Bernard Schachtel

Ibuprofen and Acetaminophen in the Relief of Acute Pain: A Randomized, Double‐Blind, Placebo‐Controlled Study

To determine the relative analgesic efficacy of ibuprofen 400 mg and acetaminophen 1000 mg, we conducted a single‐dose, double‐blind, placebo‐controlled, randomized clinical trial using a standard assay for analgesic agents, the dental pain model. At regular intervals over 6 hours, 184 patients who had undergone dental impaction surgery rated pain intensity and relief on categorical scales and pain half‐gone on a dichotomous nominal scale; a categorical overall evaluation was completed at the end of 6 hours. Both active agents were effective compared to placebo. Ibuprofen 400 mg was more effective than acetaminophen 1000 mg for Sum Pain Intensity Difference (SPID), Total Pain Relief (TOTPAR), sum pain half‐gone, and overall evaluation (P < .05 to P < .001). The time‐effect curves demonstrated a greater peak effect and longer duration of action for ibuprofen 400 mg compared to acetaminophen 1000 mg. Side effects were reported in five ibuprofen patients, 11 acetaminophen‐treated patients, and seven placebo patients. Based on the results of this clinical study, we conclude that ibuprofen 400 mg is a safe and more effective analgesic than acetaminophen 1000 mg for patients with acute pain.

Sore throat pain in the evaluation of mild analgesics

A double‐blind, single‐dose parallel study was conducted to assess refinements of a previously tested model for evaluating treatment of sore throat pain. Patients with tonsillopharyngitis randomly received either 400 mg ibuprofen (n = 39), 1000 mg acetaminophen (n = 40), or placebo (n = 41). At hourly intervals for 6 hours the patients reported pain intensity and pain relief on conventional scales and two sensory qualities of throat pain (“swollen throat” and “difficulty swallowing”) on two new visual analog scales. Both active agents were significantly more effective than placebo for all efficacy measurements (p < 0.01). Ibuprofen, 400 mg, was more effective than acetaminophen, 1000 mg, on all rating scales, conventional and new, at all time points after 2 hours and overall (p < 0.01). There were no side effects. We conclude that sore throat is a pain model that can be used to discriminate between active medication and placebo, as well as between two effective over‐the‐counter analgesics.

Ibuprofen and Acetaminophen in the Relief of Postpartum Episiotomy Pain

A single‐dose, double‐blind, randomized clinical trial was conducted to examine the relative analgesic efficacy of ibuprofen 400 mg (n = 36), acetaminophen 1000 mg (n = 37), and placebo (n = 38) in postpartum patients who had moderate to severe pain after episiotomy. At regular intervals over 4 hours, patients evaluated pain severity and relief on categorical scales and completed a categorical overall evaluation at the end of the trial. Both active agents were effective compared with placebo (P < .05). Ibuprofen 400 mg was more effective than acetaminophen 1000 mg for the sum of pain intensity difference, total pain relief, and reduction of pain by more than 50% (P < .05), suggesting a more rapid onset of action and a more prolonged effect by ibuprofen 400 mg. No adverse effects were reported. Based on the results of this conventional postpartum episiotomy pain model, both agents are considered efficacious and ibuprofen 400 mg is a more effective analgesic for the relief of acute pain than acetaminophen 1000 mg.

A placebo‐controlled model for assaying systemic analgesics in children

To assess the sore throat pain model in children as an assay for systemic analgesic agents in children under double‐blind, placebo‐controlled conditions, we conducted a single‐dose parallel study that compared 10 mg/kg ibuprofen (n = 39), a new analgesic agent for children, and 15 mg/kg acetaminophen (n = 38), an approved analgesic for children, to placebo (n = 39) in children from 2 to 12 years of age with acute sore throat. At ½, 1, 2, 3, 4, 5, and 6 hours (2 hours in the pediatricians office followed by 4 hours at home), children assessed pain intensity with a pain thermometer and pain relief with a smileyface scale. The parent and pediatrician assessed pain intensity and change in pain; the parent also provided an overall evaluation at 6 hours. The children rated ibuprofen and acetaminophen as significantly effective compared with placebo (p < 0.05) on both scales at most posttreatment time points and overall. The parent and pediatrician also rated both active medications as significantly different from placebo on both of their scales (p < 0.05) at several time points and overall. On the parents overall evaluation, ibuprofen was rated as effective compared with placebo (p < 0.05). Both active agents significantly (p < 0.05) reduced oral temperature in children with baseline temperatures >99° F. No treatment‐related adverse effects were observed. We conclude that the sore throat pain model is a sensitive assay for identification of the activity of oral analgesic drugs in children and that ibuprofen is an effective analgesic in children.

Rating scales for analgesics in sore throat

Clinical Pharmacology and Therapeutics (1984) 36, 151–156; doi:10.1038/clpt.1984.154

Demonstration of dose response of flurbiprofen lozenges with the sore throat pain model

The dose response of flurbiprofen lozenges (2.5, 5.0, and 12.5 mg) was evaluated in the treatment of sore throat. A refined version of the sore throat pain model showed that 12.5 mg flurbiprofen was significantly more effective than placebo at providing total pain relief and reducing throat soreness (p < .05). Flurbiprofen, 5.0 mg, was more effective than placebo for the reduction of throat soreness and the sensation of throat swelling (P < .05). The 2.5‐mg flurbiprofen lozenge was indistinguishable from placebo. For every milligram of increase in the dose of flurbiprofen, there was an approximately 0.3‐unit increase in total pain relief (P < .05). Flurbiprofen lozenges in all 3 dosages were well tolerated. Flurbiprofen lozenges are effective for sore throat at a dose between 5.0 mg and 12.5 mg; the sore throat pain model is a sensitive assay for demonstration of the dose‐response relationship of an analgesic agent.

Utility and Sensitivity of the Sore Throat Pain Model: Results of a Randomized Controlled Trial on the COX‐2 Selective Inhibitor Valdecoxib

The sore throat pain model was employed in this randomized, placebo‐controlled trial to examine the sensitivity of the model in testing the efficacy of valdecoxib as an acute analgesic drug. Changes were made to the study design by employing a different diagnostic index for tonsillo‐pharyngitis, a different rating scale (derived from Lasagnas pain thermometer), and alternative analyses, individual responder rates. Under double‐blind conditions, 197 patients with painful pharyngitis were randomly allocated to valdecoxib 20 mg bid (n = 65), valdecoxib 40 mg qd (n = 66), or placebo (n = 66) for 24 hours. The expanded Tonsillo‐Pharyngitis Assessment and the Lasagna Pain Scale were validated as sensitive study instruments. Both dosage regimens provided significantly greater pain relief compared with placebo on standard efficacy measures over the 24‐hour study (all P < .05). Tests for individual response (eg, percentage of patients with at least moderate relief) confirmed these results, and other response rates identified the high sensitivity of the model itself (eg, only 5% of placebo‐treated patients achieved ≥50% of maximum total pain relief over 6 hours). These findings indicate that sore throat is a sensitive model to assess analgesic efficacy.

Onset of action of a lozenge containing flurbiprofen 8.75 mg: A randomized, double-blind, placebo-controlled trial with a new method for measuring onset of analgesic activity

Summary Using frequent measurements and analyses based on definite drug response, a new onset‐of‐action model identified the early onset of action of a flurbiprofen 8.75‐mg lozenge. ABSTRACT A new onset‐of‐action model was utilized to distinguish the pharmacologic activity of flurbiprofen 8.75 mg delivered in a lozenge from the demulcent effect of the lozenge base. In a randomized, double‐blind, placebo‐controlled trial, patients with sore throat rated pain on a Sore Throat Pain Intensity Scale before taking one flurbiprofen or placebo lozenge and at frequent (2‐minute) intervals over the first hour after treatment. Further ratings of the Sore Throat Pain Intensity Scale and other patient‐reported outcomes (difficulty swallowing, swollen throat, pain relief) were obtained at varying intervals over 6 hours. Onset of pharmacologic activity was defined as the median time of first perceived pain reduction if a patient reported clinically meaningful (at least moderate) relief. The conventional method of comparing mean treatment responses at each time point was also implemented. Demulcent action was detected at the first 2‐minute assessment. By the new method, 102 flurbiprofen‐treated patients were identified as first perceiving pain relief at 12 minutes, compared with >120 minutes by 102 patients using placebo (P < 0.001). By the conventional method, mean percentage pain reduction for flurbiprofen 8.75 mg was first significantly differentiated from placebo at 26 minutes (P < 0.05). Efficacy of flurbiprofen lozenge was demonstrated for 3.5‐4 hours on the 4 patient‐reported outcomes (all P < 0.05 compared with placebo). There were no serious adverse events. This patient‐centered onset‐of‐action model identifies the initiation of pain relief in patients who are definite drug responders, here demonstrating that a flurbiprofen 8.75‐mg lozenge provides early relief of sore throat.

Efficacy of Low-Dose Celecoxib in Patients With Acute Pain

UNLABELLED The sore throat pain model was used to evaluate single-dose effects of celecoxib 50 and 100 mg over 6 hours in the treatment of acute pharyngeal pain. Multiple-dose effects of 50-mg bid and 100 mg followed by 50 mg over 6 to 24 hours were also evaluated. Under double-blind, randomized, placebo-controlled conditions, 269 adults with confirmed acute pharyngitis rated throat pain intensity, throat soreness, difficulty swallowing, and sore throat pain relief over 24 hours. For the primary efficacy analysis (SPID2), patients receiving celecoxib 100 mg during the first 2 hours after the first dose had significantly higher mean scores than patients in the placebo group (P < .0003). Efficacy was also demonstrated for celecoxib 50 and 100 mg compared with placebo for all end points (including total pain relief, summed pain intensity differences, total reduction of throat soreness, and difficulty swallowing) at all time points after the first dose and after the second 50-mg dose (P < .01). There were no differences between the dosage regimens, although a supplementary 50-mg dose of celecoxib 6 to 12 hours after the first dose appeared to provide additional efficacy over 24 hours. No serious adverse events (AEs) or discontinuations due to an AE were reported. The results of this study demonstrate that in this pain model, celecoxib is a well tolerated and efficacious analgesic in 50- and 100-mg doses. PERSPECTIVE In a double-blind, randomized, placebo-controlled trial utilizing the sore throat pain model, low-dose celecoxib (50- and 100-mg doses) was well tolerated and provided effective analgesia in patients with acute pain.

Demonstration of the Analgesic Efficacy and Dose-Response of Acetylsalicylic Acid With Pseudoephedrine

To determine acute analgesia by acetylsalicylic acid (ASA) when combined with pseudoephedrine (PSE) in patients with upper respiratory tract infection (URTI), we used the sore throat pain model to measure single‐dose effects of ASA 500 mg/PSE 30 mg, ASA 1000 mg/PSE 60 mg, and acetaminophen (APAP) 1000 mg/PSE 60 mg (serving as a positive control). Under double‐blind, randomized, placebo‐controlled conditions, 640 adult patients with confirmed acute pharyngitis and rhinosinusitis associated with URTI rated throat pain intensity and relief at intervals over 6 hours. Efficacy was demonstrated for both doses of ASA/PSE compared with placebo for all end points, including total pain relief and summed pain intensity differences, beginning at 20 minutes on both scales (all P < .05), and the efficacy of APAP/PSE compared with placebo was confirmed (P < .01). Greater differences in pain relief and intensity were also demonstrated between the higher and lower doses of ASA/PSE (P < .05), in particular, among 329 patients with severe pain, as well as between ASA 1000 mg/PSE 60 mg and APAP 1000 mg/PSE 60 mg (P < .05). No serious adverse events were reported. This study demonstrates that ASA is a well‐tolerated and effective analgesic in 500‐ and 1000‐mg doses when combined with pseudoephedrine.