Jeanette Mitchell

Comparative efficacy of ibuprofen and aspirin in episiotomy pain.

Substitutes for aspirin devoid of troublesome effects are needed. A potential candidate, ibuprofen, heretofore marketed outside the United States as an antiarthritic, was compared in single oral doses of 300 and 900 mg with aspirin, 900 mg, and placebo in a parallel balanced randomized double‐blind design in 80 patients with pain due to episiotomy. Over the 6 hours of evaluation, there was pain reduction greater than 50 per cent in 17 of 20 patients treated with either dose of ibuprofen (p < 0.01), in 18 of 20 patients treated with aspirin (p < 0.001), and in only 6 of 20 patients treated with placebo. With the two doses of ibuprofen, pain relief, as measured by pain intensity differences (PID) was similar to that with aspirin with respect to time of onset, degree and duration of analgesia. Reported side effects with ibuprofen were insignificant.

Naproxen, aspirin, and codeine in postpartum uterine pain

The analgesic efficacy of oral naproxen and its sodium saft was compared with that of aspirin and codeine in two separate trials involving 140 and 90 patients, respectively, with postpartum uterine pain in a single‐dose, parallel, stratified, randomized, placebo‐controlled, double‐blind design. With 300 or 600 mg naproxen and with 275 mg naproxen sodium, significant analgesia, measured subjectively by pain intensity differences (PID), was prolonged at least 7 or 8 hr; onset tended to be delayed 2 hr or more. With 650 mg aspirin analgesia began within 1 hr and continued until the fifth hour, while with 60 mg codeine responses were indistinguishable fram placebo responses throughout the 8‐hr time course. Although time‐effect patterns with naproxen sodium and aspirin were different, summed analgesic effects (SPID) showed equal efficacy and superiority over placebo (p < 0.005). With each of the 2 doses of naproxen, SPID separation from placebo was comparable to that above (p < 0.02 and 0.005, respectively), but analgesic dose response, though measurable, was not significant. Side effects were not significant with any of the treatments. It appears that naproxen and naproxen sodium are analgesics with efficacy equal to aspirin and may prove to be rational substitutes for currently available analgesics in some painful states in which longer pain relief would be desireable.

Aspirin and codeine in two postpartum pain models

Aspirin and codeine, standard reference analgesics, are frequently used as positive controls in clinical trials of new oral analgesics. In randomized parallel double‐blind studies, single doses of aspirin and codeine were compared with placebo in episiotomy pain (99 patients) and in postpartum uterine pain (130 patients), common models in analgesic trials. With aspirin, 600 and 1,200 mg, in episiotomy pain, analgesia as measured by pain intensity difference (PID) scores began within 1 hr, peaked at the second hour (p < 0.01), and continued to the fifth hour (p < 0.01). In uterine pain, responses with aspirin, 650 mg, were observed to be equally good. With codeine, 60 mg, in episiotomy pain measurable analgesia was present by the second hour and was significant at the fourth hour (p < 0.05); in uterine pain, responses were indistinguishable from placebo throughout an 8‐hr time‐course. Codeine seemed ineffective and therefore unacceptable as a positive control in uterine pain. These data imply that the two postpartum pain models are qualitatively different: episiotomy pain seems sensitive to both aspirin alld codeine, while uterine pain appears sensitive to aspirin but not to codeine.

Nefopam and propoxyphene in episiotomy pain.

To evaluate relative efficacy, safety, and time course of analgesia, nefopam (45 and 90 mg), a new centrally acting nonnarcotic analgesic, was compared with propoxyphene (65 mg) and placebo in a single oral dose, parallel, stratified, randomized, double‐blind trial with 100 hospitalized postpartum women with medium or severe episiotomy pain. Using subjective reports as indices of response, patients rated pain intensity and side effects at periodic interviews for 6 hr. After 45 and 90 mg nefopam, 21 of 25 and 20 of 25 patients (p < 0.01) reported more than 50% reduction of pain, whereas after 65 mg propoxyphene 18 of 25 (p < 0.05) and after placebo 11 of 25 reported reduction in pain. Relative efficacy, based on summed pain intensity differences, showed measurable but modest dose‐dependent analgesia with nefopam, suggesting that the effectiveness of 65 mg propoxyphene lay between 45 mg nefopam and placebo. Side effects included mild dizziness and hypothermia after nefopam and mild elevation of diastolic arterial pressure after nefopam and propoxyphene. Our results suggest that 45‐ and 90‐mg doses of nefopam induced more analgesia than 65 mg propoxyphene in the relief of episiotomy pain.

Analgesic sensitivity of two post-partum pain models

&NA; Post‐partum uterine cramping and episiotomy pain are established, frequently used, clinical pain models for efficacy trials of investigational new analgesic agents. To determine the respective assay sensitivity of these two models in assessing relative efficacy, we reviewed data from 6 phase II, randomized, stratified, parallel, placebo‐controlled, double‐blind, single‐dose studies involving hospitalized women with moderate or severe post‐partum uterine cramping (332 patients) or episiotomy pain (434 patients). Using subjective reports as indices of response, patients rated pain intensity and relief at periodic interviews for 6–7 h. Post‐partum uterine cramping showed excellent assay sensitivity for detecting differences among peripherally acting analgesics. In the same clinical trial this model could discriminate between a new drug and aspirin 650 mg, a standard reference analgesic, and between 2 graded doses of the new active agent (i.e., good upside sensitivity). In addition the uterine cramp model showed separation between placebo and all active agents (i.e., good downside sensitivity). Episiotomy pain demonstrated similar upside and downside discrimination in clinical trials of several weak centrally acting drugs. These data suggest that post‐partum cramping is an excellent pain model for analgesic investigation of new non‐steroidal anti‐inflammatory drugs, and episiotomy pain for new weak narcotic and opioid analgesics.

Metkephamid and meperidine analgesia after episiotomy

Metkephamid is an analog of methionine enkephalin. The efficacy, safety, and time course of analgesia with 70 or 140 mg metkephamid were compared with those of 100 mg meperidine and placebo in 59 hospitalized women with severe postpartum episiotomy pain. There were two separate trials with single intramuscular doses and identical designs, including parallel groups, randomized blocks, and double‐blind conditions. Using subjective reports as indexes of response, patients rated pain intensity, pain relief, and side effects at periodic interviews for 6 hr. Almost all measures of summed and peak analgesia exhibited important differences among the three treatments in both trials. Metkephamid at the 140‐mg dose was the most effective and meperidine, 100 mg, was next, whereas metkephamid, 70 mg, and placebo were least effective. Only metkephamid, 140 mg, and meperidine were measurably superior to placebo. Both treatments took effect within 30 min and peaked at 1 to 2 hr; with 140 mg metkephamid, maximum analgesia was sustained 6 hr, i.e., 2 hr longer than with meperidine. Metkephamid, 70 mg, could not be distinguished from placebo throughout its entire time course. Although dizziness was experienced with meperidine, the two metkephamid doses induced other side effects, including sensation of heavy limbs, dry mouth, eye redness, and nasal stuffiness. None were distressing. Our results suggest that 140 mg metkephamid compares favorably with 100 mg meperidine for analgesia after episiotomy, but it induces minor side effects more frequently.

Flurbiprofen, aspirin, codeine, and placebo for postpartum uterine pain

Flurbiprofen (Ansaid, Upjohn), a substituted phenyl propionic acid, is a new analgesic/anti-inflammatory agent. To evaluate its relative efficacy in noninflammatory pain, 159 hospitalized women with moderate or severe postpartum uterine cramps were given single oral doses of 50 mg of flurbiprofen, 650 mg of aspirin, 60 or 120 mg of codeine sulfate, or placebo in a parallel, stratified, randomized block, placebo-controlled, double-blind trial. Patients rated pain intensity, pain relief, and side effects in uniform interviews for six hours after treatment. All measures of peak and summed analgesia exhibited significant differences among the five treatments. Flurbiprofen and aspirin showed the greatest analgesic response and were significantly superior to placebo. Results of codeine treatment were equivocal with no evidence of a positive dose response. Side effects were unremarkable except for dizziness and drowsiness after the 120-mg codeine dose. These findings suggest that flurbiprofen as an analgesic for patients with postpartum uterine pain is equivalent to aspirin and superior to codeine.

Codeine and aspirin analgesia in postpartum uterine cramps: qualitative aspects of quantitative assessments.

The analgesic response to codeine of patients with postpartum uterine‐cramp pain has recently met with controversy. To readdress this question, we conducted a new study comparing codeine sulfate, 60 mg (N = 32) and 120 mg (N = 31), with aspirin, 650 mg (N = 34), and placebo (N = 32) in hospitalized women with moderate or severe postpartum uterine cramps treated with single oral doses in a parallel, stratified, randomized, double‐blind trial. Subjective reports were used as indices of response, and patients rated pain intensity, pain relief, and side effects at periodic, uniformly conducted interviews for 6 hr. Most measures of analgesia exhibited important differences among the treatments. In patients with undifferentiated pain (N = 129) and in a subset of patients with pure uterine cramps (N = 56; i.e., no concomitant episiotomy), aspirin showed the greatest response, whereas codeine responses were equivocal with no evidence of a positive dose response. In contrast, in a subset of patients with mixed episiotomy‐uterine pain (N = 73), 120 mg codeine showed good separation from placebo and compared favorably with aspirin. Codeine, 60 mg, showed a similar trend, and there was a strong suggestion of dose‐dependent analgesia. Side effects were not remarkable except for dizziness and drowsiness after 120 mg codeine in all sets and subsets of patients. The new results with codeine in pure postpartum uterine cramps confirm our earlier findings, whereas the previously unrecognized effect of codeine in mixed pain may explain the apparent contradiction in results reported by different investigating teams.

Fendosal and aspirin in postpartum uterine pain.

The analgesic efficacy of fendosal, a new nonsteroidal anti‐inflammatory agent structurally related to salicylic acid, was compared with that of aspirin and placebo in 100 patients with postpartum uterine pain in a single oral dose, parallel, stratified, randomized, double‐blind design. With 650 mg aspirin and with 200 or 400 mg fendosal, but not with 100 mg, analgesic effects, as measured subjectively by mean pain intensity scores, began within 1 hr and had similar time‐effect patterns for the first 4 or 5 hr. Thereafter with the 2 higher doses of fendosal analgesia continued to increase, reaching a peak at 6 hr (p < 0.05) and persisting beyond 7 hr (p < 0.01), whereas there was no aspirin analgesia after the fifth hour. With 100 mg fendosal time of onset tended to be delayed 2 hr or more, and duration was short. The most effective treatment (largest mean 7‐hr sum of pain intensity difference [SPID] score) was 400 mg fendosal (p < 0.01); 200 mg fendosal was rated second (p < 0.01), 650 mg aspirin, third (p < 0.05), 100 mg fendosal, fourth, and placebo, fifth. There were no significant side effects. These results demonstrate the efficacy of single doses of fendosal as well as the dose‐dependent magnitude and time course of effect on postpartum uterine pain.