William R. Thoden

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.

Nonprescription Ibuprofen and Acetaminophen in the Treatment of Tension-Type Headache

A single‐dose, double‐blind, randomized clinical trial was conducted to examine the relative analgesic effectiveness of 400 mg of ibuprofen (n = 153), 1,000 mg of acetaminophen (n = 151), and placebo (n = 151) in volunteers with muscle contraction headache. At regular intervals during a 4‐hour period, participants evaluated headache pain intensity on a 100‐mm visual analog scale and headache pain relief on a six‐category scale. Both active agents were significantly different from placebo at all time points and in reducing pain intensity and providing relief of headache overall. Similarly, ibuprofen at 400 mg differed significantly from acetaminophen at 1,000 mg on both rating scales. Participants receiving ibuprofen at 400 mg achieved complete relief of headache faster than those receiving acetaminophen at 1,000 mg or placebo, and more participants taking ibuprofen experienced complete relief of headache than those taking placebo or acetaminophen. Both ibuprofen at 400 mg and acetaminophen at 1,000 mg are efficacious analgesic agents for muscle contraction headache, and ibuprofen at 400 mg is significantly more effective than acetaminophen at 1,000 mg for treating this condition.

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.

Headache pain model for assessing and comparing the efficacy of over‐the‐counter analgesic agents

To refine the assessment of over‐the‐counter analgesic agents in the treatment of muscle‐contraction headache, we designed a single‐dose model with attention to specific methodologic features and two relevant assessments—the percentage of subjects who achieve complete relief and the time until pain is no longer experienced. Subjects were randomly assigned to receive a single dose of 1000 mg acetaminophen, 1000 mg aspirin with 64 mg caffeine, or placebo. Under double‐blind conditions, subjects rated headache pain intensity and relief over 4 hours and provided a Comparative Evaluation at the end of the trial. Both active agents were significantly distinguished from placebo on the time‐point analyses (p < 0.05) and summary end point measurements (sum of pain intensity difference [SPID], total of pain relief, percentage of patients with complete relief, percentage of treatment failures, and the Comparative Evaluation), as well as causing a faster elimination of headache (p < 0.05). The aspirin‐caffeine combination was rated higher than acetaminophen on all summary measurements, particularly SPID (p < 0.05), with significantly more patients obtaining complete relief with aspirin‐caffeine (p < 0.01) than with acetaminophen. We conclude that this headache pain model can be used to demonstrate the efficacy of over‐the‐counter analgesic agents and to assess their relative efficacy.

Inhaled Epinephrine and Oral Theophylline—Ephedrine in the Treatment of Asthma

Inhaled and oral over‐the‐counter bronchodilators are used for self‐therapy by asthmatic patients. To evaluate their safety and efficacy, we compared epinephrine and theophylline combined with ephedrine with inhaled metaproterenol and the placebo. Twelve asthmatic patients were studied in a randomized, double‐blind, placebo‐controlled, crossover trial comparing forced expiratory volume in 1 second (FEV1) after two inhalations of epinephrine (0.2 mg/inh), 1 minute apart, followed in 15 minutes by theophylline (130 mg) with ephedrine (24 mg) versus two inhalations of metaproterenol (0.65 mg/inh), 1 minute apart, versus placebo inhaler and tablets. Onset of FEV1 > 15% above baseline values occurred within 15 seconds after inhalations for 100% of epinephrine‐treated patients, 92% of metaproterenol‐treated patients, and 33% of placebo‐treated patients. FEV1 responses were significantly greater (P < .05) for epinephrine at 0.66 to 1.66 minutes compared with the responses of metaproterenol, and epinephrine and theophylline that was combined with ephedrine compared with metaproterenol beginning at 2 hours. Mean duration of activity was 5.7 hours for the epinephrine‐ and theophylline with ephedrine‐treated patients, 4.9 hours for metaproterenol‐treated patients, and 2 hours for the placebo group. There were statistically significant differences for patients receiving epinephrine and theophylline with ephedrine versus the placebo group (P < .001), metaproterenol patients versus the placebo group (P = .02), and patients receiving epinephrine and theophylline with ephedrine versus metaproterenol‐treated patients (P < .05). Compared with inhaled metaproterenol, inhaled epinephrine followed in 15 minutes by a theophylline—ephedrine tablet had a significantly earlier onset, longer duration of action, numerically greater peak effect, and patient preference. This combination of oral and inhaled bronchodilator medication is as safe and effective as inhaled metaproterenol.