I first learned of proprietary topical blends used to treat neuropathic pain when I was asked to consult for a drug company which produces a variety of these formulations. Essentially, they utilize oral medications which are already employed to treat neuropathic pain as topical formulations for application directly to the area of pain. I was tasked with finding literature to support use of these products topically. At the time, this seemed like quite a simple task for an overzealous new grad that opted for electives such as “clinical epidemiology” in pharmacy school. I soon realized the complex and multifactorial nature of neuropathic pain coupled with the lack of studies on topical medications to treat it would make the project an immense undertaking.
Initially, I thought it was unlikely that pain resulting from nerve damage could be successfully treated with the topical application of any agent. If there were an effective topical treatment, I could only presume that it must act centrally. Consider a topical preparation containing gabapentin. If it were applied topically and subsequently absorbed into the bloodstream, exerting clinical effect by passing the blood brain barrier instead of acting at synapses locally at the site of the pain, then what benefit is there over taking the medication orally? Should this be the case, there are only drawbacks in their use: increased cost, variable absorption of drug via topical administration and still the ever present array of side effects caused by anti-epileptics and anti-depressants. Given the intuitive discrepancy of using topically applied medication to treat pain associated with neuropathy, it is imperative to review the medical literature in order to discern if pharmacist recommendation of these products is warranted.
In general, we speak of two types of pain: neuropathic pain and nociceptive pain. Neuropathic pain develops subsequent to nerve damage whereas nociceptive pain is a result of tissue damage. Neuropathic pain can be caused by lesions of the peripheral or central nervous system, or both. Presentation may include weakness, numbness and pain described as stabbing or burning. There are many causes of peripheral neuropathy and, in turn, a variety of mechanisms leading to neuropathic pain. The table below illustrates the variety of causes.
|Cause of neuropathy||Examples|
|Alcoholism||Vitamin deficiency due to lack of vitamin intake|
|Autoimmune Disease||Lupus, Sjogren’s syndrome and rheumatoid arthritis|
|Bone Marrow Disorders||Monoclonal gammopathies, osteosclerotic myeloma, lymphoma|
|Diabetes||Caused by prolonged exposure to high blood sugar concentrations|
|Toxins||Exposure to mercury, lead and thallium can cause neuropathy|
|Medications||Chemotherapy, isoniazid and amiodarone|
|Infections||Epstein-Barr virus, hepatitis C, leprosy, diphtheria and HIV|
|Inherited Disorders||Charcot-Marie Tooth disease|
|Trauma to Nerve||Motor vehicle accident, falls, sports injuries|
|Tumors||Can develop on the nerve itself or put pressure on surrounding nerves|
|Vitamins||Vitamin B, E and niacin are essential for nerve maintenance|
|Other diseases||Kidney disease, liver disease, hypothyroidism|
As you can imagine, with many different causes of neuropathic pain, there are in turn a variety of different nerve groups and neurotransmitters which can potentially contribute to the sensation of pain.
This creates a difficulty in developing drugs that precisely target the cause of pain, especially since the mechanism is either ill-defined or completely unknown in most cases.
Another challenge in treating neuropathic pain is that it does not typically respond to the use of conventional analgesics such as NSAIDs or opioids that can be used to treat nociceptive pain. Certain antidepressants and anticonvulsants have shown some benefit in treating this condition by modulating neurotransmitters that contribute to neuropathy. Even still, these medications are not completely effective and most often work towards a treatment goal of bearable pain without the ability to completely eliminate it. In exchange for the modest clinical effect, patients endure intolerable side effects and can lead to discontinuation of the medication.
In theory, topical formulations of these medications would act locally and bypass centrally mediated side effects. A study comparing the treatment of diabetic neuropathy with clonidine gel against placebo, found significant pain reduction in the active treatment groups. They noted that patients with detectable clonidine in their blood had a greater pain reduction. However, the serum blood level in patients with detectable levels was well below the threshold for treating hypertension. This finding suggests that the effects of clonidine were peripheral rather than central. Thus, adverse events were similar between placebo and clonidine gel (1). In another study – following a mixed group of patients with refractory, moderate to severe peripheral neuropathic pain – patients administered topical amitriptyline 2%/ketamine 1% cream. Outcomes were measured by lab analysis and a rating and satisfaction scale given at baseline, 6 months and 12 months. At the end of the study, the majority of patients (89%) were satisfied with treatment and two patients were pain free. Minimal adverse events were reported and blood levels revealed minimal systemic absorption (2).
Currently, there are proprietary topical treatments containing a variety of pharmaceutically active components available for patients with nociceptive and neuropathic pain. For illustration, the matrix below shows the active components in these formulations.
For example, topical formulation “NC1” contains ketamine, clonidine, gabapentin, imipramine, mefenamic acid and lidocaine. The formulation “NC3” contains ketamine, lidocaine, amitriptyline, DDG, acyclovir and ketoprofen. There are over two dozen formulations with different combinations of the active ingredients in the matrix. For some of these ingredients, randomized controlled trials have demonstrated a significant analgesic effect in some types of neuropathic pain. For many of the medications, I could find no evidence of use to treat any type of pain. In trying to uncover the answers, I was left with more questions. How were the concentrations determined? Are all of these drugs, when applied topically, useful in treating pain? There are a variety of mechanisms of action included in each formulation with little evidence to support inclusion of some of the ingredients. Was the intention to have a blanket or cure-all approach since the exact mechanism of pain is usually unknown? Perhaps it is a reasonable approach given the nature of the disease, but I could not find literature to support efficacy of use in some cases.
There is evidence that pain generating neural signals arise at least, in part, in the skin. Therefore, medications which have efficacy in treating pain may also be effective when applied topically. The effect seems to be a local effect in which fewer side effects are observed. These topical formulations may be effective for certain types of neuropathic pain, but there seems to be a variable effect. Many patient characteristics could play a role in whether or not this type of treatment will be effective (age, sex, diagnosis, sensory findings and concurrent medications).
An overwhelming need for more studies exists. Ideally, there will be well-designed trials that stratify subjects by type of neuropathic pain and administer single ingredient formulations at different concentrations for at least 6-12 months. Outcomes of these studies may allow researchers to better elucidate the mechanism of different types of neuropathic pain inversely by finding out which agent best treats pain and noting the drug mechanism involved. Following collection of this data, combinations of drugs which have shown efficacy for a given type of neuropathic pain can be considered.
Is this a reasonable option for pharmacist recommendation? There is some efficacy particularly in post-herpetic neuralgia. It is reasonable to try given support for clinical efficacy and limited side effects. There may be difficulty in choosing which formulation, since it is unclear which ingredients in the formulation are contributing to the observed clinical efficacy. Cost is also a consideration. Compounded formulations are seldom covered by insurance and the cash price can be quite high. Topical treatments for neuropathic pain may be a good option in the future, but it requires further research as well as the mainstream manufacturing of well-developed formulations.
1. Campbell, C., J. Campbell, W. Schmidt, K. Brady, and B. Stouch. “Topical Clonidine Gel Reduces Pain Caused by Diabetic Neuropathy: Results of a Multicenter, Placebo-controlled Clinical Trial.” The Journal of Pain 10.4 (2009)
2. Lynch, Mary Elizabeth, Alexander John Clark, Jana Sawynok, and Michael J. Sullivan. “Topical Amitriptyline and Ketamine in Neuropathic Pain Syndromes: An Open-Label Study.” The Journal of Pain 6.10 (2005): 644-49.