Pain Intensity Difference Scores Research Articles

Inhaled fentanyl aerosol through a drug-device combination for breakthrough cancer pain: A multicenter, randomized, double-blind, placebo-controlled trial.

e24058 Background: Breakthrough cancer pain (BTcP) can significantly impact the life quality of the cancer patient. Wide-used rapid-onset opioids (ROOs) for BTcP are transmucosal fentanyl-based preparations. Inhaled fentanyl demonstrated similar pharmacokinetic properties as intravenous administration in healthy volunteers. Fentanyl aerosol can be generated via hand-held drug-device delivery system, providing rapid, consistent multi-dose administration. Fentanyl inhalant was explored as alternative treatment of BTcP in cancer patients in this study to evaluate its efficacy, safety, and tolerability in BTcP patients with well-controlled background cancer pain. Methods: Adults ≥18 years with cancer are eligible if they were experiencing persistent cancer- or treatment-related pain with above mild severity and 1-4 episode occurrences daily. Each patient was treated and observed for 6 BTcP episodes (4 with fentanyl inhalant, 2 with placebo). During each episode, patients were allowed to inhale up to six shots within 1 hour. Pain intensity was recorded using 11-point Numerical Rating Scale (NRS) at predefined time points. The primary endpoint was the time-weighted Sum of Pain Intensity Difference scores at 30 minutes (SPID30) after the first inhalation. Results: 335 BTcP episodes in 59 patients were treated. SPID30 was analyzed using mixed model of repeated measures with treatment (fentanyl inhalant or placebo), BTcP episode, baseline pain intensity score as fixed factors, and subject as random factor. Mean SPID30 ± SD was -97.4 ± 48.43 for fentanyl-treated episodes, and -64.6 ± 40.25 for placebo-treated episodes. Based on treatment adjustment in the mixed covariance model, significant difference (p < 0.001) was reported with mean treatment difference of -27.7 (LS-mean ± SD, -94.2 ± 4.49 for fentanyl and -66.5 ± 4.86 for placebo). It enlarged at 60 minutes (SPID60) with a mean treatment difference of -57.9 (LS-mean ± SD, -231.4 ±105.14 for fentanyl and -162.2 ± 91.21 for placebo, p < 0.001). Significant differences in PID for episodes treated with fentanyl versus placebo were seen 4 minutes after the first dosing and maintained up to 60 minutes. Other endpoints showed statistical significance favoring fentanyl treatment, including the proportion of NRS ≤ 3, NRS pain scores decreased ≥ 33% or ≥ 50% from baseline after completion of BTcP treatment within 30 minutes of first dose, and Pain Relief Score Within 30 Minutes of the First Dose (PR30). Only 4.4% of BTcP episodes required rescue medication in fentanyl group. Major adverse events were mild or moderate in severity and were typical for opioid drugs. Conclusions: Fentanyl inhalant is safe, effective, and well-tolerated for managing BTcP. It provides a non-invasive route for systemic drug delivery and can be self-administered or given by family caregivers as personalized and regular pain management. Clinical trial information: NCT05531422 .

Clinical validation of a fast-acting acetaminophen: a randomized, active and placebo controlled dental pain study

Objectives To address the need for faster pain relief of over-the-counter (OTC) analgesic users, a novel drug delivery technology was developed to achieve faster absorption of orally administered acetaminophen with the goal of delivering earlier onset of pain relief. Previous development studies suggested that a 1000 mg dose of this fast-acting acetaminophen (FA-acetaminophen) formulation provided faster absorption and onset of action versus, commercially available OTC fast-acting analgesics, 1000 mg of extra-strength acetaminophen (ES-acetaminophen) or 400 mg of liquid-filled ibuprofen capsules (LG-ibuprofen). This study was designed as the definitive trial evaluating the onset of pain relief of FA-acetaminophen versus these same OTC comparators. Methods This single-dose, randomized, double-blind, placebo- and active-controlled clinical trial compared analgesic onset, overall efficacy, and safety of FA-acetaminophen 1000 mg, ES-acetaminophen 1000 mg, LG-ibuprofen 400 mg, and placebo over 4 h in a postsurgical dental pain model. Following removal of 3 to 4 impacted third molars, 664 subjects with moderate-to-severe pain were randomized in a 4:4:2:1 ratio to FA-acetaminophen (249), ES-acetaminophen (232), LG-ibuprofen (124), or placebo (59). Mean age was 18.9 years; 45.5% were male; 57.5% had severe baseline pain intensity. Subjects stopped a first stopwatch if/when they had perceptible pain relief and a second stopwatch if/when their pain relief became meaningful to them. Pain intensity difference (PID) and pain relief (PAR) were obtained using an 11-point numerical rating scale. Findings FA-acetaminophen 1000 mg had faster median time to onset of pain relief (15.7 min) compared to ES-acetaminophen 1000 mg (20.2 min, p = 0.035), LG-ibuprofen 400 mg (23.2 min, p < 0.001), and placebo (non-estimable), statistically greater mean PAR and PID scores than other treatment groups at 15 and 30 min, and a statistically greater percentage of subjects with confirmed perceptible pain relief at 15 and 20 min. At 25 min, FA-acetaminophen 1000 mg had a statistically significantly greater percentage of subjects with confirmed perceptible pain relief than LG-ibuprofen 400 mg and placebo. No clinically significant adverse events were reported. Conclusions This study supports previous studies, demonstrating faster onset of analgesia with FA-acetaminophen 1000 mg compared to OTC ES-acetaminophen 1000 mg and OTC LG-ibuprofen 400 mg. ClinicalTrials.gov Identifier NCT03224403 https://clinicaltrials.gov/ct2/show/NCT03224403

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

IntroductionIbuprofen 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.ObjectivesThe present study assessed the analgesic efficacy of fixed-dose combinations (FDCs) of ibuprofen/acetaminophen (IBU/APAP) compared with ibuprofen 400 mg and placebo.MethodsThis 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.ResultsIn 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.ConclusionEach 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 RegistrationNCT01559259Electronic supplementary materialThe online version of this article (10.1007/s40268-020-00310-7) contains supplementary material, which is available to authorized users.

A randomized controlled trial comparing tapentadol with oxycodone in non-breastfeeding women post elective cesarean section

Background: Tapentadol may allow greater pain relief with reduced “opioid load” compared to oxycodone. Its use has not been studied in the obstetric population. The objective of this study was to compare the efficacy and side effect profile of tapentadol with oxycodone in patients who received spinal anesthesia for elective cesarean section. The trial was registered with EU Clinical Trials Register with CT number 2016-001621-33.Methods: This was a multicenter, randomized controlled trial. Randomized patients (n = 68) received either 50 mg tapentadol or oxycodone 10 mg 12 hourly postoperatively. The primary endpoint was the sum of pain intensity difference over the first 48 hours of treatment (SPID48). Secondary outcomes included time to rescue medications, SPID36, total pain relief (TOTPAR) scores, patient satisfaction scores, sum of total pain relief and pain intensity difference (SPRID) scores, time to rescue medications and side effects experienced. An analysis of covariance model with baseline pain intensity score as a covariate was used for statistical analysis.Results: There was no significant difference in the primary endpoint of SPID48 with adjusted mean difference -11.45 (95% CI -35.35, 12.45) p = .34). Oxycodone showed significantly greater SPID36 scores compared to tapentadol with increased time to rescue medication. Side effects experienced were similar between groups.Conclusion: Tapentadol did not provide superior pain control or improved tolerability compared to oxycodone post cesarean section. Results should be interpreted however with consideration of administration of intrathecal opioids to all patients in this study and debate over the optimal dose of tapentadol for acute pain.Trial registration: EU Clinical Trials Register identifier: 2016-001621-33.

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

BackgroundIbuprofen 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.MethodsThis 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.ResultsA 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.ConclusionsThis novel ibuprofen sodium tablet provided rapid, efficacious relief of ETTH and was well tolerated.Trial registrationClinicalTrials.gov NCT01362491.

(401) Analgesic effectiveness of a new, extended-release ibuprofen in postoperative dental pain

Analgesic effects of an immediate-release/extended-release (IR/ER) 600 mg formulation of ibuprofen (IBU) with q12h dosing were evaluated in 2 single-center, randomized, double-blind, placebo-controlled dental pain studies (Study 1: single dose, 24-hour study; Study 2: multiple doses, 48-hour study). Subjects aged 16–40 years with at least moderate pain following third molar extraction received single doses of 2 IBU 600 mg IR/ER formulations (A or B), naproxen sodium (NAP) 220 mg, or placebo (2:2:2:1 ratio) in Study 1; 4 doses IBU 600 mg IR/ER or placebo (1:1 ratio) in Study 2. Primary efficacy: Study 1, time-weighted sum of pain intensity difference (SPID) scores from 0–12 and 8–12 hours; Study 2, time-weighted sum of pain relief and pain intensity differences (SPRID) from 0–12 and 8–12 hours. In Study 1 (N=196), mean (standard deviation [SD]) SPID 0–12 scores were 0.05 (9.2), 16.87 (9.4), 17.34 (10.5), and 12.66 (10.0) and mean (SD) SPID 8–12 scores were -0.03 (4.1), 6.57 (4.4), 7.14 (5.2), and 5.14 (5.0) for placebo, IBU IR/ER A, IBU IR/ER B, and NAP, respectively (P<0.001, all comparisons vs placebo). In Study 2 (N=106), mean (SD) SPRID 0–12 scores were 18.2 (20.0) vs 41.5 (21.0) and mean (SD) SPRID 8–12 scores were 10.3 (12.0) vs 18.4 (12.1) for placebo and IBU IR/ER, respectively (P<0.001, both favoring IBU IR/ER). SPID score separation from placebo at predefined intervals was maintained throughout the 48-hour study, except for the 20- to 24-hour interval. Significantly more AEs occurred with placebo in Study 1 (P=0.045) and Study 2 (P=0.001); gastrointestinal AEs predominated in subjects receiving placebo, likely due to opioid rescue medication use. No serious AEs occurred. IBU 600 mg IR/ER administered every 12 hours provided safe and effective analgesia following both single and multiple doses. Supported by Pfizer Consumer Healthcare. Analgesic effects of an immediate-release/extended-release (IR/ER) 600 mg formulation of ibuprofen (IBU) with q12h dosing were evaluated in 2 single-center, randomized, double-blind, placebo-controlled dental pain studies (Study 1: single dose, 24-hour study; Study 2: multiple doses, 48-hour study). Subjects aged 16–40 years with at least moderate pain following third molar extraction received single doses of 2 IBU 600 mg IR/ER formulations (A or B), naproxen sodium (NAP) 220 mg, or placebo (2:2:2:1 ratio) in Study 1; 4 doses IBU 600 mg IR/ER or placebo (1:1 ratio) in Study 2. Primary efficacy: Study 1, time-weighted sum of pain intensity difference (SPID) scores from 0–12 and 8–12 hours; Study 2, time-weighted sum of pain relief and pain intensity differences (SPRID) from 0–12 and 8–12 hours. In Study 1 (N=196), mean (standard deviation [SD]) SPID 0–12 scores were 0.05 (9.2), 16.87 (9.4), 17.34 (10.5), and 12.66 (10.0) and mean (SD) SPID 8–12 scores were -0.03 (4.1), 6.57 (4.4), 7.14 (5.2), and 5.14 (5.0) for placebo, IBU IR/ER A, IBU IR/ER B, and NAP, respectively (P<0.001, all comparisons vs placebo). In Study 2 (N=106), mean (SD) SPRID 0–12 scores were 18.2 (20.0) vs 41.5 (21.0) and mean (SD) SPRID 8–12 scores were 10.3 (12.0) vs 18.4 (12.1) for placebo and IBU IR/ER, respectively (P<0.001, both favoring IBU IR/ER). SPID score separation from placebo at predefined intervals was maintained throughout the 48-hour study, except for the 20- to 24-hour interval. Significantly more AEs occurred with placebo in Study 1 (P=0.045) and Study 2 (P=0.001); gastrointestinal AEs predominated in subjects receiving placebo, likely due to opioid rescue medication use. No serious AEs occurred. IBU 600 mg IR/ER administered every 12 hours provided safe and effective analgesia following both single and multiple doses. Supported by Pfizer Consumer Healthcare.

Etoricoxib in the treatment of primary dysmenorrhea in Chinese patients: a randomized controlled trial

Objective:Assess the efficacy and safety of etoricoxib 120 mg compared with ibuprofen 600 mg qid in the treatment of moderate to severe primary dysmenorrhea in Chinese women.Methods:This multicenter, double-blind, two-period, cross-over study randomized healthy, Chinese women ≥18 years of age to etoricoxib 120 mg qd or ibuprofen up to 2400 mg (600 mg qid) upon onset of moderate or severe primary dysmenorrhea symptoms during two menstrual cycles. The primary efficacy endpoint was Total Pain Relief score over the first 6 hours (TOPAR6). Secondary endpoints included Sum of Pain Intensity Difference scores over the first 6 hours (SPID6) and Patient’s Global Evaluation (GLOBAL) of pain at 6 and 24 hours post initial dose. The primary hypothesis was that etoricoxib would be non-inferior to ibuprofen. Adverse experiences (AE) were monitored and evaluated.Results:A total of 139 patients were included in this study. Difference in least squares (LS) mean (95% CI) TOPAR6 score for etoricoxib vs. ibuprofen was 0.89 (0.03, 1.76) (p = 0.043). LS mean (95% CI) difference for etoricoxib vs. ibuprofen SPID6, GLOBAL6, and GLOBAL24 were 0.20 (−1.16, 1.57) (p = 0.768), 0.26 (0.07, 0.45) (p = 0.007), and 0.36 (0.17, 0.54) (p < 0.001), respectively. AEs were rare, with the following AEs determined to be drug-related: hypomenorrhea (two patients on etoricoxib) and allergic dermatitis (one patient on ibuprofen). Limitations of the study design include a sample size that is not adequate for evaluation of rare adverse effects, an evaluation period that was limited to 24 hours, and inconsistent frequency of active treatment doses between etoricoxib (once daily) and ibuprofen (up to four times daily).Conclusions:The primary objective of the study was met, demonstrating that etoricoxib 120 mg qd was non-inferior to ibuprofen 600 mg qid; further, etoricoxib was statistically superior to ibuprofen 600 mg qid according to the primary endpoint (TOPAR6) and patient global assessments of study medication. Etoricoxib and ibuprofen were generally well tolerated.

A Phase 3, Randomized, Double-Blind Comparison of Analgesic Efficacy and Tolerability of Q8003 vs Oxycodone or Morphine for Moderate-to-Severe Postoperative Pain Following Bunionectomy Surgery

ObjectiveCompare the efficacy and tolerability of the dual-opioid, Q8003® (morphine/oxycodone combination) 12 mg/8 mg to morphine 12 mg or oxycodone 8 mg in subjects following bunionectomy surgery.DesignThis was a randomized, double-blind study.SettingHospitalized patients.PatientsHealthy men or women aged ≥18 years with moderate or severe pain (score ≥2 on a 4-point Likert scale) and ≥4 on the 11-point numerical pain rating scale following surgery.InterventionsStudy medication was initiated after surgery and was given for 48 hours.OutcomesThe primary efficacy variable was mean sum of the pain intensity difference (SPID) scores from the postsurgical baseline.ResultsFive hundred twenty-two subjects were randomized; 31 (5.9%) discontinued, including 19 (3.6%) for adverse events. The mean total morphine equivalent dose (MED) was 182.7 mg from Q8003 12 mg/8 mg, 92.4 mg for morphine 12 mg, and 92.1 mg for oxycodone 8 mg. SPID from baseline over 24 hours and SPID from baseline over 48 hours were significantly (P < 0.02) higher for Q8003 12 mg/8 mg vs morphine 12 mg or oxycodone 8 mg. Significantly (P < 0.015) fewer subjects in the Q8003 group required ibuprofen rescue medication, used lower doses of rescue medication, and had a longer median time to first use of rescue medication. Oxygen desaturation <90% occurred in 5.3% with Q8003, 2.8% with morphine 12 mg, and 2.3% with oxycodone 8 mg, and the cumulative median dose at first desaturation was twofold greater with Q8003.ConclusionQ8003 provided superior efficacy to its individual components at twice the MED with only a modest increase in the incidence of adverse events.

Effective analgesia with low-dose ketamine and reduced dose hydromorphone in ED patients with severe pain

ObjectiveWe assessed the analgesic effect and feasibility of low-dose ketamine combined with a reduced dose of hydromorphone for emergency department (ED) patients with severe pain. MethodsThis was a prospective observational study of adult patients with severe pain at an urban public hospital. We administered 0.5 mg of intravenous (IV) hydromorphone and 15 mg of IV ketamine, followed by optional 1 mg hydromorphone IV at 15 and 30 minutes. Pain intensity was assessed at 12 intervals over 120 minutes using a 10-point verbal numerical rating scale (NRS). Patients were monitored throughout for adverse events. Dissociative side effects were assessed using the side effects rating scale for dissociative anesthetics. ResultsOf 30 prospectively enrolled patients with severe pain (initial mean NRS, 9), 14 reported complete pain relief (NRS, 0) at 5 minutes; the mean reduction in NRS pain score was 6.0 (SD, 3.2). At 15 minutes, the mean reduction in NRS pain score was 5.0 (SD, 2.8). The summed pain intensity difference and percent summed pain intensity difference scores were 25 (95% confidence interval [CI], 21-30) and 58% (95% CI, 49-68) at 30 minutes and 41 (95% CI, 34-48) and 50% (95% CI, 42-58) at 60 minutes, respectively. Most patients (80%) reported only weak or modest side effects. Ninety percent of patients reported that they would have the medications again. No significant adverse events occurred. ConclusionsLow-dose ketamine combined with a reduced dose hydromorphone protocol produced rapid, profound pain relief without significant side effects in a diverse cohort of ED patients with acute pain.

Repeat-dose steady-state pharmacokinetic evaluation of once-daily hydromorphone extended-release (OROS&amp;reg; hydromorphone ER) in patients with chronic pain

ObjectiveTo characterize the steady-state pharmacokinetic profile of hydromorphone extended-release (ER) in patients with chronic pain taking concomitant medications.MethodsThis open-label repeat-dose study enrolled 22 patients (mean age, 51.4 years; 81.8% female). All patients were receiving at least one concomitant medication; 86.4% were receiving at least two concomitant medications and 81.8% were receiving at least three. Patients receiving a stable dose of an opioid were converted to hydromorphone ER at a 5:1 ratio (morphine equivalent:hydromorphone). The dose was titrated to adequate analgesia over 3–14 days and stabilized between 8–48 mg. Oral morphine immediate-release was permitted for breakthrough pain. Area under the concentration–time curve from 0–24 hours (AUC0–24), maximum plasma concentration (Cmax), trough plasma concentration (Cmin), average plasma concentration (Cavg), and degree of fluctuation (100 × [(Cmax − Cmin) ÷ Cavg]) were calculated based on data from 14 patients.ResultsDose-normalized to 16 mg, mean pharmacokinetic parameter values were: AUC0–24, 41.1 ng · h/mL; Cmax, 2.6 ng/mL; Cmin, 1.1 ng/mL; Cavg, 1.7 ng/mL; and the degree of fluctuation was 99.6%. The pharmacokinetic profile of hydromorphone ER was linear and consistent with dose proportionality. Mean pain intensity difference scores showed statistically significant improvement from 2–21 hours after dosing. Sixteen (72.7%) patients reported at least one adverse event (AE). The most common were constipation (31.8%), headache (22.7%), and vomiting (13.6%). One patient discontinued treatment due to vomiting. No deaths, serious AEs, or unexpected AEs occurred.ConclusionThese findings replicate and extend the steady-state pharmacokinetic profile of hydromorphone ER, previously characterized in healthy volunteers, to a population of chronic pain patients taking numerous concomitant medications.

Various formulations of oral transmucosal fentanyl for breakthrough cancer pain: an indirect mixed treatment comparison meta-analysis

ObjectiveTo compare the efficacy of fentanyl effervescent buccal tablet (FBT), sublingual oral transmucosal fentanyl citrate (ODT) and compressed lozenge oral transmucosal fentanyl citrate (OTFC) for the treatment of breakthrough cancer...

Intranasal Ketorolac

Ketorolac is a member of the pyrrolo-pyrrole group of NSAIDs, and has been available in several formulations for some time, for the treatment of pain. Intranasal ketorolac has recently become available. Intranasal ketorolac was effective in providing short-term relief from postoperative pain in four well designed, phase II or III trials. In the two phase III trials, a single intranasal dose of ketorolac 31.5 mg, with or without backup analgesia, was associated with significantly higher 6-hour summed post-treatment pain intensity difference scores (primary endpoint) than placebo in adult patients with acute pain following major surgery, including abdominal and orthopaedic surgery. Intranasal ketorolac 31.5 mg up to three or four times daily for ≤5 days also had an opioid-sparing effect in these trials, with significantly less morphine used among ketorolac than among placebo recipients over the first 48 hours of treatment. Moreover, a greater proportion of ketorolac recipients experienced analgesia onset within 1 and 1.5 hours but not 2 hours than placebo recipients, indicating a more rapid onset with intranasal ketorolac. In adult patients with acute pain following major surgery, intranasal ketorolac 31.5 mg three or four times daily for ≤5 days was generally well tolerated. Most adverse events in clinical trials were considered to be of mild severity and transient in nature, with those in the phase III trials generally being characteristic of common events following major abdominal surgery and morphine administration.

Consistency of Efficacy, Patient Acceptability, and Nasal Tolerability of Fentanyl Pectin Nasal Spray Compared with Immediate-Release Morphine Sulfate in Breakthrough Cancer Pain

Context We recently reported that fentanyl pectin nasal spray (FPNS) provides superior pain relief from breakthrough cancer pain (BTCP) compared with immediate-release morphine sulfate (IRMS), with significant effects by five minutes and clinically meaningful pain relief from 10 minutes postdose. Objectives To report the consistency of efficacy, tolerability, and patient acceptability of FPNS vs. IRMS. Methods Patients ( n = 110) experiencing one to four BTCP episodes/day while taking ≥60 mg/day oral morphine (or equivalent) for background pain entered a double-blind, double-dummy (DB/DD), multiple-crossover study. Those who completed an open-label titration phase ( n = 84) continued to a DB/DD phase; 10 episodes were randomly treated with FPNS and overencapsulated placebo or IRMS and nasal spray placebo (five episodes each). Pain intensity (PI) and pain relief scores were assessed. Patient acceptability scores were assessed at 30 and 60 minutes. Safety and tolerability were assessed by adverse events (AEs) and nasal assessments. Results Per-episode analysis revealed that FPNS consistently provided relief from pain more rapidly than IRMS; by 10 minutes, there were significant differences in PI difference scores and in the percentages of episodes showing clinically meaningful pain relief ( P < 0.05). Overall acceptability scores were significantly greater for FPNS than for IRMS at 30 ( P < 0.01) and 60 ( P < 0.05) minutes. Patients were “satisfied/very satisfied” with the convenience (79.8%) and ease of use (77.2%) of FPNS. Only 4.7% of patients withdrew from titration because of AEs; no significant nasal effects were reported. Conclusion This study demonstrates that FPNS is efficacious, well accepted, and well tolerated by patients with BTCP.

Efficacy and safety of oxycodone HCl/niacin tablets for the treatment of moderate-to-severe postoperative pain following bunionectomy surgery

Objective:To evaluate the efficacy and safety of two dose strengths of oxycodone hydrochloride (HCl)/niacin tablets for the treatment of moderate-to-severe postoperative pain following bunionectomy surgery.Research design and methods:Randomized, double-blind, placebo-controlled, US multicenter, repeat-dose study (Clinicaltrials.gov: NCT00654069). A total of 606 patients aged ≥18 years with moderate-to-severe pain post-bunionectomy were screened, and 405 patients were randomized to receive placebo, 2 × 5/30 mg oxycodone HCl/niacin tablets, or 2 × 7.5/30 mg oxycodone HCl/niacin tablets administered every 6 hours for 48 hours. Ketorolac tromethamine was available as rescue medication.Main outcome measures:Primary efficacy endpoint was the sum of pain-intensity difference scores during the 48 hours (SPID48) following the initial dose of study drug. Secondary efficacy endpoints included a responder analysis and use of rescue medication. Safety evaluations included adverse events (AEs), vital signs, and clinical laboratory assessments.Results:Both doses of oxycodone HCl/niacin tablets demonstrated superior reductions in pain intensity compared with placebo as evidenced by the SPID48 (p < 0.0001 for both oxycodone HCl/niacin 2 × 5/30 mg and 2 × 7.5/30 mg). AEs were consistent with the known effects of oxycodone HCl and niacin. Most AEs were mild or moderate in intensity, and no serious AEs occurred. There were no discontinuations due to AEs in the placebo group; 2/135 (1.5%) discontinued due to AEs in the 2 × 5/30 mg group and 4/134 (3.0%) in the 2 × 7.5/30 mg group. A limitation of this study was that there was no active comparator arm.Conclusions:Oxycodone HCl/niacin tablets (5/30 mg and 7.5/30 mg) provide effective analgesia and are generally well tolerated in patients with moderate-to-severe pain following bunionectomy surgery.

A double-blind, randomised, crossover study of two doses of a single-tablet combination of ibuprofen/paracetamol and placebo for primary dysmenorrhoea

Objectives:Efficacy of pain relief may potentially be enhanced by combining two or more analgesics with different mechanisms of action. The objective of this study was to assess the efficacy and tolerability of a novel single-tablet combination of ibuprofen and paracetamol compared with placebo in females experiencing moderate-to-severe pain due to primary dysmenorrhoea, a prevalent, recurrent condition characterised by pain at the time of menses.Methods:This was a phase II/III, double-blind, randomised, cross-over, single-dose study in 94 women with moderate-to-severe dysmenorrhoea, examining the efficacy and tolerability of one or two tablets of a single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg compared with placebo.Clinical trial registration:ISRCTN42521357Results:Total pain relief over 6 hours post-dose (TOTPAR0–6h) was significantly greater following administration of two tablets of the single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg compared with placebo (LS means: 2.35, 1.85, respectively; p = 0.0001) and approached significance for one tablet (LS mean: 2.10; p = 0.054). Statistically superior pain relief and reductions in pain intensity were achieved from 2 hours and 90 minutes post-dose, respectively, with the higher dose combination, and from 4 hours with the lower dose combination compared with placebo. Overall effectiveness (sum of pain intensity difference and pain relief score [SPRID] over 6 hours) were statistically superior to placebo for both one and two tablets of the ibuprofen/paracetamol combination (p = 0.0011 and p = 0.03, respectively). Both dose combinations were well-tolerated. Adverse events were minor and their frequency and nature did not differ with either treatment compared with placebo.Conclusions:One or two tablets of a single-tablet combination of ibuprofen 200 mg/paracetamol 500 mg is well-tolerated and provides superior analgesic efficacy to placebo in patients with primary dysmenorrhoea.

Intranasal ketorolac for acute postoperative pain

Background:Efficacy and tolerability of intranasal ketorolac (SPRIX®) was assessed in abdominal surgery patients.Methods:Adult patients were randomly assigned to receive ketorolac 31.5 mg (n = 214) or placebo (n = 107) every 6 hr after surgery for 48 hr, then up to 4 times/day for up to 5 days. Morphine sulfate via patient controlled analgesia was available in both groups as needed.Results:Least square mean 6 hr summed pain intensity difference scores were significantly greater in the ketorolac group indicating better analgesic efficacy compared to placebo (117.4 vs. 89.9, p = 0.032; difference 27.6, 95% CI 2.5–52.7). Pain intensity difference indicated significantly better pain relief in the ketorolac group at 20 min after the first dose (p = 0.01). Morphine use over 48 hr decreased 26% in the ketorolac group compared to placebo (p = 0.004). Day 1 global pain control scores were significantly higher in the ketorolac group compared to placebo (p = 0.009). Quality of analgesia was rated significantly higher (p = 0.009) in the ketorolac group by 20 min after first dose. Adverse event and serious adverse event incidences were similar in both groups. Rhinalgia and nasal irritation, generally mild and transient in nature, occurred more frequently in the ketorolac group.Conclusion:Intranasal ketorolac was well tolerated and provided effective pain relief within 20 minutes with reduced opioid analgesia use. While IN ketorolac was assessed in an inpatient, conventional surgery setting in this study, IN ketorolac use may have more relevance for use in outpatient settings and ambulatory surgery or fast-track surgical procedures.

A single-tablet fixed-dose combination of racemic ibuprofen/paracetamol in the management of moderate to severe postoperative dental pain in adult and adolescent patients: A multicenter, two-stage, randomized, double-blind, parallel-group, placebo-controlled, factorial study

A single-tablet fixed-dose combination of racemic ibuprofen/paracetamol in the management of moderate to severe postoperative dental pain in adult and adolescent patients: A multicenter, two-stage, randomized, double-blind, parallel-group, placebo-controlled, factorial study

A Comparison of Change in the 0–10 Numeric Rating Scale to a Pain Relief Scale and Global Medication Performance Scale in a Short-term Clinical Trial of Breakthrough Pain Intensity

Pain intensity is commonly reported using a 0-10 Numeric Rating Scale in pain clinical trials. Analysis of the change on the Pain Intensity Numerical Rating Scale as a proportion has most consistently correlated with clinically important differences reported on the patient's global impression of change. The correlation of data from patients with breakthrough pain with a Pain Relief Scale and a different global outcome measures will extend our understanding of these measures. Data were obtained from the open titration phase of a multiple crossover, randomized, double-blind clinical trial comparing oral transmucosal fentanyl citrate with immediate-release oral morphine sulfate for the treatment of cancer-related breakthrough pain. Raw and percentage changes in the pain intensity scores from 1,307 episodes of pain in 134 oral transmucosal fentanyl citrate-naïve patients were correlated with the clinically relevant secondary outcomes of Pain Relief Verbal Response Scale and the global medication performance scale. The changes in raw and percentage change were assessed over time and compared with the ordinal Pain Relief Verbal Response Scale and Global Medication Performance Scale. The P value of the interaction between the raw pain intensity difference was significant (P = 0.034) for four 15-min time periods but not for the percentage pain intensity difference score (P = 0.26). We found similar results in comparison with the ordinal Pain Relief Verbal Response Scale (P = 0.0048 and P = 0.36 respectively) and global medication performance categories (P = 0.048 and P = 0.45, respectively). The change in pain intensity in breakthrough pain was more consistent over time and when compared with both the Pain Relief Verbal Response Scale and the Global Medication Performance Scale when the percentage change is used rather than raw pain intensity difference.

Intranasal Ketorolac for Pain Secondary to Third Molar Impaction Surgery: A Randomized, Double-Blind, Placebo-Controlled Trial

This randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of intranasal (IN) ketorolac in patients who had third molar extraction surgery with bony impactions. After surgery, patients were randomly assigned to receive IN ketorolac 31.5 mg (n = 40) or IN placebo (n = 40). Safety was assessed from spontaneously reported adverse events and measurement of vital signs. Efficacy assessments included pain intensity, which was measured on a 0- to 100-mm visual analog scale, total pain relief, and global pain evaluation up to 8 hours after dosing or until patients required rescue analgesia. The primary efficacy variable was the summed pain intensity difference score over the first 8 hours after dosing. Summed pain intensity difference values +/- SE were significantly higher (indicating better analgesia) in the ketorolac group compared with placebo (136.7 +/- 33.0 vs -105.2 +/- 29.1, P < .001). Total pain relief scores were significantly higher (P < .001) in the ketorolac group compared with placebo at all times. A larger proportion of subjects in the ketorolac group reported good, very good, or excellent pain control compared with the control group (60% vs 13%). Times to perceptible (21.5 minutes) and meaningful (66.0 minutes) pain relief were significantly shorter and the time to rescue analgesic use was significantly longer in the ketorolac group (P < .001). Eight patients in the placebo group and 3 in the ketorolac group had adverse events, none of which was serious. The 3 events in the ketorolac group were reports of mild headache. A single IN ketorolac 31.5 mg dose was well tolerated and provided rapid and effective pain relief in oral surgery patients for a period up to 8 hours.

Efficacy and safety profile of a topical methyl salicylate and menthol patch in adult patients with mild to moderate muscle strain: A randomized, double-blind, parallel-group, placebo-controlled, multicenter study

Background: An occlusive patch formulation containing 10% methyl salicylate and 3% l-menthol was recently approved by the US Food and Drug Administration for the treatment of mild to moderate pain. Despite widespread use of counterirritants, including methyl salicylate and menthol, for topical pain relief, published efficacy and safety data regarding the use of the agents alone or in combination are limited. Objective: The goal of this study was to determine the efficacy and safety profile of a patch containing 10% methyl salicylate and 3% l-menthol compared with a placebo patch in adult patients with mild to moderate muscle strain. Methods: Eligible patients were men or women aged ≥18 years with a clinical diagnosis of mild to moderate muscle strain. Patients were randomly assigned to receive either 1 active patch or 1 placebo patch applied to the skin at the affected area (ie, shoulder, upper back, upper arm, neck, calf, thigh, forearm, abdomen). Pain intensity was assessed on a 100-mm visual analog scale while at rest and with movement for 12 hours after patch application. The primary efficacy end point was the summed pain intensity difference score through 8 hours (SPID8) with movement. Analyses included use of descriptive statistics and an ANOVA model. Safety data, including adverse events, and secondary efficacy end points were also evaluated. Results: A total of 208 patients (104 men, 104 women; age range, 18–78 years) were randomized to 1 of 2 study groups (105 in the active-patch group [mean age, 37.3 years], 103 in the placebo-patch group [mean age, 38.1 years]). The primary efficacy analysis (SPID8 with movement) indicated that patients receiving the active patch experienced significantly greater pain relief (~40%) than those patients receiving a placebo patch (mean [SD], 182.6 [131.2] vs 130.1 [144.1]; P = 0.005). Analysis of the per-protocol population also found significantly more relief ( P = 0.024) in the active-patch group (176.2 [131.4]; n = 92) versus the placebo-patch group (130.2 [144.0]; n = 96). Statistical analysis of secondary efficacy measures supported the primary end-point results. The number of patients experiencing any type of adverse event was comparable between study groups (active patch, 6.7% [7 events]; placebo patch, 5.8% [6 events]). No serious adverse events were reported during the study. Conclusion: A single, 8-hour application of a patch containing methyl salicylate and l-menthol provided significant relief of pain associated with mild to moderate muscle strain in these adult patients compared with patients receiving a placebo patch.