Celecoxib-tramadol co-crystal in patients with moderate-to-severe pain following bunionectomy with osteotomy: Secondary analyses by baseline pain intensity and use of rescue medication of a phase 3, randomized, double-blind, factorial, active- and placebo-controlled trial.

BACKGROUND: In the randomized, phase 3, SUSA-301 trial, celecoxib-tramadol co-crystal (CTC) provided significantly greater analgesia compared with celecoxib, tramadol, or placebo in adults with acute, moderate-to-severe, postoperative pain. This post hoc, secondary analysis further evaluated the use of rescue medication and the incidence of treatment-emergent adverse events (TEAEs). METHODS: Patients (N = 637) were randomized 2:2:2:1 to receive oral CTC 200 mg twice daily (BID; n = 184), tramadol 50 mg four times daily (QID; n = 183), celecoxib 100 mg BID (n = 181), or placebo QID (n = 89). Post hoc analyses were conducted on the use of rescue medications up to 4 and 48 h post-study drug dose, stratified by baseline pain intensity (moderate/severe), and on the incidence of TEAEs, stratified by rescue medication use. RESULTS: A significantly lower proportion of patients received any rescue medication within 4 h post-study dose with CTC (49.5%) versus tramadol (61.7%, p = 0.0178), celecoxib (65.2%, p = 0.0024), and placebo (75.3%, p = 0.0001); this was also seen for oxycodone use. Fewer patients in the CTC group received ≥3 doses of rescue medication compared with the other groups, irrespective of baseline pain intensity. In patients who did not receive opioid rescue medication, CTC was associated with a lower incidence of nausea and vomiting TEAEs versus tramadol alone. In patients who received rescue oxycodone, the incidence of nausea was similar in the CTC and tramadol groups, and higher versus celecoxib and placebo. CONCLUSION: Celecoxib-tramadol co-crystal was associated with reduced rescue medication use and an acceptable tolerability profile compared with tramadol or celecoxib alone in adults with acute, moderate-to-severe, postoperative pain.

Safety and Efficacy of Vocacapsaicin for Management of Postsurgical Pain: A Randomized Clinical Trial.

BACKGROUND: Nonopioid management of postsurgical pain remains a major unmet need. Few studies have evaluated transient receptor potential vanilloid subfamily member 1 agonists for analgesia after surgery. This study examines intraoperative vocacapsaicin, a novel prodrug of the transient receptor potential vanilloid subfamily member 1 agonist capsaicin, in a validated model of postsurgical pain. METHODS: This was a triple-blinded, randomized, placebo-controlled, dose-ranging trial in patients undergoing bunionectomy. Patients were randomized 1:1:1:1 to surgical site administration of 14 ml of placebo or one of three vocacapsaicin concentrations: 0.30, 0.15, or 0.05 mg/ml. The prespecified primary endpoint was the area-under-the-curve of the numerical rating scale pain score at rest through 96 h for the 0.30 mg/ml group. Prespecified ordered, secondary endpoints for the 0.30 mg/ml group included the percentage of patients who did not require opioids from 0 to 96 h, total opioid consumption through 96 h, and the area-under-the-curve of the numerical rating scale pain score for the first week. RESULTS: The 147 patients were randomized. During the first 96 h, vocacapsaicin (0.30 mg/ml) reduced pain at rest by 33% versus placebo (primary endpoint, 95% CI [10%, 52%], effect size [Cohen's d] = 0.61, P = 0.005). Of patients receiving vocacapsaicin (0.30 mg/ml), 26% did not require postoperative opioids for analgesia (P = 0.025) versus 5% of patients receiving placebo. Vocacapsaicin (0.30 mg/ml) reduced opioid consumption over the first 96 h by 50% versus placebo (95% CI [26%, 67%], effect size = 0.76, P = 0.002). Vocacapsaicin (0.30 mg/ml) reduced pain over the first week by 37% versus placebo (95% CI [12%, 57%], effect size = 0.62, P = 0.004). The treatment effect persisted for at least 2 weeks. All study endpoints showed an administered concentration-versus-response relationship. Vocacapsaicin was well tolerated with no differences between groups in any safety parameter. CONCLUSIONS: A single, local administration of vocacapsaicin during surgery reduced pain and opioid consumption for at least 96 h after surgery compared to control.

Celecoxib-tramadol co-crystal in patients with moderate-to-severe pain following bunionectomy with osteotomy: A phase 3, randomized, double-blind, factorial, active- and placebo-controlled trial.

BACKGROUND: Celecoxib-tramadol co-crystal (CTC) is a first-in-class analgesic co-crystal of celecoxib and racemic tramadol with an improved pharmacologic profile, conferred by the co-crystal structure, compared with its active constituents administered alone/concomitantly. AIM: We evaluated CTC in moderate-to-severe acute postoperative pain. MATERIALS AND METHODS: This randomized, double-blind, factorial, active- and placebo-controlled phase 3 trial (NCT03108482) was conducted at 6 US clinical research centers. Adults with moderate-to-severe acute pain following bunionectomy with osteotomy were randomized to oral CTC (200 mg [112 mg celecoxib/88 mg rac-tramadol hydrochloride] every 12 h), tramadol (50 mg every 6 h), celecoxib (100 mg every 12 h), or placebo for 48 h. Patients, investigators, and personnel were blinded to assignment. The primary endpoint was the 0-48 h sum of pain intensity differences (SPID0-48) in all randomized patients. Pain intensity was assessed on a 0-10 numerical rating scale (NRS). Safety was analyzed in patients who received study medication. Funded by ESTEVE Pharmaceuticals. RESULTS: In 2017 (March to November), 1323 patients were screened and 637 randomized to CTC (n = 184), tramadol (n = 183), celecoxib (n = 181), or placebo (n = 89). Mean baseline NRS was 6.7 in all active groups. CTC had a significantly greater effect on SPID0-48 (least-squares mean: -139.1 [95% confidence interval: -151.8, -126.5]) than tramadol (-109.1 [-121.7, -96.4]; p < 0.001), celecoxib (-103.7 [-116.4, -91.0]; p < 0.001), or placebo (-74.6 [-92.5, -56.6]; p < 0.001). Total treatment-emergent adverse events (TEAEs) were 358 for CTC and 394 for tramadol. Drug-related TEAEs occurred in 37.7% patients in the CTC group, compared with 48.6% in the tramadol group. There were no serious TEAEs/deaths. CONCLUSION: CTC provided greater analgesia than comparable daily doses of tramadol and celecoxib, with similar tolerability to tramadol. CTC is approved in the United States.

Extending the safety profile of the post-operative administration of an intravenous acetaminophen/ibuprofen fixed dose combination: An open-label, multi-center, single arm, multiple dose study.

PURPOSE: Postoperative pain is typically treated with multimodal analgesia, using systemic acetaminophen and/or nonsteroidal anti-inflammatory drugs in conjunction with opioids as required. The present study aimed to determine the safety and tolerability of repeated doses of an intravenous fixed-dose combination (FDC) of acetaminophen and ibuprofen. METHODS: This multicenter, open-label, single arm, multiple dose study was conducted at 4 centers across New Zealand and the United States between July 2019 and July 2020. Adults (>18 years) requiring multiple doses of parenteral nonopioid analgesics over multiple days following non-laparoscopic general, plastic or orthopedic surgery were eligible. The study drug (acetaminophen 1000 mg+ibuprofen 300 mg) was administered 6-hourly as a 5 min infusion for between 48 h and 5 days. Adverse event data was collected throughout the study, in addition to scheduled vital sign assessments, laboratory tests and electrocardiograms. Participants completed a global evaluation of the FDC at the end of the treatment period. FINDINGS: 232 participants received ≥ 1 dose of the FDC. Most were female (62.1%), White (56.5%) or Black or African American (39.2%), and had undergone orthopedic surgery (85.3%). There was a broad age range (19-87 years), with a mean age of 53.4 years, and 26.3% of participants aged ≥ 65 years. The FDC was safe when used for 48 h to 5 days. Treatment-emergent adverse events (TEAEs) affected 56.0% of participants, the most common were infusion site pain, nausea, infusion site extravasation, constipation, and headache. Minimal changes in vital signs were observed at scheduled timepoints. No clinically significant changes in electrocardiogram assessments occurred. Transient elevations in the hepatic enzymes ALT and AST to < 3 times the upper limit of normal (ULN) affected 10.5% and 9.6% of subjects, elevations to ≥ 3 times the ULN affected 2.6% and 2.2% of subjects, respectively. There were no apparent differences in the safety profile of the FDC in older participants. The FDC was well tolerated; most TEAEs were mild or moderate in severity. Five participants discontinued treatment due to TEAEs, none were considered treatment-related. The FDC was perceived well by study participants; the majority rated their experience as 'excellent' (40.1%) or 'very good' (35.3%). IMPLICATIONS: The safety profile was comparable to previous studies with no novel safety concerns. The FDC was safe, well tolerated, and perceived positively by participants treated for acute pain between 48 h and 5 days following orthopedic or plastic surgery, supporting a favorable risk benefit profile.

Efficacy and Safety of Intravenously Administered Tramadol in Patients with Moderate to Severe Pain Following Bunionectomy: A Randomized, Double-Blind, Placebo-Controlled, Dose-Finding Study.

INTRODUCTION: This study is part of the registrational program for intravenously administered (IV) tramadol in the USA and compared the analgesic benefit and tolerability of two doses of IV tramadol (50 mg and 25 mg) to placebo in adult patients undergoing bunionectomy, an orthopedic surgical model. METHODS: This was a phase 3, multicenter, double-blind, three-arm, randomized, placebo-controlled, multiple-dose, parallel-group trial to evaluate IV tramadol in the management of postoperative pain following bunionectomy. Eligible patients were randomized (1:1:1 ratio) to IV tramadol 50 mg, 25 mg, or placebo. Primary endpoint was summary of pain intensity differences over 48 h (SPID48). Key secondary endpoints included SPID24, total consumption of rescue analgesia, and patient global assessment of efficacy (PGA). Safety assessments included treatment emergent adverse events (TEAEs), clinical laboratory tests, vital signs, and electrocardiograms (ECGs). Assessment of the dose-response was an important objective of the study. RESULTS: The study established a dose response, with IV tramadol 50 mg demonstrating statistically significant benefit (p < 0.05) over placebo for primary and all key secondary efficacy endpoints, whereas tramadol 25 mg demonstrated intermediate results between the 50 mg and placebo arms. IV tramadol 50 mg was well tolerated; most common TEAEs were nausea and vomiting; and there were no meaningful differences among treatments for vital signs, ECG, and laboratory assessments. The largest proportion of patients completed tramadol 50 mg (98.6%) compared to tramadol 25 mg (91.8%) and placebo (88.2%). CONCLUSION: IV tramadol 50 mg was effective and well tolerated as treatment for postoperative pain following bunionectomy surgery, while IV tramadol 25 mg, although well tolerated, was judged an ineffective dose for the treatment of pain in this setting. IV tramadol 50 mg was further developed in the registrational program for the USA. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03290378.

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

PURPOSE: Multimodal 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. METHODS: This 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. FINDINGS: A 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. IMPLICATIONS: The 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.

Evaluation of the safety and efficacy of an intravenous nanocrystal formulation of meloxicam in the management of moderate-to-severe pain after bunionectomy.

OBJECTIVE: This randomized, double-blind, placebo-controlled study evaluated the safety and efficacy of an intravenous (IV) nanocrystal formulation of meloxicam in subjects with moderate-to-severe pain following a standardized unilateral bunionectomy. METHODS: Fifty-nine subjects aged 18-72 years were randomized to receive doses of either 30 mg (n=20) or 60 mg (n=20) meloxicam IV or placebo (n=19), administered once daily as bolus IV injections over 15-30 seconds (two or three doses). Safety, the primary objective, was assessed by physical examination, clinical laboratory tests, and the incidence of adverse events (AEs). Efficacy was evaluated by examining summed pain intensity differences over the first 48 hours (SPID48) using analysis of covariance models. Use of opioid rescue analgesic agents was evaluated. RESULTS: Generally, AEs were mild-to-moderate in intensity, and their incidence was similar across the three treatment groups. No serious AEs were reported; there were no withdrawals due to AEs, including injection-related AEs. The estimated effect size for SPID48 versus placebo was 1.15 and 1.01 for meloxicam IV doses 30 mg and 60 mg, respectively (P≤0.01). Both doses produced significantly greater pain reductions versus placebo (P≤0.05) at all evaluated times/ intervals during the 48-hour period. The proportions of subjects with ≥30% and ≥50% overall reduction in pain from baseline after 6 and 24 hours were significantly higher with meloxicam IV 30 mg doses versus placebo, but not with meloxicam IV 60 mg doses. The time to first use of rescue medication was significantly longer versus placebo with meloxicam IV 60 mg (P<0.05), but not with meloxicam IV 30 mg doses. CONCLUSION: Meloxicam IV was generally safe and well tolerated in subjects with moderate-to-severe post-bunionectomy pain. Once-daily administration of meloxicam IV 30 mg and 60 mg exhibited rapid onset of analgesia (as early as 15 minutes) with maintenance of analgesic effect for two consecutive 24-hour periods.

Efficacy and Safety of Intravenous Meloxicam in Patients With Moderate-to-Severe Pain Following Bunionectomy: A Randomized, Double-Blind, Placebo-controlled Trial.

OBJECTIVE: To evaluate the analgesic efficacy and safety of a novel intravenous (IV) formulation of meloxicam (30 mg) in patients with moderate-to-severe pain following a standardized, unilateral bunionectomy with first metatarsal osteotomy and internal fixation. MATERIALS AND METHODS: Patients who met the criteria for moderate-to-severe postoperative pain were randomized to receive bolus injections of meloxicam IV 30 mg (n=100) or placebo (n=101) administered once daily. The primary efficacy endpoint was the Summed Pain Intensity Difference over 48 hours (SPID48). Secondary efficacy endpoints included sum of time-weighted pain intensity differences (SPID) values at other timepoints/intervals, time to first use of rescue analgesia, and number of rescue doses taken. Safety assessments included the incidence of adverse events (AEs), physical examinations, laboratory tests, 12-lead electrocardiography, and wound healing. RESULTS: Patients randomized to meloxicam IV 30 mg exhibited a statistically significant difference in SPID48 versus the placebo group (P=0.0034). Statistically significant differences favoring meloxicam IV over placebo were also observed for secondary efficacy endpoints, including SPID at other times/intervals (SPID6: P=0.0153; SPID12: P=0.0053; SPID24: P=0.0084; and SPID24-48: P=0.0050) and first use of rescue medication (P=0.0076). Safety findings indicated that meloxicam IV 30 mg was generally well tolerated; no serious AEs or bleeding events were observed. Most AEs were assessed by the investigator to be mild in intensity, and no patients discontinued due to AEs. There were no meaningful differences between the study groups in vital signs, electrocardiographic findings, or laboratory assessments. In most cases, investigators found that wound healing followed a normal course and mean wound-healing satisfaction scores were similar for meloxicam IV 30 mg and placebo. DISCUSSION: Meloxicam IV doses of 30 mg provided effective pain relief when administered once daily by bolus injection to patients with moderate-to-severe pain following bunionectomy, and had an acceptable safety profile.

Diclofenac potassium liquid-filled soft gelatin capsules in the management of patients with postbunionectomy pain: a Phase III, multicenter, randomized, double-blind, placebo-controlled study conducted over 5 days.

BACKGROUND: Diclofenac potassium liquid-filled soft gelatin capsule (DPSGC) is a rapidly absorbed formulation of diclofenac potassium developed for the treatment of mild to moderate acute pain. OBJECTIVE: The present study was conducted to assess the efficacy and safety profile of DPSGC 25 mg in patients with pain after first-metatarsal bunionectomy. METHODS: This was a Phase III, multicenter, randomized, double-blind, parallel-group, placebo-controlled study conducted over 5 days. Patients experiencing the requisite level of pain (score > or = 4 on an 11-point numeric pain rating scale [NPRS] from 0 = no pain to 10 = worst possible pain) on the day after bunionectomy were randomized to receive DPSGC 25 mg or matching placebo. A second dose was given when patients requested additional medication for pain. Subsequent doses were given every 6 hours over a 48-hour inpatient multiple-dose period and continued over an additional 48-hour outpatient multiple-dose period. Opioid rescue medication was available as needed after the second dose of study medication. The primary efficacy end point was the mean NPRS score over the 48-hour inpatient multiple-dose period. Additional measures included NPRS scores at predefined times over 48 hours, the summed pain intensity difference over 48 hours (SPID48), the time-weighted sum of pain relief scores over the first 8 hours, the mean dosing interval (the time from dosing to the time rescue medication or the next dose of study medication was administered, whichever was less), the proportion of patients requiring rescue medication, and the onset of perceptible and meaningful pain relief (2-stopwatch method). Tolerability was assessed based on physician monitoring and patient reporting of adverse events (AEs) and the results of standard laboratory tests. RESULTS: Of 201 randomized patients (102 DPSGC 25 mg, 99 placebo; 86.6% female; 58.2% white; mean [SD] age, 45.2 [11.5] years; weight range, 49.4-108.0 kg), 198 completed the study. Mean baseline NPRS scores did not differ significantly between the DPSGC and placebo groups (6.9 and 7.3, respectively). DPSGC was associated with significant improvements compared with placebo in mean NPRS score over 48 hours (2.5 vs 5.6, respectively; P < 0.001), mean SPID48 (210.0 vs 90.3; P < 0.001), and overall mean dosing interval (331.5 vs 263.9 min; P < 0.001). Significant differences in NPRS scores between DPSGC 25 mg and placebo were noted at all time points from baseline through 48 hours (P < 0.001). The proportion of patients requiring rescue medication was significantly lower in the DPSGC group compared with the placebo group (39.2% vs 87.9% on day 1; 21.6% vs 64.6% on day 2; both, P < 0.001). Patients receiving DPSGC had a significantly faster onset of meaningful pain relief compared with those receiving placebo (P = 0.008). The most commonly reported AEs were nausea (7.8% vs 18.2%), headache (5.9% vs 9.1%), vomiting (3.9% vs 9.1%), and constipation (3.9% vs 2.0%). The overall incidence of AEs occurring in > or = 2% of patients was significantly lower in the DPSGC group than in the placebo group (20.6% vs 44.4%; P < 0.05); no patient receiving DPSGC had a serious AE. CONCLUSIONS: DPSGC 25 mg taken every 6 hours was effective in reducing postbunionectomy pain in the patients studied. DPSGC was well tolerated, suggesting that it may be a practicable option for the treatment of mild to moderate acute pain. ClinicalTrials. gov identifier: NCT00366444.