Double-blind comparison of meclofenamate sodium with codeine and placebo for the pain of episiotomy

Meclofenamate sodium, a nonsteroidal anti-inflammatory agent, was compared at two dose levels (100 mg and 200 mg) with codeine (60 mg) and placebo in a double-blind, randomized study of 218 women after normal vaginal delivery. The purpose was to determine the analgesic efficacy and safety of meclofenamate sodium for the short-term treatment of acute episiotomy pain. Meclofenamate sodium was significantly better than placebo in most measures of pain relief and reduction of pain intensity. The 100-mg dose of meclofenamate sodium was significantly better than codeine in relieving pain. Adverse experiences with the study medications were minimal (6.4%). Patients receiving codeine reported more side effects than did those receiving either dose of meclofenamate sodium. Meclofenamate sodium is a safe, effective analgesic for acute episiotomy pain.     

Comparison of meclofenamate sodium with codeine and placebo for the treatment of episiotomy pain

Meclofenamate sodium, a nonsteroidal anti-inflammatory drug with proven analgesic effects, was compared at two dose levels (200 mg and 100 mg) with codeine (60 mg) and placebo in a double-blind, randomized study of 327 women experiencing episiotomy pain after normal delivery. Meclofenamate sodium at either dose was significantly better than codeine or placebo in reducing pain intensity and increasing pain relief, and it had a longer duration of action. Adverse effects were minimal, and their frequency did not differ significantly among treatment groups. Meclofenamate sodium appears to be as safe as and more effective than codeine for the management of episiotomy pain.     

Comparison of the analgesic efficacy of rofecoxib and enteric-coated diclofenac sodium in the treatment of postoperative dental pain: a randomized,placebo-controlled clinical trial

BACKGROUND: Rofecoxib is a selective cyclooxygenase-2 inhibitor indicated for the treatment of acute pain, with similar analgesic efficacy to ibuprofen and naproxen sodium. Diclofenac sodium is the most commonly prescribed nonsteroidal anti-inflammatory drug worldwide; it is effective for the treatment of pain as well as the signs and symptoms associated with the painful conditions of osteoarthritis and rheumatoid arthritis. OBJECTIVE: The aim of this study was to compare the analgesic efficacy and tolerability of a single dose of rofecoxib 50 mg, 3 doses of enteric-coated diclofenac sodium 50 mg, and placebo over 8-hour and 24-hour periods in patients with moderate to severe pain after oral surgery. METHODS: In this double-blind, placebo- and active comparator-controlled, parallel-group study, patients experiencing moderate to severe pain after the surgical extraction of > or = 2 third molars were randomized to receive a single dose of rofecoxib 50 mg, 3 doses of enteric-coated diclofenac sodium 50 mg (50 mg given every 8 hours), or placebo. Patients rated pain intensity, pain relief, and global assessments at prespecified times throughout the 24-hour period after initial dosing. Overall analgesic efficacy was determined by total pain relief over 8 hours (TOPAR8) and 24 hours (TOPAR24) and patient global assessments at 8 and 24 hours. Onset of analgesic effect was determined by using the 2-stopwatch method for confirmed perceptible pain relief. Peak analgesic effect was the maximum pain relief attained during the first 8 hours. The duration of analgesic effect was determined by median time to rescue analgesia use. RESULTS: A total of 305 patients were randomized to treatment: 121 received rofecoxib, 121 received diclofenac sodium, and 63 received placebo. The baseline demographics were similar among the groups. Overall, 61.3% experienced moderate pain and 38.7% experienced severe pain; 53.1% were female; and the mean age was 23.4 years. The overall analgesic efficacy, as assessed by TOPAR8, of a single dose of rofecoxib 50 mg was significantly greater than a single dose of enteric-coated diclofenac sodium 50 mg (20.5 vs 8.2) and placebo (20.5 vs 5.9). Patient global assessment at 8 hours was also significantly better for rofecoxib compared with enteric-coated diclofenac sodium and placebo. TOPAR24 was significantly greater for a single dose of rofecoxib 50 mg compared with 3 doses of enteric-coated diclofenac sodium 50 mg (64.1 vs 25.1) and placebo (64.1 vs 19.2). At 24 hours, the patient global assessment for rofecoxib was significantly better than that achieved with enteric-coated diclofenac sodium and placebo. The onset of analgesic effect was significantly more rapid for rofecoxib than for enteric-coated diclofenac sodium and placebo (median times: 31 minutes, >4 hours, and >4 hours, respectively). The peak analgesic effect was significantly greater for rofecoxib compared with enteric-coated diclofenac sodium (3.2 vs 1.5) and placebo (3.2 vs 1.1). The duration of analgesia was significantly longer for rofecoxib than enteric-coated diclofenac sodium (median times: >24 hours vs 1 hour and 37 minutes) and placebo (>24 hours vs 1 hour and 37 minutes). Enteric-coated diclofenac sodium was numerically greater than placebo for the key end points measuring overall efficacy (total pain relief and patient global assessment), but diclofenac sodium did not provide as much analgesic effect as expected for a drug effective for pain, osteoarthritis, and rheumatoid arthritis and did not differ significantly from placebo. Overall, both rofecoxib and enteric-coated diclofenac sodium were generally well tolerated, although the rofecoxib group had a significantly lower incidence of clinical and drug-related adverse events than the enteric-coated diclofenac sodium group. CONCLUSIONS: A single 50-mg dose of rofecoxib provided greater overall analgesic efficacy over 8 hours, more rapid onset of analgesia, greater maximum analgesic effect, and longer duration of effect than a single 50-mg dose of enteric-coated diclofenac sodium in patients with moderate to severe pain associated with oral surgery. Compared with 3 doses of enteric-coated diclofenac sodium 50 mg (50 mg every 8 hours), a single dose of rofecoxib 50 mg provided greater overall analgesic efficacy over 24 hours.     

Naproxen, aspirin, and codeine in postpartum uterine pain.

The analgesic efficacy of oral naproxen and its sodium salt 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 from 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 less than 0.005). With each of the 2 doses of naproxen, SPID separation from placebo was comparable to that above (p less than 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.     

Oral aspirin in postoperative pain: a quantitative systematic review.

OBJECTIVES: A systematic review of the analgesic efficacy and adverse effects of single-dose aspirin compared with placebo in postoperative pain. DESIGN: Published studies were identified from systematic searching of bibliographic databases and reference lists of retrieved reports. Summed pain intensity and pain relief data were extracted and converted into dichotomous information to yield the number of patients with at least 50% pain relief. This was used to calculate the relative benefit and number-needed-to-treat for one patient to achieve at least 50% pain relief. For adverse effects, relative risk and number-needed-to-harm were calculated. Sensitivity analyses were planned to test the impact of different pain models, pain measurements, sample sizes, quality of study design, and study duration on the results. RESULTS: Seventy-two randomized single-dose trials met our inclusion criteria, with 3253 patients given aspirin, and 3297 placebo. Significant benefit of aspirin over placebo was shown for aspirin 600/650 mg, 1000 mg and 1200 mg, with numbers-needed-to-treat for at least 50% pain relief of 4.4 (4.0-4.9), 4.0 (3.2-5.4) and 2.4 (1.9-3.2) respectively. Single-dose aspirin 600/650 mg produced significantly more drowsiness and gastric irritation than placebo, with numbers-needed-to-harm of 28 (19-52) and 38 (22-174) respectively. Type of pain model, pain measurement, sample size, quality of study design, and study duration had no significant impact on the results. CONCLUSIONS: There was a clear dose-response for pain relief with aspirin, even though these were single dose studies. Adverse effects, drowsiness and gastric irritation were also evident in the single dose studies. The pain relief achieved with aspirin was very similar milligram for milligram to that seen with paracetamol.     

Onset and duration of analgesia of diclofenac potassium in the treatment of postepisiotomy pain.

A double-blind, placebo-controlled, parallel group study was performed to compare the analgesic efficacy of diclofenac potassium (25, 50, or 100 mg) with that of aspirin (650 mg), or placebo. Two hundred fifty-five inpatients with severe postepisiotomy pain were randomly assigned to receive a single oral dose of one of the four active treatments or placebo. Analgesia was assessed over an 8-hour period. Treatments were compared on the basis of standard scales for pain intensity and relief and a number of derived variables based on these data, as well as two global ratings of the study medication. All active treatments were effective analgesics statistically superior to placebo for many hourly and summary measures, including the global ratings. Diclofenac potassium (50 and 100 mg) was statistically significantly superior to aspirin at half-hour and for many other hourly scores from hour 3 on. The 4- and 8-hour sum of the pain intensity difference and total pain relief scores reflected the superiority of diclofenac potassium to aspirin. In addition, the 100-mg dose was significantly more efficacious than the 25-mg dose of diclofenac potassium. The probability of obtaining onset was significantly better for all active treatments than for placebo; however, the median onset times were similar for all treatments. The duration of effect, as measured by mean pain intensity difference and relief scores, was better for diclofenac potassium than aspirin, and these differences were significant for the 50- and 100-mg doses. The probability of pain returning to baseline was significantly less for the diclofenac groups than for placebo or aspirin groups. In addition, significantly fewer patients treated with diclofenac (25, 50, or 100 mg) or aspirin (650 mg) required remedication during the 8-hour study period as compared with those treated with placebo. Diclofenac potassium is an effective analgesic in the range of aspirin (650 mg) at the 25-mg dose and superior in efficacy and longer lasting than aspirin at the 50- and 100-mg doses. The onset of analgesia was similar for aspirin and diclofenac potassium.     

Ibuprofen, zomepirac, aspirin, and placebo in the relief of postepisiotomy pain

Our purpose was to compare the analgesic efficacy of single oral doses of ibuprofen, zomepirac, aspirin, and placebo in severe postepisiotomy pain. One hundred twenty subjects participated in a double-blind, single-dose, parallel-group, 4-hr trial comparing 400 mg ibuprofen, 100 mg zomepirac sodium, 600 mg aspirin, and placebo. For most parameters, including the sum of the pain intensity differences (SPID) and the sum of the hourly pain relief values (TOTAL), which are summary variables, each of the drugs was more effective than placebo. Ibuprofen was more effective than aspirin and zomepirac. Zomepirac and aspirin were equally effective for most of the analgesic variables. There were no adverse effects. Ibuprofen, 400 mg, is an effective oral analgesic and is more effective than 100 mg zomepirac and 600 mg aspirin in most parameters of pain.     

Analgesic effect of aspirin, mefenamic acid and their combination in post-operative oral surgery pain

A double-blind randomized single dose study of the analgesic effects of 650 mg aspirin, 250 mg mefenamic acid, the combination of 650 mg aspirin and 250 mg mefenamic acid and placebo on 120 patients with pain following oral surgery was conducted. Patients evaluated their pain intensity and extent of pain relief at 1, 2, 3 and 4 h after drug administration. For most parameters, including the sum of the pain intensity differences and the sum of the hourly pain relief scores, each of the drugs was more effective than placebo. Aspirin-mefenamic acid in combination was more effective than both drugs alone, and aspirin and mefenamic acid alone were equally effective for most of the analgesic variables.     

Analgesic efficacy of bromfenac, ibuprofen, and aspirin in postoperative oral surgery pain.

We recently demonstrated that 25 mg of bromfenac, a new nonsteroidal anti-inflammatory analgesic, is at least as effective as 400 mg of ibuprofen in relieving postoperative oral surgery pain. Our objective in this study was to determine whether higher doses were significantly more effective. Two hundred eighty (280) outpatients with postoperative pain after the surgical removal of impacted third molars were randomly assigned, on a double-blind basis, a single oral dose of 10, 25, 50, or 100 mg bromfenac; 650 mg aspirin; 400 mg ibuprofen; or placebo. Subjects rated their pain and its relief for 8 hours. All active treatments were significantly superior to placebo, and bromfenac and ibuprofen were significantly superior to aspirin. The slope of the dose-response curve of bromfenac was significant. The 100 mg bromfenac dose was significantly more effective than the 400 mg ibuprofen dose and had a significantly longer duration of analgesic action.     

Indoprofen, a new analgesic and anti-inflammatory drug in cancer pain.

Evaluation of the analgesic activity of indoprofen was carried out in patients with cancer pain under double-blind conditions and compared with aspirin and placebo. A randomized experimental design was followed. Single oral doses were given of the test drug (100 and 200 mg), aspirin (600 and 1,000 mg), and placebo. For measuring analgesia, 5-point pain intensity and pain relief semiquantitative scales were used. Potency ratio between drugs was calculated on SPID (sum of pain intensity differences) and TOTPAR (total pain relief) and resulted in 10.3 by combination of estimates. In a group of only 24 patients, the data supported the following conclusions: indoprofen at 100 and 200 mg single doses is effective in relieving cancer pain; it displays a dose-related analgesic effect comparable to that of aspirin with only one-tenth the dose.     

A double-blind randomized study of an aspirin/caffeine combination versus acetaminophen/aspirin combination versus acetaminophen versus placebo in patients with moderate to severe post-partum pain

In a double-blind, randomized controlled trial among 500 post-partum patients experiencing moderate to severe pain, a single oral dose of an aspirin/caffeine combination (800 mg aspirin, 65 mg caffeine) provided significantly more pain relief at 2 hours than did a higher dose of an acetaminophen/aspirin combination (648 mg acetaminophen, 648 mg aspirin) and a higher dose of acetaminophen alone (1000 mg acetaminophen). At 3 and 4 hours, the acetaminophen/aspirin combination as well as the aspirin/caffeine combination were significantly superior to acetaminophen alone. At all times, all three drugs were significantly superior to placebo. There were no clinically significant adverse reactions. These results provide evidence of a potentiating effect of caffeine on aspirin's analgesic potency.     

Double-blind comparison of single oral doses of oxaprozin, aspirin, and placebo for relief of post-operative oral surgery pain

The safety and efficacy of single oral doses of oxaprozin (1200 mg), aspirin (650 mg), and placebo were compared in an 8-hour double-blind study of 105 patients with moderate to severe post-operative dental-surgical pain. As measured by mean and cumulative mean scores obtained with the pain intensity and verbal pain relief scales, both active drugs produced significantly (p less than 0.05) more analgesia than did placebo. A significantly (p less than 0.05) greater proportion of patients reported effective (moderate or better) pain relief in the oxaprozin and aspirin groups than in the placebo group at 2, 3, and 4 hours; significant (p less than 0.05) differences between the oxaprozin and placebo groups continued for the entire 8 hours. Oxaprozin provided more pain relief than aspirin during the latter part of the study. There were no statistically significant differences, however, in any of the efficacy assessments between the oxaprozin and aspirin groups. By the end of the 8-hour observation, significantly (p less than 0.01) fewer patients taking oxaprozin (27%) than placebo (60%) were considered treatment failures and needed a replacement analgesic. Of those taking aspirin, 41% were treatment failures, not statistically different from the proportion of treatment failures with placebo. Adverse effects were infrequent, mild, comparable between the active treatment and placebo groups, and not definitely related to drug therapy. Oxaprozin provided greater pain relief than placebo and was comparable to aspirin during the first 4 hours of the evaluation; thereafter, greater pain relief occurred in the oxaprozin-treated group than either the aspirin or placebo-treated group.     

A controlled comparative evaluation of acetaminophen and aspirin in the treatment of postoperative pain

The analgesic effects of acetaminophen (1 gm), aspirin (650 mg), and placebo were evaluated in a double-blind, randomized parallel study. The subjects were 162 outpatients who had experienced moderate or severe pain as a result of dental surgery involving bone removal. Patients evaluated the intensity of their pain and the extent of their relief from pain at 30 minutes, at one hour, and at each subsequent hour for six hours after the administration of the study medication. During the six-hour period, 135 of the 162 patients were remedicated. At the end of the six-hour period each patient assessed overall treatment. Two measures of analgesia were derived from patients' evaluations of the intensity of pain, and three other measures were derived from evaluations of relief from pain. On all six measures used, the groups receiving acetaminophen and aspirin reported analgesic effects significantly superior (P less than 0.05) to those of placebo. Acetaminophen was significantly better than aspirin with respect to the maximum difference in the intensity of pain (P less than 0.05) and the maximum pain relief achieved (P less than 0.03) and according to the global evaluation (P less than 0.02). These differences were most striking in patients with severe initial pain.     

Oral nefopam and aspirin.

Analgesia through nefopam (30 mg, 60 mg, 90 mg), aspirin (325 mg, 650 mg), and placebo were compared in 122 hospitalized patients with moderate to severe postoperative, fracture, or other somatic pain. A double-blind noncrossover study design was used, and patients were evaluated for pain intensity and pain relief over a 6-hr period. Based on sum of pain intensity differences (SPID) scores, treatment effects were consistent and indicative of good dose response to both active medications. Pain relief scores were more variable but were generally in accordance with SPID values. Time-effect curves were similar. Estimated relative potency of nefopam to aspirin was 10.4 with a 95% confidence interval of 6.3 to 20.8 for SPID, indicating that the analgesic potency of nefopam, 60 mg, was equivalent to that of aspirin, 650 mg. Side effects were minimal.     

No need for rescue medication (NNR) as an easily interpretable efficacy outcome measure in analgesic trials: validation in an individual‐patient meta‐analysis of dental pain placebo‐controlled trials of naproxen

What is known and Objective: In analgesic trials, pain relief is often assessed using a pain‐relief score. We aimed to assess, through a meta‐analysis, whether absence of need for rescue medication (NNR) is a reliable outcome measure in the evaluation of acute pain relief. Methods: Individual‐patient meta‐analysis of placebo‐controlled trials of single‐dose naproxen sodium 220 or 440 mg in dental pain. Efficacy estimates were based on NNR and compared with the more commonly used 50% maximum total pain relief score (50% TOTPAR). The trials included were the full set of trials sponsored by one manufacturer. Results and Discussion: Need for rescue medication and 50% TOTPAR gave comparable estimates of efficacy of naproxen sodium (220 and 440 mg) relative to placebo in dental pain at both 8 and 12 h after dosing. What is new and Conclusion: No need for rescue medication is a reliable outcome measure for use in acute pain trials. As it is more readily understandable than 50% TOTPAR, it should be the preferred primary outcome measure in acute pain trials.     

Aspirin and aspirin-caffeine in postpartum pain relief.

In two double-blind randomized, balanced, single oral dose studies with 140 women, a combination of 800 mg aspirin and 64 mg caffeine (aspirin-caffeine) was compared to 650 mg aspirin and to placebo. In patients with moderate to severe uterine or episiotomy pain, there was greater analgesic response with active drugs when the initial pain intensity was more severe. In patients with severe episiotomy pain, aspirin-caffeine was more effective than 650 mg aspirin (p less than 0.05) at the second and third hours. There was no difference between analgesic effects of aspirin and aspirin-caffeine in women with severe uterine pain.     

Efficacy and Speed of Onset of Pain Relief of Fast-Dissolving Paracetamol on Postsurgical Dental Pain: Two Randomized,Single-Dose,Double-Blind,Placebo-Controlled Clinical Studies

Background

Paracetamol (APAP), also known as acetaminophen, is the most commonly used over-the-counter analgesic for the treatment of mild-to-moderate pain. However, the speed of onset of pain relief is limited mainly to the standard, immediate-release formulation. Efficacy and speed of onset of pain relief are critical in acute pain situations such as postsurgical dental pain, because reducing pain can improve clinical outcome and reduce the risk of transition from acute pain to more chronic pain. Efficacy and rapid onset also reduce the risk of excessive dosing with the analgesic.

Objective

We sought to investigate the dose–response efficacy and speed of onset of pain relief of a fast-dissolving APAP formulation compared with lower doses of APAP and placebo in dental patients after impacted third molar extraction.

Methods

Two single-center, single-dose, randomized, placebo-controlled, double-blind, double-dummy, parallel-group studies (Study I and Study II) were conducted to evaluate the efficacy and speed of onset of pain relief of different doses of a fast-dissolving APAP tablet (FD-APAP), standard APAP, and placebo in patients with postsurgical dental pain following third molar extraction. In Study I, a single dose of FD-APAP 1000 mg, FD-APAP 500 mg, or placebo was given to 300 patients; in Study II, a single dose of FD-APAP 1000 mg, standard APAP 650 mg, or placebo was given to 401 pateints. All 701 patients from both studies were included in the analysis and safety assessment.

Results

FD-APAP 1000 mg demonstrated significantly greater effect compared with FD-APAP 500 mg, APAP 650 mg, and placebo for all efficacy measurements, including sum of pain relief and pain intensity difference, total pain relief, sum of pain intensity difference, pain intensity difference, and pain relief score during 6 hours after the dose. Onset of confirmed first perceptible relief in subjects treated with FD-APAP 1000 mg was 15 minutes, which was 32% and 25% significantly shorter than onset of pain relief of FD-APAP 500 mg (22 minutes) and standard APAP 650 mg (20 minutes), respectively. FD-APAP 500 mg and APAP 650 mg demonstrated efficacy over placebo for most of the measurements; however, their effects were significantly lower and lasted for a shorter period of time than for FD-APAP 1000 mg. All study treatments were well tolerated.

Conclusions

FD-APAP 1000 mg tablets demonstrated efficacy over placebo. Also, FD-APAP 1000 mg had significantly superior effect, faster onset, and longer duration of pain relief compared with FD-APAP 500 mg and APAP 650 mg tablets. ClinicalTrials.gov identifiers: NCT01082081 and NCT01075243.     

Pain and analgesic response after third molar extraction and other postsurgical pain

There is uncertainty over whether the patient group in which acute pain studies are conducted (pain model) has any influence on the estimate of analgesic efficacy. Data from four recently updated systematic reviews of aspirin 600/650 mg, paracetamol 600/650 mg, paracetamol 1000 mg and ibuprofen 400 mg were used to investigate the influence of pain model. Area under the pain relief versus time curve equivalent to at least 50% maximum pain relief over 6 h was used as the outcome measure. Event rates with treatment and placebo, and relative benefit (RB) and number needed to treat (NNT) were used as outputs from the meta-analyses. The event rate with placebo was systematically statistically lower for dental than postsurgical pain for all four treatments. Event rates with analgesics, RB and NNT were infrequently different between the pain models. Systematic difference in the estimate of analgesic efficacy between dental and postsurgical pain models remains unproven, and, on balance, no major difference is likely.     

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.(ABSTRACT TRUNCATED AT 250 WORDS)