Sum Of Pain Intensity Differences Research Articles

Efficacy, safety, and tolerability of sublingual fentanyl orally disintegrating tablet in the treatment of breakthrough cancer pain: a randomized, double-blind, placebo-controlled study

Breakthrough pain (BTP) is an important challenge in treatment and requires a rapid onset of action for pain control. BTP should be adequately controlled with a stable dose of a short-acting oral opioid. So far, no drug is available for the treatment of BTP in cancer patients in Iran, so we designed the first study in Iran to investigate the effect of sublingual fentanyl in relief of pain episodes in these patients.The purpose of this study was to evaluate the efficacy and safety of sublingual fentanyl in the treatment of breakthrough pain in cancer patients.This study was a randomized double-blind placebo-controlled clinical trial in cancer patients with breakthrough pain (at least 1-4 episodes of acute pain with moderate to severe pain daily) referred to the pain clinic of Akhtar and Masih Daneshvari hospitals in 2019. The study consisted of two stages: 100 patients were selected by simple, non-random sampling and entered the open-label titration phase. The primary efficacy endpoint was the sum of pain intensity difference over 30 min post-administration. Secondary efficacy endpoints included pain intensity difference (PID) and pain relief (PR) throughout the 60-min post-dose assessment period. In the double-blind study, patients were randomly divided into two groups of placebo (n=50) and intervention (sublingual fentanyl tablet) (n=50). For evaluation of efficacy, 10 episodes were treated in each group and the results were recorded by the patient. (Clinical trial registration: IRCT20131124015515N8).A total of 100 patients entered the titration phase, primary efficacy of sublingual fentanyl was 3.5±0.6 and secondary efficacy of sublingual fentanyl (60 min, after treatment) was 0.3±0.6 which was statistically significant. In the titration phase, the treatment success rate was 100%. In the double-blind phase of the study, the pain intensity in multiple episodes showed a significant improvement at 15, 30, 45, and 60 min after drug administration (P=0.0001). The intensity of pain in each episode was significantly decreased compared to the next episode (P=0.0001). The mean frequency of pain episodes in the sublingual fentanyl group showed a significant decrease (P=0.0001). The most common adverse drug events in the titration phase were drowsiness (20%), dizziness (7%), and nausea 4%, and in the double-blind phase only drowsiness (12%). (Cancer Research Center, Shahid Beheshti University of Medical Sciences, Survey).Sublingual fentanyl appears to be effective for patients with rapid-onset analgesia, has short-acting duration, is effective medication, safe, and well tolerated. It is a suitable choice in Iranian patients with chronic cancer-related pain controlled suffering from acute pain episodes related to cancer.

Evaluation of topical morphine for treatment of oral mucositis in cancer patients.

Oral mucositis is a painful side effect to chemotherapy. Orally applied opioids may offer analgesia with fewer side effects than systemic opioids. A randomized trial comparing the analgesic effect of a morphine oromucosal solution (OM) to placebo and a positive control group receiving intravenous (IV) morphine as an add-on treatment to morphine patient-controlled analgesia (PCA) in a mixed population of paediatric and adult haematology patients. All patients in the study were equipped with a morphine PCA pump and the participating patients were instructed to use this pump as an escape. Primary outcome was morphine consumption (mg/kg/hour) on the PCA pump. Secondary outcomes included pain intensity difference at rest and when performing oral hygiene, time to first PCA bolus, nutrition intake and adverse events. A total of 60 patients (38 children <18 years) were randomized. Thirty patients were allocated to morphine OM/placebo IV (group MO), 15 patients to placebo OM/morphine IV (group MI) and 15 patients to placebo OM/placebo IV (group P). The median morphine consumption in the MO group (22.7 mcg/kg/hour 95% confidence interval (CI) 19.4-29.4 mcg/kg/hour, p = 0.38) was not significantly different from the placebo group (24.6 mcg/kg/hour 95% CI 16.8-34.4 mcg/kg/hour, p = 0.44) or the MI group (13.7 mcg/kg/hour 95% CI 9.7-37.8 mcg/kg/hour). For the secondary outcomes, the analysis of summed pain intensity difference after the first, third and fourth administrations of study medication indicated a reduction in pain for the MI group compared to the P and MO groups. No serious adverse events were reported. The findings indicate that the analgesic effect of peripherally applied morphine is not significantly different from placebo, and parenteral opioids should continue to be the standard of care.

Oliceridine is Associated with Reduced Risk of Vomiting and Need for Rescue Antiemetics Compared to Morphine: Exploratory Analysis from Two Phase 3 Randomized Placebo and Active Controlled Trials.

IntroductionUse of parenteral opioids is a major risk factor for postoperative nausea and vomiting. Conventional opioids bind to µ-opioid receptors (MOR), stimulate both the G-protein signaling (achieving analgesia); and the β-arrestin pathway (associated with opioid-related adverse effects). Oliceridine, a next-generation IV opioid, is a G-protein selective MOR agonist, with limited recruitment of β-arrestin. In two randomized, placebo- and morphine-controlled phase 3 studies of patients with moderate-to-severe acute pain following bunionectomy or abdominoplasty, oliceridine at demand doses of 0.1, 0.35, and 0.5 mg provided rapid and sustained analgesia vs. placebo with favorable gastrointestinal (GI) tolerability. In this exploratory analysis, we utilized a clinical endpoint assessing gastrointestinal tolerability, “complete GI response” defined as the proportion of patients with no vomiting and no use of rescue antiemetic to characterize the GI tolerability profile of oliceridine vs. morphine.MethodsA logistic regression model was utilized to compare oliceridine (pooled regimens) vs. morphine, after controlling for analgesia (using the sum of pain intensity difference [SPID]-48/24 [bunionectomy/abdominoplasty] with pre-rescue scores carried forward for 6 h). This analysis excluded patients receiving placebo and was performed for each study separately and for pooled data from both studies.ResultsIn the unadjusted analysis, a significantly greater proportion of patients in the placebo (76.4%), oliceridine 0.1 mg (68.0%), and 0.35 mg (46.2%) demand dose achieved complete GI response vs. morphine 1 mg (30.8%), p ≤ 0.005. In the adjusted analysis, after controlling for analgesia, the odds ratio of experiencing a complete GI response with oliceridine (pooled regimens) vs. morphine was 3.14 (95% CI: 1.78, 5.56; p < 0.0001) in bunionectomy study and 1.92 (95% CI: 1.09, 3.36; p = 0.024) in abdominoplasty study.ConclusionsWhen controlled for the analgesic effects (constant SPID-48/24), the odds ratio for complete GI response was higher with oliceridine than morphine, suggesting better GI tolerability with oliceridine. Oliceridine is Associated with Reduced Risk of Vomiting and Need for Rescue Antiemetics Compared to Morphine: Exploratory Analysis from Two Phase 3 Randomized Placebo and Active Controlled Trials - Talking-head video (1,06,013 kb) Electronic Supplementary MaterialThe online version of this article (10.1007/s40122-020-00216-x) contains supplementary material, which is available to authorized users.

CYP450 polymorphisms and clinical pharmacogenetics of ibuprofen after lower third molar extraction.

This study hypothesized that drugs accumulate in the bloodstream of poor-metabolizing patients and may have more adverse effects and different pain perceptions and aimed to investigate the influence of CYP450 polymorphisms on acute postoperative pain, swelling, and trismus controlled by ibuprofen (600mg) in 200 volunteers after dental extraction. In addition, surgical outcomes can determine pain, edema, and trismus and indicate inflammatory reactions after oral surgeries. Genetic sequencing was performed to identify CYP450 polymorphisms and the surgical parameters evaluated: pre and postoperative swelling, trismus, and temperature; self-reported postoperative pain with visual analog scale (VAS); rescue medication consumed; and severity of adverse reactions. A multiple linear regression model with independent variables [single nucleotide polymorphisms (SNPs), BMI (body mass index), duration, and difficulty of surgery] and dependent variables [postoperative pain by sum of pain intensity difference (SPID), trismus, and swelling] was used for analysis. The duration of surgery was a predictor for pain at 8h and 96h after surgery, and BMI was a predictor for both swelling and trismus on the 2nd postoperative day. When evaluating CYP2C8 and C9 genotyped SNPs, it was observed that normal metabolizers showed higher pain levels than the intermediate/poor metabolizers on the postoperative periods as compared with time 0h. In another analysis, the poor metabolizers for CYP2C8 and C9 presented lower levels of postoperative pain after 8h and used rescue medication earlier than normal metabolizers. Ibuprofen 600mg was very effective in controlling inflammatory pain after lower third molar surgeries, without relevant adverse reactions; although in a very subtle way, patients with poor metabolism had higher levels of pain in the first hours, and no longer after 8h, and used pain relief medication earlier. The study was registered with ClinicalTrials.gov ID (NCT03169127), on March 16th, 2017.

Efficacy of non-opioid analgesics to control postoperative pain: a network meta-analysis

BackgroundThe aim of this network meta-analysis (NMA) was to evaluate the safety and efficacy of intravenous (IV) Meloxicam 30 mg (MIV), an investigational non-steroidal anti-inflammatory drug (NSAID), and certain other IV non-opioid analgesics for moderate-severe acute postoperative pain.MethodsWe searched PubMed and CENTRAL for Randomized Controlled Trials (RCT) (years 2000–2019, adult human subjects) of IV non-opioid analgesics (IV NSAIDs or IV Acetaminophen) used to treat acute pain after abdominal, hysterectomy, bunionectomy or orthopedic procedures. A Bayesian NMA was conducted in R to rank treatments based on the standardized mean differences in sum of pain intensity difference from baseline up to 24 h postoperatively (sum of pain intensity difference: SPID 24). The probability and the cumulative probability of rank for each treatment were calculated, and the surface under the cumulative ranking curve (SUCRA) was applied to distinguish treatments on the basis of their outcomes such that higher SUCRA values indicate better outcomes. The study protocol was prospectively registered with by PROSPERO (CRD42019117360).ResultsOut of 2313 screened studies, 27 studies with 36 comparative observations were included, producing a treatment network that included the four non-opioid IV pain medications of interest (MIV, ketorolac, acetaminophen, and ibuprofen). MIV was associated with the largest SPID 24 for all procedure categories and comparators. The SUCRA ranking table indicated that MIV had the highest probability for the most effective treatment for abdominal (89.5%), bunionectomy (100%), and hysterectomy (99.8%). MIV was associated with significantly less MME utilization versus all comparators for abdominal procedures, hysterectomy, and versus acetaminophen in orthopedic procedures. Elsewhere MME utilization outcomes for MIV were largely equivalent or nominally better than other comparators. Odds of ORADEs were significantly higher for all comparators vs MIV for orthopedic (gastrointestinal) and hysterectomy (respiratory).ConclusionsMIV 30 mg may provide better pain reduction with similar or better safety compared to other approved IV non-opioid analgesics. Caution is warranted in interpreting these results as all comparisons involving MIV were indirect.

Efficacy and tolerability of orally administered tramadol/dexketoprofen fixed-dose combination compared to diclofenac/thiocolchicoside in acute low back pain: experience from an Italian, single-centre, observational study

Objectives To compare the analgesic efficacy and tolerability of tramadol/dexketoprofen 75/25 mg (TRAM/DKP) versus diclofenac/thiocolchicoside 75/4 mg (DIC/THIO) in patients with moderate-to-severe acute low back pain (LBP). Methods Single-centre, observational study in 82 adult outpatients with LBP due to disc herniation (≥4 Numerical Rating scale, NRS) who received either oral TRAM/DKP (n = 44) or intramuscular DIC/THIO (n = 38), both given every 12 h for 5 days. The primary endpoint was the change from baseline in pain intensity (PI) at pre-specified post-dose time points (t day1, t day3, t day7) and compared between the two treatments. Additional endpoints, all evaluated at day 7, included: the sum of PI difference (SPID), percentage of responders in terms of PI reduction versus baseline and change from baseline in Douleur Neuropathique (DN4) score. Tolerability and safety were also assessed. Results Both treatment groups were comparable for demographic characteristics and comorbidities. Over the 5-day treatment period and up to day 7, compared to DIC/THIO, TRAM/DKP provided a significantly greater and sustained analgesia at day 3 and day 7 (p < .0001), with a higher proportion of responders at each time point [75% versus 71.1% (p = 0.687) at day 1, 93.2% versus 73.7% at day 3 (p = .016) and 95.5% versus 71.1% at day 7 (p = .003)], higher values of SPID (770.9 ± 23.5 vs. 507.1 ± 22.6; p < .0001) and significantly greater reduction in DN4 score [–62.7 ± 25.6 vs. −39.7 ± 31.2 (p < .0001)]. Both treatments were well tolerated. Conclusions Orally administered TRAM/DKP 75/25 mg can be a valuable and effective option in patients with acute LBP.

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.

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. 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. 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. 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.

Analgesic Efficacy and Tolerability of Tramadol Versus Low Dose Tramadol-Paracetamol in Patients with Gastro Intestinal Surgery

INTRODUCTION: Analgesic regimens with an improved efficacy and tolerability balance have potential to improve acute pain management, and thus reduce the progression into chronic pain. Hence, an opportunity was gained to compare analgesic efficacy and tolerability of Tramadol (T) 1.5 mg/kg versus low dose Tramadol 1mg/kg-Paracetamol 1000mg (T-P) in patient with Gastro Intestinal (GI) surgery.&#x0D; MATERIAL AND METHODS: The study was a hospital based prospective, observational study conducted in sixty post-operative GI surgery patient at Universal College of Medical Sciences-Teaching Hospital, Ranigaon, Bhairahawa, Nepal. One group received Tramadol 1.5mg/kg (n=30) while the other group received Tramadol 1mg/kg with Paracetamol 1000 mg (n=30). The primary efficacy outcome measures were pain intensity difference (PID) and sum of pain intensity difference (SPID) whereas secondary efficacy measures included number of patient who require rescue medication, haemodynamic parameter, their quality of sleep in the night and satisfaction with their medication. For tolerability, adverse effect was noted that occurred during study time intervals.&#x0D; RESULTS: Mean pain intensity differences assessed on Numerical Rating Scores (NRS) were significantly better for Group T-P compared to Group T at all the points except 0.5, 1 and 6 hrs. The sum of pain intensity difference over 8, 16, 24, 48 hrs for Group T-P was significantly superior to Group T. Two patients in Tramadol group required rescue medication. Satisfaction to the pain medication was comparatively higher for Tramadol-Paracetamol group.&#x0D; CONCLUSION :- Tramadol-Paracetamol had more pronounced analgesic effect with lower incidence of side effect than Tramadol alone. Thus, low dose Tramadol-Paracetamol is better option for management of post-operative pain in patient with GI surgery.

Pooled Dosing and Efficacy Analysis of the Sufentanil Sublingual Tablet 30 mcg Across Demographic Subgroups for the Management of Moderate-to-Severe Acute Pain

To aid nurses in dosing sufentanil sublingual tablet (SST) 30 mcg administered via a single-dose applicator, dosing requirements and efficacy of SST 30 mcg were analyzed across age, sex, race, and body mass index subgroups. Patient characteristics were pooled from three postoperative studies (two placebo-controlled and one open-label) and one open-label emergency department study. Drug dosing and efficacy data were pooled from the postoperative studies. Efficacy was assessed through summed pain intensity difference to baseline during 12hours across subgroups. Mean (standard deviation) drug doses administered from 0 to 12hours was 3.9 (2.0) for SST 30 mcg and was less frequent for older (≥65years) versus younger patients. The summed pain intensity difference to baseline during 12hours was superior with SST 30 mcg versus placebo across all subgroups. SST 30 mcg is a sublingual opioid analgesic with efficacy across demographic subgroups.

A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Ambroxol Hard-Boiled Lozenges in Patients with Acute Pharyngitis.

IntroductionThe aim of this study was to evaluate the efficacy and safety of a new hard-boiled lozenge formulation containing ambroxol 20 mg versus placebo for the relief of sore throat in patients with acute pharyngitis.MethodsThis was a phase 3, randomized, double-blind, placebo-controlled, parallel-group multicenter trial conducted between June and September 2018 in South Africa. Patients with a diagnosis of acute pharyngitis, onset ≤ 72 h, and sore throat pain of at least moderate intensity were randomized to receive either ambroxol 20 mg or placebo hard-boiled lozenges. The primary efficacy endpoint was the normalized time-weighted sum of pain intensity differences (SPID) from baseline over 3 h following administration of the first lozenge (SPIDnorm,0–3h). Secondary efficacy endpoints included SPID 24 h after the first lozenge intake (SPIDnorm,0–24h) and patient assessment of efficacy at 3 and 24 h after the first lozenge.ResultsOf 422 patients from 11 centers, 390 were randomized to one of the two treatment groups (n = 196, ambroxol; n = 194, placebo) and 388 were analyzed (modified intention-to-treat). The mean ± standard deviation SPIDnorm,0–3h values were −0.386 (0.259) and −0.366 (0.243) in the ambroxol and placebo groups, respectively, and the adjusted mean ± standard error SPIDnorm0–3h difference between ambroxol and placebo was −0.020 (0.025) (p = 0.443). Comparable results between treatment groups were also found for SPIDnorm,0–24h and patient assessment of efficacy at 3 and 24 h after the first lozenge. The incidence of treatment-emergent adverse events (TEAEs) was similar between treatment groups (11.7% for ambroxol versus 9.3% for placebo).ConclusionAlthough marked pain relief was observed over the first 3 h of treatment, superiority of ambroxol 20 mg hard-boiled lozenges versus placebo was not demonstrated in this study.Trial RegistrationNCT03583658.FundingSanofi-Aventis Group.Electronic supplementary materialThe online version of this article (10.1007/s41030-019-00100-w) contains supplementary material, which is available to authorized users.

Significant, long-lasting pain relief in primary dysmenorrhea with low-dose naproxen sodium compared with acetaminophen: a double-blind, randomized, single-dose, crossover study

Objectives: Many women experience menstrual cramps, which adversely affects quality-of-life. Both naproxen and acetaminophen are indicated to relieve menstrual pain. This study assessed the analgesic efficacy of a single, maximum non-prescription dose of naproxen sodium compared with that of acetaminophen in the treatment of primary dysmenorrhea.Methods: Healthy females with primary dysmenorrhea were included in our double-blind, randomized, crossover study (trial registration no. NCT03448536). When pain was moderate (≥5 on 0–10 numerical rating scale), subjects took a single dose of naproxen sodium (440 mg) and crossed over to acetaminophen (1000 mg) in the next cycle, or vice versa. Total pain relief over 12 h (TOTPAR0-12) was the primary outcome, while secondary outcomes included summed pain intensity differences (SPID) and TOTPAR scores throughout 12 h, and subject overall evaluation of treatment.Results: The per protocol population (n = 189) used naproxen sodium (n = 170) and acetaminophen (n = 160). TOTPAR0-12 was significantly greater with naproxen sodium than acetaminophen (least-squares (LS) mean difference = 4.31; p < .001), and pain intensity was significantly lower (SPID0-12 LS mean difference = 9.80; p < .001). Some measures of pain intensity favoring naproxen sodium became significant at earlier time points (e.g. SPID4-6 LS mean difference = 1.49; p = .02). After 6 h post-dose, naproxen sodium was significantly more effective than acetaminophen, maintained for 12 h (SPID6-12 LS mean difference = 8.27; TOTPAR6-12 LS mean difference = 3.75; both p < .001). Significantly more subjects rated naproxen sodium as good-to-excellent (70.6%) vs acetaminophen (63.1%) (p = .002).Conclusions: A single, maximum non-prescription dose of naproxen sodium was more effective than acetaminophen over 12 h.Trial registration: ClinicalTrials.gov identifier: NCT03448536.

Longer analgesic effect with naproxen sodium than ibuprofen in post-surgical dental pain: a randomized, double-blind, placebo-controlled, single-dose trial

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are recommended as first-line medications in mild-to-moderate acute pain. However, comparative data regarding the duration of analgesia for commonly-used NSAIDs at non-prescription doses is lacking. This study evaluated the time to rescue medication following a single dose of naproxen sodium (NAPSO) vs ibuprofen (IBU) and placebo in subjects with moderate-to-severe post-surgical dental pain.Methods: This single-center, randomized, double-blind, parallel group, placebo-controlled study included healthy subjects with moderate-to-severe baseline pain (Categorical Pain Intensity Scale) who also rated their pain ≥ 5 on a 0–10 pain intensity Numerical Rating Scale following extraction of two impacted mandibular third molars. A single oral dose of NAPSO (440 mg), IBU (400 mg), or placebo was administered. The primary efficacy endpoint was the time to first rescue medication, while secondary endpoints included the sum of pain intensity difference (SPID) and total pain relief (TOTPAR) over 24 h. ClinicalTrials.gov trial registration number: NCT03404206 (EudraCT 2017-005049-67).Results: In the per protocol population (n = 385; mean age = 19 years), the time to rescue medication was significantly (p < .001) longer with NAPSO than IBU and placebo. After treatment, the greatest separation of NAPSO from IBU occurred at 9–14 h and from placebo at 1–6 h. Fewer NAPSO subjects required rescue medication (58/166, 34.9%) compared with IBU (137/165, 83.0%) and placebo (44/54, 81.5%). SPID 0–24 h and TOTPAR 0–24 h were both greater with NAPSO than IBU or placebo.Conclusions: The duration of pain relief after a single dose of NAPSO was significantly longer than after IBU, and significantly fewer NAPSO-treated subjects required rescue medication over a 24-h period.Trial registration: ClinicalTrials.gov identifier: NCT03404206.

Efficacy and Safety of an Intravenous Acetaminophen/Ibuprofen Fixed-dose Combination After Bunionectomy: a Randomized, Double-blind, Factorial, Placebo-controlled Trial

PurposeMultimodal analgesia with acetaminophen and/or nonsteroidal anti-inflammatory drugs is recommended for the treatment of postoperative pain. Although oral fixed-dose combinations (FDCs) are available, parenteral administration may be clinically justified. The goal of this study was to investigate the clinical efficacy and safety of an intravenous FDC of ibuprofen and acetaminophen after bunionectomy. MethodsThis study was a prospective, randomized, double-blind, multicenter, placebo-controlled factorial clinical trial conducted at 2 clinical research centers in the United States between November 2016 and June 2017. Eligible patients (male and female subjects, aged 18–65 years, reporting pain intensity levels ≥40 mm on a 100-mm visual analog scale (VAS) after distal, first metatarsal bunionectomy) were randomized (3:3:3:2) to receive the FDC (ibuprofen 300 mg + acetaminophen 1000 mg), ibuprofen 300 mg, acetaminophen 1000 mg, or placebo (vehicle), administered as 15-minute intravenous infusions every 6 hours for 48 hours. The primary efficacy end point was the time-adjusted sum of pain intensity differences from baseline over 48 hours (SPID48). In addition to VAS pain intensity scores, pain relief scores, time to perceptible and meaningful pain relief, the use of rescue medication, and participant's global evaluations of the study drug were recorded. Adverse events occurring during the 48-hour treatment period were included in the safety analysis. FindingsA total of 276 participants were enrolled; most were female (82%), the mean age was 42.4 years, and the median baseline VAS was 67 mm, indicating moderate to severe pain. SPID48 was significantly higher for the FDC (23.4 [2.5] mm) than for ibuprofen (9.5 [2.5] mm), acetaminophen (10.4 [2.5] mm), and placebo (−1.3 [3.1] mm; all, P < 0.001). The superior analgesic effect of the FDC was supported by a range of secondary end points, including reduced opioid usage rates (75% for FDC, 92% for ibuprofen, 93% for acetaminophen, and 96% for placebo; all, P < 0.005). The safety profile of the FDC was comparable to that of intravenous ibuprofen or acetaminophen alone. Three participants withdrew from the study due to adverse events: 2 in the ibuprofen group and 1 in the acetaminophen group. ImplicationsThe study found that repeated administration of an intravenous FDC of ibuprofen and acetaminophen provided statistically significant improvement in SPID48 over comparable doses of either monotherapy without an increase in adverse events. ClinicalTrials.gov identifier: NCT02689063.

Effect of a New Synergistic Combination of Low Doses of Acetylsalicylic Acid, Caffeine, Acetaminophen, and Chlorpheniramine in Acute Low Back Pain.

The present paper continues a more complex research related to the increased synergism in terms of both anti-inflammatory and analgesic effect obtained by the addition of chlorpheniramine (CLF) to the common acetylsalicylic acid (ASA), acetaminophen (PAR), and caffeine (CAF) combination. This synergistic effect was previously highlighted both in vitro in rat models and in vivo in the treatment of migraine. The aim of the research was to further evaluate the analgesic effect of a synergistic low-dose ASA–PAR–CAF–CLF combination in the treatment of low back pain, in a parallel, multiple-dose, double-blind, active controlled clinical trial. A number of 89 patients with low back pain of at least moderate intensity were randomly assigned to receive Algopirin® (ALG), a combinational product containing 125 mg ASA, 75 mg PAR, 15 mg CAF, and 2 mg CLF, or PAR 500 mg, a drug recognized by American Pain Society as “safe and effective” in the treatment of low back pain. One tablet of the assigned product was administered three times a day for seven consecutive days. The patients evaluated their pain level using a Visual Analog Scale prior to administration, and at 1, 2, 4, and 6 h after the morning dose. Time course of effect was similar in structure and size for both treatments. Pain relief appeared rapidly and steadily increased over 4 h after drug administration. Differential pain curves of ALG and PAR were very similar and comparable with the previously determined ALG analgesia pattern in migraine. Differences between the daily mean pain scores were not statistically significant for the two treatments. Similar results were obtained for the Sum of Pain Intensity Differences (SPID) for 0–4 h and 0–6 h intervals as well as for the time course of the proportion of patients with at least 30% and at least 50% pain relief. In conclusion, in spite of very small doses of active components, ALG proved equally effective to the standard low back pain treatment and therefore a viable therapeutic alternative, mainly for patients with gastrointestinal and hepatic sensitivity. Trial Registration: www.ClinicalTrials.gov, identifier EudraCT No.: 2015–002314–74.

The Efficacy of Antivenin Latrodectus (Black Widow) Equine Immune F(abʹ)2 Versus Placebo in the Treatment of Latrodectism: A Randomized, Double-Blind, Placebo-Controlled, Clinical Trial

The antivenom currently available for treatment of systemic black widow envenomation (latrodectism) is composed of equine whole immunoglobin. Although considered effective, it has been associated with anaphylaxis and 2 reported fatalities. We test the efficacy and safety of new equine antivenom composed of purified F(ab')2 antibody fragments. A randomized, double-blind, placebo-controlled trial was conducted at 16 sites across the United States. Subjects aged 10 years or older with moderate to severe pain because of black widow spider envenomation received F(ab')2 antivenom or placebo. The primary outcome measure was treatment failure, which was defined as failure to achieve and maintain clinically significant reduction in pain for 48 hours posttreatment. Secondary measures of pain intensity differences and summed pain intensity difference were computed. Adverse events were recorded. Sixty patients were treated (29 antivenom and 31 placebo). The mean age was 39 years and 68% were male. There were 15 treatment failures in the antivenom group and 24 in the placebo group (P=.019). Differences in pain intensity difference between groups were lower at each postbaseline point, and the mean summed pain intensity difference was greater for the antivenom group (difference 2,133; 95% confidence interval 177 to 4,090). No deaths or serious drug-related adverse events were detected. The F(ab')2 antivenom met the predefined primary outcome of reduced treatment failures. Secondary outcomes of pain intensity difference and summed pain intensity difference also supported efficacy. The rate of symptom improvement in the placebo group was higher than expected, which may be related to enrollment criteria or placebo effect.

(406) Comparative Effectiveness of CL-108 and Ibuprofen for Acute Postoperative Pain

Comparative effectiveness studies can provide clinically meaningful and useful evidence of drug performance. The comparative effectiveness of ibuprofen and CL-108 (hydro-codone 7.5 mg/acetaminophen 325 mg/low-dose promethazine 12.5 mg) for acute postoperative pain was examined post hoc when it was noted that all patients in the placebo treatment group in a randomized controlled trial1 had used multiple doses of ibuprofen as needed throughout the 48-hour treatment evaluation period. Pharmacologically, these were ibuprofen-treated patients. This observation provided an opportunity to compare the effectiveness of treatment with only ibuprofen or CL-108. After unilateral first metatarsal bunionectomy, patients with moderate or severe pain measured on a categorical pain intensity scale and a 0-to-10 numeric pain intensity rating scale (PI-NRS) were randomly assigned to use CL-108 or placebo under double-blind conditions. Patients were administered study medication every 4-6 hours while under observation for 48 hours and could use open-label ibuprofen 400 mg as rescue analgesic medication (without any other analgesic) every 4-6 hours as needed for pain. At regular intervals over the 48-hour treatment evaluation period, patients rated pain intensity on the PI-NRS. Summed pain intensity differences were calculated based on the patients’ pain intensity ratings (i.e., without imputation) over 24 hours and over 48 hours (SPID24, SPID48), comparing analgesic effectiveness for patients who used CL-108 (n=99) and patients in the placebo group (n=50), all of whom used ibuprofen (IBU). Over the initial 24 hours of treatment, patients using CL-108 had 127% greater SPID24 values than IBU-treated patients (75.8 and 33.4, respectively, p<0.001). Over the entire 48-hour treatment evaluation period, patients using CL-108 had 62% greater SPID48 values than IBU-treated patients (178.5 and 110.0, p<0.001). These analgesic outcomes indicate that treatment with CL-108 is more effective than as-needed ibuprofen for acute postoperative pain. Comparative effectiveness studies can provide clinically meaningful and useful evidence of drug performance. The comparative effectiveness of ibuprofen and CL-108 (hydro-codone 7.5 mg/acetaminophen 325 mg/low-dose promethazine 12.5 mg) for acute postoperative pain was examined post hoc when it was noted that all patients in the placebo treatment group in a randomized controlled trial1 had used multiple doses of ibuprofen as needed throughout the 48-hour treatment evaluation period. Pharmacologically, these were ibuprofen-treated patients. This observation provided an opportunity to compare the effectiveness of treatment with only ibuprofen or CL-108. After unilateral first metatarsal bunionectomy, patients with moderate or severe pain measured on a categorical pain intensity scale and a 0-to-10 numeric pain intensity rating scale (PI-NRS) were randomly assigned to use CL-108 or placebo under double-blind conditions. Patients were administered study medication every 4-6 hours while under observation for 48 hours and could use open-label ibuprofen 400 mg as rescue analgesic medication (without any other analgesic) every 4-6 hours as needed for pain. At regular intervals over the 48-hour treatment evaluation period, patients rated pain intensity on the PI-NRS. Summed pain intensity differences were calculated based on the patients’ pain intensity ratings (i.e., without imputation) over 24 hours and over 48 hours (SPID24, SPID48), comparing analgesic effectiveness for patients who used CL-108 (n=99) and patients in the placebo group (n=50), all of whom used ibuprofen (IBU). Over the initial 24 hours of treatment, patients using CL-108 had 127% greater SPID24 values than IBU-treated patients (75.8 and 33.4, respectively, p<0.001). Over the entire 48-hour treatment evaluation period, patients using CL-108 had 62% greater SPID48 values than IBU-treated patients (178.5 and 110.0, p<0.001). These analgesic outcomes indicate that treatment with CL-108 is more effective than as-needed ibuprofen for acute postoperative pain.

(405) What is the Effect on Acute Pain when a Patient's Sleep is Disturbed by Opioid-Induced Nausea and Vomiting (OINV)?

Sleep is an important factor in postoperative recovery, especially for patients experiencing moderate-to-severe acute pain. In contrast, sleep disturbance may have deleterious effects on patient recovery, including increased pain and length-of-stay.1 However, it is unclear if nausea and vomiting interfere with sleep and with what analgesic consequence. Is there evidence of OINV-related sleep disturbance and its effect on acute pain in a randomized controlled trial (RCT)? In a previous RCT,2 it was noted that some patients using hydrocodone 7.5mg/acetaminophen 325mg (HC/APAP) awoke with nausea, retching and/or vomiting, requesting antiemetic therapy. In the current RCT,3 therefore, patients were observed while asleep so that emetic symptoms and pain could be documented if they awoke. Following first metatarsal bunionectomy, patients with moderate or severe pain on a categorical pain intensity scale and a 0-to-10 pain intensity scale (PI-NRS) were randomly assigned to take HC/APAP or placebo under double-blind conditions every 4-6 hours. Patients were monitored regularly as in-patients over 48 hours, including, in particular, during periods of sleeping between 9 pm and 7 am: if patients awoke from sleep, episodes of retching, vomiting and other adverse events were documented if present and patients rated nausea intensity on a 0-to-10 Likert scale and pain intensity on the PI-NRS. Of 113 HC/APAP-treated patients who developed OINV over the 48-hour treatment period, 29 patients (26%) awoke from sleep complaining of moderate-to-severe nausea, retching or vomiting, requesting an antiemetic. Compared to the summed pain intensity differences (SPID48) of these patients with OINV-related sleep disturbance (63.2), SPID48 values were 108% higher for the 137 HC/APAP-treated patients without OINV-related sleep disturbance (131.1, p<0.001). We conclude that OINV causes sleep disturbance, interfering with pain reduction and contributing to less effective pain relief. Future research should examine the effect of sleep disturbance of any etiology on pain control. Sleep is an important factor in postoperative recovery, especially for patients experiencing moderate-to-severe acute pain. In contrast, sleep disturbance may have deleterious effects on patient recovery, including increased pain and length-of-stay.1 However, it is unclear if nausea and vomiting interfere with sleep and with what analgesic consequence. Is there evidence of OINV-related sleep disturbance and its effect on acute pain in a randomized controlled trial (RCT)? In a previous RCT,2 it was noted that some patients using hydrocodone 7.5mg/acetaminophen 325mg (HC/APAP) awoke with nausea, retching and/or vomiting, requesting antiemetic therapy. In the current RCT,3 therefore, patients were observed while asleep so that emetic symptoms and pain could be documented if they awoke. Following first metatarsal bunionectomy, patients with moderate or severe pain on a categorical pain intensity scale and a 0-to-10 pain intensity scale (PI-NRS) were randomly assigned to take HC/APAP or placebo under double-blind conditions every 4-6 hours. Patients were monitored regularly as in-patients over 48 hours, including, in particular, during periods of sleeping between 9 pm and 7 am: if patients awoke from sleep, episodes of retching, vomiting and other adverse events were documented if present and patients rated nausea intensity on a 0-to-10 Likert scale and pain intensity on the PI-NRS. Of 113 HC/APAP-treated patients who developed OINV over the 48-hour treatment period, 29 patients (26%) awoke from sleep complaining of moderate-to-severe nausea, retching or vomiting, requesting an antiemetic. Compared to the summed pain intensity differences (SPID48) of these patients with OINV-related sleep disturbance (63.2), SPID48 values were 108% higher for the 137 HC/APAP-treated patients without OINV-related sleep disturbance (131.1, p<0.001). We conclude that OINV causes sleep disturbance, interfering with pain reduction and contributing to less effective pain relief. Future research should examine the effect of sleep disturbance of any etiology on pain control.

Prevention of Opioid-Induced Nausea and Vomiting During Treatment of Moderate to Severe Acute Pain: A Randomized Placebo-Controlled Trial Comparing CL-108 (Hydrocodone 7.5 mg/Acetaminophen 325 mg/Rapid-Release, Low-Dose Promethazine 12.5 mg) with Conventional Hydrocodone 7.5 mg/Acetaminophen 325 mg.

To evaluate the prevention of opioid-induced nausea and vomiting (OINV) and the relief of moderate to severe acute pain by CL-108, a novel drug combining a low-dose antiemetic (rapid-release promethazine 12.5 mg) with hydrocodone 7.5 mg/acetaminophen 325 mg (HC/APAP) was used. This was a multicenter, randomized, double-blind, placebo- and active-controlled multidose study. After surgical extraction of two or more impacted third molar teeth (including at least one mandibular impaction), 466 patients with moderate to severe pain (measured on a categorical pain intensity scale [PI-CAT]) were randomized to CL-108, HC/APAP, or placebo. Over the next 24 hours, patients used the PI-CAT to assess pain at regular intervals whereas nausea, vomiting, and other opioid-related side effects were also assessed prospectively. Study medications were taken every four to six hours as needed; supplemental rescue analgesic and antiemetic medications were permitted. Co-primary end points were the incidence of OINV and the time-weighted sum of pain intensity differences over 24 hours (SPID24). Relative to HC/APAP treatment alone, CL-108 treatment reduced OINV by 64% (P < 0.001). Treatment with CL-108 significantly reduced pain intensity compared with placebo (SPID24 = 16.2 vs 3.5, P < 0.001). There were no unexpected or serious adverse events. CL-108 is a safe and effective combination analgesic/antiemetic for the prevention of OINV during treatment of moderate to severe acute pain.

Efficacy and Safety of Combination of NSAIDs and Muscle Relaxants in the Management of Acute Low Back Pain.

IntroductionLow back pain is a common problem worldwide causing deterioration of health and quality of life. Low back pain is often associated with muscle spasm. We investigated the combined effect of muscle relaxants and pain killers for low back pain.MethodsIn this open-label, prospective, multicenter study, patients with acute low back pain received a single tablet of either the fixed dose combination of chlorzoxazone 500 mg and ibuprofen 400 mg (manufacturer: Dr. Reddy’s Laboratories, India) (C + I group) or ibuprofen 400 mg (I group) thrice daily for up to 7 days. Primary outcomes were improvement in pain by Visual Analogue Scale (VAS) and Summed Pain Intensity Difference (SPID) at 3 and 7 days post-treatment.ResultsA total of 406 patients were included in this study. When compared to baseline, the absolute mean change in VAS scores on Day 7 was 62.39 ± 18.78 and 57.34 ± 16.29 in the C + I and I groups, respectively (P = 0.0001). In the C + I and I groups, the mean SPID at Days 3 and 7 were 51.27 ± 24.44 and 47.80 ± 22.91, and 300.82 ± 92.40 and 277.16 ± 81.83, respectively. No deaths or serious adverse events were reported. Common adverse events included gastritis, stomach pain, fever, cold, and headache. At the end of the study, excellent to good response was reported in 94.08% and 77.33% of patients in the C + I and I groups, respectively. Excellent to good tolerability was observed in 96.05% and 89.65% patients in the two groups, respectively.ConclusionFixed dose combination of chlorzoxazone and ibuprofen demonstrated superior efficacy than ibuprofen monotherapy in acute low back pain. Both drugs were well-tolerated and should be considered as judicious therapeutic options in patients with acute low back pain.Trial RegistrationThis trial is registered with Clinical Trial Registry of India—CTRI/2016/10/007348.FundingDr. Reddy’s Laboratories Ltd.

Tapentadol immediate release for moderate to severe acute post-surgery pain.

To investigate efficacy and tolerability of tapentadol immediate release (IR) in the treatment of moderate to severe acute pain in three surgical pain models. Three randomized, double-blind, placebo- and active-controlled, multicenter, phase 3 trials were performed in total hip replacement surgery, abdominal hysterectomy, and bunionectomy with trial medications administered every 4-6 hours as needed for up to 72 hours. Tapentadol IR was included in all trials, oxycodone IR in the total hip replacement trial, and morphine IR in the abdominal hysterectomy and bunionectomy trials; active controls ensured assay sensitivity. The primary efficacy endpoint was the sum of pain intensity differences over the first 24 hours of treatment (SPID24) in the abdominal hysterectomy trial and SPID48 in the other two trials. Tolerability was assessed by adverse events reporting. A total of 330, 832, and 285 patients with total hip replacement, abdominal hysterectomy, and bunionectomy, respectively, were assessed for efficacy. All three trials demonstrated statistically significant improvements of tapentadol IR on the primary endpoint versus placebo and similar improvements compared to morphine IR or oxycodone IR. These findings were consistent with results of total pain relief assessments and patients' global impressions of change in their overall health status after 72 hours (abdominal hysterectomy, bunionectomy). The tolerability profile of tapentadol IR was as expected for a centrally acting analgesic in the post-surgery setting. Tapentadol IR has strong analgesic efficacy and is well tolerated in multiple post-surgery conditions of moderate to severe pain.