Palliative care physicians proposed to add topical analgesics into the WHO stepladder in the treatment of cancer-related pain to have more treatment possibilities without side effects. The WHO stepladder for pain consists of 3 steps: 

  1. Non-opioid with or without adjuvants
  2. Adding weak opioid
  3. Adding strong opioid

The authors propose to add topical analgesics depending on the type of pain. In the presence of neuropathic pain characterized by hyperalgesia, allodynia and radiating pain, they propose to use a topical analgesic containing ketamine with or without clonidine, gabapentin, methadone, bupivacaine.

Topical Innovations has gathered quite some supportive information related to this topic which points in the same direction. By targeting the skin a number of pain states are treatable by topicals which were previously considered non-treatable.


Winegarden JA, Daniel CB, Ylisabyth BS. Topical Ketamine with Other Adjuvants: Underutilized for Refractory Cancer Pain? A Case Series and Suggested Revision of the World Health Organization Stepladder for Cancer Pain. J Palliat Med. 2020 Sep;23(9):1167-1171.

In March 2020 a milestone paper related to the peripheral pathogenesis of sciatic pain has been published by us, in collaboration with a Canadian pain specialist. Increasingly we and colleagues all over the world finder phenytoin cream quite remarbable, sometimes even in indications one would not expect phenytoin cream to reduce pain. Sciatic pain is such an indication. Based on a very convincing case description we postulate a new hypothesis explaining pain in sciatic nerve impingement.

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.

Phenytoin cream surprises us and patients more often than not…

Russel, AL, Kopsky DJ, Keppel Hesselink JM. Phenytoin cream for the treatment of sciatic pain: clinical effects and theoretical considerations: case report. J Pain Palliat Care Pharmacother. 2020 March 2: 1-7.

TI presents first double-blind data supporting phenytoin 10% cream in painful polyneuropathies at FIGON Dutch Medicines Days

David Kopsky presents poster at FIGON daysEvery year FIGON (Federatie Innovatie Geneesmiddel Onderzoek Nederland: Dutch Federation Innovative Medicine Research) is organizing a 2-day conference. On the 23rd of September 2019 at  the FIGON Dutch Medicines Days David Kopsky on behalf of TI has presented the first double-blind data gathered with phenytoin 10% cream in a mixed population suffering from painful polyneuropathies (poster).
Title of the poster: Double-blind placebo-controlled response test with phenytoin 10% and placebo creams in patients with painful polyneuropathies, abstract number: ABS-67542729
He presented the results of the first series of 14 patients where we tested the DOBRET. The series can be regarded as a collection of N-of-1 or single subject clinical trials, presenting level 1 evidence according to the Oxford Centre for Evidence-Based Medicine. Pre-treatment pain intensity scores on the 11-point numerical rating scale (NRS) in both groups were comparable, around 6. Six patients (42.9%) were labeled as responders, and in this group the mean pain was reduction in the phenytoin 10% cream applied area was 3.1 (SD: 0.3) compared to 1.8 (SD: 0.4) in the placebo cream applied area. No side effects were detected. These data were in line with the outcome of our first single blind case collection of 21 patients, our case collection of 70 patients, and our first case reports supporting further development of topical phenytoin cream in peripheral neuropathic pain.

Topical Innovation’s strategy supported: focus on broad-acting sodium channel blocker has higher likelihood of success

Nature’s review of April 8, 2019 is a further supportive piece of evidence for Topical Innovation’s strategy of developing a broad-acting sodium channel blocker as a topical treatment for neuropathic pain.

Author Kingwell points out that despite compelling genetic validation, drug developers are still struggling to unlock the therapeutic promise of the Nav1.7 sodium channel as a pain target.

But after several failures in the phase II development, skepticism is rising whether such a selective target has a therapeutic potential in the real world.  Andrea  Houghton, executive director of pharmacology at Merck & Co  pointed out that “Just because a target is genetically validated, it doesn’t necessarily mean to say it’s very druggable, Nav1.7 as a target is very hard to drug.”

When researchers reported in 2006 that patients with null mutations in the voltage-gated sodium channel Nav1.7 were impervious to pain, they kicked off an industry-wide hunt for novel analgesics. Genetic target validation was gaining traction as a means of improving drug development success rates, and Nav1.7 promised to be a poster child example of the drug development future. Instead, a slew of failures attest to how hard it can be to translate even the most compelling targets into therapeutics.

“Just because a target is genetically validated, it doesn’t necessarily mean to say it’s very druggable,” says Andrea Houghton, executive director of pharmacology at Merck & Co. “Nav1.7 as a target is very hard to drug.”

The most recent setbacks failure in this field was announced in October 2018, when Biogen pulled its Nav1.7 blocker vixotrigine in painful lumbosacral radiculopathy, due to a a failed phase II trial. phase III trial is still planned in trigeminal neuralgia and a phase II trial is ongoing in small fibre neuropathy. But the perspectives are now dim.

Interestingly, many other selective ligands failed in the recent past:

PF-05089771 from Pfizer was discontinued in 2015 after failed phase II trial in painful diabetic peripheral neuropathy;

TV-45070 from Teva/Xenon was discontinued in 2017 after failed phase II trial in post-herpetic neuralgia;

RG-6029/GDC-0310 from Roche/Genentech/Xenon was discontinued in 2018 prior to phase II initiation.

Topical Innovations (TI) has started their development of a topical formulation of the broad acting sodium channel blocker some years ago, and collected an impressive safety package, as well proof of concept in peripheral neuropathic pain, and is currently, after consultation with the Dutch MEB, starting preparations for two pivotal studies in diabetic painful neuropathy.

David Hackos, senior scientist at Genentech, pointed out that with the current huge unmet need for new pain relief options, and with the ongoing opioid crisis going on in the United States and starting in Europe: “many drug companies remain committed to Nav1.7. But they have tempered their views.”  He now thinks this inroad is really difficult, but still possible.

The director of pharmacology at Merck & Co points out that there are fairly limited small-molecule opportunities, looking at all the screening people have done, most of the publications and structures are quite closely related to each other. There’s not a lot of novelty here.

It was further pointed out that non-selective Nav blockers can provide useful pain relief but the generalized nerve block and unwanted side effects such as dizziness underscore the need for enhanced selectivity to tap wider pain markets. The other option to decrease the side-effects has been explored by Topical Innovations and clearly directs us in a different direction: broad acting sodium blockage, but not entering the bloodstream, and acting locally.

To date, TI approach is seen as a new innovative approach, potentially creating a block-buster based on an old repurposed drug in a new formulation and in a field of a new indication. TI is currently discussing with potential partners who would take over phase III development of the treatment on a world-wide or regional scale.

Phenytoin and Phenytoin cream should be considered in case of chronic incapacitating fibromyalgia

We received the following letter, which stresses the importance of considering phenytoin in chronic pain:

I am a 63 year old female who was diagnosed with fibromyalgia more than 30 years ago. I was suffering massive muscle pain all over but with a focal point in my lower left back which would prevent me from walking even short distances. I was suffering for 2 years before diagnosis. My family doctor at the time said after trying heat and cold treatments and giving me Tylenol 3 that he felt the pain was in my mind due to the stress of my fourth year in university at Queens. I can’t explain how badly this made me feel. I was 4 credits away from graduating but could no longer walk from class to class, I was basically crippled. I had even seen a chiropractor for several months who gave me massages, spinal correction and ultrasound treatments. Nothing helped and I was forced to quit school.

I was diagnosed by a medical professor with fibromyalgia. He said that I needed to go and live in Arizona where the weather was more stable. Even though the diagnosis was awful at least I wasn’t crazy. He prescribed exercise and water aerobics as helpful in dealing with the pain. Again nothing seemed to help. From time to time I would lose the use of my legs for short periods – few hours at a time. Of course, this was extremely frightening but nothing helped and other doctors would all agree that it was in my head. Living with this condition had ruined my romantic relationships and now I am single and have given up pursuing and involvement.

Over the years I found that changes in the seasons, unstable seasons and extremes in the weather made me so much worse. Freezing rain and drastic temperature change (10-15°C and more) for some reason were the most painful. I stopped and avoided the weather forecasts for fear of psychosomatic pain. Still I swear to this day I can predict a storm or drastic change with at least 70% accuracy.

Around 2007 I started seeing a new pain specialist, Dr. R. I had been diagnosed with carpal tunnel, torticolis or just extreme fibromyalgia. Thankfully Dr R. sent me for an MRI and discovered I needed a cervical laminectomy with fusion from C2 to T1. In the course of treating me during my recovery with Marcaine injections we also tackled my fibromyalgia. Of course, it was attacking my neck and shoulders. Marcaine injections saved my life as I believe I would never have worked again.

In addition, Dr R. started me on phenytoin topical. Nothing else helped with the fibromyalgia, until the phenytoin topical. There was some improvement! With that Dr R. started me on phenytoin and things began to rapidly improve. Today I am on it 4 times a day 50 mg on morning, 50 mg at noon and 100 mg at bedtime.

I am now enjoying at least a 50% decrease in pain. Last week we had temperatures of -22°C that swung to +8°C in 24 hours with freezing rain to boot. Normally I would have been in acute pain days before and days after, as well as, unable to work. Now I was in pain but it was manageable and I did not miss any work.

After 30plus years of suffering I feel that I just might get my life back. This needs to be shared with physicians who treat sufferers. I believe that this treatment is the answer. Thank you Dr R. for your help and sharing the work you have done.

New Paradigm makes use of placebo controlled tests in daily practice: an innovation

The physicians of topical innovations have developed at their center in the Netherlands, patients a new placebo controlled test paradigm. In order to identify putative responders and exclude an (initial) placebo-response, first a single-blind and subsequently a double-blind placebo-controlled response tests has been developed.

This 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 the January 2019 paper in the Journal of Pain research, the authors present for the first time 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.


Keppel Hesselink JM, Kopsky DJ, Bhaskar AK. Ethical justification of single-blind and doubleblind placebo-controlled response tests in neuropathic pain and N-of-1 treatment paradigm in clinical settings. J. Pain Res. 2019; 12: 345–352. (PDF)

Topical Treatment of painful chemotherapy-induced neuropathy: new evidence

Julien Rossignol et al. (2019) from Inserm and University Paris Descartes, Paris, France published a paper on the effects of high dose topical amitriptyline in painful chemotherapy-induced neuropathy: 10%. We advocated such high dose already years ago based on our clinical data. (Kopsky DJ, Hesselink JM (2012) High doses of topical amitriptyline in neuropathic pain: two cases and literature review. Pain Pract 12(2):148–153). Rossignol et al organized a prospective, pilot study and they could show that 10% topical amitriptyline cream alleviated chemotherapy-induced neuropathic pain in cancer patients, with no local or systemic safety concerns. Baseline pain intensity was moderate to severe: mean pain scores NRS 7. After 1 week of topical amitriptyline treatment, there was already a decrease of at least 3 points in all patients.

We took up high dosing in 2012, and meanwhile have also gone to high dose topical phenytoin (10-20%), with good efficacy and virtually no side effects

Ref: Rossignol J, Cozzi B, Liebaert F, Hatton S, Viallard ML, Hermine O, Greco C. High concentration of topical amitriptyline for treating chemotherapy-induced neuropathies. Support Care Cancer. 2019 Jan 4. doi: 10.1007/s00520-018-4618-y.

Publication on topical analgesics

In the Dutch Pain Journal, “Nederlandstalig Tijdschrift Pijnbestrijding” we recently published an article about topical analgesia for the treatment of neuropathic pain. Read the whole artilce here.

English Abstract
Old co-analgesics such as amitriptyline, ketamine and phenytoin are worth of being re-evaluated in compounded creams for the treatment of peripheral neuropathic pain. We call that process repositioning or repurposing. Due to the different mechanisms of action, these agents can become valuable in the treatment of various forms of peripheral neuropathic pain. There are indications that in a number of these neuropathic pain disorders, the pathogenesis is localized in the epidermis. Small lipophilic co-analgesics such as phenytoin are therefore ideally suited for repositioning in these indications as compounded creams. Since most patients indicate that the analgesic effect of such compounded topical formulation is noticeable within 30 minutes after application, we have developed a placebo-controlled response test for use in practice. We believe that an individualized pain treatment becomes possible in this way, because patients can indicate within 30 minutes which cream they benefit most.

Phenytoin cream at The EFIC 2018 Pain School Bergamo

The Pain Schools such as the upcoming Pain School at Bergamo, Italy, October 2018, are courses aimed at young (preferably under 45 years) European medical doctors and allied health professionals who are interested in further developing their knowledge and expertise in the field of pain management.

The courses run for 4-5 days and include an evidence-based approach to the assessment, diagnosis and comprehensive management of patients with chronic pain.

At the 10th EFIC BERGAMO PAIN SCHOOL IN: “NEUROPHATIC PAIN” 8th – 11th October 2018 on WEDNESDAY, 10th October, Professor Keppel Hesselink will present a talk on

‘Topical innovation in the treatment of localized peripheral neuropathic pain: the case of phenytoin. The intimate relation between pathogenesis and mechanism of action’. Program can be found here.

Patient suffering from PDN discusses his experience after application of 10% phenytoin cream

We have presented many patients in our recent papers, but it is always good to hear the story from the patient’s mouth. Here we hear the story of a 56-year old man, suffering from diabetes type II in the last 10 years, and burning pain in both feet. His pain score on the NRS is 6-7, and pain is disturbing, especially when resting in bed. It is prickling as well as burning pain. After the application of phenytoin 10% cream, pain vanishes completely within 30 minutes. He needs to apply the cream only once a day, and only in case of much walking he needs to re-apply the cream after 10-12 hours. In the following video the single-blind response test is explained.