A double-blind comparison of nefopam and placebo in post-operative pain.

Nefopam (90 mg), an analgesic, was compared with placebo in a double-blind trial in patients who had undergone total abdominal hysterectomy operations. Analgesic activity was assessed by patients rating their pain before and 1 hour after administration of each treatment, by sequential analysis of patient and observer preference for treatment, and by calculation of the time interval between doses of the two treatments. Nefopam was found by observer preference to be significantly better than placebo in relieving post-operative pain. In patients with severe initial pain, the time between doses after nefopam was significantly longer than after placebo.     

Efficacy and safety of pantoprazole 20 mg once daily treatment in patients with ulcer-like functional dyspepsia*

ABSTRACT

Objective: To investigate the efficacy of pantoprazole 20 mg once daily (o.d.) in relieving epigastric pain associated with ulcer-like functional dyspepsia.

Research design and methods: In this double-blind, placebo-controlled, multicentre study, patients experiencing ulcer-like functional dyspepsia, with epigastric pain as the predominant symptom, were randomised to receive pantoprazole 20 mg or placebo o.d. for 28 days. Primary endpoint was the complete relief (i.e. absence) from epigastric pain after 28 days’ treatment. The odds ratio (OR) for pantoprazole/placebo and its 95% confidence intervals (CIs) were determined. Significant superiority of pantoprazole was concluded if the value 1.0 was above this interval.

Results: Of 419 patients (intention-to-treat [ITT]) randomised to treatment, 207 received pantoprazole and 212 received placebo. Epigastric pain relief was achieved after 28 days’ treatment in 55% of pantoprazole recipients and 45% of placebo recipients (per-protocol [PP]: 58% and 47%, respectively). Pantoprazole demonstrated statistically significant superiority compared with placebo in the ITT (OR: 0.68; 95% CI: 0.46?0.99) and PP populations (OR: 0.64; 95% CI: 0.42?0.98). Pantoprazole was more efficacious than placebo in relieving heartburn and acid regurgitation after 7, 14 and 28 days of treatment. The sum score of gastrointestinal symptoms after 28 days was statistically significantly lower in the pantoprazole than placebo group. Fewer patients receiving concomitant psychotropic medication experienced relief from epigastric pain than those not receiving such medication. Adverse events did not significantly differ between pantoprazole and placebo.

Conclusions: Results of this study suggest that pantoprazole 20 mg is more efficacious than placebo, and is a well-tolerated treatment for relieving epigastric pain in patients with ulcer-like functional dyspepsia. Further research is needed to confirm these findings.     

A double-blind study with placebo control of intramuscular ketorolac tromethamine in the treatment of cancer pain

The analgesic efficacy of ketorolac tromethamine was compared to placebo in 126 patients suffering moderate or severe chronic pain due to cancer in a double-blind parallel randomized study. Ketorolac was administered intramuscularly in doses of 10, 30 or 90 mg. Pain intensity and pain relief were assessed for 6 hours by scoring standard verbal scales and an overall assessment of the medication was given by the patients and the observer on completion of the study. Each dose of ketorolac was statistically superior to placebo for the sum of pain intensity difference (SPID) but no difference was seen between the three ketorolac regimens. When the ketorolac groups are combined, there was a significantly better pain relief as compared to placebo. The global evaluation scores were also statistically superior in the ketorolac groups combined than in the placebo group. A total of 15 patients reported minor adverse events, 10 being after ketorolac doses. This study shows that single intramuscular doses of ketorolac of 10 mg and above are effective in the relief of cancer pain, and are associated with a low incidence of side-effects.     

A randomized controlled study comparing rofecoxib,diclofenac sodium,and placebo in post-bunionectomy pain

SUMMARY

Objective: The relative efficacy of rofecoxib, diclofenac sodium, and placebo were compared in the treatment of acute pain after bunionectomy surgery.

Research design and methods: This was a double-blind, randomized, two-part study of 252 patients with moderate-to-severe pain the day after first metatarsal bunionectomy. Patients were treated with a single dose of rofecoxib 50?mg (N = 85), enteric-coated diclofenac sodium 100?mg (N = 85), or placebo (N = 82) on study Day 1 (Part I), and subsequently with daily rofecoxib 50?mg or placebo (diclofenac patients switched to placebo) over study Days 2–5 (Part II). Patients rated their pain at 16 time points over the first 24?h. Primary endpoint was total pain relief over 8?h (TOPAR8). Pre-specified secondary endpoints on Day 1 included onset of analgesia, peak pain relief, and duration of response. For Part II, supplemental analgesia use with rofecoxib compared to placebo was pre-specified for analysis over Days 2–5, with the focus on Days 2–3. Adverse experiences were recorded over Days 1–5.

Results: For TOPAR8 scores, rofecoxib 50?mg was significantly more effective than placebo (9.5 vs. 3.7, p < 0.001) and diclofenac (9.5 vs. 5.0, p < 0.001). Onset of analgesia was more rapid with rofecoxib than placebo (?p = 0.003) and diclofenac (?p = 0.019); proportion of patients achieving onset within 4?h with rofecoxib, diclofenac, and placebo was 46%, 27%, and 23%, respectively. Peak pain relief was greater with rofecoxib (1.8) than diclofenac (1.2, p = 0.004) and placebo (1.0, p < 0.001). Diclofenac and placebo patients required supplemental analgesia sooner than rofecoxib patients (2:03?h vs. 4:02?h, p < 0.001 and 1:41?h vs. 4:02?h, p < 0.001). Rofecoxib patients used significantly less (?p < 0.001) supplemental analgesia than placebo patients over Days 2–3 (1.1?tablets/day vs. 2.1?tablets/day) and Days 2–5 (0.9?tablets/day vs. 1.8?tablets/day). No significant differences in adverse experiences between treatments were seen.

Conclusion: Rofecoxib 50?mg was significantly more effective than placebo on all measures of treatment of post-bunionectomy pain. Rofecoxib 50?mg was significantly more effective than diclofenac sodium 100?mg based on Day 1 endpoints of total pain relief, onset time, and duration of response. All study medications were generally well tolerated.     

A double-blind comparison of diflunisal and aspirin in the treatment of post-operative pain after episiotomy

Summary

A double-blind randomized trial was carried out in 161 primiparous women suffering from moderate to severe post-episiotomy pain to compare the analgesic efficacy of single doses of diflunisal (125?mg, 250?mg, or 500?mg), aspirin (600?mg), and placebo. The results of pain rating assessments made before and at hourly intervals after drug administration showed that both the active drugs were more effective than placebo and produced similar pain relief over the first 4 hours. The analgesic efficacy of aspirin tailed off after 4 hours but pain relief with 500?mg diflunisal was still evident after 8 hours. Over 65% of patients in the diflunisal group had effective relief of pain at 8 hours whereas there was no significant difference between the aspirin and placebo-treated groups by the seventh and eighth hour.     

The efficacy of pregabalin in patients with moderate and severe pain due to diabetic peripheral neuropathy

Objective To compare the therapeutic response to pregabalin in patients with moderate or severe painful diabetic peripheral neuropathy (pDPN).

Research design and methods Data were pooled from 11 placebo-controlled trials to evaluate the efficacy of pregabalin flexible or fixed dose (150, 300 or 600?mg/day) in pDPN patients with mean baseline pain scores of ≥4 to <7 (moderate) or ≥7 to ≤10 (severe). Last observation carried forward imputation was used.

Study number/ClinicalTrials.gov identifier 1008-014/-, 1008-029/-, 1008-040/-, 1008-131/-, 1008-149/-, 1008-000-155/-, A0081030/NCT00156078, A0081060/NCT00159679, A0081071/NCT00143156, A0081081/NCT00301223, A0081163/NCT00553475.

Main outcome measures Pregabalin-mediated change in pain, pain-related sleep interference (PRSI) and patient global impression of change (PGIC) were compared versus placebo and between moderate and severe pain cohorts. Adverse events (AEs) were reported.

Results At baseline, 1816 patients had moderate pain (pregabalin, n?=?1189) and 1119 patients had severe pain (pregabalin, n?=?720). Pregabalin significantly reduced pain scores at endpoint compared with placebo when patients of all pain levels were combined (all doses; p?<?0.05). In the moderate and severe pain cohorts, pregabalin treatment (300, 600?mg/day or flexible) significantly reduced mean pain scores at endpoint compared with placebo (p?<?0.01). Pain reduction was greatest in patients with severe baseline pain compared with moderate baseline pain (pregabalin 300, 600?mg/day or flexible; p?<?0.0001). Pregabalin improved PRSI and PGIC in the moderate and severe cohorts compared with placebo. The greatest improvement in PRSI also occurred in the severe cohort. Treatment-emergent AEs, most commonly dizziness, somnolence and peripheral edema, occurred more frequently in patients treated with pregabalin compared with placebo.

Conclusions Pregabalin was effective in pDPN patients with both moderate and severe baseline pain. Patients with severe pain exhibited greater improvements in pain and PRSI than patients with moderate pain. Pain severity may, in part, predict therapeutic response to pregabalin.     

Efficacy of single-dose,extended-release naproxen sodium 660 mg in postsurgical dental pain: two double-blind,randomized, placebo-controlled trials

Objective:

To evaluate the efficacy of a novel formulation of extended-release/immediate-release (ER) naproxen sodium over 24?h in a dental pain model.

Research design and methods:

Two randomized, double-blind, placebo-controlled trials in moderate to severe pain after extraction of one or two impacted third molars (at least one partial mandibular bony impaction). Treatment comprised oral ER naproxen sodium 660?mg (single dose), placebo (both studies) or immediate-release (IR) naproxen sodium 220?mg tid (study 2).

Main outcome measures:

Primary efficacy endpoint: 24-h summed pain intensity difference (SPID). Secondary variables included total pain relief (TOTPAR), use of rescue medication. All treatment-emergent adverse events were recorded.

Clinical trial registration:

NCT00720057 (study 1), NCT01389284 (study 2).

Results:

Primary efficacy analyses: pain intensity was significantly lower over 24?h with ER naproxen sodium vs. placebo (p?<?0.001), with significant relief from 15?min (study 2). In study 2, ER naproxen sodium was non-inferior to IR naproxen sodium, reducing pain intensity to a comparable extent over 24?h. TOTPAR was significantly greater with ER and IR naproxen sodium vs. placebo at all time points, with generally comparable differences between active treatments. Significantly more placebo patients required rescue medication vs. ER and IR naproxen sodium from 2–24?h post-dose. Once daily ER naproxen sodium was generally safe and well tolerated, with a similar safety profile to IR naproxen sodium tid.

Limitations:

The studies were single dose, with limited ability to assess efficacy or safety of multiple doses over time. As the imputed pain score meant that estimated treatment differences may have been biased in favor of ER naproxen sodium, a post hoc analysis evaluated the robustness of the results for pain relief.

Conclusions:

A single dose of ER naproxen sodium 660?mg significantly reduced moderate to severe dental pain vs. placebo and was comparable to IR naproxen sodium 220?mg tid. Significant pain relief was experienced from 15?min and sustained over 24?h, resulting in a reduced need for rescue medication. ER naproxen sodium 660?mg once daily is a convenient and effective therapy providing 24?h relief of pain.     

Analgesic effect of ciramadol in patients with chronic pain

Summary

A double-blind, crossover study was carried out in 15 patients with chronic pain due to cancer to assess the effectiveness of two different doses of a new analgesic, ciramadol, compared with placebo. Patients received single oral doses of the three medications, in random order, on successive days. Assessments of pain intensity and relief were made on a 4-point rating scale at hourly intervals for 4 hours after the dose. The results showed that ciramadol produced significantly more pain relief than did placebo and this analgesic effect increased with the dose administered. Peak activity was observed at about 2 hours, and pain relief was still marked at 4 hours. No side-effects were reported.     

Section 2 Fenoprofen in the treatment of osteoarthrosis

Summary

Three controlled trials were carried out in a total of 58 patients with osteoarthrosis to assess the effectiveness of and patient preference for fenoprofen compared with paracetamol, ibuprofen and phenylbutazone. Subjective assessments of pain relief showed fenoprofen to be superior to paracetamol and placebo, and that it provided slightly better and more effective treatment than ibuprofen. These differences, however, were not statistically significant, neither was that between the subjective and objective assessments of fenoprofen and phenyibutazone.     

Efficacy of a paracetamol–pseudoephedrine combination for treatment of nasal congestion and pain-related symptoms in upper respiratory tract infection

ABSTRACT

Objective: This study compared the efficacy of 1000?mg of paracetamol combined with 60?mg of pseudoephedrine, with that of either paracetamol or pseudoephedrine alone and placebo for the treatment of symptomatic URTI.

Research design and methods: A double‐blind, parallel group study was performed on 305 patients with URTI (nasal airflow resistance [NAR] of > 0.25 Pa cm³ s and a global pain score of at least moderate intensity). NAR and pain relief/intensity scores were measured over 4?h after initial dose. Patients then dosed up to three times daily for 3 days and recorded nasal congestion and pain intensity scores.

Main outcome measures: Nasal airflow conductance (NAC) and pain relief after the initial dose were primary objectives. NAC was calculated from NAR. Pain relief was measured on a 5‐point verbal rating scale (VRS) and pain intensity and nasal congestion on a 4‐point VRS. Data were analysed using analysis of covariance. Safety was assessed by adverse events.

Results: A single dose of the combination was superior to paracetamol and placebo for NAC (?p = 0.0001) and was superior to pseudoephedrine and placebo for pain relief (?p ≤ 0.048). Multiple doses of the combination were also superior to paracetamol and placebo for decongestion (?p ≤ 0.021) and were superior to pseudoephedrine and placebo for pain reduction (?p ≤ 0.0057). All treatments were well tolerated.

Conclusions: The combination treatment provided a greater decongestant effect than either paracetamol or placebo and better pain relief than either pseudoephedrine or placebo. The additive effect of the combination was apparent for both single and multiple doses.     

Comparative efficacy of soluble aspirin and aspirin tablets in postoperative dental pain

Summary The efficacy of single doses (1.2 g) of soluble aspirin and aspirin tablets was determined in a randomised, placebo-controlled, double-blind, parallel study in 90 patients (45 females) with postoperative pain after removal of impacted lower third molars. Also investigated was the relationship between plasma aspirin esterase activity and overall pain scores after both aspirin preparations. Patients reported significantly less pain (p<0.001) after treatment with aspirin than after treatment with placebo. However, patients receiving soluble aspirin reported both an earlier onset and a longer duration of pain relief than those who received aspirin tablets. A significant correlation was observed between plasma aspirin esterase activity and overall pain scores after both soluble aspirin (r=0.57,p<0.01) and aspirin tablets (r=0.51,p<0.02). It is concluded that soluble aspirin is the preferred aspirin formulation for treating postoperative pain after third molar surgery and that plasma aspirin esterase activity is a determinant of a patient's analgesic response to aspirin in postoperative dental pain.     

Successful treatment of biliary colic with intravenous ketoprofen or lysine acetylsalicylate

Summary

In a double-blind trial, 60 patients with biliary colic were allocated at random to receive 200?mg ketoprofen, 1.8?g lysine acetylsalicylate or placebo by intravenous bolus. The patients were asked to rate their pain at intervals within 3 hours of injection and to indicate their overall pain experience on a visual analogue scale. Both ketoprofen and lysine acetylsalicylate proved significantly more effective than placebo in relieving pain, with no significant difference between them. A good analgesic response, reflected by complete or almost complete relief of pain within 30 minutes of injection, was recorded in 4, 17, and 16 patients, respectively, in the placebo, ketoprofen, and lysine acetylsalicylate treatment groups. All drugs were well tolerated. It is concluded that the results provide further evidence for a useful therapeutic role of prostaglandin inhibitors in the treatment of biliary colic.     

Dose Response and Safety of Cizolirtine Citrate (E-4018) in Patients with Pain Following Extraction of Third Molars

Summary

The objectives of this study were to determine the dose response and safety of the oral analgesic cizolirtine citrate (E-4018) in patients with postoperative pain after third molar extraction. This was a placebo-controlled, double-blind, randomised, parallelgroup study. Doses of E-4018 were 50 mg, 100 mg, or 150 mg. The primary outcome measure of efficacy was patient assessment of pain severity, determined from serial visual analogue scales (VAS) over a four-hour investigation period. Other efficacy measures included the number of patients taking escape analgesic and the time before it was taken, and an overall assessment of pain relief on a four-point categorical scale.

There was no significant difference between any of the E-4018 treatment groups and placebo in terms of the AUC for VAS pain scores over time. The percentages of patients who took paracetamol within five hours of their dose were 100%, 95%, 78% and 82% for the placebo, 50 mg, 100 mg and 150 mg E-4018 groups, respectively. The time to first use of paracetamol was significantly different for the 100 mg and 150 mg E-4018 groups compared to placebo. There were 17 adverse events, of which five were possibly related to the study medication (one in the placebo group and four in the 150 mg E-4018 group).

We conclude that there was a dose-related trend in the percentage of patients requiring paracetamol within five hours of their study medication, and in the percentage of patients that recorded the treatment as providing good or excellent treatment of pain. There was, however, no firm evidence of a dose-related analgesic effect over the dose range of Cizolirtine chosen for this study. E-4018 was well tolerated in all patients.     

An investigation into the efficacy of intravenous diclofenac in post-operative dental pain

Objective: To evaluate the efficacy of single doses of intravenous diclofenac sodium (25, 50 and 75 mg) in patients with post-operative pain after third-molar surgery in a randomised, placebo-controlled study. Methods: Two hundred and sixty-nine patients (168 females) who required the removal of their impacted third molars participated in the study, which had received prior ethical approval. Surgery was completed under general anaesthesia and, during the early post-operative period, patients received either a single intravenous dose of diclofenac (25, 50 or 75 mg) or matched placebo in random, double-blind order. Pain intensity was assessed on 10-cm visual analogue scales at fixed time points throughout a 4-h investigation period. Other efficacy variables obtained included time until rescue medication and overall assessment at 4, 6, 12 and 24 h after dosing. Results: Throughout the 4-h investigation period, patients treated with diclofenac reported significantly less pain than those treated with placebo (P < 0.001). No differences were observed among the three doses of diclofenac (P=0.22). Similar results were observed at 6, 12 and 24 h after dosing. Significant differences were also noted between the placebo group and all the diclofenac treatment groups with respect to time until rescue medication (P < 0.001) and the proportion of patients taking such medication. Conclusion: Single doses of i.v. diclofenac (25, 50 and 75 mg) provide significant pain relief after third-molar surgery. The efficacy of this preparation does not appear to be dose related. Received: 20 January 2000 / Accepted in revised form: 18 May 2000     

Section 1 Ibuprofen in osteoarthritis

Summary

In a multi-centre, double-blind crossover trial of 1800?mg. ibuprofen daily, 3.6 g. aspirin daily, and placebo, 437 patients with osteoarthrosis affecting various large joints were studied for 8 weeks. Judged by patient preference for drug or placebo treatment periods, both drugs were found to be superior to placebo and about equally as effective in relieving pain and in improving the ability to perform a selected activity. Gastro-intestinal side-effects were substantially fewer in patients receiving ibuprofen.     

Onset of pain relief with rofecoxib in chronic low back pain: results of two four-week,randomized, placebo-controlled trials

SUMMARY

Objective: We recently reported the efficacy of rofecoxib in two randomized controlled trials in chronic low back pain (CLBP). The objectives of this report are to present data regarding the onset of efficacy of rofecoxib from these trials and propose methods for reporting onset.

Research design and methods: Patients were aged 18-75, with non-radicular CLBP for >3 months. Patients were randomized to rofecoxib 25?mg, 50?mg, or placebo once daily for 4 weeks. Assessments included Low Back Pain and Bothersomeness scales every morning and Relief from Starting Pain after the first dose at 0.5,1, 2, 3,4h, bedtime, and next morning. Onset of meaningful relief was measured by Time to Confirmed 50% Reduction in Pain and Time to Confirmed 'Slightly' or 'Not At All' Bothersome Pain. Onset of perceptible pain relief was measured by Time to At Least 'A Little' Confirmed Pain Relief.

Results: 690 patients entered. Significantly more patients treated with rofecoxib had meaningful relief compared to placebo: 60.4,58.4, and 34.7% for rofecoxib 25mg, 50mg, and placebo (p?<?0.001). Median time to meaningful relief for rofecoxib was 2 days, 1 day sooner than placebo. Rofecoxib was superior to placebo by bedtime after the first dose.

Conclusions: Approximately 2/3 of patients achieved meaningful pain relief with rofecoxib compared with 1/3 receiving placebo. Median time to onset of meaningful relief was about 2 days, but superior relief over placebo was seen by bedtime after the first dose. Onset of perceptible pain relief was within 2?h. We propose that measures of onset of analgesic effect include the proportion of patients who achieve meaningful pain relief and in this subgroup, the time-to-onset of confirmed meaningful reduction in pain intensity, time-to-onset of confirmed pain relief, and time to first separation from placebo in the proportion of patients who achieve meaningful pain relief.     

Controlled clinical trial of oral and parenteral nefopam hydrochloride. A novel and potent analgesic drug.

The results of a controlled, double-blind clinical trial are reported demonstrating the potency of analgesia produced by orally and parenterally administered nefopam HCl in hospitalized patients with pain principally of skeletal and neuromuscular origin. The drug is an analogue of orphenadrine, consisting of a cyclization of the diphenhydramine molecule. A double-blind, crossover study was made of the analgesic effects of intramuscular doses of 20 mg nefopam HCl, 50 mg pethidine, and saline placebo in 20 patients. Nefopam and pethidine were found to be equally effective and statistically superior to placebo. A double-blind, randomized study was made of orally administered nefopam HCl, 60 mg t.i.d., for three days and of placebo t.i.d. for three days in 80 patients. Nefopam was distinctly superior to placebo in analgesic effectiveness, both in the initial single dose and in maintaining therapeutic benefit for the duration of the three-day trial. It was concluded that nefopam is a potent analgesic of novel structure and unique physiologic properties.     

A controlled comparison of dipyrone and paracetamol in post-episiotomy pain

Summary

A double-blind, placebo-controlled trial was carried out in 299 patients suffering from post-episiotomy pain to compare the analgesic effectiveness and tolerance of single doses of 500?mg dipyrone and 500?mg paracetamol. Assessments of pain relief over a 6-hour period showed that dipyrone produced significantly better results than placebo within half an hour of intake mid maintained this superiority throughout the 6 hours. It also afforded consistently better pain relief than paracetamol and was significantly more effective at the 6-hour assessment. Side-effects were few and mild.