It has been estimated that 9% of the US population suffers from moderate to severe non-cancer-related pain. Acute pain resulting from conditions such as headache, muscle spasms, dental problems or following surgery, affects 90 million Americans every year. Chronic pain is more troubling as it sparks a viscous cycle of clinical problems and often precipitates depression and/or life-style changes. Furthermore, establishing prolonged analgesia, free of serious side effects is a particularly challenging area of medicine. Estimates of the number of Americans suffering chronic pain range from 40-70 million. The total economic cost of pain is $100 (US) billion in the US alone and the estimated worldwide market for pain and inflammation treatments has been estimated as $18.7 (US) billion. It is therefore not surprising that the development of analgesics has represented a major pharmaceutical objective.

In a recent DiscoveryDossier we describe the therapeutic potential of 5-HT7 receptor antagonists in the unmet field of migraine prophylaxis. 5-HT7 receptors are similar pharmacologically to 5-HT1A receptors that have also been reported to mediate pain and hyperalgesia in peripheral sensory neurons via direct activation of C-type fibers.

Researchers from bioMerieux-Pierre Fabre have, in a recent series of studies, investigated the analgesic effects of 5-HT1A receptor activation by the very-high-efficacy, selective 5-HT1A receptor agonist F 13640. This molecule was discovered to produce broad-spectrum analgesia via a novel central mechanism of action that, remarkably, grows rather than decays with chronicity. This therefore contrasts with other analgesics such as morphine which decay in efficacy following long-term treatment eventually producing hyperalgesia. Although, in rodents not exposed to nociception, F 13640 induces its analgesic effect only after having initially induced hyperalgesia this effect can be minimized by progressively increasing doses of F 13640 over a 5-week period. Of interest, F 13640 does not appear to produce hyperalgesia in animals with experimental pain of high intensity. In addition to offering a highly attractive profile of anagesia, the bioMerieux-Pierre Fabre group found that increasing the dose of F 13640 induced tachyphylaxis to the 5-HT syndrome, a syndrome thought to be related to 5-HT1A receptor activation and characterized by alteration in cognition, behavior, autonomic nervous system function, and neuromuscular activity. This finding is of key importance since the appearance of the 5-HT syndrome necessitates drug withdrawal.

F-13640 is under development by bioMerieux-Pierre Fabre as an antidepressant and anxiolytic. Despite the relatively large number of 5-HT1A agonists in development or on the market, the use of most of these has been restricted to psychiatric conditions and few have been developed as analgesics. These data and data from other studies demonstrating therapeutic efficacy in models of neuropathic pain suggest that F-13640 or its derivatives may be an exception to this trend. Clinical data from analgesia trials are eagerly awaited.

Adapted from Pomonis et al, J Pharmacol Exp Ther 2003 Apr 29; [epub ahead of print]

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