Prostaglandins, Aspirin-like Drugs and Analgesia

Abstract

THE importance of prostaglandins in inflammation has been emphasized by the discovery that aspirin-like anti-inflammatory drugs inhibit their synthesis^1–3. The anti-inflammatory and anti-pyretic effects of this group of drugs could be explained on this basis¹, but their analgesic properties could not, then, be firmly linked to inhibition of prostaglandin synthesis. This was because the only subjective effect reported on intradermal injection of prostaglandin was a sensation of warmth and a slight itching*, and on the blister base PGE₂ (up to 100 µg/ml.) failed to produce pain⁵. Several reports now describe the pain-producing activity of prostaglandins infused i.v. and injected intramuscularly^6–8 in man. Collier and Schneider have shown that PGE₁ is the most powerful agent in producing writhing responses in mice⁹. Vane¹ suggested that rabbit aorta contracting substance (RCS)¹⁰ which may be the unstable cyclic peroxide intermediate in the biosynthesis of prostaglandins¹¹, may be involved in the production of pain in inflammation. I tried to test this hypothesis by comparing the pain producing activity of fatty acid hydroperoxides with that of high concentrations of acetylcholine, bradykinin, histamine and PGE₁ on intradermal injection in man. The intensity of the pain induced by the hydroperoxides was greater than that induced by the other agonists but for all except PGE₁ the pain was transitory. On testing subdermal infusions to mimic the continuous release of an endogenous mediator of pain, two important properties of E-type prostaglandins were revealed. First, they increase the pain sensitivity to chemical and mechanical stimulation. Second, their effects are cumulative and depend not only on their concentrations but also on the time of exposure. The term “pain” is used to denote the overt pain evoked chemically during the infusions; hyperalgesia is used when pain was elicited only by applying slight pressure on the infusion area. Studies were carried out in five male volunteers each of whom received a full explanation of the nature of the experiment before giving his consent. The experiments were double blind.