In the October 2002 issue of Diabetes Care, we reported (1) the benefit of isosorbide dinitrate (ISDN) in the treatment of painful diabetic neuropathy. This stance was based on the speculation that the impaired nitric oxide (NO) generation might play a role in the pathogenesis of neuropathic pain through defects in local vasodilatation. This was a double-blind, randomized, placebo-controlled, two-period, crossover design study of 22 diabetic patients. The ISDN spray reduced overall neuropathic pain (P = 0.02) and burning sensation (P = 0.006). Fifty percent of the patients reported improvement in their quality of life and wanted to continue the ISDN spray. Since then, this publication has received considerable interest, with numerous inquiries from clinicians and patients wishing to try ISDN spray but unable to obtain it. Unfortunately, the company who provided with spray and placebo material has stopped manufacturing the ISDN spray. Nevertheless, we believe the following information regarding the use of glyceryl trinitrate (GTN) patches may be of interest and helpful for those who would like to try this therapy.

We had originally intended to use GTN patches to test our hypothesis after finding benefit in a small number of index cases with chronic painful neuropathy. In this pilot study the majority (four of six subjects) reported improvement in the pain. Based on this observation, we designed a placebo-controlled study, but were unable to obtain placebo patches from any of the manufacturers of GTN patches. It was the availability of placebo material that led us to explore our hypothesis using ISDN spray as the NO donor.

Since publication and the unavailability of ISDN, we have reverted to using GTN patches. A total of 18 patients (10 men, 15 with type 2 diabetes, age 57 ± 2.3 years [mean ± SD]) have now been treated. We present the following observations from our experiences with these patients. However, it should be stressed that this is not a placebo-controlled study.

Our clinical practice is to prescribe a 5-mg patch to be applied to the dorsum of one foot in the early evening, which is to be replaced with a new patch by the patient the following evening. The rationale behind this was to avoid headaches from prescribing too large a dose at the outset. If no headache occurred after several days we recommended the patients to use one 5-mg patch on each foot. If this produced headaches, then the patients are instructed to halve the patch and apply 2.5 mg to each foot.

Among the 18 patients, 8 (44%) reported reduction in pain and wished to continue using the patches. Of the subjects who noted an improvement, it occurred with the first or second application or within the first week. Two patients had to discontinue using the patches; one because of headache and the other due to a skin rash, but both had reported definite benefit. There were no other systemic adverse events reported. Thus, similar to the ISDN spray, GTN patches are helpful in some patients with painful diabetic peripheral neuropathy.

It is of interest that during the initial period, when only one patch was used, most patients reported a reduction in pain solely in the leg to which the patch was applied. This suggests a local mechanism rather than a systemic effect.

Thus, further placebo-controlled studies with larger patient numbers are required to confirm the potential of GTN patches in alleviating sensory symptoms associated with painful diabetic neuropathy. The mechanism remains speculative, and the apparent local effect, if confirmed, is intriguing.

Yuen KC, Baker NR, Rayman G: Treatment of chronic painful diabetic neuropathy with isosorbide dinitrate spray: a double-blind placebo-controlled cross-over study.
Diabetes Care