Effect of inhibition of nitric oxide synthase on chronic tension-type headache: a randomised crossover trial

Lancet. 1999 Jan 23;353(9149):287-9. doi: 10.1016/s0140-6736(98)01079-4.


Background: Studies in animals have shown that nitric oxide plays an important part in central sensitisation and that inhibitors of nitric oxide synthase (NOS) decrease sensitisation in models of persistent pain. The efficacy of inhibitors of NOS has not been tested in patients with tension-type chronic headache. We aimed to show whether N(G)-monomethyl-L-arginine hydrochloride (L-NMMA), an inhibitor of NOS, is effective in relieving pain in such patients.

Methods: We undertook a randomised double-blind, crossover trial of 16 patients with chronic-tension-type headache. Patients were assigned intravenous infusion of 6 mg/kg L-NMMA or placebo on 2 days separated by at least 1 week in a randomised order. Headache intensity was measured on a 100 mm visual analogue scale, and on a verbal rating scale at baseline and at 30 min, 60 min, and 120 min after start of treatment. The primary endpoint was reduction of pain intensity on the visual analogue scale by the active treatment compared with placebo.

Findings: L-NMMA reduced pain intensity on the visual analogue scale significantly more than placebo: 120 min after start of treatment, the mean pain score was decreased from 49 to 33 with L-NMMA and from 44 to 40 with placebo (p=0.01). Pain intensity on the verbal rating scale was also significantly lower for treatment with L-NMMA than for treatment with placebo (p=0.02).

Interpretation: Inhibition of NOS had an analgesic effect in chronic tension-type headache. Further tests are required before clinical application.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Double-Blind Method
  • Enzyme Inhibitors / therapeutic use*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Nitric Oxide Synthase / antagonists & inhibitors*
  • Pain Measurement
  • Tension-Type Headache / drug therapy*
  • omega-N-Methylarginine / therapeutic use*


  • Enzyme Inhibitors
  • omega-N-Methylarginine
  • Nitric Oxide Synthase