TRPV1 antagonistic analgesic effect: a randomized study of AZD1386 in pain after third molar extraction.

The effects of a TRPV1 antagonist (AZD1386) were investigated in patients with acute pain. After removal of a mandibular third molar and at request of analgesia 103 patients randomly received 95 mg AZD1386 (n = 40), placebo (n = 40) or 500 mg naproxen (n = 23) in a double-blind manner. Plasma samples were drawn, and pain intensity and body temperature were measured during 8 h after drug administration. The pain intensity difference from drug intake was calculated as a percentage (PID%) and as a weighted sum over the 8 h (SPID%0-8 h). The time to first perceptible and first meaningful pain relief was recorded. SPID%(0-8) h showed no significant difference between AZD1386 and placebo (P = .132) but between naproxen and placebo (P = .038). AZD1386 had a rapid short-lasting analgesia and compared to placebo, PID% was significantly higher (P ≤ .026) at 0.25, 0.50, 0.75 and 1.00 h after drug administration. Correspondingly, for naproxen significantly higher PID% (P ≤ .021) was seen at 2.5, 3, 4, 5, 6, 7 and 8 h. The frequency of patients obtaining perceptible and meaningful pain relief was about 85% and 48% after AZD1386 and about 53% and 25% after placebo. The occurrence of perceptible and meaningful pain relief was significantly faster (P = .002 and P = .031) for AZD1386 compared to placebo. Adverse events were similar to placebo with the exception of 2 patients reporting chills. The highest individual body temperature after AZD1386 was 38.1°C, recorded in 2 patients. In summary, AZD1386 was well tolerated with a rapid analgesia that was short lasting despite sustained plasma concentration.

Evaluation of the analgesic efficacy of AZD1940, a novel cannabinoid agonist, on post-operative pain after lower third molar surgical removal.

Aim To evaluate the analgesic efficacy of AZD1940, a novel peripherally acting cannabinoid CB1/CB2 receptor agonist, in patients undergoing third molar surgical removal. Methods This was a randomized, double-blind, placebo-controlled study in patients scheduled for surgical removal of an impacted lower third molar. Patients received a single oral dose of 800 µg AZD1940, 500 mg naproxen or placebo 1.5 h before surgery. The dose of 800 µg AZD1940 was selected based on earlier data from a single dose study in man, in which it was identified as the highest well tolerated dose. Ongoing post-operative pain (primary variable) and pain on jaw movement were assessed on a visual analog scale (VAS, 0-100 mm) from 0 to 8h postoperatively, deriving the area under the curve of ongoing pain (VAS AUC0-8h), and of pain on jaw movement (VASJM AUC0-8h). The time to requesting rescue medication (acetaminophen) was recorded. Subjective cannabinoid effects were assessed by the visual analog mood scale (VAMS). Results In total, 151 patients were randomized to AZD1940 (n = 61), placebo (n = 59) or naproxen (n = 31). There was no statistically significant difference in pain VAS AUC0-8h or in VASJM AUC0-8h between AZD1940 and placebo. Naproxen significantly reduced both pain VAS AUC0-8h and VASJM AUC0-8h as compared with placebo (p < 0.0001 for both). Significantly fewer patients on naproxen requested rescue medication and the duration of time to rescue was greater, as compared with placebo, whereas there were no significant differences between AZD1940 and placebo in these outcome variables. Statistically significant increases in VAMS items "sedated" and "high" were observed after AZD1940 compared with placebo. The increases in VAMS were numerically small compared with previous findings with a centrally acting cannabinoid. The most commonly observed adverse events (AE) on treatment with AZD1940 were postural dizziness (80% of subjects), nausea (26%), hypotension (21%) and headache (13%), most AE being mild to moderate. Conclusion The CB1/CB2 receptor agonist AZD1940 did not reduce post-operative pain after lower third molar surgical removal at doses exerting subjective cannabinoid effects. Implications Activation of peripheral CB1/CB2 receptors per se is probably of less clinical relevance for the treatment of acute nociceptive pain in man.