A Closer Look At Pharmacologic Compounds For Painful Diabetic Peripheral Neuropathy

Andrew H. Rice, DPM, FACFAS, and Sarah Edgar, DPM

   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.


There are podiatrists who now use low dose bupivacaine (local anesthetic) in the form of ankle blocks to treat somatic sensory peripheral neuropathy in the feet. It is administered twice weekly for 2 to 2,5 months. Excellent symptomatic treatment. Low dose bupivacaine acts as an analgesic by inhibiting over expressed over active sodium ion channels in axons of neuropathic somatic sensory peripheral nerves. It is these overactive overexpressed sodium ion channels that create sub-threshold oscillation membrane potentials that are the spontaneous aberrant electrical signals that are transmitted to the somatosensory cortex of the brain, which then manifest as the somatic sensory symptoms of burning, pins and needles, and tingling in the feet as well as numbness. Low dose bupivacaine ankle blocks are used in conjunction with EST (electrical signal treatment) and with TENS (transcutaneous electrical nerve stimulation) unit, generating excellent symptomatic relief from somatic sensory neuropathy.

Combination treatment (i.e. oral Lyrica + cutaneous Lidoderm Patches + low dose bupivacaine nerve blocks) is the best way to treat somatic sensory peripheral neuropathy in the feet. Such combination treatment is symptomatic treatment, not a cure, that the neuropathy patient needs for life as needed.

More placebo double blind studies (randomized control trials) are needed with these topical medications. The two RCTs published so far revealed that there is no medical evidence that these topical medications actually are medically necessary in treating neuropathy in the feet. There should be about 10 more published RCTs required to ascertain whether these topical medications are medically necessary or not. It is still premature to know for now with only two RCTs published.

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