The Indian group administered trinitrate in a spray on the skin, just as we did with the cream. They conducted a double blind study in 48 patients, and patients were asked to spray the drug or a similar looking placebo spray on both feet with one actuation each (0.4 mg/ actuation) before retiring to bed at night.

Using a cross over design patients were asked to fill in a short-form, McGill pain questionnaire (SF-MPQ), visual analogue score (VAS), present pain intensity (PPI) and 11 point Lickert scale, initially in the beginning of the study and then after end of phase-1, wash out period and phase-2.  

All measurements showed clinical significant difference between placebo and verum:

VAS scores decreased significantly ( p < 0.001) from 7.18  to 4.68  in group A and from 7.52  to 4.57   in group B when treated with GTN spray. On placebo the changes in pain scores were from 7.05  to 6.45 and 7.57  to 6.90  in groups A and B, respectively VAS as a parameter of pain relief.

Safety profile Of the 43 patients who received GTN drug, two developed palpitation, two developed headache and one developed minor faintness, all disappearing after repeated dosing. Only one patient continued to show headache, palpitation and faintness and had to stop treatment. 

The authors ended with the following speculation regarding the mechanism of action: 

We speculate that the improve- ment in pain and burning sensation demonstrated with GTN spray in our study may be associated with the increased generation of NO (nitric oxide); prompting vasodilation with secondary improvement in micro- vascular blood flow. Recently, several investigators have revealed vasa nervosum angiogenesis in diabetic rats following experiment using vasodilator therapy [32,33]. The vasodilation induced by the increased generation of NO after GTN treatment may induce angiogenesis of the vasa nervosum, and this may also explain gradual increase in analgesic effects of spray. ^[1]

Recently the same group expanded on these data. ^[2]

Topical glyceryl trinitrate treatment has also demonstrated short- to mid-term efficacy in chronic noninsertional Achilles tendinopathy. Tendinopathy is currently seen as a variant of degenerative neuronal induced inflammation. Acute topical glyceryl trinitrate facilitates capillary venous outflow in painful Achilles tendons.  ^[3] However, there are many conflicting reports in this area, and the previous claim that topical trinitrate might in fact heal the tendonitis is recently found to be uncorrect. ^[4] But pain relief remains piossible. ^[5]

NO and neuropathic pain 

The data related to NO and neuropathic pain are quite confusing. There is abundant preclinical literature pointing ourt that NO might even enhance neuropathic pain.Recently it was demonstrated that nNOS increases after peripheral nerve injury and this may contribute to the increase of NO production observed after peripheral neuropathy.^[6] Anyhow, the proof of the pudding is in the eating and for now it seems that nitrates have the possibility to decrease neuropathic pain, at least in a subcohort of patients.  

June 2010, Jan M. Keppel Hesselink, MD, PhD 

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