheral neuropathic", and "mechanism". The result of our search was 23 randomized controlled trials (RCT), 9 open-label studies, 16 retrospective studies, 20 case (series) reports, 8 systematic reviews, 66 narrative reviews, and 140 experimental studies. The data from preclinical studies revealed that active compounds of topical treatments exert multiple mechanisms of action, directly or indirectly modulating ion channels, receptors, proteins, and enzymes expressed by neuronal and non-neuronal cells, and thus contributing to antinociception. However, which mechanisms and the extent to which the mechanisms contribute to pain relief observed in humans remain unclear. The evidence from RCTs and reviews supports 5% lidocaine patches, 8% capsaicin patches, and botulinum toxin A injections as effective treatments in patients with peripheral neuropathic pain. In turn, single RCTs support evidence of doxepin, funapide, diclofenac, baclofen, clonidine, loperamide, and cannabidiol in neuropathic pain states. Topical administration of phenytoin, ambroxol, and prazosin is supported by observational clinical studies. For topical amitriptyline, menthol, and gabapentin, evidence comes from case reports and case series. For topical ketamine and baclofen, data supporting their effectiveness are provided by both single RCTs and case series. The discussed data from clinical studies and observations support the usefulness of topical treatments in neuropathic pain management. This review may help clinicians in making decisions regarding whether and which topical treatment may be a beneficial option, particularly in frail patients not tolerating systemic pharmacotherapy.

Post-traumatic stress disorder symptoms and pain intensity in persons with spinal cord injury.

STUDY DESIGN: Cross-sectional. OBJECTIVES: To examine the association between post-traumatic stress disorder (PTSD) symptoms and pain intensity, taking symptoms of anxiety and depression into account within persons with spinal cord injury (SCI). SETTING: Persons with SCI, who visited a Dutch rehabilitation centre between 2005 and 2010, were invited to complete a survey. METHODS: PTSD symptoms were measured with the Trauma Screening Questionnaire (TSQ), pain intensity with an 11-point Numerical Rating Scale (NRS), and symptoms of anxiety and depression with the Hospital Anxiety and Depression Scale (HADS). To determine associations between PTSD symptoms and pain intensity, linear regression analyses were performed. Confounding variables representing anxiety and depression were added to the final model. RESULTS: In total, 175 participants (55.8% traumatic, 29.1% complete) were included (response rate of 31.7%). Of them, 11.4% had clinically relevant symptoms of probable PTSD (TSQ score ≥ 6) 69.8% experienced moderate to severe pain levels (NRS ≥ 4), 14.9% had symptoms of anxiety and 20.8% symptoms of depression (HADS scores ≥ 11). Levels of PTSD symptoms were strongly associated with symptoms of anxiety (0.54) and depression (0.49). Bivariate analyses showed a moderate significant association (0.30) between PTSD symptoms and pain intensity. This association became small (0.10) when anxiety and depression comorbidity were factored into the final regression model. CONCLUSIONS: No independent association between PTSD symptoms and pain intensity was shown when adjusted for anxiety and depression. Results of this study suggest the usefulness of screening for PTSD in persons with SCI (regardless of injury cause or type/level) who score high on symptoms of anxiety/depression.

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

PURPOSE: Topical analgesics are an upcoming treatment option for neuropathic pain. In this observational study, we performed a double-blind placebo-controlled response test (DOBRET) in patients with polyneuropathy to determine the personalized analgesic effect of phenytoin 10% cream. PATIENTS AND METHODS: In a double-blind fashion, 12 consecutive adult patients with symmetrical painful polyneuropathy and equal pain intensity of ≥4 on the 11-point numerical rating scale (NRS) applied phenytoin10% cream on one painful area and a placebo cream on the corresponding contralateral area. We defined responders as patients who experienced a pain reduction ≥2 NRS points from baseline and ≥1 NRS point difference in pain reduction in favour of phenytoin 10% cream compared with placebo cream within 30 minutes after application. We also evaluated the percentage of pain reduction and frequency of 30% and 50% pain relief from baseline. RESULTS: Six patients (50%) were responders. Compared with placebo cream, pain reduction was higher in phenytoin 10% cream-applied areas with mean difference in pain reduction of 1.3 (95% CI: 1.1 to 1.8; p<0.001) on the NRS and mean percentage difference in pain reduction of 22% (95% CI: 13% to 32%; p =0.03). All responders had at least 30% pain reduction, and 4 out of 6 had at least 50% pain reduction in the phenytoin 10% cream applied area. All non-responders had less than 30% pain reduction. No side effects were reported. CONCLUSION: A DOBRET is easy to perform, quickly identifies an analgesic effect in responders and could be a useful tool to personalize neuropathic pain treatment with topical formulations.

Phenytoin Cream for the Treatment of Sciatic Pain: Clinical Effects and Theoretical Considerations: Case Report.

Chronic sciatic pain is difficult to treat. Patients often suffer from considerable pain and are severely hampered in their everyday activities. Most pharmacologic analgesic treatments have disappointing effects, and often are limited due to adverse events. New treatments are therefore needed. Surprisingly we found fast pain reduction after applying topical phenytoin cream at the painful dermatome in a 55-year-old patient suffering from sciatic pain due to pathology of a disc. This patient was treatment resistant for 13 years. Prescribing topical analgesic cream seemed to us at first sight quite counter-intuitive. The clear response in a treatment-resistant patient however provoked us to look deeper in the pathophysiology of sciatic nerve impingement. Recently it has been documented that proximal nerve lesions are followed by small fiber pathology in the skin. This might be a responsible peripheral wind-up generator for the chronification of pain in sciatic nerve compression. Topical application of the broad-acting voltage-gated sodium channel blocker phenytoin could reduce neuropathic pain in our case completely, supporting a peripheral mechanism of action for phenytoin cream in sciatic pain.

Ethical justification of single-blind and double-blind placebo-controlled response tests in neuropathic pain and N-of-1 treatment paradigm in clinical settings.

At our center in the Netherlands, patients, who very often are treatment resistant to the analgesics recommended in the guidelines, suffering from symmetrical peripheral neuropathic pain are treated exclusively. We have developed a number of compounded topical formulations containing classical co-analgesics such as ketamine, baclofen, amitriptyline, and phenytoin for the treatment of neuropathic pain in treatment-resistant patients. In order to identify putative responders and exclude an (initial) placebo-response, we developed single-blind and double-blind placebo-controlled response tests. The test can be performed when the patient has a symmetrical polyneuropathy with a pain score difference of not more than 1 point on the 11-point numerical rating scale (NRS) between bilateral pain areas. On one area (eg, left foot) the placebo cream and on the other area (eg, right foot) the active cream will be applied. Within a time frame of 30 minutes, patients are considered responders if they rate a pain difference of at least 2 points on the NRS between the bilateral areas on which the active cream and placebo cream are applied. Response tests can be easily conducted during the first consultation. In this paper, we explore the ethical context of using a placebo in clinical practice in a single-blind and double-blind fashion to improve and individualize treatment of neuropathic pain outside a context of a formal clinical trial.

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

BACKGROUND: Phenytoin cream applied topically has been explored in neuropathic pain conditions. In several case series, phenytoin 5% and 10% cream could reduce pain in a clinically relevant way with a fast onset of action within 30 min, and with positive effects on sleep. OBJECTIVE: To evaluate a single-blind placebo-controlled response test (SIBRET) for use in clinical practice. MATERIALS AND METHODS: Patients with localized neuropathic pain, having an equal pain intensity in at least 2 areas (e.g., both feet), and a pain intensity of at least 4 on the 11-point numerical rating scale (NRS), were selected to perform the SIBRET. In one area, placebo cream consisting of the base cream was applied, and on the other area, phenytoin 10% cream was applied with separate hands to avoid contamination. Responders were defined as patients who experienced within 30 min at least 2-points difference as scored on the NRS, between the phenytoin 10% and the placebo cream applied areas, in favor of the former. Responders were subsequently prescribed phenytoin 10% cream. RESULTS: Of the 21 patients, 15 patients (71.45%) were classified as responders. The mean pain reduction after 30 min as measured with the NRS in the phenytoin 10% cream area was 3.3 (SD: 1.3) and in the placebo cream area 1.2 (SD: 1.1). The difference of the mean percentage pain reduction between phenytoin 10% cream and placebo cream was 33.2% (SD: 17.6, p < 0.001). Using a 50% reduction on the NRS as a full response criterion, we could identify 57.1% of responders on phenytoin 10% cream and only 9.5% responders on placebo cream. CONCLUSIONS: The SIBRET helps patients and clinicians to quickly identify the appropriate treatment and can thus be seen as an important contributor to the domain of personalized medicine in pain. These results can also be regarded as a proof of principle for the analgesic activity of 10% phenytoin cream.

Phenytoin Cream for the Treatment for Neuropathic Pain: Case Series.

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.

Podiatric Adverse Events and Foot Care in Cancer Patients and Survivors Awareness, Education, and Literature Review.

Cancer is one of the leading causes of mortality and morbidity worldwide. Recent improved therapies have resulted in more patients surviving cancer and living longer. Despite these advances, the majority of patients will develop adverse events from anticancer therapies. Foot alterations, including nail toxicities, hand-foot syndrome, edema, xerosis, hyperkeratosis, and neuropathy, are frequent among cancer patients. These untoward conditions may negatively impact quality of life, and in some cases may result in the interruption or discontinuation of cancer treatments. Appropriate prevention, diagnosis, and management of podiatric adverse events are essential to maintain foot function and health-related quality of life, both of which are critical for the care of cancer patients and survivors. This article shows results related to complaint and impact on quality of life of the Oncology Foot Care program and reviews publications specific to podiatric adverse events related to cancer treatments.

Phenytoin: neuroprotection or neurotoxicity?

Phenytoin is an 80-year young molecule and new indications are still emerging. The neuroprotective potential of phenytoin has been evaluated for decades. Recently, a positive phase II trial supported its further development in the treatment of optic neuritis in multiple sclerosis. In 1942, however, peripheral neuritis was first reported to be an adverse event of phenytoin, and since then a small but steady stream of publications discussed peripheral polyneuropathy as being a possible adverse event of phenytoin. We have reviewed the literature and concluded there is some supportive evidence for a reversible polyneuropathy after the oral use of phenytoin, though with no evidence for clear neurotoxicity on the level of peripheral nerves. This is probably due to the fact that the pharmacological effects of phenytoin, based on the stabilizing effect of the voltage-gated sodium channels, make impairment of nerve conduction in asymptomatic and symptomatic reversible polyneuropathies plausible. Clear toxically-induced phenytoin-related polyneuropathies, however, are extremely rare and are always related to high dose or high plasma levels of phenytoin, mostly developing during many years of therapy. We could only find one case of a probable reversible chronic phenytoin intoxication resulting in a biopsy proven axonal atrophy with secondary demyelination and signs of remyelination. All case series and case reports published are insufficient in detail to prove a clear causal relation between phenytoin intake and the induction of a peripheral polyneuropathy. Phenytoin does not lead to irreversible toxicity of the peripheral nerves and might, on the other hand, have neuroprotective properties.

Bottlenecks in the development of topical analgesics: molecule, formulation, dose-finding, and phase III design.

Topical analgesics can be defined as topical formulations containing analgesics or co-analgesics. Since 2000, interest in such formulations has been on the rise. There are, however, four critical issues in the research and development phases of topical analgesics: 1) The selection of the active pharmaceutical ingredient. Analgesics and co-analgesics differ greatly in their mechanism of action, and it is required to find the most optimal fit between such mechanisms of action and the pathogenesis of the targeted (neuropathic) pain. 2) Issues concerning the optimized formulation. For relevant clinical efficacy, specific characteristics for the selected vehicle (eg, cream base or gel base) are required, depending on the physicochemical characteristics of the active pharmaceutical ingredient(s) to be delivered. 3) Well-designed phase II dose-finding studies are required, and, unfortunately, such trials are missing. In fact, we will demonstrate that underdosing is one of the major hurdles to detect meaningful and statistically relevant clinical effects of topical analgesics. 4) Selection of clinical end points and innovatively designed phase III trials. End point selection can make or break a trial. For instance, to include numbness together with tingling as a composite end point for neuropathic pain seems stretching the therapeutic impact of an analgesic too far. Given the fast onset of action of topical analgesics (usually within 30 minutes), enrichment designs might enhance the chances for success, as the placebo response might decrease. Topical analgesics may become promising inroads for the treatment of neuropathic pain, once sufficient attention is given to these four key aspects.

Topical phenytoin for the treatment of neuropathic pain.

We developed and tested a new putative analgesic cream, based on the anticonvulsant phenytoin in patients suffering from treatment refractory neuropathic pain. The use of commercial topical analgesics is not widespread due to the facts that capsaicin creams or patches can give rise to side effects, such as burning, and analgesic patches (e.g., lidocaine 5% patches) have complex handling, especially for geriatric patients. Only in a few countries, compounded creams based on tricyclic antidepressants or other (co-)analgesics are available. Such topical analgesic creams, however, are easy to administer and have a low propensity for inducing side effects. We, therefore, developed a new topical cream based on 5% and 10% phenytoin and described three successfully treated patients suffering from neuropathic pain. All patients were refractory to a number of other analgesics. In all patients, phenytoin cream was effective in reducing pain completely, without any side effects, and the tolerability was excellent. The onset of action of the phenytoin creams was within 30 minutes. Phenytoin cream might become a new treatment modality of the treatment of neuropathic pain.

Phenytoin: 80 years young, from epilepsy to breast cancer, a remarkable molecule with multiple modes of action.

In 1908 phenytoin (5,5-diphenylhydantoin) was first synthesized as a barbiturate derivative in Germany by professor Heinrich Biltz (1865-1943) and subsequently resynthesized by an American chemist of the pharmaceutical company Parke-Davis in 1923 in Detroit. Screening phenytoin did not reveal comparable sedative side effects as barbiturates and, thus, Parke-Davis discarded this compound as a useful drug. In 1936, phenytoin's anticonvulsive properties were identified via a new animal model for convulsive disorders, developed by Putnam and Merritt, who also evaluated its clinical value in a number of patients in the period 1937-1940. For many diseases, mechanism of action of phenytoin remains obscure. The voltage-gated sodium channel was and is generally regarded as the main target to explain phenytoin's activity as an anticonvulsant and an anti-arrhythmic drug. This target, however, does not explain many of the other clinical properties of phenytoin. We will explore a number of original articles on phenytoin published in its 80 years history and give extra attention to the various hypothesis and experiments done to elucidate its mechanisms of action. Phenytoin has been explored in over 100 different disorders; the last two promising indications tested in the clinic are breast cancer and optic neuritis. Most probably, there are multiple targets active for these various disorders, and the insight into which targets are relevant is still very incomplete. It is remarkable that many pharmacological studies tested one dose only, mostly 50 or 100 µM, doses which most probably are higher than the non-plasma bound phenytoin plasma levels obtained during treatment.

Skin matters! The role of keratinocytes in nociception: a rational argument for the development of topical analgesics.

Treatment of neuropathic pain using topical formulations is still in its infancy. Only few topical analgesic formulations have become available for clinical use, and among these, analgesic creams are still rare. This is unfortunate because analgesic creams offer a number of advantages over patches, such as convenience, ease of adapting the frequency of application, and dose, and "rubbing cream where it hurts" involves the patient much more in the therapeutic process compared to patches and other localized treatment modalities. Although the literature supporting the efficacy and safety of analgesic creams (mostly compounded) is growing since the last decade, most pain physicians have not yet noticed and appreciated the therapeutic potential and clinical value of these creams. This is most probably due to a prejudice that topical application should need to act transdermally, more or less as a slow-release formulation, such as in patches delivering opioids. We will discuss this prejudice and show that there are multiple important targets in the skin to be reached by topical analgesic or anti-inflammatory compounds, and that the keratinocyte is one of those targets. By specifically targeting the keratinocyte, analgesia seems possible, effective, and safe, and thus topical analgesic creams may hold promise as a novel treatment modality for neuropathic pain.

Autologous tumor immunizing devascularization of an invasive colorectal cancer: A case report and literature review.

Colorectal cancer is the third most common cancer. Approximately 20% of patients have at the time of presentation metastasized colorectal cancer, which is incurable in ~80% of cases. The present case report describes a typical case diagnosed with an advanced invasive colorectal adenocarcinoma, with two suspect hypodense lesions in the liver, as revealed by sonography. Judged inoperable for a curative outcome by radical resection, the patient was treated with a novel surgical technique based on stimulating the immune system, termed 'autologous tumor immunizing devascularization' (ATID). The tumor was isolated from its surroundings by ligature of arteries and veins, and subsequently the completely devascularized tumor was left in situ. The distal part of the rectum was closed, and a stoma was made from the proximal part of the colon. Following ATID, the stressing pathophysiological condition of the completely isolated tumor provoked a generalized cellular immune response, which led to the elimination of the devascularized tumor and distant lesions without causing sepsis. The patient did not experience any serious side-effects following the operation, and refused any adjuvant chemo- and/or radiotherapy. To date, the patient has no complaints and remains in good health after the ATID intervention, already more than 14 years. The present case study provides a typical demonstration of the clinical safety of ATID, and also indicates both the immunizing and the curative potential of the method.