Clinical Trials with NK1 Receptor Antagonists

16 May

Only a single clinical study, with CP-99,994 in post-operative dental pain, has demonstrated analgesic activity in man (Dionne et al. 1999). In this study, CP-99,994 was administered  as an intravenous  infusion  over 5 h, starting

30 min prior to surgery (total dose 0.75 mg/kg). CP-99,994 had comparable clinical efficacy to ibuprofen (Dionne et al. 1998). In contrast, the long-acting

orally active NK1 receptor antagonist aprepitant  (300 mg p.o. given 2 h prior to surgery)  was ineffective in post-operative  dental  pain  (Reinhardt  et al.

1998). The dental pain model is unlikely to be ideal for testing the analgesic effects of NK1 receptor antagonists, especially as these agents are not effective against acute noxious stimuli in rodents (Urban and Fox 2000). A recent study which has utilised NK1 receptor  internalisation to determine  the extent of substance  P release in the spinal cord following dental  tooth  extraction  in rodents  (Sabino et al. 2002) demonstrated NK1 receptor  internalisation in neurons in the trigeminal nucleus caudalis and cervical spinal cord (100% of neurons within lamina I and 65% in lamina II–V) within 5 min following incisor extraction. The effect was relatively short-lived with only few neurons showing internalised receptor at 60 min. This suggests that substance P may play only a minor  role in mediating  pain associated with tooth extraction, limited to the initial phase of pain, which is not typically assessed in the clinical studies. A more appropriate model to evaluate NK1 receptor antagonists may be dental pain associated with pulpal inflammation where elevated levels of substance P are found in dental pulp (Awawdeh et al. 2002).

NK1 receptor  antagonists  have also been evaluated in patients  with neu- ropathic  pain  and  aprepitant  (300 mg p.o. for 2 weeks) was ineffective in patients with established post-herpetic neuralgia (PHN; duration of 6 months to 6 years; Block et al. 1998). Lanepitant  (LY303870; 50, 100 or 200 mg p.o. b.i.d. for 8 weeks) had no significant effect on pain intensity (daytime or night time) when compared to placebo in patients with painful diabetic neuropathy (Goldstein et al. 1999). Lanepitant (10, 30, 100, or 300 mg p.o. for 3 weeks) was also without effect in patients with moderate to severe osteoarthritis (Gold- stein et al. 1998). To date, lanepitant and aprepitant  are the only NK1 receptor antagonists which have been evaluated in chronic pain conditions. The nega- tive data obtained with aprepitant  in PHN is not due to insufficient dose, as the same dose was shown by positron  emission tomography  (PET) to block central NK1 receptors in man (Hargreaves 2002). Destruction of peptidergic C-fibre function has been reported  in patients with long-established disease, and this loss in substance P function could therefore account, at least in part, for the failure of aprepitant  to produce analgesia in patients with PHN.

Finally, clinical trials with NK1 receptor antagonists for acute migraine and migraine prophylaxis have also been disappointing. L-758,298, an intravenous pro-drug  of aprepitant  (20, 40 or 60 mg i.v) failed to abort migraine pain as

measured  either by the time to meaningful relief or the number  of patients reporting  pain relief within 4 h (Norman  et al. 1998). Similarly, GR205171 (25 mg i.v.; Connor et al. 1998) and lanepitant (30, 80 or 240 mg p.o., Goldstein et al. 1997) were ineffective as abortive treatments  for migraine  headache. Furthermore,  prophylactic administration of lanepitant (200 mg p.o. per day) for 1 month  had no effect on migraine frequency and severity compared  to placebo (Goldstein et al. 1999). The hypothesis that NK1 receptor antagonists would be effective anti-migraine  agents was based on their ability to inhibit dural plasma extravasation (Shepheard et al. 1993), an effect shared with known anti-migraine  drugs such as the triptans (Williamson et al. 1997; Williamson and Hargreaves 2001) but not established as the reason for their efficacy in migraine treatment.

The lack of clinical efficacy of aprepitant  or GR205171 in pain or migraine trials is not due to insufficient dose or lack of brain penetration.  At the dose used in the analgesia trials, aprepitant  was found to produce more than 90% NK1 receptor occupancy using PET (Hargreaves 2002) and is anti-emetic  in cancer patients  following chemotherapy  (Navari et al. 1999). Similarly, the dose of GR205171 employed in the migraine trial was based on NK1 receptor adequate occupancy calculated from PET studies (Connor et al. 1998). In view of these largely negative findings it has been concluded  that  NK1 receptor antagonists are not effective as analgesic agents in man.

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