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.

APOLLO-2: A Randomized, Placebo and Active-Controlled Phase III Study Investigating Oliceridine (TRV130), a G Protein-Biased Ligand at the µ-Opioid Receptor, for Management of Moderate to Severe Acute Pain Following Abdominoplasty.

OBJECTIVES: The clinical utility of conventional IV opioids is limited by the occurrence of opioid-related adverse events. Oliceridine is a novel G protein-biased µ-opioid receptor agonist designed to provide analgesia with an improved safety and tolerability profile. This phase III, double-blind, randomized trial (APOLLO-2 [NCT02820324]) evaluated the efficacy and safety of oliceridine for acute pain following abdominoplasty. METHODS: Patients received a loading dose of either placebo, oliceridine (1.5 mg), or morphine (4 mg), followed by demand doses via patient-controlled analgesia (0.1, 0.35, or 0.5 mg oliceridine; 1 mg morphine; or placebo) with a 6-minute lockout interval. The primary endpoint was the proportion of treatment responders over 24 hours for oliceridine regimens compared to placebo. Secondary outcomes included a predefined composite measure of respiratory safety burden (RSB, representing the cumulative duration of respiratory safety events) and the proportion of treatment responders vs. morphine. RESULTS: A total of 401 patients were treated with study medication. Effective analgesia was observed for all oliceridine regimens, with responder rates of 61.0%, 76.3%, and 70.0% for the 0.1-, 0.35-, and 0.5-mg regimens, respectively, compared with 45.7% for placebo (all P < 0.05) and 78.3% for morphine. Oliceridine 0.35- and 0.5-mg demand dose regimens were equi-analgesic to morphine using a noninferiority analysis. RSB showed a dose-dependent increase across oliceridine regimens (mean hours [standard deviation], 0.1 mg: 0.43 [1.56]; 0.35 mg: 1.48 [3.83]; 0.5 mg: 1.59 [4.26]; all comparisons not significant at P > 0.05 vs. placebo: 0.60 [2.82]). The RSB measure for morphine was 1.72 (3.86) (P < 0.05 vs. placebo). Gastrointestinal adverse events increased in a dose-dependent manner across oliceridine demand dose regimens (0.1 mg: 49.4%; 0.35 mg: 65.8%; 0.5 mg: 78.8%; vs. placebo: 47.0%; and morphine: 79.3%). In comparison to morphine, the proportion of patients experiencing nausea or vomiting was lower with the 2 equi-analgesic dose regimens of 0.35 and 0.5 mg oliceridine. CONCLUSIONS: Oliceridine is a safe and effective IV analgesic for the relief of moderate to severe acute postoperative pain in patients undergoing abdominoplasty. Since the low-dose regimen of 0.1 mg oliceridine was superior to placebo but not as effective as the morphine regimen, safety comparisons to morphine are relevant only to the 2 equi-analgesic dose groups of 0.35 and 0.5 mg, which showed a favorable safety and tolerability profile regarding respiratory and gastrointestinal adverse effects compared to morphine. These findings support that oliceridine may provide a new treatment option for patients with moderate to severe acute pain where an IV opioid is warranted.

Exploring the Interplay between Rescue Drugs, Data Imputation, and Study Outcomes: Conceptual Review and Qualitative Analysis of an Acute Pain Data Set.

In placebo-controlled acute surgical pain studies, provisions must be made for study subjects to receive adequate analgesic therapy. As such, most protocols allow study subjects to receive a pre-specified regimen of open-label analgesic drugs (rescue drugs) as needed. The selection of an appropriate rescue regimen is a critical experimental design choice. We hypothesized that a rescue regimen that is too liberal could lead to all study arms receiving similar levels of pain relief (thereby confounding experimental results), while a regimen that is too stringent could lead to a high subject dropout rate (giving rise to a preponderance of missing data). Despite the importance of rescue regimen as a study design feature, there exist no published review articles or meta-analysis focusing on the impact of rescue therapy on experimental outcomes. Therefore, when selecting a rescue regimen, researchers must rely on clinical factors (what analgesics do patients usually receive in similar surgical scenarios) and/or anecdotal evidence. In the following article, we attempt to bridge this gap by reviewing and discussing the experimental impacts of rescue therapy on a common acute surgical pain population: first metatarsal bunionectomy. The function of this analysis is to (1) create a framework for discussion and future exploration of rescue as a methodological study design feature, (2) discuss the interplay between data imputation techniques and rescue drugs, and (3) inform the readership regarding the impact of data imputation techniques on the validity of study conclusions. Our findings indicate that liberal rescue may degrade assay sensitivity, while stringent rescue may lead to unacceptably high dropout rates.

Pregabalin for the treatment of postoperative pain: results from three controlled trials using different surgical models.

PURPOSE: To evaluate the efficacy and safety of pregabalin (150 or 300 mg/d) as an adjunctive therapy for the treatment of postoperative pain. PATIENTS AND METHODS: This study reports findings from three separate, multicenter, randomized, double-blind, placebo-controlled trials of adjunctive pregabalin for the treatment of postoperative pain. Patients underwent one of three categories of surgical procedures (one procedure per study): elective inguinal hernia repair (post-IHR); elective total knee arthroplasty (post-TKA); or total abdominal hysterectomy (posthysterectomy). The primary endpoint in each trial, mean worst pain over the past 24 hours, was assessed 24 hours post-IHR and posthysterectomy, and 48 hours post-TKA. Patients rated their pain on a scale from 0 to 10, with higher scores indicating greater pain severity. RESULTS: In total, 425 (post-IHR), 307 (post-TKA), and 501 (posthysterectomy) patients were randomized to treatment. There were no statistically significant differences between the pregabalin and placebo groups with respect to the primary endpoint in any of the three trials. The least squares mean difference in worst pain, between 300 mg/d pregabalin and placebo, was -0.7 (95% confidence interval [CI] =-1.4, -0.1; Hochberg adjusted P=0.067) post-IHR; -0.34 (95% CI =-1.07, 0.39; P=0.362) post-TKA; and -0.2 (95% CI =-0.66, 0.31; P=0.471) posthysterectomy. CONCLUSION: There were no significant differences between pregabalin and placebo with respect to the primary pain intensity measure in each of the three clinical trials. These studies encompass a large dataset (1,233 patients in total), and their results should be considered when assessing pregabalin's effectiveness in postoperative pain. Further studies are required to determine the potential pain-reducing benefit of pregabalin in the postoperative setting.

IV acetaminophen: Efficacy of a single dose for postoperative pain after hip arthroplasty: subset data analysis of 2 unpublished randomized clinical trials.

Inadequate control of postoperative pain after orthopedic procedures may trigger complications that increase morbidity. Multimodal analgesia is used to manage pain effectively after surgical procedures and reduce the need for rescue analgesia. Intravenous (IV) acetaminophen (OFIRMEV; Cadence Pharmaceuticals, Inc.), an analgesic that has been studied and used in the multimodal management of acute pain after major orthopedic procedures, combines the safety seen with oral and rectal formulations with a preferred route of administration. Two double-blind, randomized, placebo-controlled clinical trials were conducted (total 130 patients) to determine the efficacy and safety of single-dose IV acetaminophen in patients following total hip arthroplasty. Although both studies were stopped prematurely, overlap in patient populations, study design, and methodologies in the single-dose phase of these studies allowed for analysis of their results to be presented concurrently. Both trials demonstrated IV acetaminophen having greater efficacy than placebo in terms of primary endpoints [pain intensity differences from T0.5 to T3 (P < 0.05 in both studies)]. The use of IV acetaminophen also reduced the need for rescue opioid consumption, with patients receiving IV acetaminophen consuming, on average, less than half the amount of rescue medication as those receiving placebo. IV acetaminophen was effective in treating moderate-to-severe pain after total hip arthroplasty and reduced the need for rescue opioid consumption.

A dose-finding study of sufentanil sublingual microtablets for the management of postoperative bunionectomy pain.

BACKGROUND: Sufentanil sublingual microtablets (SSMs) at a dose of 15 µg per tablet have been studied for postoperative patient-controlled analgesia with a 20-minute lockout via a bedside handheld system over 2 days to 3 days of use. For more short-term (<24 hours) management of acute moderate-to-severe pain, such as in the ambulatory surgical setting, a single, higher-strength SSM dose administered via a health care provider would be of benefit as it would require less frequent administration and avoid the setup of a drug delivery system. METHODS: This study was a two-center, randomized, double-blind, placebo-controlled trial for 12 hours in patients 18 years to 80 years of age who were undergoing bunionectomy alone or with hammertoe repair. Patients were randomly assigned at a 2:2:1 ratio to treatment with SSM 20 µg, SSM 30 µg, or placebo. The primary endpoint was time-weighted summed pain intensity difference to baseline over 12 hours (SPID12). Patients had to have a pain intensity score of 4 or higher just before initial microtablet dosing. Additional doses were administered when requested by the patient, with a minimum redosing interval of 1 hour. RESULTS: One hundred patients were randomized and received study drug. The SSM 30 µg was superior in the treatment of postbunionectomy surgical pain compared with placebo as demonstrated by the SPID12 score (6.53 vs. -7.12, respectively; p = 0.003) as well as all other secondary efficacy end points. The SSM 20-µg dosage strength was not superior to placebo for primary or secondary efficacy measures. Adverse events were similar among the three groups with the exception of nausea, vomiting, and somnolence, which demonstrated a dose-dependent increase in occurrence. CONCLUSION: The SSM 30 µg may be an effective, noninvasive alternative to health care provider-administered intravenous, intramuscular, or oral opioids for the management of moderate-to-severe acute pain. LEVEL OF EVIDENCE: Therapeutic study, level I.

A comparison of the clinical and experimental characteristics of four acute surgical pain models: dental extraction, bunionectomy, joint replacement, and soft tissue surgery.

When a clinical trial of an analgesic produces a negative finding, it is important to consider the influence (if any) of experimental error on the validity of that result. Although efforts to identify and minimize experimental error in chronic pain investigations have begun in earnest, less work has been performed on the optimization of acute pain methodology. Of the acute surgical pain methodology articles that have been published over the last decade, almost all focus on either the dental or bunion model. Analgesics are typically evaluated in a variety of surgical models that eventually include hospital-based models (eg, joint replacement and soft tissue surgery). Every surgical procedure has unique clinical characteristics that must be considered to optimize study design and conduct. Much of the methodological knowledge garnered from bunion and dental studies is applicable to other surgical models, but some extrapolations are hazardous. The purposes of this review were (1) to qualitatively describe the clinical and experimental characteristics of the 4 classic surgical models: dental extraction, bunionectomy, joint replacement, and soft tissue surgery; and (2) to quantitatively compare the models by analyzing 3 factors: effect size, enrollment rate, and demographics. We found that the dental extraction and bunionectomy models had higher assay sensitivity than the joint replacement and soft tissue surgery models. It is probable that this finding is secondary to the superior experimental conditions under which the dental and bunion models are executed (utilization of few centers that have the ability to reduce surgical, anesthetic, and postoperative confounders).

Pharmacokinetics of sublingual sufentanil tablets and efficacy and safety in the management of postoperative pain.

BACKGROUND AND OBJECTIVES: A sublingual sufentanil tablet is being developed as a potential alternative to intravenous (IV) opioids for the management of postoperative pain. The objective of these studies was to evaluate the pharmacokinetics, efficacy, and safety of sublingual sufentanil tablets for postoperative pain management. METHODS: The pharmacokinetics of sublingual sufentanil 10 and 80 µg were compared with IV sufentanil in 12 subjects in a phase 1 study. The safety and efficacy of sublingual sufentanil (5-15 µg) were evaluated in double-blind, randomized, placebo-controlled phase 2 studies in patients undergoing knee replacement surgery (n = 101) or open abdominal (ABD) surgery (n = 94). The primary efficacy measurement was the summed pain intensity difference compared with baseline over 12 hours (SPID-12). RESULTS: Sublingual sufentanil pharmacokinetics were dose proportional following single doses of 10 and 80 µg. Plasma half-time (time from peak plasma concentration to 50% of peak concentration) was 80 to 90 minutes for sublingual sufentanil compared with 15 minutes or less for IV sufentanil. In the phase 2 studies, greater SPID-12 scores (ie, lower pain intensity) compared with placebo were observed for sublingual sufentanil 15 µg in the knee replacement study (P < 0.05) and for 10 and 15 µg in the ABD study (P < 0.01). All doses of sublingual sufentanil were well tolerated, and the incidence of adverse events was similar between the sublingual sufentanil and placebo groups. CONCLUSIONS: Sufentanil formulated as a sublingual solid dosage form provides a duration of action that allows effective analgesia for postoperative patients in a medically supervised setting.

Safety and immunogenicity of recombinant human thrombin: a pooled analysis of results from 10 clinical trials.

STUDY OBJECTIVE: To evaluate the safety and immunogenicity of recombinant human thrombin (rThrombin), an active topical stand-alone hemostatic agent. DESIGN: Analysis of pooled data from 10 rThrombin clinical trials. PATIENTS: A total of 644 adult and pediatric patients treated with rThrombin; 609 patients were included in the immunogenicity analysis. MEASUREMENTS AND MAIN RESULTS: In all studies, rThrombin was applied during a single surgical procedure (day 1); the procedures consisted of spinal procedures, major hepatic resection, peripheral arterial bypass, arteriovenous graft formation for hemodialysis access, and synchronous burn wound excision and skin grafting. A dosage of 1000 IU/ml of rThrombin was administered for more than 99% of patients. Adverse events and clinical laboratory values were monitored through day 29. Blood samples were obtained for immunogenicity analyses before the procedure and on day 29. Adverse events were mild or moderate in severity for the majority of patients; no patients discontinued from an rThrombin study due to adverse events. The most commonly reported adverse events in the 644 patients were incision site pain (305 patients [47.4%]), procedural pain (215 patients [33.4%]), and nausea (170 patients [26.4%]). Five patients (0.8%) died during the studies; all deaths were considered unrelated to rThrombin treatment. Antibodies to the rThrombin product developed in 5 (0.8%, 95% confidence interval 0.4-2.8%) of 609 patients by day 29, approximately 1 month after treatment; these antibodies did not neutralize the activity of native human thrombin. The development of antibodies did not appear to differ substantively by type of surgical procedure, amount of rThrombin administered, or patient age. CONCLUSION: Recombinant human thrombin was well tolerated, and adverse events were consistent with those reported in the postoperative setting in the surgical populations studied. Approximately 1 month after treatment, less than 1% of the patients had developed antibodies to the rThrombin product, and these antibodies did not neutralize the activity of native human thrombin. These results support the safety of rThrombin when used as a topical aid to hemostasis in numerous surgical settings and for patients of differing ages.

Plasma and cerebrospinal fluid pharmacokinetic parameters after single-dose administration of intravenous, oral, or rectal acetaminophen.

BACKGROUND: This is the first study to compare plasma and cerebrospinal fluid (CSF) pharmacokinetics of intravenous (IV), oral (PO), or rectal (PR) formulations of acetaminophen. METHODS: Healthy male subjects (N = 6) were randomized to receive a single dose of IV (OFIRMEV(®) ; Cadence) 1,000 mg (15 minute infusion), PO (2 Tylenol(®) 500 mg caplets; McNeil Consumer Healthcare), or PR acetaminophen (2 Feverall(®) 650 mg suppositories; Actavis) with a 1-day washout period between doses. The 1,300 mg PR concentrations were standardized to 1,000 mg. Acetaminophen plasma and CSF levels were obtained at T0, 0.25, 0.5, 0.75, 1, 2, 3, 4, and 6 hours. RESULTS: IV acetaminophen showed earlier and higher plasma and CSF levels compared with PO or PR administration. CSF bioavailability over 6 hours (AUC(0-6)) for IV, PO, and PR 1 g was 24.9, 14.2, and 10.3 µg·h/mL, respectively. No treatment-related adverse events were reported. One subject was replaced because of premature failure of his lumbar spinal catheter. The mean CSF level in the IV group was similar to plasma from 3 to 4 hours and higher from 4 hours on. Absorption phase, variability in plasma, and CSF were greater in PO and PR groups than variability with IV administration. CONCLUSIONS: These results demonstrate that earlier and greater CSF penetration occurs as a result of the earlier and higher plasma peak with IV administration compared with PO or PR.

Immunogenicity and safety of re-exposure to recombinant human thrombin in surgical hemostasis.

BACKGROUND: This Phase 4, open-label study evaluated the immunogenicity and safety of a second exposure to recombinant human thrombin (rThrombin) in adult patients with previous exposure to rThrombin. STUDY DESIGN: Topical rThrombin was applied as a hemostatic aid during a surgical procedure (day 1). Adverse events and clinical laboratory abnormalities were monitored to day 29 (study end). Immunogenicity samples were collected on days 1 and 29. Thirty-one patients were treated at 9 study sites; 30 patients completed the study. RESULTS: Mean age was 59.5 years; 61.3% of patients were male. Study operations types included spinal (n = 23 of 31; 74.2%), arterial reconstruction or peripheral arterial bypass (n = 4; 12.9%), arteriovenous vascular access procedure (n = 3; 9.7%), and other (n = 1; 3.2%). A median of 10 mL rThrombin (1,000 IU/mL; range 5 to 60 mL) was prepared per patient. Median elapsed time since previous rThrombin exposure was 1.3 years (range 19 days to 3.3 years). Recombinant human thrombin was not observed to be immunogenic; no patients (n = 0 of 30, 0%; 95% CI 0.0%, 11.6%) became positive for anti-rThrombin product antibodies at day 29, approximately 1 month after the second exposure to rThrombin. The most commonly reported adverse events were procedural pain (n = 23 of 31, 74.2%), constipation (n = 8, 25.8%), and nausea (n = 8, 25.8%) All adverse events and clinical laboratory abnormalities were considered unrelated to treatment. For the majority of patients, maximal severity of any adverse event was mild or moderate. CONCLUSIONS: The immunogenicity and safety results of this Phase 4 rThrombin trial suggest that patients with known previous exposure may be safely re-exposed to topical rThrombin.

Persistence of antibodies to the topical hemostat bovine thrombin.

BACKGROUND: Immunoassays that detect antibovine thrombin product antibodies are not widely available. However, knowing whether these antibodies are present preoperatively would be useful because re-exposure to bovine thrombin-containing products is contraindicated in patients with pre-existing antiproduct antibodies due to the risk of developing immune-mediated coagulopathies. In these exploratory analyses, we characterized one aspect of immune sensitization, the persistence of circulating antibodies after exposure to bovine thrombin product. STUDY DESIGN: Elapsed time since a historical surgical procedure with documented or highly likely use of bovine thrombin product was determined for 204 patients enrolled in a recently completed trial. After study completion, baseline samples were assayed for antibovine thrombin product antibodies using validated immunoassays. Antibody data were sorted by time elapsed since the historical procedure. The proportion of patients with antibovine thrombin product antibodies and 95% confidence interval (CI) were determined for each 1-year period, providing an estimate for antibody persistence. RESULTS: Antibovine thrombin product antibodies were detected in 20.7% of patients (23 of 111; 95% CI 14.2%, 29.2%) with ≤1 year since the historical surgical procedure; 6.8% of patients (3 of 44; 95% CI 1.68%, 18.9%) with 1 to <2 years; 16.1% of patients (5 of 31; 95% CI 6.62%, 33.1%) with 2 to <3 years; and 5.6% of patients (1 of 18; 95% CI 0.00%, 27.6%) with ≥3 years since the historical procedure. CONCLUSIONS: The proportion of patients with antibovine thrombin product antibodies ranged from 5.6% to 20.7% across the multiyear postoperative window. Clinicians should be aware that antibodies to bovine thrombin products may persist for years after exposure.

Phase II study to evaluate the safety and efficacy of the oral neurokinin-1 receptor antagonist casopitant (GW679769) administered with ondansetron for the prevention of postoperative and postdischarge nausea and vomiting in high-risk patients.

BACKGROUND: In recent years, there has been an increased interest in using a multimodal approach with combined agents to treat postoperative nausea and vomiting. This study evaluated whether the addition of an oral dose of the neurokinin-1 receptor antagonist casopitant improved the antiemetic efficacy of an intravenous dose of ondansetron hydrochloride. METHODS: The authors enrolled 702 premenopausal or perimenopausal, nonsmoking, female patients aged 18-55 yr with a history of postoperative nausea and vomiting and/or motion sickness undergoing a laparoscopic or laparotomic gynecologic surgical procedure or laparoscopic cholecystectomy with general anesthesia. Subjects were randomized to one of five treatment arms: standard ondansetron 4 mg with casopitant at 0, 50, 100, or 150 mg, or 0 mg ondansetron with casopitant at 150 mg (the latter arm was considered an exploratory study group and was included in the safety analysis but not in the efficacy analysis). RESULTS: A significantly greater proportion of patients in all of the active casopitant plus ondansetron groups achieved a complete response (i.e., no vomiting, retching, rescue medication, or premature withdrawal) during the first 24 h postoperatively versus those in the ondansetron-alone group (59-62% vs. 40%, respectively; P = 0.0006). All active doses seemed to be well tolerated; headache, dizziness, and constipation were the most frequently reported adverse events. CONCLUSIONS: Compared with ondansetron alone, the casopitant and ondansetron combination results in superior emesis prevention during the first 24 h postoperatively in female patients with known risk factors for postoperative nausea and vomiting.

Safety and immunogenicity observations pooled from eight clinical trials of recombinant human thrombin.

BACKGROUND: We evaluated safety and immunogenicity observations pooled from 8 clinical trials of recombinant human thrombin (rThrombin), an active topical hemostatic agent. STUDY DESIGN: Recombinant thrombin was applied with an absorbable gelatin sponge or spray applicator during a surgical procedure (day 1). Adverse events and laboratory parameters were monitored until study end (day 29). Immunogenicity was evaluated after study completion on plasma samples collected at baseline and on day 29. RESULTS: Studies included 583 rThrombin-treated patients (median age, 59 years; 54% men). Surgical procedures included: spinal, 33% of patients; hepatic resection, 14%; peripheral arterial bypass, 23%; arteriovenous graft formation for hemodialysis access, 18%; and skin graft after burn wound excision, 12%. Adverse events reported for >or= 10% patients included incision site pain, procedural pain, nausea, constipation, pyrexia, anemia, insomnia, vomiting, and pruritus. Five of 552 patients developed antibodies to rThrombin (0.9%; 95% CI, 0.3 to 2.1; day 29); antibodies did not neutralize the biologic activity of native human thrombin. At baseline, 12 patients had pre-existing, antibodies recognizing rThrombin (12 of 552; 2.2%; 95% CI, 1.1 to 3.8); these patients had no previous exposure to rThrombin and their antibody titer did not increase >or= 1.0 unit (>or= 10-fold) at day 29. CONCLUSIONS: Results from 8 clinical trials collectively demonstrated that rThrombin is well tolerated in numerous surgical settings when used as a topical adjunct to hemostasis. Adverse events and changes in laboratory parameters were consistent with commonly reported postoperative events. Less than 1% of patients developed antibodies to rThrombin; the antibodies did not neutralize native human thrombin.

A randomized, double-blind, placebo-controlled, multicenter, repeat-dose study of two intravenous acetaminophen dosing regimens for the treatment of pain after abdominal laparoscopic surgery.

BACKGROUND: Intravenous acetaminophen has been approved in Europe and elsewhere for the treatment of acute pain and fever, and was recently approved by the US Food and Drug Administration (FDA) for the management of mild to moderate pain, the management of moderate to severe pain with adjunctive opioid analgesics, and the reduction of fever. OBJECTIVE: The aim of this work was to evaluate the analgesic efficacy and safety of repeated doses of 2 dosing regimens of intravenous acetaminophen compared with placebo over 24 hours in subjects with moderate to severe pain after abdominal laparoscopic surgery. METHODS: This double-blind, placebo-controlled, parallel-group study was conducted at 17 sites in the United States and enrolled adult subjects (aged 18-80 years) who were randomized to 4 groups (IV acetaminophen 1000 mg [100 mL] q6h; IV acetaminophen 650 mg [65 mL] q4h; IV placebo 100 mL q6h; or IV placebo 65 mL q4h), each given as a 15-minute infusion after surgery for 24 hours. An open-label extension was offered to all subjects who remained in the hospital beyond the study period. Two subjects (1 in the placebo 100 mL q6h group and 1 in the IV acetaminophen 1000 mg q6h group) were enrolled in the open-label extension and were eligible to receive unblinded IV acetaminophen 1000 mg. Before randomization, the choice of opioid for patient-controlled analgesia (PCA) rescue was left to the investigator; however, acetaminophen-containing products, NSAIDs, and aspirin were not allowed. The morning after abdominal laparoscopic surgery procedure, subjects' PCA was withheld until pain intensity (PI) was moderate (2) or severe (3) on a categorical scale (range, 0-3) and between 40 and 70 mm, inclusive, on a 100-mm visual analog scale, at which point they were randomized. After the first dose of study medication, intravenous rescue was restricted to morphine or hydromorphone, and oral rescue was restricted to morphine or oxycodone immediate-release tablets. Efficacy analyses were performed using the modified intent-to-treat (mITT) population, defined as all randomized subjects who received ≥ 1 complete dose of study medication before requesting rescue medication, and who had ≥ 1 completed PI/pain relief (PR) assessment after baseline. The primary efficacy end point was the weighted sum of PI differences over 24 hours (SPID24) using an ANCOVA model. Time to meaningful PR was documented after the first dose of study medication using a double-stopwatch method: at T0, 2 stopwatches were started, and subjects were instructed to stop the first stopwatch when they felt perceptible PR and the second when it became meaningful. Safety was assessed via spontaneous adverse event (AE) reporting and laboratory tests. RESULTS: A total of 349 subjects were screened before elective surgery for eligibility. Of these, 244 subjects were randomized to a study arm (IV acetaminophen 1000 mg [n = 92]; IV acetaminophen 650 mg [n = 42]; IV placebo 100 mL [n = 43]; or IV placebo 65 mL [n = 67]) and included in the ITT population, of whom 81.1% (198/244) were women and 87.3% (213/244) were white; the mean (SD) age was 46.2 (12.51) years (range, 18-78 years), and the mean weight was 174.3 (35.7) lb (range, 103-284 lb). There was an allocation error in the contract research organization's program linking group assignment and kit randomization; therefore, the original randomization procedure was replaced with a modified randomization schedule created by an independent biostatistician under the supervision of the FDA. The mITT population included 241 subjects; of these, 227 completed 24 hours of treatment. Four subjects withdrew before completing treatment because of AEs (1 subject in the placebo group because of fever and 3 in the IV acetaminophen 1000 mg q6h group because of infusion-site pain [n = 1] or infiltration [n = 2]), 8 because of withdrawal of consent, 2 because of early discharge from the hospital, and 2 for other reasons. Only 2 subjects participated in the elective open-label extension. Both intravenous acetaminophen dosing regimens were associated with significantly reduced SPID24 compared with placebo (1000 mg q6h, P < 0.007; 650 mg q4h, P < 0.019). Among the mITT population, SPID24 (using nonimputed data after first rescue: 1000 mg q6h, P < 0.001; 650 mg q4h, P = 0.020), sum of PR scores over 24 hours (1000 mg q6h, P < 0.001; 650 mg q4h, P = 0.003) and 12 hours (1000 mg q6h, P < 0.001; 650 mg q4h, P = 0.001), and subjects' global evaluations at 24 hours (1000 mg q6h, P < 0.001; 650 mg q4h, P = 0.005) were statistically significant in favor of both acetaminophen dosing regimens compared with the combined placebo group. Time to meaningful PR (by double stopwatch method) after the first dose was significantly shorter among subjects who received IV acetaminophen 1000 mg compared with subjects in the placebo 100 mL group (median of 24.9 vs 53.9 minutes, respectively). The most common overall AEs (ie, those that occurred in >10% of any group) were constipation, flatulence, nausea, and headache. The frequency of treatment-emergent AEs (TEAEs) across the treatment groups was not statistically significant. Most TEAEs were deemed to be unrelated to study medication. There were 6 subjects with serious TEAEs (1 [0.9%] in the IV acetaminophen 1000 mg group, 3 [7.0%] in the IV acetaminophen 650 mg group, and 2 [1.8%] in the placebo group). There was 1 (2.3%) related hepatic TEAE (transaminase increased) in the placebo group. CONCLUSION: Both regimens of intravenous acetaminophen (1000 mg q6h and 650 mg q4h) were associated with statistically significant analgesic efficacy compared with placebo and were well tolerated in these adults after abdominal laparoscopic surgery. ClinicalTrials.gov identifier: NCT00564486.

A phase 3b, open-label, single-group immunogenicity and safety study of topical recombinant thrombin in surgical hemostasis.

BACKGROUND: The immunogenicity and safety of recombinant human thrombin (rThrombin) were evaluated in this phase 3b, open-label, single-group, multisite study of 209 adult vascular and spinal operation patients at high risk for preexisting anti-bovine thrombin product antibodies. STUDY DESIGN: Patients received rThrombin applied as a topical hemostat during a surgical procedure (day 1). Immunogenicity samples were collected at baseline and approximately 1 month after operation (day 29) and were analyzed after study participation. RESULTS: Mean patient age was 61.5 years; median number of previous surgical procedures was 5.0 (range, 1 to 25). Operation types included spinal (n = 89 of 209 [43%]), arterial reconstruction (including peripheral arterial bypass; n = 75 of 209 [36%]), and arteriovenous vascular access procedures (n = 45 of 209 [22%]). All patients had confirmed or highly likely previous bovine thrombin exposure; at baseline, 15.6% of patients (n = 32 of 205) had preexisting anti-bovine thrombin antibodies. Of 200 patients with complete immunogenicity evaluations, 31 had preexisting anti-bovine thrombin antibodies (15.5%), and 4 had preexisting anti-rThrombin product antibodies (2.0%). None of the 200 patients became antibody positive for rThrombin antibodies on day 29 (seroconversion or > or = 10-fold increase in titer). Adverse events and laboratory results were consistent with a surgical population with substantial comorbidities. Patients with preexisting antibodies to bovine thrombin were older (p = 0.04) and had undergone more surgical procedures previously (p < 0.001) than patients without preexisting antibodies. CONCLUSIONS: Results of this study confirm the low immunogenicity of rThrombin and suggest that rThrombin can be used safely as an aid to hemostasis in patients with or without preexisting anti-bovine thrombin antibodies. A sizeable proportion of this vascular and spinal operation patient population (15.6%) had preexisting anti-bovine thrombin antibodies; these patients are at risk for immune responses after reexposure to bovine thrombin.

Safety and efficacy of the cyclooxygenase-2 inhibitors parecoxib and valdecoxib after noncardiac surgery.

BACKGROUND: Valdecoxib and its intravenous prodrug parecoxib are reported to increase thromboembolic risk after coronary artery bypass grafting. The authors conducted a randomized trial to examine their safety and analgesic efficacy in patients recovering from major noncardiac surgical procedures. METHODS: The trial was randomized and double-blind, with 10 days of treatment and 30 days of follow-up. Patients (n = 1,062) received either parenteral parecoxib for 3 days and oral valdecoxib for the rest of the treatment period or placebo medications throughout. The frequency of predefined adjudicated postrandomization adverse events, including cardiovascular thromboembolism, renal dysfunction, gastroduodenal ulceration, and wound-healing complications, was assessed in each group. Secondary efficacy endpoints included patients' pain ratings, opioid analgesic consumption (recorded as morphine equivalents), and reports of opioid-related adverse effects. RESULTS: Predefined adjudicated adverse events had similar frequencies among patients who received parecoxib and valdecoxib (2.7%) and placebo patients (3.2%) (P = 0.58), including cardiovascular thromboembolic events (1.0% in each group; P = 1.0). Placebo patients consumed more morphine equivalents (66.2 +/- 92.4 mg) than did patients receiving parecoxib and valdecoxib (43.2 +/- 65.7 mg) (P < 0.001). Placebo patients had higher mean pain ratings on each of study days 2-10 (P < 0.01) and reported more opioid-related symptom distress on days 2-6 (P < 0.01). CONCLUSIONS: Parecoxib and valdecoxib are useful adjuncts to opioids for the treatment of postoperative pain in noncardiac surgical patients. Further study will be required to determine the safety profile of parecoxib and valdecoxib administered to patients with known atherosclerotic disease after noncardiac surgery.