Sum Of Pain Intensity Differences Research Articles

Dexketoprofen Trometamol and Tramadol Hydrochloride Fixed-Dose Combination in Moderate to Severe Acute Low Back Pain: A Phase IV, Randomized, Parallel Group, Placebo, Active-Controlled Study (DANTE).

Dexketoprofen/tramadol 25/75 mg (DKP/TRAM) is a fixed-dose combination of a cyclooxygenase inhibitor and opioid receptor agonist. To better understand the efficacy and safety of DKP/TRAM in the treatment of moderate to severe acute lower back pain (LBP) with or without radiculopathy, we carried out a large explorative phase IV international, multicenter, prospective, randomized, double-blind, parallel group, placebo-controlled study (DANTE). A total of 538 patients with or without a history of LBP and experiencing acute LPB of moderate to severe intensity [Numerical Rating Scale-Pain Intensity (NRS-PI) score > 5] were randomized 4:4:1:1 to DKP/TRAM 25/75 mg every 8 h (n = 211), tramadol (TRAM) 100 mg (n = 207), placebo-matched DKP/TRAM (n = 59), or placebo-matched TRAM (n = 61). The proportion of patients achieving the primary endpoint, defined as the time to first achieve NRS-PI score < 4 or pain intensity reduction ≥ 30% from drug intake up to 8 h after the first dose, was higher in the DKP/TRAM arm than in the placebo group, but the difference was not statistically significant (46.1% vs. 42.6%, respectively; hazard ratio 1.11; 95% confidence interval 0.775, 1.595; p = 0.566). DKP/TRAM achieved superiority over TRAM in total pain relief at 4, 6, and 8 h (p < 0.05). Conversely, in relation to the secondary endpoints, a significantly greater reduction in NRS-PI score was seen with DKP/TRAM versus placebo starting from 1 h, and this reduction remained numerically lower throughout 8 h. Summed pain intensity difference values were also significantly lower at 4, 6, and 8 h with DKP/TRAM compared to TRAM (p < 0.05). Overall, DKP/TRAM was well tolerated. Although the primary endpoint was not met, secondary efficacy analyses suggest the superiority of DKP/TRAM over placebo and TRAM alone in terms of total pain relief. DKP/TRAM can be considered to be an effective and safe option for the treatment of moderate to severe acute LBP. EudraCT number: 2019-003656-37; ClinicalTrials.gov Identifier: NCT05170841.

Efficacy of Co-Crystal of Tramadol-Celecoxib (CTC) in Patients with Acute Moderate-to-Severe Pain: A Pooled Analysis of Data from Two Phase 3 Randomized Clinical Trials.

New acute pain medications are needed that provide effective analgesia while minimizing side effects and opioid exposure. Clinical trials of co-crystal of tramadol-celecoxib (CTC) have demonstrated an improved benefit/risk profile versus tramadol or celecoxib alone. We pooled data from two phase 3 clinical trials to evaluate the efficacy of CTC 200mg twice daily (BID) in acute moderate-to-severe pain. Efficacy data were pooled from STARDOM1 [acute pain following oral surgery (NCT02982161)] and ESTEVE-SUSA-301 [acute pain following bunionectomy (NCT03108482)]. The primary efficacy outcome was sum of pain intensity difference from 0 to 48 h (SPID0-48). A total of 344 patients received CTC 200mg BID, 342 received tramadol 50 or 100mg four times a day, 181 received celecoxib 100mg BID, and 172 received placebo. The least-squares mean difference in SPID0-48 was -21.8 (p = 0.002) for CTC versus tramadol and -72.8 (p < 0.001) for CTC versus placebo. A similar pattern of SPID0-48 was observed with CTC versus comparator whether patients had moderate or severe pain at baseline. Reduction in pain intensity was faster and reached mild intensity earlier with CTC versus comparators. Patients were significantly (p ≤ 0.005) less likely to receive rescue medication within 4 or 48 h with CTC compared with tramadol or placebo. This pooled analysis reinforces the efficacy profile of CTC versus tramadol and, given that CTC permits lower daily tramadol dosing and thereby reduces unnecessary opioid use, this highlights its improved benefit/risk profile and its potential for the management of moderate-to-severe pain.

A comparison of fascia iliaca compartment block with intravenous analgesia to improve pain control in patients with femoral fracture.

The most common approach to managing severe pain following femoral fracture is with intravenous systemic analgesics, such as opioid analgesics and non-steroidal anti-inflammatory drugs associated with side effects such as respiratory depression, nausea, and vomiting. These side effects might be intolerable in trauma patients and may result in under treatment of pain. Improving the quality of analgesia may reduce these intolerable side effects. Our study compared the efficacy of fascia iliaca compartment block (FICB) with intravenous analgesics for preoperative pain management of femoral fractures. The study was a quality improvement prospective randomised study, where 50 patients aged between 18 and 65 years, and American society of anesthesiologists I and II were recruited into two groups. Group A received FICB with a combination of 0.4 mL/kg of 0.5% plain bupivacaine and adrenaline 1:200,000 made up to 30 mL, while group B received placebo FICB using 30 mL normal saline. Also, group B received a combination of intravenous paracetamol 15 mg/kg not exceeding 900 mg and tramadol 1 mg/kg not exceeding 100 mg, while group A received an equal volume as normal saline intravenously. The study revealed no significant difference in age, gender, associated injuries, X-ray description of fractures, and mechanism of injuries; however, there was a significant difference in the NRS-pain score at 30 min, summed pain intensity difference for 4 h and patient satisfaction in the FICB group compared to the standard group. The study revealed that FICB results in better pain control compared to a combination of intravenous tramadol and paracetamol in patients with femoral fractures.

A randomized, double-blind study to compare the efficacy and safety of nalbuphine nasal spray and injectable solution in patients after orthopaedic interventions and traumatological procedures.

Our previous 3-period crossover study in healthy volunteers comparing the pharmacokinetics of nalbuphine nasal spray Apain with parenteral nalbuphine solution demonstrated high bioavailability of the nasal spray and close similarity of pharmacokinetic profiles after intranasal and intramuscular administration, especially within 30 min postdose. The aim of the present study was a noninferiority assessment of nalbuphine nasal spray vs. intramuscular injection for pain relief in postoperative patients. Ninety orthopaedic and traumatology patients were enrolled in this double-blind, randomized study of the effectiveness and tolerance of a single 10.5mg dose of nalbuphine nasal spray vs. 10mg intramuscular injection. The summed pain intensity difference (SPID0-6) calculated using visual analogue scale scores was the primary study endpoint. Of 90 subjects enrolled, the per-protocol efficacy population comprised 79 patients; 6 patients in the reference group and 5 patients in the test group were excluded due to remedication. The mean values of study endpoints with 95% confidence interval were as follows in reference and test groups, respectively: SPID0-6= 228.08 (205.73-250.43) vs. 248.73 9 (225.83-271.63), time to pain relief onset =0.28 h (0.25-0.31) vs. 0.27 h (0.25-0.29), duration of analgesia =5.55 h (5.17-5.93) vs. 5.51 h (5.10-5.92), area under the curve = 119.30 (91.17-147.43) vs. 99.81 (74.52-107.10). No statistically significant differences were revealed. Nalbuphine nasal spray Apain has been proven to be a safe, noninvasive alternative to intramuscular nalbuphine to relieve severe postoperative pain. Designed for self-administration and dose-adjusting, the noncontrolled opioid analgesic nalbuphine spray can be used for patient-controlled analgesia in out-of-hospital, field and home settings.

Screening of herbal extracts for rapid effect on activity-induced knee joint discomfort: a randomized and placebo-controlled pilot study

Background: A feasibility study was conducted to investigate the effect of different proprietary extracts on joint discomfort associated with repeated episodes of physical activity. Methods: A single-dose randomized, double-blind, placebo-controlled cross-over study was conducted in three phases with different extract combinations. Seventeen individuals aged 40-60 years with a history of knee joint pain aggravation on physical stress were randomized to receive the investigational product or the placebo in a 1:1 ratio. The primary outcome was the time taken to achieve meaningful pain relief (MPR) from baseline using a pain visual analog scale (VAS) compared to the placebo. The secondary outcomes were the pain intensity difference (PID) and joint discomfort at 1-, 2-, 3-, and 4-hours post-product administration and the time-weighted sum of pain intensity difference (SPID) over 4 hours compared to placebo. Results: Participants in two out of eight investigational product groups achieved MPR successfully. The proprietary combination ZV-E (consisting of Z. officinale and V. negundo) showed the fastest pain reduction with more than 50% of the participants achieving meaningful relief. The BS-ZP (consisting of B. serrata + Z. officinale + P. lanceolata) group also had more than 50% of participants reporting MPR at 4 hours post-IP administration. Subsequently, the SPID was found to be lowest in the participants of above stated groups. Conclusions: The proprietary combination of Z. officinale and V. negundo extracts, 200 mg could be a promising lead to conduct a further trial to investigate its effect on joint pain.

Analgesic efficiency of dexketoprofen trometamol in third molar surgery: a systematic review and meta-analysis.

This study aims to compare the analgesic efficacy of dexketoprofen trometamol (DT) with other analgesic drugs for pain relief after third molar surgery. The PubMed, Scopus, and Web of Science databases were searched to identify randomized controlled trials comparing DT with other analgesics for third molar surgery. The outcome measures were the sum of pain intensity differences (SPID), total pain relief (TOTPAR) at the 6th and 8th postoperative hours, time to rescue medication, and tolerability. In total, four studies met our inclusion criteria. A total of 660 third molar surgeries were performed: 365 in the DT group and 295 in the active control group. Compared to other analgesics, DT produced significantly better pain relief at the 6th postoperative hour: SPID (MD, 0.33; P = 0.01) and TOTPAR (MD, 0.41; P = 0.02). However, there were no statistically significant differences in the efficiency of pain relief at the 8th postoperative hour, time to rescue medication, or tolerability. Overall, a 25 mg dose produced the best results for pain relief. In conclusion, DT (25 mg) is a viable alternative to contemporary analgesics for pain relief after third molar surgery, particularly during the early postoperative period.

Randomised controlled trial of analgesia for the management of acute severe pain from traumatic injury: study protocol for the paramedic analgesia comparing ketamine and morphine in trauma (PACKMaN)

BackgroundPrehospital analgesia is often required after traumatic injury, currently morphine is the strongest parenteral analgesia routinely available for use by paramedics in the United Kingdom (UK) when treating patients with severe pain. This protocol describes a multi-centre, randomised, double blinded trial comparing the clinical and cost-effectiveness of ketamine and morphine for severe pain following acute traumatic injury.MethodsA two arm pragmatic, phase III trial working with two large NHS ambulance services, with an internal pilot. Participants will be randomised in equal numbers to either (1) morphine or (2) ketamine by IV/IO injection. We aim to recruit 446 participants over the age of 16 years old, with a self-reported pain score of 7 or above out of 10. Randomised participants will receive a maximum of 20 mg of morphine, or a maximum of 30 mg of ketamine, to manage their pain. The primary outcome will be the sum of pain intensity difference. Secondary outcomes measure the effectiveness of pain relief and overall patient experience from randomisation to arrival at hospital as well as monitoring the adverse events, resource use and cost-effectiveness outcomes.DiscussionThe PACKMAN study is the first UK clinical trial addressing the clinical and cost-effectiveness of ketamine and morphine in treating acute severe pain from traumatic injury treated by NHS paramedics. The findings will inform future clinical practice and provide insights into the effectiveness of ketamine as a prehospital analgesia.Trial registration: ISRCTN, ISRCTN14124474. Registered 22 October 2020, https://www.isrctn.com/ISRCTN14124474

Analgesic effect of oral paracetamol 1000 mg/ibuprofen 400 mg, paracetamol 1000 mg/codeine 60 mg, paracetamol 1000 mg/ibuprofen 400 mg/codeine 60 mg, or placebo on acute postoperative pain: a single-dose, randomized, and double-blind study

PurposeCombining analgesics with different mechanisms of action may increase the analgesic efficacy. The multidimensional pharmacodynamic profiles of ibuprofen 400 mg/paracetamol 1000 mg, ibuprofen 400 mg/paracetamol 1000 mg/codeine 60 mg, and paracetamol 1000 mg/codeine 60 mg and placebo were compared.MethodsA randomized, double-blind, placebo-controlled, parallel-group, single-centre, outpatient, and single-dose study used 200 patients of both sexes and homogenous ethnicity after third molar surgery (mean age 24 years, range 19–30 years). Primary outcome was sum pain intensity over 6 h (SPI). Secondary outcomes were time to analgesic onset, duration of analgesia, time to rescue drug intake, number of patients taking rescue drug, sum pain intensity difference (SPID), maximum pain intensity difference, time to maximum pain intensity difference, number needed to treat, prevent remedication and harm values, adverse effects, and patient-reported outcome measure (PROM).ResultsAnalgesia following ibuprofen and paracetamol combination with or without codeine was comparable. Both were better than paracetamol combined with codeine. Secondary variables supported this finding. Post hoc analysis of SPI and SPID revealed a sex/drug interaction trend in the codeine-containing groups where females experienced less analgesia. PROM showed a significant sex/drug interaction in the paracetamol and codeine group, but not in the other codeine-containing group. Especially females reported known and mild side effects in the codeine-containing groups.ConclusionCodeine added to ibuprofen/paracetamol does not seem to add analgesia in a sex-mixed study population. Sex may be a confounding factor when testing weak opioid analgesics such as codeine. PROM seems to be more sensitive than traditional outcome measures.Trial registrationClinicalTrials.gov June 2009 NCT00921700.

Effect of Turmeric-Boswellia-Sesame Formulation in Menstrual Cramp Pain Associated with Primary Dysmenorrhea-A Double-Blind, Randomized, Placebo-Controlled Study.

Primary dysmenorrhea is a common menstrual disorder that significantly impacts women's quality of life, productivity, and healthcare utilization. In this randomized, double-blinded, placebo-controlled trial, sixty women with primary dysmenorrhea were randomly divided into two groups with thirty participants each, and were allocated either turmeric-boswellia-sesame formulation (treatment) or placebo. The participants were advised to take two softgels of 500 mg as a single dose of allocated study intervention (total dose 1000 mg) when their menstrual pain reached 5 or more on a numerical rating scale (NRS). Menstrual cramp pain intensity and relief were evaluated every 30 min post-dose until 6 h. Results indicated a promising role of turmeric-boswellia-sesame formulation for menstrual pain relief compared to the placebo. The mean total pain relief (TOTPAR) of the treatment group (18.9 ± 0.56) was found to be 12.6 times better than the placebo group (1.5 ± 0.39). The NRS analysis showed that there was a statistically significant difference in pain intensity between the treatment and placebo groups (p < 0.001) at every timepoint. Additionally, the sum of pain intensity difference at 6 h (SPID6) of the treatment group (34.32 ± 1.41) showed a significant difference (p < 0.0001) and was 20.19 times better when compared to placebo (1.7 ± 0.56). Based on the study results, the turmeric-boswellia-sesame formulation exhibited remarkable menstrual pain relief as compared to the placebo.

Sample Size Estimation for a Non-inferiority Pain Management Trial

Introduction: Measuring pain and pain relief are the primary concerns in pain management. Sample size estimation in pain management with non-inferiority (NI) study design and assessment of specific-NI margin endpoints may be challenging as pain and its improvement are measured and reported on different endpoints. Methods: Multiple endpoints were reported frequently to measure pain and pain improvement. The sum of pain intensity difference (SPID[0-t]) at a specific time is the recommended endpoint for the measurement of pain by the United States Food and Drug Administration. Statistical information on SPID and other endpoints reported in multiple works in the literature (preferably from placebo-controlled trials) was collected and compared to identify a suitable NI margin. A difference of 20% was considered the default NI margin for evaluation, and the sample size was calculated for each endpoint. Results: The sample size based on the FDA-recommended primary endpoint SPID was found to be larger. This may be a concern for overall clinical operation and the availability of patients for recruitment in time. The sample size obtained for the minimal clinically important difference (MCID) endpoint was feasible and justifiable from an operational and clinical standpoint. Conclusion: Evaluation and assessment of multiple endpoints before designing an NI study enable rapid decision-making on endpoint selection and increase operational efficiency.

Acute Postoperative Pain Due to Dental Extraction in the Adult Population: A Systematic Review and Network Meta-analysis

This study compares the effectiveness of pharmacological treatments to develop guidelines for the management of acute pain after tooth extraction. We searched Medline, EMBASE, CENTRAL, and US Clinical Trials registry on November 21, 2020. We included randomized clinical trials (RCTs) of participants undergoing dental extractions comparing 10 interventions, including acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, and combinations to placebo. After duplicate screening and data abstraction, we conducted a frequentist network meta-analysis for each outcome at 6 h (i.e., pain relief, total pain relief [TOTPAR], summed pain intensity difference [SPID], global efficacy rating, rescue analgesia, and adverse effects). We assessed the risk of bias using a modified Cochrane RoB 2.0 tool and the certainty of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation approach. We implemented the analyses in RStudio version 3.5.3 and classified interventions from most to least beneficial or harmful. We included 82 RCTs. Fifty-six RCTs enrolling 9,095 participants found moderate- and high-certainty evidence that ibuprofen 200 to 400 mg plus acetaminophen 500 to 1,000 mg (mean difference compared to placebo [MDp], 1.68; 95% confidence interval [CI], 1.06–2.31), acetaminophen 650 mg plus oxycodone 10 mg (MDp, 1.19; 95% CI, 0.85–1.54), ibuprofen 400 mg (MDp, 1.31; 95% CI, 1.17–1.45), and naproxen 400–440 mg (MDp, 1.44; 95% CI, 1.07–1.80) were most effective for pain relief on a 0 to 4 scale. Oxycodone 5 mg, codeine 60 mg, and tramadol 37.5 mg plus acetaminophen 325 mg were no better than placebo. The results for TOTPAR, SPID, global efficacy rating, and rescue analgesia were similar. Based on low- and very low-certainty evidence, most interventions were classified as no more harmful than placebo for most adverse effects. Based on moderate- and high-certainty evidence, NSAIDs with or without acetaminophen result in better pain-related outcomes than opioids with or without acetaminophen (except acetaminophen 650 mg plus oxycodone 10 mg) or placebo.

Fast pain relief in exercise-induced acute musculoskeletal pain by turmeric-boswellia formulation: A randomized placebo-controlled double-blinded multicentre study.

Background:Plant extracts with analgesic properties are seldom considered for treatment of acute musculoskeletal pain due to delay in onset of analgesia. Turmeric (Curcuma longa) and boswellia (Boswellia serrata) extracts are well-studied anti-inflammatory compounds gaining in popularity and used as an alternative to conventional treatments for musculoskeletal pain. This study analyzed the analgesic effect of a formulation of turmeric and boswellia extracts in sesame oil (Rhuleave-K, TBF) in reducing exercise-induced acute musculoskeletal pain in healthy participants.Methods:In this randomized double-blinded placebo-controlled, single-dose, single-day, multicentre study, a total of 232 participants (TBF n = 116; placebo n = 116) having moderate-to-severe exercise-induced acute musculoskeletal pain were randomized in an allocation concealed 1:1 ratio to receive a single dose of 1000 mg of TBF or placebo. The outcome measures were numerical rating scale (NRS), categorical pain relief scale (PRS), onset of analgesia, and short form of McGill questionnaire (SF-MPQ). NRS and PRS were measured from predose to every 30 minutes interval of postdose up to 6 hours at rest, with movement and applying pressure on the affected part. The onset of analgesia was measured from the time of dosage and censored at 6 hours of postdose. The sum of pain intensity difference (SPID6) and total pain relief (TOTPAR6) at 6 hours was, respectively, analyzed from NRS and PRS scores.Results:TBF showed a significant reduction in pain intensity (SPID6rest) with 97.85% improvement in cumulative responder analysis compared with 2.46% in placebo. The onset of pain relief was fast and highly significant in the TBF group with 99% of participants having a mean perceptible pain relief at 68.5 minutes (95% confidence interval, 59.5–77.4) and 96% of participants having a mean meaningful pain relief at 191.6 minutes (95% confidence interval, 176.7–206.4) compared to the placebo group. Highly significant and continuous improvement in pain relief was observed in the TBF group with 93% of participants having ≥ 50% of maximum TOTPAR6 with a number needed to treat of 1.1 at rest.Conclusion:Exercise-induced acute musculoskeletal pain can be effectively relieved by TBF (Rhuleave-K) in about 3 hours signifying its strong analgesic activity.

Continuous Intravenous Ketamine for Pain Control After Tibial or Femoral Osteotomy.

The purpose of this case series is to evaluate the potential of continuous intravenous ketamine administration as part of a multimodal strategy to reduce opioid requirements after high tibial osteotomy (HTO) and distal femoral osteotomy (DFO). We examined the average postoperative numerical rating scale pain intensity score from admission to the postanesthesia care unit to 8am of the first postoperative day of four patients who underwent HTO or DFO. Pain scores were analyzed as the time-weighted sum of pain intensity differences using the trapezoidal rule of the curve, resulting in an area under the curve (AUC). Patient A had an AUC of 2,828 over 1,180 minutes with an average pain score of 2.4/10. Patient B had an AUC of 1,418 over 1,285 minutes with an average pain score of 1.1/10. Patient C had an AUC of 4,217 over 1,155 minutes with an average pain score of 3.7/10. Patient D had an AUC of 4,498 over 1,030 minutes with an average pain score of 4.4/10. All were able to go home on postoperative day 1. This novel perioperative pain pathway including multiple non-opioid pain adjuncts and a low-dose continuous ketamine infusion is an effective method for pain management in knee periarticular osteotomies. Level 4; Case Series.

Randomised control trial of oral morphine and intramuscular pethidine for post-caesarean section analgesia in South-Western Nigeria

Background: The search for the ideal analgesia following caesarean section remains elusive but opioids provide good postoperative analgesia. Intramuscular opioid induces pain at the site of injection and its repeated administration proved to be more demanding for caregivers. Oral opioids especially morphine have become increasingly accessible in our environment and may be more effective than the conventional parenteral opioids for postcaesarean analgesia. Aim: To compare the efficacy of multiple doses of 10 mg oral morphine with that of 50 mg intramuscular pethidine in treatment of postcaesarean pain among parturients in Abeokuta, Nigeria. Patients, Materials and Methods: The study was a randomised controlled trial among parturients who had elective caesarean section in Abeokuta between November 2019 and August 2020. A total of 136 consenting and eligible pregnant women were randomised into two groups. Group A received multiple doses of 10 mg oral morphine while Group B had multiple doses of 50 mg intramuscular pethidine. The summed pain intensity difference (SPID) of the two groups was calculated and compared using the Chi-square and P < 0.05 was statistically significant. Results: The mean ± standard deviation (SD) of SPID at rest for morphine group and pethidine group was 6.00 ± 76.25 and 8.51 ± 77.60, respectively (t = −0.439 P = 0.662); the mean ± SD of SPID on movement for morphine and pethidine group was 29.13 ± 75.25 and 25.52 ± 28.47 (t = 0.139, P = 0.890). The median maternal satisfaction reported was similar in both groups (χ2 = 2.773, P = 0.4963) and somnolence was experienced in 3.1% of parturients in morphine group. Conclusion: The efficacy and maternal satisfaction of oral morphine in the control of postcaesarean section pain was similar to that of intramuscular pethidine. Hence, oral morphine is an acceptable alternative to intramuscular pethidine in management of pain following Caesarean section.

Analgesic efficacy of naproxen sodium versus hydrocodone/acetaminophen in acute postsurgical dental pain: a randomized, double-blind, placebo-controlled trial

ABSTRACT Objectives Opioid/acetaminophen combinations may be overly prescribed in many post-surgical situations where a non-steroidal anti-inflammatory drug with equal or greater efficacy, fewer central nervous system side effects, and no risk for opioid abuse could be substituted. We compared a single, non-prescription dose of naproxen sodium 440 mg (NapS) against hydrocodone plus acetaminophen 10/650 mg (HYD+APAP) in post-impaction surgery pain. Methods Single-center, randomized, double-blind, placebo-controlled study in moderate-severe pain after surgical removal of impacted third molars (ClinicalTrials.gov: NCT04307940). Patients (n = 212) received NapS, HYD+APAP, or placebo and were assessed over 12 hours. Primary endpoint: summed pain intensity difference from 0 to 12 hours (SPID0-12). Secondary endpoints: pain intensity, pain relief, time to rescue medication, duration of pain at least half gone. Others: onset of pain relief, global assessment of treatment, adverse events. Results All 221 randomized patients formed the safety population and were included in the intention-to-treat sensitivity analysis. Nine patients discontinued treatment or had protocol violations, and 212 patients were included in the per-protocol, primary efficacy population. Both active treatments were significantly more effective than placebo. NapS was significantly more effective than HYD+APAP regarding SPID0-12 (p = 0.01; primary endpoint), total pain relief (0–6 and 0–12 hours; p < 0.05), time to rescue medication (p < 0.001), and duration of pain at least half gone (p < 0.001). HYD+APAP was not statistically superior to NapS for any endpoint. More adverse events were reported with HYD+APAP (n = 63) than NapS (n = 2) and placebo (n = 20), including nausea, vomiting, and dizziness. Conclusion In moderate-to-severe postsurgical dental pain, a single dose of NapS was at least as effective as HYD+APAP in the early hours, significantly more effective at reducing pain intensity and providing greater pain relief over 12 hours, and was better tolerated. When not contraindicated, NapS should be considered a preferred alternative to opioid combinations for acute pain. (ClinicalTrials.gov, Identifier: NCT04307940; https://clinicaltrials.gov/ct2/show/NCT04307940)

Analgesic effect of oral ibuprofen 400, 600, and 800\xa0mg; paracetamol 500 and 1000\xa0mg; and paracetamol 1000\xa0mg plus 60\xa0mg codeine in acute postoperative pain: a single-dose, randomized, placebo-controlled, and double-blind study

PurposeEffect size estimates of analgesic drugs can be misleading. Ibuprofen (400 mg, 600 mg, 800 mg), paracetamol (1000 mg, 500 mg), paracetamol 1000 mg/codeine 60 mg, and placebo were investigated to establish the multidimensional pharmacodynamic profiles of each drug on acute pain with calculated effect size estimates.MethodsA randomized, double-blind, single-dose, placebo-controlled, parallel-group, single-centre, outpatient, and single-dose study used 350 patients (mean age 25 year, range 18 to 30 years) of homogenous ethnicity after third molar surgery. Primary outcome was sum pain intensity over 6 h. Secondary outcomes were time to analgesic onset, duration of analgesia, time to rescue drug intake, number of patients taking rescue drug, sum pain intensity difference, maximum pain intensity difference, time to maximum pain intensity difference, number needed to treat values, adverse effects, overall drug assessment as patient-reported outcome measure (PROM), and the effect size estimates NNT and NNTp.ResultsIbuprofen doses above 400 mg do not significantly increase analgesic effect. Paracetamol has a very flat analgesic dose–response profile. Paracetamol 1000/codeine 60 mg gives similar analgesia as ibuprofen from 400 mg, but has a shorter time to analgesic onset. Active drugs show no significant difference in maximal analgesic effect. Other secondary outcomes support these findings. The frequencies of adverse effects were low, mild to moderate in all active groups. NNT and NTTp values did not coincide well with PROMs.ConclusionIbuprofen doses above 400 mg for acute pain offer limited analgesic gain. Paracetamol 1000 mg/codeine 60 mg is comparable to ibuprofen doses from 400 mg. Calculated effect size estimates and PROM in our study seem not to relate well as clinical analgesic efficacy estimators.Trial registrationNCT00699114.

Cost-effectiveness analysis of domiciliary topical sevoflurane for painful leg ulcers

The general anesthetic sevoflurane is being repurposed as a topical analgesic for painful chronic wounds. We conducted a Bayesian cost-effectiveness analysis (CEA) comparing the addition of domiciliary topical sevoflurane to conventional analgesics (SEVOFLURANE, n = 38) versus conventional analgesics alone (CONVENTIONAL, n = 26) for the treatment of nonrevascularizable painful leg ulcers in an outpatient Pain Clinic of a Spanish tertiary hospital. We used real-world data collected from charts to conduct this CEA from a public healthcare perspective and with a one-year time horizon. Costs of analgesics, visits and admissions were considered, expressed in €2016. Analgesic effectiveness was measured with SPID (Sum of Pain Intensity Difference). A Bayesian regression model was constructed, including "treatment" and baseline characteristics for patients ("arterial hypertension") and ulcers ("duration", "number", "depth", "pain") as covariates. The findings were summarized as a cost-effectiveness plane and a cost-effectiveness acceptability curve. One-way sensitivity analyses, a re-analysis excluding those patients who died or suffered from leg amputation, and an extreme scenario analysis were conducted to reduce uncertainty. Compared to CONVENTIONAL, SEVOFLURANE was associated with a 46% reduction in costs, and the mean incremental effectiveness (28.15±3.70 effectiveness units) was favorable to SEVOFLURANE. The estimated probability for SEVOFLURANE being dominant was 99%. The regression model showed that costs were barely influenced by any covariate, whereas effectiveness was noticeably influenced by "treatment". All sensitivity analyses showed the robustness of the model, even in the extreme scenario analysis against SEVOFLURANE. SEVOFLURANE was dominant over CONVENTIONAL as it was less expensive and much more effective.

Oliceridine Exhibits Improved Tolerability Compared to Morphine at Equianalgesic Conditions: Exploratory Analysis from Two Phase 3 Randomized Placebo and Active Controlled Trials.

IntroductionIn the management of postoperative acute moderate-to-severe pain, opioids remain an important component. However, conventional opioids have a narrow therapeutic index and are associated with dose-limiting opioid-related adverse events (ORAEs) that can result in worse patient outcomes. Oliceridine, a new intravenous µ-opioid receptor agonist, is shown in nonclinical studies to be biased for G protein signaling (achieving analgesia) with limited recruitment of β-arrestin (associated with ORAEs). In two phase 3 randomized controlled studies of patients with moderate-to-severe acute pain following hard or soft tissue surgery, in which analgesia was measured using Sum of Pain Intensity Differences (SPID) from baseline over 48 and 24 h (SPID-48 and -24 respectively, oliceridine at demand doses of 0.1, 0.35, or 0.5 mg was highly effective compared to placebo, with a favorable safety profile compared to morphine. This exploratory analysis was conducted to determine whether the safety benefits seen with oliceridine persisted when adjusted for equal levels of analgesia compared to morphine.MethodsPresence of at least one treatment-emergent ORAE (based on Medical Dictionary for Regulatory Activities [MedDRA]-coded events: hypoxemia, nausea, vomiting, sedation, pruritus, or dizziness) was used as the composite safety endpoint. A logistic regression model was utilized to compare oliceridine (pooled regimens) versus morphine, after controlling for analgesia (using SPID-48 or SPID-24 with pre-rescue scores carried forward 6 h). This analysis excluded patients receiving placebo and was repeated for each study and for pooled data.ResultsAt a given level of SPID-48 or SPID-24, patients receiving oliceridine were less likely to experience the composite safety endpoint. Although not statistically significant at the 0.05 level in the soft tissue model, the odds ratio (OR) showed a consistent numerical trend for oliceridine, being approximately half that observed with morphine in both the hard (OR 0.499; 95% confidence interval [CI] 0.255, 0.976; p = 0.042) and soft (OR 0.542; 95% CI 0.250, 1.175; p = 0.121) tissue studies. Results from the pooled data were consistent with those observed in the individual studies (OR 0.507; 95% CI 0.304, 0.844; p = 0.009).ConclusionFindings from this exploratory analysis suggest that at comparable levels of analgesia, patients receiving oliceridine were less likely to experience the composite safety endpoint consisting of ORAEs compared to patients treated with morphine. Oliceridine Exhibits Improved Tolerability Compared to Morphine at Equianalgesic Conditions: Exploratory Analysis from Two Phase 3 Randomized Placebo and Active Controlled Trials- A Video (MP4 99188 kb)Supplementary InformationThe online version contains supplementary material available at 10.1007/s40122-021-00299-0.

A Meta-Analysis of the Analgesic Efficacy of Single-Doses of Ibuprofen Compared to Traditional Non-Opioid Analgesics Following Third Molar Surgery.

The purpose of this systematic review was to determine the analgesic efficacy and adverse effects of ibuprofen in comparison with other traditional non-opioid analgesics after third molar surgery. A total of 17 full texts were identified in PubMed and assessed using the Cochrane Collaboration’s risk of bias tool by two independent researchers. The sum of pain intensity differences, total pain relief, the overall evaluation, the number of patients requiring rescue analgesics, and adverse effects were collected. Data were analyzed using the Review Manager Software 5.3. for Windows. A total of 15 articles met the criteria. The qualitative and quantitative analysis showed that ibuprofen is more effective to relieve post-operative dental pain than acetaminophen, meclofenamate, aceclofenac, bromfenac, and aspirin. Moreover, ibuprofen and traditional non-steroidal anti-inflammatory drugs have a similar safety profile. In conclusion, ibuprofen 400 mg appears to have good analgesic efficacy and a safety profile similar to other traditional non-steroidal anti-inflammatory drugs after third molar surgery.

Efficacy and safety of single-dose DFN-15 for treatment of acute postsurgical dental pain: a randomized, double-blind, placebo-controlled study.

The analgesic efficacy and safety of DFN-15, a new oral liquid formulation of celecoxib with more rapid absorption than the capsule, were evaluated in the treatment of acute pain in adult patients after dental surgery. In this randomized, double-blind, placebo-controlled, dose-ranging study, 120 otherwise healthy adults who underwent the extraction of bilateral impacted mandibular third molar teeth and experienced moderate to severe pain postsurgery were randomly assigned, in a 1:1:1:1 ratio, to receive one dose of either placebo or DFN-15 at 3 doses: 62.5, 125, and 250 mg. Participants were evaluated at prespecified time points over 8 hours after study drug administration, using several instruments, including the 11-point Numerical Pain Rating Scale, 5-point Pain Relief Scale, and 5-point Treatment Satisfaction Scale. Rescue analgesic (oxycodone / acetaminophen) was permitted. The primary endpoint was the summed pain intensity difference (SPID) over the 6-hour postdose period (SPID6), which was compared between each DFN-15 dose and placebo using analysis of covariance. Other assessments of pain relief, use of rescue medication, and safety were also analyzed. All 3 doses of DFN-15 were significantly superior to placebo in SPID6 (least square mean difference over placebo: -756.6, -1120.7, and -1355.1, P < 0.0001 for all comparisons). In addition, DFN-15 was generally superior to placebo in other endpoints, including reduction of pain intensity, speed and magnitude of pain relief, treatment satisfaction, and rescue medication use. DFN-15 was similar to placebo in the incidence of adverse events with no apparent dose-related effects.