Nitrates in neuropathic pain?

The Indian group of Agrawal and colleagues (2007) explored the analgesic effects of glyceryl nitrates spray in neuropathic pain. They suggested that impaired nitric oxide (NO) synthesis may play an important role in the pathogenesis of painful diabetic neuropathy.

94996382-Mast3r-Dreamstime-INP Nitrates in neuropathic painSome studies demonstrated impaired neuronal nitric oxide generation in diabetic rats induces hyperalgesia. And in other studies a decreased nitric oxide production was seen to a reduction in endoneural blood flow in type 2 diabetic patients with neuropathy.

Both iso-sorbide dinitrate and glyceryl trinitrate may act as potent nitric oxide donor and have similar pharmacological activity compared to endothelial derived relaxing factor, a nitric oxide dependent enzyme with vasodilator capacity. In our Institute we have now gathered quite some experience using isosorbide dinitrate cream in neuropathic pain, with good results.

Spray of cream on the skin

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 palpitations, two developed headache and one developed minor faintness, all disappearing after repeated dosing. Only one patiënt 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 improvement 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.

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

Conflicting reports

Topical glyceryl trinitrate treatment has also demonstrated short- to mid-term efficacy in chronic non insertional 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 incorrect.[4] But pain relief remains possible.[5]

NO and neuropathic pain 

The data related to NO and neuropathic pain are quite confusing. There is abundant preclinical literature pointing out that NO might even enhance neuropathic pain. Recently it was demonstrated that NOS 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 sub cohort of patients.  

June 2010, Jan M. Keppel Hesselink, MD, PhD
‘Nitrates in neuropathic pain’

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[1] Agrawal RP, Choudhary R, Sharma P, Sharma S, Beniwal R, Kaswan K, Kochar DK. | Glyceryl trinitrate spray in the management of painful diabetic neuropathy: a randomized double blind placebo controlled cross-over study. | Diabetes Res Clin Pract. | 2007 Aug;77(2):161-7. Epub 2007 Feb 21.

[2] Agrawal RP, Goswami J, Jain S, Kochar DK. | Management of diabetic neuropathy by sodium valproate and glyceryl trinitrate spray: a prospective double-blind randomized placebo-controlled study. | Diabetes Res Clin Pract. | 2009 Mar;83(3):371-8.

[3] Osadnik R, Redeker J, Kraemer R, Vogt PM, Knobloch K. | Microcirculatory effects of topical glyceryl trinitrate on the Achilles tendon microcirculation in patients with previous Achilles tendon rupture. | Knee Surg Sports Traumatol Arthrosc. | 2010 Jul;18(7):977-81. Epub 2009 Oct 31.

[4] Murrell GA. | Using nitric oxide to treat tendinopathy. | Br J Sports Med. | 2007 Apr;41(4):227-31. Epub 2007 Feb 8.

[5] Hervera A, Negrete R, Leánez S, Martín-Campos J, Pol O. | The role of nitric oxide in the local antiallodynic and antihyperalgesic effects and expression of delta-opioid and cannabinoid-2 receptors during neuropathic pain in mice. | J Pharmacol Exp Ther. | 2010 Sep 1;334(3):887-96. Epub 2010 May 24.

[6] Chacur M, Matos RJ, Alves AS, Rodrigues AC, Gutierrez V, Cury Y, Britto LR. | Participation of neuronal nitric oxide synthase in experimental neuropathic pain induced by sciatic nerve transection. | Braz J Med Biol Res. | 2010 Apr;43(4):367-76. Epub 2010 Mar 19.

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