Efficacy of a Fixed-Dose Combination of Ibuprofen and Acetaminophen Compared With Individual Monocomponents in Adult Male Subjects With Endotoxin-Induced Fever: A Randomized Controlled Trial.

PURPOSE: This study evaluated antipyretic efficacy and onset of a novel fixed-dose combination (FDC) of ibuprofen (IBU; 250 mg) and acetaminophen (APAP; 500 mg) compared with placebo and IBU or APAP monocomponents. MET: This single-center, randomized, double-blind, placebo-controlled, full-factorial study was conducted in healthy males aged 18 to 55 years with pyrexia induced by intravenous administration of reference standard endotoxin (RSE). After attainment of an oral temperature ≥38.1°C, subjects were randomized 3:3:3:1 to a double-blind single oral dose of FDC IBU/APAP 250 mg/500 mg, APAP 500 mg, IBU 250 mg, or placebo. Oral temperature was measured every 10 minutes for 2 hours, then every 30 minutes until 8 hours postdose. Time-weighted sum of temperature differences from baseline to 8 hours (WSTD0-8) after study medication administration was the primary efficacy end point. Secondary end points included WSTD scores from 0 to 2 hours, 0 to 4 hours, 0 to 6 hours, and 6 to 8 hours; time to return to "normal" temperature; time to rescue medication use; and global drug evaluation. Safety was assessed via adverse events (AEs). FINDINGS: Two hundred ninety subjects were randomized; 273 were included in the primary efficacy analysis. WSTD0-8 was significantly better for FDC IBU/APAP 250 mg/500 mg (P = 0.002), IBU 250 mg (P = 0.030), and APAP 500 mg (P = 0.023) versus placebo; there were no significant differences between active treatments. For WSTD0-2, only the FDC was statistically significant versus placebo (P = 0.004). All active treatments were significantly better (P < 0.05) for WSTD0-4 and WSTD0-6 versus placebo; there were no differences in WSTD6-8 between cohorts. Temperature returned to normal during the 8-hour treatment period in ∼50% of subjects in each cohort. Only 1 subject (IBU cohort) took rescue medication. Post hoc analyses at early time points revealed significant treatment differences favoring FDC versus placebo and IBU for the WSTD from baseline during the 50- to 110-minute posttreatment window; for WSTD from baseline during the 80- to 110-minute posttreatment window, FDC provided significant treatment differences versus placebo and both monocomponents. Overall, 223 (76.9%) of 290 subjects experienced AEs related to RSE; only 2 subjects experienced treatment-related AEs (FDC, rash; placebo, ear pain). IMPLICATIONS: Although the primary end point was not met, these results suggest that FDC IBU/APAP 250 mg/500 mg provides effective antipyresis with a faster onset versus equal doses of IBU and APAP alone. ClinicalTrials.gov identifier: NCT02761980.

Safety and tolerability of fixed-dose combinations of ibuprofen and acetaminophen: pooled analysis of phase 1-3 clinical trials.

OBJECTIVES: An ibuprofen (IBU)/acetaminophen (APAP) fixed-dose combination (FDC) for over-the-counter (OTC) use was developed with the goal of providing the same effective analgesic activity as full doses of the individual monocomponents, while reducing individual monocomponent drug exposures. Here, the safety and tolerability of the FDC is characterized using pooled safety data from phase 1-3 clinical trials in the FDC development program. METHODS: We conducted a pooled safety analysis of data from 7 clinical trials: three phase 1 pharmacokinetic trials, a phase 2 proof-of-concept trial, and three phase 3 trials (a single- and a multiple-dose trial in a dental pain model and a single-dose trial in an induced-fever model). Safety and tolerability of the FDC were assessed by adverse events (AEs) for the total group and subgroups (age, sex, race). RESULTS: A total of 1,477 participants were enrolled in the 7 trials; 715 were treated with FDC IBU/APAP, 432 with IBU monotherapy, 330 with APAP monotherapy, and 156 with placebo. Most subjects were white (86.5%), and 44% were female. Two trials enrolling 195 adolescents accounted for 13.2% of the overall study population. All-causality treatment-emergent AEs (TEAEs) occurred in 19.7% of the 1477 participants. Nausea (13.5%), vomiting (7.4%), dizziness (4.5%), headache (1.2%), and feeling hot (1.0%) were the only TEAEs reported in ≥1% of subjects. Treatment-related AEs occurred in 1.8% of the subjects in the overall population. The incidence of AEs, including treatment-related AEs, was consistently lower in all active treatment groups than in the placebo group; this also applied to subgroups according to sex, race, and age, including adolescents aged 12-17 years. The higher rate of AEs with placebo was likely due to lack of pain/fever control. CONCLUSION: Single-dose or short-course FDC IBU/APAP OTC use was well tolerated, with an AE profile similar to its IBU and APAP monocomponents. CLINICALTRIALS.GOV REGISTRATION: NCT01559259; NCT02912650; NCT02837952; NCT02761980. The pharmacokinetic studies (n = 3) did not require registration.

Evaluation of Fixed-Dose Combinations of Ibuprofen and Acetaminophen in the Treatment of Postsurgical Dental Pain: A Pilot, Dose-Ranging, Randomized Study.

INTRODUCTION: Ibuprofen and acetaminophen provide analgesia via different mechanisms of action and do not exhibit drug-drug interactions; therefore, combining low doses of each may provide greater efficacy without compromising safety. OBJECTIVES: The present study assessed the analgesic efficacy of fixed-dose combinations (FDCs) of ibuprofen/acetaminophen (IBU/APAP) compared with ibuprofen 400 mg and placebo. METHODS: This 12-h, double-blind, proof-of-concept study compared three FDCs of IBU/APAP (200 mg/500 mg, 250 mg/500 mg, and 300 mg/500 mg) with ibuprofen 400 mg and placebo in patients with moderate-to-severe pain following third molar extraction. The primary endpoint was the time-weighted sum of pain relief and pain intensity difference scores from 0 to 8 h after dosing (SPRID[4]0-8). Time to meaningful pain relief (TMPR), duration of pain relief, and adverse events (AEs) were also assessed. RESULTS: In total, 394 patients were randomized. All active treatments were superior to placebo for SPRID[4]0-8 (all p < 0.001) but not significantly different from ibuprofen 400 mg. Median TMPR with FDCs and ibuprofen (44.5-54.1 and 56.2 min, respectively) was faster than with placebo (> 720 min; all p < 0.001 vs. placebo). Duration of pain relief was similar with the FDCs and ibuprofen 400 mg (9.7 -11.1 h) and longer than with placebo (1.6 h; all p < 0.001). AE incidence was comparable with all treatments. CONCLUSION: Each IBU/APAP FDC provided analgesic efficacy comparable to that with ibuprofen 400 mg and superior to that with placebo. Each FDC provided MPR in < 1 h, duration of pain relief > 9 h, and tolerability similar to that with ibuprofen and placebo. CLINICALTRIALS. GOV REGISTRATION: NCT01559259.

Efficacy and Safety of Single and Multiple Doses of a Fixed-dose Combination of Ibuprofen and Acetaminophen in the Treatment of Postsurgical Dental Pain: Results From 2 Phase 3, Randomized, Parallel-group, Double-blind, Placebo-controlled Studies.

OBJECTIVES: A previous pilot study demonstrated that various fixed-dose combinations (FDCs) of ibuprofen (IBU) and acetaminophen (APAP) provided analgesic efficacy comparable to a higher dose of IBU, with the same safety profile. These studies further evaluated the chosen FDC IBU/APAP 250/500 mg formulation. MATERIALS AND METHODS: Two phase 3 dental pain studies enrolled healthy young patients with ≥moderate pain after ≥3 third molar extractions who received single-dose FDC IBU/APAP 250/500 mg, IBU 250 mg, APAP 650 mg, or placebo evaluated over 12 hours (study 1) or multiple-dose FDC or placebo every 8 hours, evaluated over 48 hours (study 2). Time-weighted sum of pain intensity differences over 8 (SPID[11]0-8) and 24 (SPID[11]0-24) hours were primary outcomes, respectively. Time to meaningful pain relief and duration of pain relief were assessed; tolerability was evaluated by adverse events. RESULTS: Five hundred sixty-eight patients were randomized in study 1; 123 in study 2. Study 1: SPID[11]0-8 favored FDC significantly over placebo, IBU, and APAP (P<0.001, P=0.008, and P<0.001, respectively); study 2: SPID[11]0-24 significantly favored FDC over placebo (P<0.001), with sustained efficacy during multiple dosing. Time to meaningful pain relief occurred within 1 hour; pain relief duration was >8 hours in both studies. Adverse event rates were lowest with the FDC. DISCUSSION: FDC IBU/APAP 250/500 mg provides superior analgesic efficacy to individual monocomponents (IBU 250 mg and APAP 650 mg), a rapid onset of action, >8-hour duration of pain relief, is generally well tolerated, and may provide an additional nonopioid treatment option for acute pain.

Phase I Pharmacokinetic Study of Fixed-Dose Combinations of Ibuprofen and Acetaminophen in Healthy Adult and Adolescent Populations.

INTRODUCTION: A fixed-dose combination (FDC) of ibuprofen and acetaminophen has been developed that provides greater analgesic efficacy than either agent alone at the same doses without increasing the risk for adverse events. METHODS: We report three clinical phase I studies designed to assess the pharmacokinetics (PK) of the FDC of ibuprofen/acetaminophen 250/500 mg (administered as two tablets of ibuprofen 125 mg/acetaminophen 250 mg) in comparison with its individual components administered alone or together, and to determine the effect of food on the PK of the FDC. Two studies in healthy adults aged 18-55 years used a crossover design in which subjects received a single dose of each treatment with a 2-day washout period between each. In the third study, the bioavailability of ibuprofen and acetaminophen from a single oral dose of the FDC was assessed in healthy adolescents aged 12-17 years, inclusive. RESULTS: A total of 35 and 46 subjects were enrolled in the two adult studies, respectively, and 21 were enrolled in the adolescent study. Ibuprofen and acetaminophen in the FDC were bioequivalent to the monocomponents administered alone or together. With food, the maximum concentration (Cmax) for ibuprofen and acetaminophen from the FDC was reduced by 36% and 37%, respectively, and time to Cmax (i.e. tmax) was delayed. Overall drug exposure to ibuprofen or acetaminophen in the fed versus fasted states was similar. In adolescents, overall exposure to acetaminophen and ibuprofen was comparable with that in adults, with a slightly higher overall exposure to ibuprofen. Exposure to acetaminophen and ibuprofen in adolescents aged 12-14 years was slightly higher versus those aged 15-17 years. Adverse events were similar across all treatment groups. CONCLUSIONS: The FDC of ibuprofen/acetaminophen 250/500 mg has a PK profile similar to its monocomponent constituents when administered separately or coadministered, indicating no drug-drug interactions and no formulation effects. Similar to previous findings for the individual components, the rates of absorption of ibuprofen and acetaminophen from the FDC were slightly delayed in the presence of food. Overall, adolescents had similar exposures to acetaminophen and ibuprofen as adults, while younger adolescents had slightly greater exposure than older adolescents, probably due to their smaller body size. The FDC was generally well tolerated.

Symptomatic treatment of dengue: should the NSAID contraindication be reconsidered?

Consensus guidelines for treatment of dengue fever from the World Health Organization and US Centers for Disease Control recommend acetaminophen to manage pain and fever but contraindicate nonsteroidal anti-inflammatory agents (NSAIDs) because of potentially increased bleeding risk, with thrombocytopenia as a complication. Neither acetaminophen nor ibuprofen (the NSAID with lowest bleeding risk) have been evaluated for dengue treatment in randomized, controlled clinical trials. Epidemiologic and cohort studies and case series describing NSAID use in dengue generally point to minimal or no significant increase in bleeding risk, except for aspirin. Given the lack of data on use of NSAIDs in dengue, we assessed the literature for the risk of postoperative bleeding with NSAID use, with a particular focus on ibuprofen, as a potential surrogate marker of bleeding risk in dengue. Ibuprofen at over-the-counter doses used to treat pain and fever (i.e. up to 1,200 mg/d for up to 10 days) is associated with zero to minimally increased risk for postoperative bleeding events. Where detected, statistically significant increases in bleeding incidence and/or bleed volume were not clinically meaningful. Because hepatitis is also a frequent dengue complication, acetaminophen-associated hepatotoxicity (the most common cause of drug-induced liver disease and acute liver failure in the United States and Europe) raises the possibility of severe hepatic injury with acetaminophen treatment. Data suggesting that conditions associated with chronic liver damage reduce the dosing threshold for induction of liver failure are of particular concern. Meta-analyses of clinical studies across a range of clinical settings consistently conclude that ibuprofen, at non-prescription doses, provides equivalent or superior analgesic and antipyretic activity compared with acetaminophen, with comparable safety. These data suggest that the consensus guideline recommendations for acetaminophen and against NSAID use in dengue treatment should be reconsidered in light of current evidence regarding the risks and benefits of each agent.

Antipyretic Efficacy and Safety of Ibuprofen Versus Acetaminophen Suspension in Febrile Children: Results of 2 Randomized, Double-Blind, Single-Dose Studies.

Two blinded single-dose studies randomized children 6 months to 11 years old with fever to receive ibuprofen (IBU) pediatric suspension 7.5 mg/kg or acetaminophen (APAP) suspension 10 to 15 mg/kg. The primary efficacy parameter was time-weighted sum of temperature differences (TWSTD) from baseline through 8 hours for each study. Secondary end points included TWSTD from baseline through 6 hours, time to onset and duration of temperature control, and proportion with temperature control. Studies were pooled for post hoc analyses of efficacy and adverse event end points. The primary efficacy parameter significantly favored IBU over APAP in study 1 and the pooled analysis (both P < .001), but was not significant in study 2. Onset of temperature control significantly favored IBU in study 2 ( P = .007). Individual and pooled secondary efficacy outcomes supported significant advantages ( P < .05) of IBU over APAP. IBU pediatric suspension provided greater temperature reduction versus acetaminophen in febrile children, with a comparable safety profile.

Onset of analgesia and efficacy of ibuprofen sodium in postsurgical dental pain: a randomized, placebo-controlled study versus standard ibuprofen.

OBJECTIVES: A novel, immediate-release tablet formulation of ibuprofen (IBU) sodium dihydrate, Advil Film Coated Tablets (IBUNa), has been developed that is absorbed faster than standard IBU tablets. The objective of the current study was to compare the efficacy and onset of analgesia of this new formulation with standard IBU tablets after a single dose. MATERIALS AND METHODS: Patients (N=316) with at least moderate baseline postsurgical dental pain were randomized to 400 mg IBUNa, Advil (IBUAdv), Motrin (IBUMot), or placebo. Primary endpoints were time-weighted sum of pain relief (PR) and pain intensity differences over 8 hours (SPRID 0-8) and time to onset of meaningful pain relief (TMPR) measured by the double-stopwatch method. RESULTS: SPRID 0-8 was significantly greater for IBUNa and the other active treatments versus placebo (P<0.001). IBUNa had a significantly earlier TMPR versus placebo, pooled IBUAdv/IBUMot, and IBUMot (P<0.001 for all), and a marginally faster TMPR (P=0.075) versus IBUAdv. Results for secondary endpoints were similar. Adverse events were comparable across treatment groups, with gastrointestinal disorders being most frequently reported. Most adverse events were mild or moderate. DISCUSSION: This novel formulation of IBUNa provided superior overall PR compared with placebo and more rapid onset of analgesic effect compared with standard IBU tablets. Rapid PR is important in the treatment of acute pain, including dental pain, and this IBUNa formulation represents a new treatment option for rapid PR.

Onset of analgesia with ibuprofen sodium in tension-type headache: a randomized trial.

BACKGROUND: Ibuprofen is known to be efficacious in the treatment of tension-type headache, the most common form of primary headache. A novel tablet formulation of ibuprofen sodium is more rapidly absorbed than standard ibuprofen. This study evaluated onset of analgesia and overall efficacy of ibuprofen sodium in episodic-type tension headache (ETTH) compared with standard ibuprofen and placebo. METHODS: This randomized, double-blind, single-center, parallel-group study included adults aged 18-65 years with ≥4 moderately severe ETTHs per month for 6 months. Within 45 minutes of onset of at least moderately severe ETTH, subjects were randomized 2:2:1 to receive a single oral dose of ibuprofen sodium tablets (Advil® Film Coated; 2 × 256 mg [equivalent to 400 mg standard ibuprofen]), standard ibuprofen tablets (Motrin®; 2 × 200 mg), or placebo. The coprimary end points were time-weighted sum of pain relief rating and pain intensity difference scores over 3 hours (SPRID 0-3) and time to meaningful pain relief (MPR) assessed by double-stopwatch method. RESULTS: A total of 226 subjects were randomized to ibuprofen sodium (n = 91), standard ibuprofen (n = 89), and placebo (n = 46). Demographics and baseline characteristics were comparable between treatment groups. Mean SPRID 0-3 scores were significantly superior (P < .001) for ibuprofen sodium (9.6) and standard ibuprofen (9.8) versus placebo (3.5), but were not significantly different from each other (P = .812). Time to MPR was significantly (P < .001) shorter for ibuprofen sodium and standard ibuprofen compared with placebo (median 40.6, 48.5, and >180 minutes, respectively). Time to MPR was numerically faster for ibuprofen sodium than standard ibuprofen. This difference was not statistically significant (P = .253) using the protocol-specified analysis but was (P = .022) in a post hoc analysis using the Gehan-Wilcoxon test, which assigns higher weights to earlier events. (The post hoc analysis was performed because Kaplan-Meier graphs and results for time to first perceptible relief favored ibuprofen sodium over standard ibuprofen at earlier time points.) There were no adverse events. CONCLUSIONS: This novel ibuprofen sodium tablet provided rapid, efficacious relief of ETTH and was well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov NCT01362491.

Safety of a novel formulation of ibuprofen sodium compared with standard ibuprofen and placebo.

BACKGROUND: Ibuprofen (IBU) is an efficacious over-the-counter analgesic/antipyretic with adverse event (AE) rates comparable to placebo. IBU sodium (IBU(Na)) is a newer, more soluble form that is absorbed faster than standard IBU, leading to more rapid analgesia. Although its safety and tolerability are expected to be comparable to standard IBU, this has not yet been reported. METHODS: Pooled analysis comparing the safety of single-dose IBU(Na) (512 mg; equivalent to 400 mg IBU free acid; n = 362) with standard IBU tablets (400 mg; n = 342) and placebo (n = 187) across five Phase III, randomized, placebo-controlled, double-blind studies evaluating IBU(Na) for treatment of postoperative dental pain, tension-type headache, or fever. RESULTS: Treatment-emergent AEs (TEAEs) occurred in 5% of cases in the IBU(Na) group (25 events), 6.4% of cases in the standard IBU group (41 events), and 10.2% of cases in the placebo group (31 events). The most frequent TEAEs were in the following Medical Dictionary for Regulatory Activities (MedDRA) System Organ Classes: gastrointestinal disorders (2.8, 3.2, and 5.9% for IBU(Na), standard IBU, and placebo, respectively), nervous system disorders (1.4, 3.5, and 3.7% for IBU(Na), standard IBU, and placebo, respectively), and general disorders and administration-site conditions (1.1, 1.5, and 2.1% for IBU(Na), standard IBU, and placebo, respectively). Nausea was the most common TEAE (2.5, 2.6, and 5.9% for IBU(Na), standard IBU, and placebo, respectively). Only two AEs were considered related to treatment: pruritus (n = 1, IBU(Na)) and nausea (n = 1, placebo). Of those subjects reporting ≥ 1 TEAE, 44.4, 36.4, and 89.5% of subjects in the IBU(Na), standard IBU, and placebo groups, respectively, received rescue medication. CONCLUSION: IBU(Na) has a favorable safety profile comparable to those of standard IBU tablets and placebo in single-dose studies evaluating analgesic or antipyretic efficacy. ClinicalTrials.gov Registry Numbers: Dental pain studies: NCT01098747 and NCT01216163; headache studies: NCT01077973 and NCT01362491; pyresis study: NCT01035346.

Ibuprofen sodium is absorbed faster than standard Ibuprofen tablets: results of two open-label, randomized, crossover pharmacokinetic studies.

BACKGROUND: A novel ibuprofen (IBU) formulation, Advil(®) Film-Coated Tablets (IBUNa), was developed. OBJECTIVE: Pharmacokinetic comparison of IBUNa versus other IBU formulations. STUDY DESIGN: Two randomized, single-dose, open-label, five-way crossover pharmacokinetic studies. SETTING: Inpatient research clinic. SUBJECTS: Seventy-one healthy adult volunteers. INTERVENTION: Study 1: In three periods, fasted subjects received 400-mg IBU dose equivalents as IBUNa 2 × 256 mg, Advil(®) Liqui-Gels(®) (IBULG) 2 × 200 mg, and Motrin(®) IB (IBUMot) 2 × 200 mg tablets. In two periods following a high-fat breakfast, subjects received 400-mg IBU dose equivalents as IBUNa 2 × 256 mg and IBULG 2 × 200 mg. Study 2: In five study periods, fasted subjects received 400-mg IBU dose equivalents as IBUNa 2 × 256 mg, Advil(®) FastGel(®) (IBUFG) 2 × 200 mg, Nurofen(®) (IBUNur) 2 × 200 mg, Advil(®) (IBUAdv) 2 × 200 mg, and Nurofen(®) Express containing IBU lysinate (IBULys) 2 × 342 mg. MAIN OUTCOME MEASURE: Log-transformed area under the plasma concentration versus time curve to last observable concentration (AUCL) and maximum plasma concentration (C max) were the primary pharmacokinetic parameters; time to maximum measured plasma concentration (T max) was analyzed post hoc. RESULTS: IBUNa was bioequivalent to IBULG (fasted and fed) and IBUFG and IBULys (fasted) for rate (C max) and extent (AUCL) of IBU absorption. After fasting, AUCL was bioequivalent for IBUNa and IBUMot, IBUAdv, and IBUNur, but C max occurred significantly earlier with IBUNa. After fasting, median IBUNa T max was comparable to that for IBULG, IBUFG, and IBULys, but was much shorter than that for IBUMot, IBUNur, and IBUAdv. Food slowed absorption of IBUNa and IBULG similarly. All treatments were tolerated similarly. CONCLUSION: IBUNa is absorbed faster but to a similar extent as standard IBU formulations.

Modeling the onset and offset of dental pain relief by ibuprofen.

Onset and offset of dental pain relief by ibuprofen following third molar extraction were modeled in a randomized, double-blind, placebo-controlled, parallel-group, 8-hour study of patients receiving either a novel effervescent ibuprofen tablet (400 mg; N = 30), standard ibuprofen tablets (Nurofen(®) 2 × 200 mg; N = 22), or placebo (N = 37). An Emax model was fit to pain relief scores. Linear hazard models were used to analyze the time to first perceptible relief (TFPR), the time to meaningful pain relief (TMPR), and time to remedication (REMD). Nomograms were created to correlate TFPR, TMPR, and REMD with different ibuprofen pharmacokinetic profiles. Effervescent ibuprofen was absorbed rapidly with 95% completion within 15 minutes. Maximum pain relief score by ibuprofen was 1.8 units greater than placebo, with an EC50 (effect-site) for ibuprofen concentration of 10.2 µg·mL(-1). The likelihood to achieve TFPR and TMPR was doubled for every 10 µg·mL(-1) increase in ibuprofen plasma concentration. REMD risk decreased 40-fold as the categorical pain relief score increased from 0 to 3. Rapid absorption of ibuprofen effervescent resulted in an earlier TFPR and TMPR, and a lower REMD rate than standard ibuprofen. The nomograms may be useful in predicting the onset and offset of new faster acting ibuprofen formulations, based on pharmacokinetic profiles.

Children's ibuprofen suspension for the acute treatment of pediatric migraine.

OBJECTIVE: To compare the efficacy of a single over-the-counter dose (7.5 mg/kg, p.o.) of children's ibuprofen suspension vs. placebo for the acute treatment of pediatric migraine. BACKGROUND: Migraine occurs in 4% of young children. There is a paucity of controlled clinical research in the treatment of childhood migraine and there are currently no approved drugs in the USA for treatment of migraine in children < or = 12 years of age. The purpose of this study is to assess the efficacy and tolerability of a single OTC dose of ibuprofen suspension for the acute treatment of childhood migraine. METHODS: Prospective, double-blind, placebo-controlled, parallel group, randomized study of children 6-12 yrs with migraine (I.H.S.-R 1997) treating 1 attack with a 7.5 mg/kg liq. ibuprofen vs matching placebo. Efficacy measures: (1). Headache severity based upon a 4 pt scale (severe, mod., mild, no headache) at 30, 60, 90, 120, 180 and 240 minutes post dose, and (2). nausea, vomiting, and photo/phonophobia at 120 min. The 1 degrees endpoint was cumulative % of responders (severe or mod. headache reduced to mild or none) by 120 minutes. Secondary endpoints were headache recurrence within 4-24 hours and need for rescue medicines within 4 hours. RESULTS: 138 enrolled; 84 treated/completed diary. 45 active agent, 39 placebo. The 2 groups were comparable (active: placebo) - Ages: 9: 9.1, gender boy/girl - 1.25: 1.6, and diagnosis: migraine w/o aura - 86%: 79%. Concomitant use of prophylactic Rx: 24%: 10% (Table 3). Nausea was eliminated in 60% of the ibuprofen treated patients and 39% of the placebo group (p<0.001). Vomiting, photophobia and phonophobia had marginal, but not statistically significant, decreases at 2 hours. A striking gender difference was noted (Table 4): No AE's were reported. CONCLUSION: Children's ibuprofen suspension at an OTC dose of 7.5 mg/kg is an effective and well-tolerated agent for pain relief in the acute treatment of childhood migraine, particularly in boys. There is a striking difference in gender response rates and placebo responder rates between girls and boys. The boys responded at a statistically significant rate, and girls failed to do so because of a very high placebo responder rate. Multi-center trials are recommended.

Spinal co-administration of cholecystokinin antagonists with morphine prevents the development of opioid tolerance.

The effects of intrathecal (i.t.) co-administration of the cholecystokinin (CCK) antagonists lorglumide or proglumide with a "low" (1 microgram) and "high" (10 micrograms) dose of i.t. morphine on the development of opioid tolerance were determined using the rat tail-flick assay. Although co-injection of 7 ng lorglumide or 20 ng proglumide (doses which have been demonstrated to acutely enhance 1 microgram morphine, i.t.) were without effect, co-administration of 70 ng lorglumide or 64 ng proglumide with 1 microgram morphine for 6 days inhibited development of tolerance to this dose of opioid. Higher doses of CCK antagonists (1400 ng lorglumide and 1280 ng proglumide) were required to prevent the tolerance induced by 10 micrograms morphine. These findings provide further evidence that CCK mediates, at least partially, tolerance which develops to the analgesic effect of opioids and indicate the involvement of CCK pathways in the spinal cord. The results are also consistent with a mechanism in which the level of activation of compensatory, anti-opioid CCK circuitry is increased in proportion to the functional level of opioid pathways.

Opioid-monoamine interactions in spinal antinociception: evidence for serotonin but not norepinephrine reciprocity.

Anatomical and electrophysiological studies have demonstrated that enkephalinergic, noradrenergic, and serotonergic pathways projecting from the brain-stem to the dorsal horn inhibit nociceptive transmission at the spinal level. Previous attempts to delineate interactions between opioids, norepinephrine (NE), and serotonin (5-HT) in the production of spinal analgesia have produced conflicting results. The present study determined the effect of intrathecal (i.t.) pretreatment with opioid, NE, and 5-HT antagonists upon i.t. monoamine- and morphine-induced antinociception as assessed with the rat tail-flick model. Naloxone, at a dose which antagonized i.t. morphine analgesia, had no effect upon i.t. NE but inhibited i.t. 5-HT antinociception. Corynanthine or yohimbine (NE antagonists) reduced analgesia elicited by i.t. NE but not morphine, while pretreatment with methysergide or ketanserin (5-HT antagonists) attenuated both i.t. 5-HT- and morphine-induced antinociception. These results suggest that (1) an opioid link mediates spinal 5-HT but not NE antinociception, and (2) 5-HT but not NE participates in spinal morphine analgesia.

Contrasting effects of acute vs. chronic tricyclic antidepressant treatment on central morphine analgesia.

Antinociception following central opioid microinjection in rats was assessed weekly via a tail-flick procedure during chronic tricyclic antidepressant (TCA) treatment. (1) Daily TCA: Subcutaneous injections of desipramine (DMI), 30 mg/kg, chlorimipramine (CMI), 10 mg/kg, or saline, 1 ml/kg, were given daily for 22 days. Morphine sulfate (M), 5 micrograms, was microinjected into the ventrolateral periaqueductal gray (VLPAG) at 7 day intervals. On day 1, DMI or CMI enhanced M analgesia whereas saline did not. Augmentation of M disappeared by days 8 and 15 for CMI and DMI, respectively, and was replaced by attenuation which was still observed on day 22 for both TCAs. L-Tryptophan (LT), 100 mg/kg, i.p., on days 15 and 22 temporarily restored TCA enhancement of M. Fourteen days after cessation of all daily TCA treatments, enhancement of M by CMI was similar to that observed on day 1, whereas recovery of DMI-induced facilitation was incomplete. (2) Weekly TCA: Weekly treatment with DMI, CMI, or saline in the same doses as above had similar effects. M analgesia was enhanced by the TCAs but not saline on day 1; this facilitation was absent by day 15. Attenuation of M by DMI or CMI was evident on day 22; 2 weeks after cessation of all weekly TCA treatments, complete recovery of TCA-induced augmentation was observed. Loss of M facilitation during chronic daily or weekly TCA administration may be related to reduction of central opioid and/or 5-HT2 receptors.