A Proof-of-concept Study Using Quantitative Sensory Threshold Analysis to Compare Two Intraoral Topical Anesthetics.

PURPOSE: CTY-5339A is an investigational topical anesthetic spray containing 14% benzocaine/2% tetracaine in a metered canister. Each spray delivers ∼0.2 mL of solution. This double-blind, randomized, crossover study compared the local anesthetic effect of CTY-5339A versus 14% benzocaine alone by using 2 quantitative sensory threshold experimental pain paradigms on the maxillary gingiva: pin prick test pain intensity (PPT PI) and heat pain threshold (HPT). METHODS: American Society of Anesthesiology Class 1 and 2 subjects (N = 50) were enrolled in this study. To qualify for the study, subjects were tested on the anterior maxillary gingiva with both PPT and HPT. Subjects had to report a PPT PI of ≥3 on a 0 to 10 numeric pain intensity scale on 1 of 2 consecutive pin pricks separated by 10 s, with at least one score ≥4. After PPT, mean HPT following 2 ramps in the same location had to be ≤ 46.5 °C, with each ramp beginning at 35 °C and an automatic cutoff of 50.6 °C. For treatment visits, subjects were randomly administered either 1 spray of CTY-5339A or 14% benzocaine to the anterior maxillary gingiva within 3 weeks of screening and then the alternative treatment 5 days to 2 weeks later. PPT PI and HPT were recorded immediately before drug application. After drug administration, PPT PI was recorded every minute through 5 min. Commencing at 5 min, PPT PI and HPT were recorded every 5 min through 60 min. For assessment of methemoglobin concentrations, venous blood (5 mL) was drawn from the antecubital fossa both before and 60 min after drug application. Oxygen saturation was recorded via pulse oximetry at baseline and every 10 min. FINDINGS: The AUCs for pain intensity difference from 0-30 and 0-60 min after PPT and HPT differences were significantly greater (P < 0.0001) for CTY-5339A compared with 14% benzocaine. Multiple time points on the time-action curves for PPT PI difference and HPT difference statistically (P < 0.05) favored CTY-5399A. Methemoglobin and oxygen saturation levels did not change compared with baseline after dosing with either treatment. IMPLICATIONS: Recommended doses of CTY-5339A provided significantly more profound and sustained local anesthesia than 14% benzocaine when applied to the maxillary gingiva. Significant changes in methemoglobin or oxygen saturation concentrations did not occur for either drug. ClinicalTrials.gov identifier: NCT03233737.

Lack of Methemoglobin Elevations After Topical Applications of Benzocaine Alone or Benzocaine Plus Tetracaine to the Oral Mucosa.

PURPOSE: This study evaluated changes in methemoglobin and oxygen saturation concentrations after the administration of recommended doses of 14% benzocaine alone or 14% benzocaine combined with 2% tetracaine. METHODS: American Society of Anesthesiology class 1 and 2 subjects (n = 40) were enrolled in this modified crossover study. Subjects were administered 0.2 mL of 14% benzocaine alone, 0.2 mL of 14% benzocaine plus 2% tetracaine, or 0.4 mL of 14% benzocaine plus 0.2% benzocaine to their cheek mucosa. Venous blood (5 mL) was drawn from the antecubital fossa before and 60 minutes after drug application for methemoglobin analyses. Oxygen saturation was also recorded via pulse oximetry at baseline and every 10 minutes through 60 minutes after drug application. FINDINGS: Methemoglobin and oxygen saturation levels did not change from baseline after the administration of benzocaine alone or when combined with tetracaine. IMPLICATIONS: Recommended doses of benzocaine or benzocaine combined with tetracaine when applied to the cheek mucosa do not induce even clinically insignificant elevations in methemoglobin levels. Metered dosing, such as that used in this study, can help avoid this overdose phenomena with these drugs. ClinicalTrials.gov identifier: NCT02908620.

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.

Continuous low-level heatwrap therapy relieves low back pain and reduces muscle stiffness.

BACKGROUND: Low back pain is a common and costly health care problem. This pilot study evaluated the sensitivity of the 2-stopwatch and Paris plinth methodologies for assessing time-to-onset of pain relief and flexibility, respectively, with continuous, low-level heatwrap therapy. RESEARCH DESIGN AND METHODS: Subjects aged 18 to 55 years with at least moderate baseline acute low back pain were randomly assigned to either heatwrap or oral placebo for 8 hours. Unheated wrap (sham) and oral ibuprofen were included for blinding purposes only. RESULTS: Sixty-one subjects were randomly assigned to either heatwrap (n = 26), oral placebo (n = 25), sham wrap (n = 5), or oral ibuprofen (n = 5). Median time to confirmed first perceptible pain relief and to meaningful pain relief were significantly shorter for the heatwrap group compared with those assigned to oral placebo (96.5 vs > 240.0 min and 215.7 vs > 240.0 min, respectively; P < 0.05 for both). Among subjects receiving the heatwrap, 53.8% reported first perceptible and meaningful relief, compared with 28.0% receiving oral placebo. Subjective measures of pain relief, back stiffness, and global evaluation were more sensitive in detecting treatment differences than the plinth assessments of flexibility, range of motion, and pain. Three adverse events were reported as mild in severity and considered unrelated to study treatment. CONCLUSIONS: The 2-stopwatch methodology is a viable approach for assessing onset of analgesia in low back pain; however, the plinth may not be a reliable method for assessing flexibility. Consistent with published studies involving much larger sample sizes, the heatwrap provided significantly faster and sustained pain relief than oral placebo in subjects with acute low back pain. Clinical Trial Identifier: NCT01045993.

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.

Addition of ibuprofen to pseudoephedrine and chlorpheniramine in the treatment of seasonal allergic rhinitis.

BACKGROUND: Patients with seasonal allergic rhinitis experience many nasal and concomitant nonnasal symptoms. Many patients also experience headaches and facial pain, pressure, or discomfort. Standard over-the-counter therapy with antihistamines and nasal decongestants often does not completely relieve all symptoms associated with allergic rhinitis. OBJECTIVE: To establish the contribution of ibuprofen when used with pseudoephedrine and chlorpheniramine, a standard over-the-counter regimen, to relieve the symptoms of seasonal allergic rhinitis. METHODS: In this 7-day, multicenter, randomized, placebo-controlled, double-blind, double-dummy, parallel-group trial, qualified subjects were randomly assigned to 1 of 4 treatment groups that received combined ibuprofen/pseudoephedrine/chlorpheniramine (200/30/2 mg or 400/60/4 mg), combined pseudoephedrine/chlorpheniramine (30/2 mg), or placebo. Therapy began when the subject experienced a minimum of moderate allergy-associated pain, and it continued 3 times a day for 7 consecutive days. RESULTS: Mean pain intensity reduction in both ibuprofen/pseudoephedrine/chlorpheniramine treatment groups was 40% greater than in the placebo group and 33% greater than in the pseudoephedrine/chlorpheniramine treatment group (P < .001). Mean changes from baseline in total and nonpain symptom scores for both ibuprofen/pseudoephedrine/chlorpheniramine doses were significantly greater than for placebo (P < .001) and pseudoephedrine/chlorpheniramine (P < .001-.05) but were not different from each other. Ibuprofen enhanced the chlorpheniramine and pseudoephedrine effects, resulting in incremental 33% to 34% pain relief and 17% to 22% allergy symptom relief compared with pseudoephedrine/chlorpheniramine. CONCLUSIONS: In both doses of the triple combination, ibuprofen added to the effects of chlorpheniramine and pseudoephedrine, resulting in superior relief of pain and all nonpain allergy symptoms compared with pseudoephedrine/chlorpheniramine treatment. Furthermore, the superior efficacy of the lower dose of the triple combination allowed for a decrease in the incidence of adverse effects.

Efficacy and tolerability of nonprescription ibuprofen versus celecoxib for dental pain.

Many clinicians appear confused about the purported clinical advantages of the new generation COX-2 inhibitors compared to both over-the-counter and prescription nonsteroidal anti-inflammatory analgesic agents (NSAIDs). Infact, there is a paucity of published information comparing the safety and efficacy of these two classes of drugs when used to treat acute pain. This study was designed to compare the safety and analgesic efficacy of an over-the-counter (OTC) analgesic, ibuprofen (Advil Liqui-Gels), to the leading prescription COX-2 inhibitor celecoxib (Celebrex). Ibuprofen liquigel is an encapsulated, solubilized potassium salt of ibuprofen that has a higher Cmax and shorter tmax than traditional ibuprofen solid-dosage formulations. This trial evaluated the maximum approved OTC dosing regimen (400 mg x 3, q4-6h) of ibuprofen liquigels compared to a single dose of celecoxib (200 mg) and placebo in 174 patients with moderate orsevere pain following surgical extraction of impacted third molars. The study design was multiple dose, randomized (stratified by baseline pain and gender), placebo controlled, double blind, double dummy, and parallel group. The onset of pain relief was determined using a two-stopwatch procedure. Treatments were also compared using standard indices of pain intensity and pain relief. The study demonstrated assay sensitivity in that both active medications were significantly more effective than placebo for all efficacy measures. In comparing the two active medications, the time to meaningful relief was significantly shorter, and the mean 4-, 8-, and 12-hour summed pain relief combined with pain intensity difference scores were significantly higher for ibuprofen liquigels compared with celecoxib (p < 0.001). Analyses of other key efficacy variables, including the time to rescue medication and the patients' overall assessment of study medication, confirmed the superior efficacy of ibuprofen liquigels over celecoxib. Both active treatments were well tolerated, with no differences in incidence or severity of adverse events. Of particular interest, there were no differences in gastrointestinal-related side effects when comparing these doses of ibuprofen liquigels to celecoxib. In conclusion, ibuprofen liquigels were a significantly more effective analgesic and provided relief significantly faster compared with celecoxib in the treatment of postsurgical pain.