Topical analgesia better than oral analgesia

Topical analgesia better than oral analgesia

Professor Cruccu and colleagues studied the efficacy of a topical analgesic formulation of capsaicin and compared its effect with the oral intake of pregabalin (150–600 mg/day administered in two or three doses). They focused on the effects of both analgesic strategies on allodynia, a common peripheral neuropathic pain symptom. Allodynia in quite common in neuropathic pain disorders with prevalence of 30% and 80%, depending on the etiology of neuropathic pain. Low-threshold, mechano-sensitive C fibres (C tactile fibres), may play a role in mechanical allodynia. The authors postulated that acting on C fibres that supply the pain area, would subsequently lead to a reduction in peripheral and central sensitization and thus to subsequent attenuation of allodynia.

To directly target the C-fibers they applied a capsaicin plaster and compared the effect in a cohort of around 500 patients via a randomized, open-label, head-to-head, 8-week, non- inferiority study. They included patients from 18–80 years; with a documented diagnosis of probable or definite peripheral neuropathic pain due to post-herpetic neuralgia,  peripheral nerve injury or nondiabetic painful polyneuropathy, who had an average Numeric Pain Rating Scale score ≥4 at screening (over at least four consecutive days).

The change in intensity of allodynia, from baseline to Week 8, was  2.98 in the capsaicin group and 2.35 in the pregabalin group, significantly in favor of the capsaicin treatment. Treatment-emergent adverse events leading to permanent treatment discontinuation were only reported for pregabalin therapy.

One conclusion was that while pregabalin acts only on central sensitization, the superiority of the capsaicin may be due to its local ability to act on both central and peripheral sensitization.

This is the first study underlining the potential superiority of topical administration of analgesics over oral administration.


Cruccu G, Nurmikko TJ, Ernault E, Riaz FK, McBride WT, Haanpää M. Superiority of capsaicin 8% patch versus oral pregabalin on dynamic mechanical allodynia in patients with peripheral neuropathic pain. Eur J Pain. 2017 Dec 1. doi: 10.1002/ejp.1155.

Chronic pain in the elderly leads to memory decline

Chronic pain in the elderly leads to memory decline

Chronic pain is associated with accelerated memory decline and development of dementia in the elderly patients.

According new findings, published in the last quarter of 2017, elderly patients suffering from chronic pain experienced an accelerated decline in functional independence.

Elizabeth L. Whitlock, MD, investigator of the study said “Based on these results, there is a small but statistically significant rate of accelerated cognitive decline and dementia in persistent pain sufferers.”

In summary, the authors demonstrated that a persistent moderate to severe pain is associated with accelerated cognitive decline and increased dementia probability in a large population-representative data set of elders. The conclusion was:

Clinicians should be aware of this association, which persisted after extensive statistical adjustment for con- founding health and demographic factors. Patients reporting ongoing pain may be at higher risk for current and incident cognitive impairment and physical debility.”

Antidepressants are therefore not an optimal choice for this population, as antidepressants in itself can have a negative impact on cognition. Topical analgesic approaches, such as Topical Innovations currently develop, without such side effects due to their local mechanism of actions, can become a better therapy for elderly suffering from chronic pain.

Source: Whitlock, E. L., Diaz-Ramirez, L. G., Glymour, M. M., Boscardin, W. J., Covinsky, K. E., & Smith, A. K. (2017). Association Between Persistent Pain and Memory Decline and Dementia in a Longitudinal Cohort of Elders. JAMA Intern Med. 2017 Aug 1;177(8):1146-1153. doi: 10.1001/jamainternmed.2017.1622.

No relevant changes in the neuropathic pain treatment landscape

No relevant changes in the neuropathic pain treatment landscape

In the 2017 Review of the Canadian Pain Society, the consensus statement regarded the therapy of neuropathic pain we can see how disappointing the progress in this field is. Nothing new, only slight shifts in recommendations. Although many pharmacological treatment modalities exist for the treatment of neuropathic pain, nothing new emerged since the entry of the lidocaine plaster. The recommended first line therapies are still based on gabapentinoids and antidepressants. How sad. Both products are troublesome in the elderly due to negative side effects on cognition and behavior. Antidepressants have also been associated with tachycardia and myocardial infarction, while Somnolence, dizziness, edema, and weight gain are common side effects of gabapentin and pregabalin.

Opioids are promoted to second line choices and the only little positive shift is that cannabinoids have been moved from a fourth-line to a third-line treatment option for neuropathic pain. The fact that opioids including tramadol have been moved from third-line to second-line treatment is a sad one indeed, given the massive problems opioids induce, especially in the elderly.

TI hopes to contribute to a shift in the way we think about treatment of treating neuropathic pain, and are confident, based on new POP that phenytoin cream will become a viable treatment option in the near future. Trial design discussions for phase IIb in 2 academic centers are ongoing. Phase II is scheduled to start in 2018.

Source: Alex Mu, Erica Weinberg, Dwight E. Moulin and Hance Clarke.  Canadian Family Physician, November 2017, 63 (11) 844-852;

Topical phenytoin gains momentum

Topical phenytoin gains momentum

In a recent overview, published in the Pubmed indexed peer reviewed journal ‘Pain Management’ of November 2017: Management of chronic neuropathic pain with single and compounded topical analgesics’ a number of references to the work of Topical Innovations on phenytoin cream can be found.

In the introduction of the paper we find as a separate bullet:

  • Phenytoin 10% cream, a nonselective voltage-gated Na channel stabilizer, GABA receptor agonist, showed promising results in allodynia reduction.

The phenytoin cream and the work on the keratinocyte hypothesis is referenced at multiple paragraphs, and in table 3:

Table 3. ‘Topical compounds: gabapentin, phenytoin and baclofen for peripheral neuropathy’, where we can read on phenytoin:


– Nonselective voltage-gated Na channel stabilizer
– Dose-dependent inhibition of sodium channel Nav1.7 (which is present in the epidermal-free nerve ending)
– Inhibits voltage dependent L-type Ca2+ channels
– GABAA receptor agonist
– Decreases the synaptic excitation through NMDA receptor antagonism
– Possible reduction of conduction velocity in unmyelinated C fibers
– Gingiva and skin might play a role in the extra-hepatic site metabolism

In the same table, various reports of clinical effects of phenytoin cream are summarized:

– Phenytoin 5% cream reduced allodynia for 8 h in a patient with diabetic neuropathic pain and phenytoin 10% cream completely relieved the symptoms for more than 12 h in the same patient
– A patient with combined chronic idiopathic axonal polyneuropathy had a pain score decrease from 8 to 3 on NRS following phenytoin 5% cream application that lasted for at least 5 h

– Chemotherapy-induced polyneuropathy patient compared the pain reduction with baclofen 5% cream and phenytoin 5% cream: 7–3 (NRS) and 7–0 (NRS), respectively. Phenytoin 10% increased the effect duration from 4 h to 6 h, compared with phenytoin 5% in the same patient

– Phenytoin 10% cream for trigeminal neuralgia patient and post-herpetic neuralgia patient showed superiority over the control ketamine 10% cream in both cases

Clearly this is a new sign that the work on phenytoin cream in neuropathic pain is receiving international recognition.

Source: Knezevic NN, Tverdohleb T, Nikibin F, Knezevic I, Candido KD. Management of chronic neuropathic pain with single and compounded topical analgesics. Pain Manag. 2017 Nov 10. doi: 10.2217/pmt-2017-0020.

New analgesic formulation of phenytoin acts via the skin

New analgesic formulation of phenytoin acts via the skin

Amsterdam, the Netherlands, 07-11-2017.

Topical Innovations BV introduced today a new important paradigm to treat localized neuropathic pain (LNP). LNP is the most common presentation of neuropathic pain, affecting about 60% of all patients suffering from neuropathic pain. The war against opioids is ongoing to guard patients from abuse, misuse and dependency, sometimes leading to death. Topical analgesics may play a major role in this field, potentially saving lives of many patients.

Transdermal formulations of painkillers are well known and much appreciated. Much less is known about topical analgesics you can rub in the skin, and which act directly in the skin. Researchers from the company Topical Innovations published new and remarkable data supporting the old and established anticonvulsive compound phenytoin as a topical painkiller. They found good painkilling properties of this cream, without the need for phenytoin to enter the blood via the skin. They pointed out the importance of these findings in a paper which will go on line later this month. Authors are patent holders of two patents related to the topical formulations of phenytoin in the treatment of pain.

Reference: Keppel Hesselink JM, Kopsky DJ. Topical analgesia: transdermal or ‘intradermal’ mechanisms of action?. Sci J Neurol Neurosurg. 2017;3(3): 068-069.

It is time for Topiceuticals to fight the opioid overdose epidemic!

It is time for Topiceuticals to fight the opioid overdose epidemic!

The USA organization Centers for Disease Control and Prevention (CDC) created a nationwide campaign featuring real-life accounts of people recovering from opioid misuse or opioid disorder. They also let people talk who have lost family members to prescription opioid overdose.

It is very necessary to increase awareness and knowledge among the people about the risks of prescription opioids, in the hopes of stopping inappropriate use. The slogan of the CDC is: “It only takes a little to lose a lot”.

“This campaign is part of CDC’s continued support for states on the frontlines of the opioid overdose epidemic,” said CDC Director Brenda Fitzgerald, MD. “These heartbreaking stories of the devastation brought on by opioid abuse have the potential to open eyes and save lives.”

Recent publications point out that the use of topiceuticals in neuropathic pain associated with all kinds of disorders, including malignancy as a valuable option with many advantages over systemic treatments. Topical compounded creams deserve a place in the modern armamentarium of the pain physician.


CDC launches campaign to help states fight prescription opioid epidemic

Phenytoin inhibits inflammation in the skin

Phenytoin inhibits inflammation in the skin

In dermatological conditions, topical phenytoin has been evaluated in the treatment of ulcers, epidermolysis bullosa, and in other inflammatory conditions of the skin. Topical phenytoin (2% to 5% in cream) was effective in treating the ulcers of epidermolysis bullosa simplex, and has also been used in treating discoid lupus erythematosus.

In a recent study in 28 patients from Dermatology Outpatient Clinic, Faculty of Medicine, Menoufia University, USA phenytoin was tested in vitiligo. After treatment punch biopsies were taken from patients under local anesthesia from the lesional skin. Patients were treated with a topical phenytoin 2% gel twice daily for 3 months duration. The ratio for the concentration of 2% was not given.

Sixteen out of 28 investigated patients were evaluated by a post phenytoin therapy biopsy after 3 months duration from starting therapy. The results showed that the presence of dermal inflammatory cells have been decreased. Moderate density of inflammation was identified in 4 patients before therapy (4/16, 25%) compared to 2 patients after receiving phenytoin (2/16, 12.5%). Inflammation density was higher in responders compared to non-responders, and nearly reached statistical significance. The study however tested phenytoin only as 2% concentrated gel and only for 3 months, which is a relatively short duration for the indication; there were no side effects reported. The conclusion was: “These results indicate that topical phenytoin of low concentrations may have beneficial effects through immunomodulatory activity by affecting CD4 and CD8 counts and subsequently the ratio between them.”

Source: Abdou AG, Abdelwahed Gaber M, Elnaidany NF, Elnagar A. Evaluation of the effect and mechanism of action of local phenytoin in treatment of vitiligo. J Immunoassay Immunochem. 2017;38(5):523-537. doi: 10.1080/15321819.2017.1344129.

Increasing interest in topical treatment of chronic pain

Increasing interest in topical treatment of chronic pain

Topical treatments in pain are increasingly mentioned as important for the treatment of localized neuropathic pain. In the graph below we see a steady increase of papers related to the item ‘topical treatment of pain’.

Moreover, topical analgesics have many advantages, such as:

  • No systemic exposure
  • Low propensity for side effects and drug-drug interactions
  • Absence of addictive and abuse potential
  • No gastric disturbances, first-pass hepatic metabolism, and variable serum concentrations
  • Rub it in where it hurts
  • Localized relief of localized pain
  • No loss of sensation (compared to topical anaesthetics)
  • Combinations between various compounds feasible
  • Potential of value of various formulations in a number of pain states: peripheral neuropathic pain such as diabetic neuropathic pain, post-herpetic neuralgia, chemotherapy induced polyneuropathy, chronic idiopathic axonal polyneuropathy, small fiber neuropathy, complex regional pain syndrome, phantom pain, post-thoracic pain, scar-pain, etc.

Topical Analgesics in Real Life: results

Topical Analgesics in Real Life: results

The results of a new study on topical analgesics ‘Optimizing Patient Experience and Response to Topical Analgesics (OPERA) Study’ was published in the Journal of Pain Research in October 2017. The results indicate that topical treatments may provide an effective and safer treatment alternative to opioids and prescription NSAIDs for the management of chronic pain.

Despite of many treatment options in chronic pain, only around 30-40% of patients treated for chronic pain respond favorably to therapy.
Analgesics such as opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) have their drawbacks in that these are associated with serious adverse effects including abuse, addiction, and death. Opioid misuse and overdose have meanwhile reached epidemic proportions.

The results of this study are therefore very much welcomed, and demonstrate that topical analgesics were associated with reductions of up to 60% in the use of concurrent pain medications, including oral opioid analgesics.
Topical agents have come into a new focus since this century, and many studies supported their efficacy without the risk of side effects, drug-drug interactions, abuse, misuse, and addiction.

The results of the study again made clear that topical analgesics are effective and safe for the relief of moderately severe chronic pain. The population explored in this study suffered from chronic pain, related to arthritis, neuropathy, and musculoskeletal disorders. Treated patients also reported to prefer topical treatments both for their convenience and ease of use. Only 0.5% of patients reported side effects while using the topical treatments.

Jeffrey A Gudin, et al. Changes in pain and concurrent pain medication use following compounded topical analgesic treatment for chronic pain: 3- and 6-month follow-up results from the prospective, observational Optimizing Patient Experience and Response to Topical Analgesics studyJ Pain Res. 2017; 10: 2341–2354.

Presenting phenytoin cream on EFIC 2017 Copenhagen

Presenting phenytoin cream on EFIC 2017 Copenhagen

Andrea Truini had a very interesting presentation at the EFIC 2017 pain conference in Copenhagen. The title of his talk was PAINFUL NEUROPATHIES. HOW NEUROPHYSIOLOGICAL TESTING AND SKIN BIOPSY HELP IN DIAGNOSING AND IDENTIFYING NEUROPATHIC PAIN. This presentation was a part of the workshop: NEUROPATHIC PAIN. CAN WE PREDICT AND PREVENT NEUROPATHIC PAIN?

One of the results of his studies was that in skin biopsies that sprouting of nerves in the periphery corresponds with more spontaneous burning pain. The sprouting of the nerves was captured with the clonal anti-body GAP45. This technique could get more insight in the pathophysiology of peripheral neuropathic pain.

David Kopsky, one of the inventors of the phenytoin cream shared the single blind response test with phenytoin 10% cream and placebo cream. The placebo cream will be applied on one pain area, and phenytoin 10% cream on an other pain area (e.g. left and right foot). Responders can indentify pain reduction in the area where the phenytoin 10% cream is applied. This new fast technique in revealing responders, is very valuable to prescribe phenytoin 10% cream to only responders.