5-HT3 receptor antagonists as analgesics

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, and 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 (click here for "Pain 2002" an analysis of future directions in analgesic therapeutics).

Serotonin (5-hydroxytryptamine; 5-HT) is involved in a wide variety of physiological processes by binding to multiple 5-HT receptors grouped into seven major families (5-HT1-5-HT7). Application of molecular cloning techniques has revealed the existence of at least 14 different genes, each encoding a distinct 5-HT receptor subtype.

In a recent DiscoveryDossier we describe the therapeutic potential of 5-HT7 receptor antagonists in the unmet field of migraine prophylaxis (click here for further details) due to their ability to modulate both pain pathways and vascular tone. 5-HT1A receptors are also involved in mediating pain and hyperalgesia in peripheral sensory neurons via direct activation of C-type fibers and in a recent edition of TherapeuticAdvances we reported on the development of the 5-HT1A receptor agonist, F 13640, by bioMerieux-Pierre Fabre as a treatment of pain.

Most recently Gary McCleane and colleagues report on the possible use of 5-HT3 receptor antagonists for the treatment of neuropathic pain. The origins of pain range from nociceptive (caused by tissue injury or inflammation) to neuropathic, a condition that can have many underlying causes. Approximately 26 million patients worldwide (10 million in the US) suffer from some form of neuropathic pain, spending an estimated $2-3 billion annually on treatments.

Although selective 5-HT3 receptor antagonists such as ondansetron are currently utilized as anti emetics, they may also have analgesic properties. To evaluate this Dr McCleane and colleagues conducted a double blind, placebo controlled crossover study of 26 patients with chronic neuropathic pain of mixed etiology that were unresponsive to currently available opioid analgesics, non steroidal anti-inflammatory drugs, tricyclic antidepressants and anticonvulsants. A single iv administration of 8mg of ondansetron produced analgesic activity at 4hours post-administration. Although the efficacy was modest and short-lived it should be noted that steady state plasma levels would not be achieved using the single iv dose protocol used in the present study. Furthermore ondansetron penetrates the blood brain barrier quite poorly and it remains possible that 5-HT3 antagonists with greater CNS activity and which are administered over a longer time period may produce efficacy of considerably greater extent. That said, the efficacy noted by patients in the present study is remarkable in that the cohort studies were unresponsive to other standard treatments. Further investigation of ondansetron or other 5-HT3 antagonists is therefore warranted.

Entry date Monday, December 08, 2003

Adapted from McCleane et al, Anesth Analg. 2003 Nov;97(5):1474-8.