Gender and the placebo analgesic effect in acute pain.

OBJECTIVE: Our objective was to examine the placebo arms from a series of clinical trials in which the post-third molar extraction dental pain model was used to elucidate the time course of the placebo effect and the proportion of the population that are responders, as well as to evaluate whether the placebo analgesic response of female subjects may differ from that of male subjects. METHODS: We performed a meta-analysis of 596 subjects included in the placebo treatment arm of 16 double-blind, post-third molar extraction dental pain (moderate to severe) studies submitted to the Food and Drug Administration electronically. The inclusion and exclusion criteria were practically identical in all studies. Pain relief and pain intensity measurements used the same metrics in all studies. The measurements were recorded just before drug administration and at least at postdose hours 0.5, 1, 1.5, 2, 3, 4, 5, and 6. RESULTS: There were 325 female subjects and 271 male subjects. They were all otherwise healthy, with a mean age of 21.6 years for female subjects and 22.3 years for male subjects. The postoperative baseline pain was greater in female subjects than in male subjects, and this difference was statistically significant. Both pain intensity and pain relief scores demonstrate the well-established placebo effect in 10% of the pooled subjects, as well as in all the individual studies. Over time, however, the mean pain intensity and pain relief scores for the female and male treatment groups were not noticeably different at any time point after medication. Further analysis of the data showed no gender difference in duration of action of the placebo. CONCLUSIONS: The results demonstrated no gender difference in response to placebo. These results were obtained from the post-third molar extraction situation, in which the least possible confounding factors were present. To fully establish the generality of this phenomenon, studies should be carried out in other pain models.

A search for sex differences in response to analgesia.

BACKGROUND: It is generally accepted that males and females respond differently to painful conditions. With few exceptions, according to the published literature, females demonstrate a lower pain threshold and a lower tolerance of painful stimuli. There is some support in the literature that females experience greater analgesic efficacy than do males after the administration of narcotic analgesics. We compared the analgesic response of females and males to ibuprofen in a post-third-molar extraction dental pain model. METHODS: We performed a meta-analysis of 314 subjects included in the ibuprofen treatment arm of 7 double-blind, post-third-molar extraction dental pain (moderate to severe) studies, which were submitted to the agency electronically. The inclusion and exclusion criteria were practically identical in all studies. Pain relief and pain intensity measurements used the same metrics in all studies and were recorded just before and at least at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, and 6. 0 hours after drug administration. RESULTS: The study included 195 female subjects and 119 male subjects (mean age, 21 years). Other than requiring dental extractions, the subjects were all healthy. Postoperative baseline pain was greater in females than in males to a statistically significant degree (P =.006). Both pain intensity and pain relief scores demonstrated the well-established analgesic effect of ibuprofen in the pooled data set as well as in all the individual studies. Moreover, the mean pain intensity and pain relief scores over time for the female and male treatment groups were not noticeably different at any time point after drug administration, with no imputation for missing values. Analysis of the data using the "baseline observation carried-forward" technique for remedicated subjects (the technique recommended by the Food and Drug Administration for efficacy analysis of acute analgesic medications) produced the same results, which were confirmed by analysis of variance and t tests at each time point of the study. CONCLUSIONS: Our results demonstrated no sex effect on the analgesic response to ibuprofen. These results were obtained under the post-third-molar extraction setting, in which the least possible confounding factors are present. To fully establish the generality of this phenomenon, studies should be carried out in other pain models and using analgesic medications with different mechanisms of action. Arch Intern Med. 2000;160:3424-3428.

Baseline pain and response to analgesic medications in the postsurgery dental pain model.

In designing clinical trials for the treatment of acute pain, enrollment of patients with moderate to severe pain is recommended even when the desired indication is treatment of mild pain. To test this approach, the authors explored the results of two studies that had the same standard placebo-controlled, parallel-group design and that compared the study medication to a single dose of ibuprofen 400 mg. One study had 25 subjects, the other 50 in its ibuprofen arm. Subjects indicating moderate or severe pain (on a scale ranging from 0 = none, 1 = mild, 2 = moderate, 3 = severe) following a surgical extraction of two or more third molars were enrolled. There was a difference between the ibuprofen groups in these two studies in average baseline pain intensity (PI) (2.88 +/- 0.33 vs. 2.26 +/- 0.44). In the higher baseline group, PI decreased faster, achieving lower levels of PI that were maintained for the rest of the study period. The results of pain relief measurements paralleled those of PI. The authors conclude that including patients with a higher degree of baseline pain in the postoperative dental pain model has the potential to increase discrimination of analgesic properties of new drugs.