A Closer Look At Pharmacologic Compounds For Painful Diabetic Peripheral Neuropathy

The treatment of diabetic neuropathic pain is complex and often unsatisfactory clinical results plague the patient with diabetes and the treating physician. Historically, physicians have used systemic pharmacologic treatments with mixed results and undesirable side effects. These have included antidepressants, anticonvulsants, N-methyl-D-aspartate (NMDA) receptor antagonists and opiate analgesics.¹    More recently, topical pharmacologic compounds have started to play a role in the treatment of patients with diabetic neuropathic pain. Topical treatments offer a new multimodal arm in addressing chronic pain states as the treatments have limited absorption and an excellent safety profile in comparison to the systemic treatment options.² These options offer an advantage over many of the medications physicians have used historically and can also offer benefits as adjunctive treatments.    A consensus report from the International Association for the Study of Pain in 2010 suggested that topical analgesics may be beneficial in a setting of “localized neuropathic pain.”³ These topical medications are also beginning to serve as a treatment option for difficult to manage pain in patients with osteoarthritis, postherpetic neuralgia and complex regional pain syndrome.    When one applies the topical medications to the skin, they exert their analgesic action by increasing drug concentration locally at the application site with minimal systemic uptake and low serum concentration. Given the complexity of treating neuropathic pain, topical analgesic formulations that use multiple agents with varied mechanisms of action may increase the efficacy of pain treatment and improve the chances of successful therapy.²

A Closer Look At Topical Compounds

A variety of medications are in common use as topical pain treatments. These modalities include nonsteroidal anti-inflammatory drugs (NSAIDs), local anesthetics, capsaicin, tricyclic antidepressants, ketamine and gabapentin (Neurontin, Pfizer) with options for use alone or in combination. In one study, 5% topical lidocaine applied as a patch or in a medicated plaster formulation were as successful in treating diabetic neuropathy as oral pregabalin, showing a 65 to 66 percent favorable response rate.⁴    Adverse effects of these medications are minimal and avoid many of the complications associated with systemic treatments. Adverse effects of the topical treatments can include local skin rashes, itchiness and irritations.    Compounded creams and ointments of topical analgesics use mixtures of water, glycerin, propylene glycol, methylparaben and conventional emulsifiers as carriers of the active substance.⁴    The formulation we use in our treatment population is delivered through a vehicle that is a proprietary mixture of base components called Lipoderm ActiveMax (Professional Compounding Centers of America). This theoretically delivers a greater local response to the tissues by the active compounds included within the QmedRx diabetic peripheral neuropathy pain pharmaceutical topical cream, and effectively allows the delivery of a number of compounds simultaneously through the human skin. With this system, dosing accuracy and uniformity occur through a specific QmedRx pump bottle.

Case Studies In Using Compounds For Neuropathy

We would like to present three brief case presentations using identical pain compounds from the QmedRx Pharmacy. Each individual used an equal volume of pain cream three to four times per day on the bilateral lower extremities. The cream consisted of lidocaine 2%, prilocaine 2%, topiramate 2.5% and meloxicam 0.09%.    A 71-year-old male patient presented with a history of type 2 diabetes mellitus and a mixture of large and small fiber peripheral neuropathy. He had failed other systemic treatments. The patient previously used a topical pharmaceutical pain cream for six weeks. At the onset of treatment in our clinic, he rated his baseline pain level at 6/10 on the Visual Analogue Scale. After applying the topical therapy four times per day to his right and left lower extremities for four weeks, his pain decreased to 3/10. No cutaneous or systemic side effects occurred throughout treatment.    A 73-year-old male patient with a past medical history of type 2 diabetes, painful diabetic neuropathy, hyperlipidemia and hypertension presented to our clinic complaining of moderate to severe pain with radiation and tingling in both feet that shot to the digits. Clinically, the pain was consistent with small fiber peripheral neuropathy. At presentation, the patient rated the level of pain at 7/10 on the Visual Analogue Scale. After six weeks of treatment with application of the compounded pharmaceutical pain cream four times per day, the pain decreased and he rated it at 2/10. No cutaneous or systemic side effects occurred throughout treatment.    A 55-year-old female patient presented with a history of type 2 diabetes, painful diabetic neuropathy and peripheral vascular disease. She complained of shooting sensations on the outer aspect to her fifth toes of both feet and radiating pain overlying the anterior leg to the dorsal aspect of her feet. The epicritic sensation was clinically intact. Her vibratory sensation was diminished, sharp/dull discrimination was absent and she had hyperesthesia.    We diagnosed her with diabetic small fiber neuropathy. At presentation, the patient rated her pain to be 10/10 on the Visual Analogue Scale and stated that she was unable to carry on her normal activities of daily life because the pain was so severe. After starting treatment with the topical pain cream four times per day for a duration of six weeks, her level of pain decreased to a level of 2/10. No cutaneous or systemic side effects occurred throughout treatment.

What The Research Reveals

In a 2013 publication by the Mayo Clinic, there was strong evidence for the use of topical diclofenac (Voltaren, Novartis) and topical ibuprofen in the treatment of acute soft tissue injuries and chronic joint conditions like osteoarthritis.⁴ There was also evidence to support the use of lidocaine in the treatment of postherpetic neuralgia and diabetic neuropathy.    However, in a randomized, placebo-controlled, double-blinded study looking at the use of topical ketamine cream in treating painful diabetic neuropathy, both the placebo group and ketamine treatment group had an improvement in their symptoms over time with no differences.⁵    In another double-blinded, placebo-controlled trial, patients randomly received one of four creams (placebo, 2% amitriptyline, 1% ketamine, or 2% amitriptyline-1% ketamine combined).⁶ Researchers found no difference between treatment groups with decreased pain in all groups. There was no significant systemic absorption and minimal side effects in all groups.    There have been several case reports of higher concentrations of some of these topical agents producing significant analgesia and some systemic side effects so optimization of the dosage is required.

In Conclusion

Although additional comprehensive double-blinded trials must occur to prove or disprove the efficacy of compounded medications in the treatment painful diabetic neuropathy, it is our belief that these compounds have a place in the treatment of this condition and many other pain conditions. They have demonstrated safety and efficacy for a wide range of pain conditions of the lower extremity.    It will be important to determine the appropriate formulations and combinations of different topical medications in the treatment of specific clinical pathologies. The low risk of adverse events makes it encouraging to continue researching the use of these medications in the treatment of a variety of situations, including the diabetic neuropathic patient.    Dr. Rice is an Assistant Clinical Professor in the Department of Orthopedics and Rehabilitation at Yale University School of Medicine. He is in private practice at Fairfield County Foot Surgeons in Norwalk, Conn. He is a Fellow of the American College of Foot and Ankle Surgeons.    Dr. Edgar is the Chief Resident of Podiatric Medicine and Surgery at Yale-New Haven Hospital in New Haven, Conn. References 1. Muthuraman A, Singh N, Jaggi AS, Ramesh M. Drug therapy of neuropathic pain: current developtments and future perspectives. Curr Drug Targets 2013 Oct 3 (Epub ahead of print). 2. Anitescu M, Benzon H, Argoff C. Advances in topical analgesics. Curr Opinion in Anaesthesiology. 2013; 26(5):555-561 3. Mick G, Baron R, Finnerup NB, et al. What is localized neuropathic pain? A first proposal to characterize and define a widely used term. Pain Manage 2012; 2:71-77. 4. Argoff CR. Topical analgesics in the management of acute and chronic pain. Mayo Clin Proc 2013; 88(2):195-205. 5. Mahoney JM, Vardaxis V. Topical ketamine cream in the treatment of painful diabetic neuropathy: randomized placebo-controlled, double-blind initial study. J Am Podiatr Med Assoc. 2012; 102(3):178-183. 6. Lynch ME. Topical 2% amitriptyline and 1% ketamine in neuropathic pain syndromes: randomized, double-blind, placebo-controlled trial. Anesthesiology 2005; 103(1):140-146.