Eugene R. Viscusi

Efficacy and Safety of Single and Repeated Administration of 1 Gram Intravenous Acetaminophen Injection (Paracetamol) for Pain Management after Major Orthopedic Surgery

Background: Intravenous acetaminophen injection (paracetamol) is marketed in Europe for the management of acute pain. A repeated-dose, randomized, double-blind, placebo-controlled, three-parallel group study was performed to evaluate the analgesic efficacy and safety of intravenous acetaminophen as compared with its prodrug (propacetamol) and placebo. Propacetamol has been available in many European countries for more than 20 yr. Methods: After orthopedic surgery, patients reporting moderate to severe pain received either 1 g intravenous acetaminophen, 2 g propacetamol, or placebo at 6-h intervals over 24 h. Patients were allowed “rescue” intravenous patient-controlled analgesia morphine. Pain intensity, pain relief, and morphine use were measured at selected intervals. Safety was monitored through adverse event reporting, clinical examination, and laboratory testing. Results: One hundred fifty-one patients (intravenous acetaminophen: 49; propacetamol: 50; placebo: 52) received at least one dose of study medication. The intravenous acetaminophen and propacetamol groups differed significantly from the placebo group regarding pain relief from 15 min to 6 h (P < 0.05) and median time to morphine rescue (intravenous acetaminophen: 3 h; propacetamol: 2.6 h; placebo: 0.8 h). Intravenous acetaminophen and propacetamol significantly reduced morphine consumption over the 24-h period: The total morphine doses received over 24 h were 38.3 ± 35.1 mg for intravenous acetaminophen, 40.8 ± 30.2 mg for propacetamol, and 57. 4 ± 52.3 mg for placebo, corresponding to decreases of −33% (19 mg) and −29% (17 mg) for intravenous acetaminophen and propacetamol, respectively. Drug-related adverse events were reported in 8.2%, 50% (most of them local), and 17.3% of patients treated with intravenous acetaminophen, propacetamol, and placebo, respectively. Conclusion: Intravenous acetaminophen, 1 g, administered over a 24-h period in patients with moderate to severe pain after orthopedic surgery provided rapid and effective analgesia and was well tolerated.

A randomized, double-blind, dose-ranging study comparing wound infiltration of DepoFoam bupivacaine, an extended-release liposomal bupivacaine, to bupivacaine HCl for postsurgical analgesia in total knee arthroplasty.

INTRODUCTION DepoFoam bupivacaine is a novel liposomal formulation of bupivacaine designed to provide prolonged postsurgical analgesia. This dose-ranging study evaluated extent and duration of analgesia following administration of DepoFoam bupivacaine in patients undergoing total knee arthroplasty (TKA). METHODS Efficacy, safety, and pharmacokinetics of DepoFoam bupivacaine doses of 133, 266, 399, or 532 mg were compared with bupivacaine HCl (150 mg) with epinephrine given as single injections via wound infiltration in TKA patients (N=138). Primary efficacy measure was AUC of pain intensity scores assessed by numeric rating scale with activity (NRS-A) through Day 4 postsurgery. Other assessments included pain intensity at rest (NRS-R), postsurgical opioid consumption, and safety, among others. RESULTS Mean AUC of NRS-A scores through Day 4 were 20.7, 19.5, 18.8, and 19.1 for the 133-mg, 266-mg, 399-mg, and 532-mg DepoFoam bupivacaine groups vs 20.4 for bupivacaine HCl. With DepoFoam bupivacaine 532-mg, differences in NRS-R scores reached statistical significance (P<0.05) vs bupivacaine HCl on Days 1 and 5 and mean AUC NRS-R scores were significantly lower through Days 2-5; a dose-response trend was demonstrated. Mean rating for blinded care providers satisfaction with analgesia was significantly higher for DepoFoam bupivacaine 532 mg vs bupivacaine HCl (P ≤ 0.05). Other efficacy measures showed no statistically significant differences. CONCLUSION Exposure to bupivacaine increased in a dose-related manner, as reflected by mean and maximum plasma bupivacaine concentrations, and AUC(0-∞). Treatment with DepoFoam bupivacaine 532 mg was associated with statistically significantly greater analgesia while patients were at rest after surgery compared with bupivacaine HCl.

Alvimopan, a peripherally acting mu-opioid receptor antagonist, compared with placebo in postoperative ileus after major abdominal surgery Results of a randomized, double-blind, controlled study

BackgroundAlvimopan is a peripherally acting mu-opioid receptor (PAM-OR) antagonist for accelerating gastrointestinal recovery after surgery.MethodsPatients undergoing open laparotomy (bowel resection, n = 418; hysterectomy, n = 197) were randomized to receive alvimopan 6 or 12 mg or placebo orally ≥2 h before surgery and then b.i.d. until hospital discharge (up to 7 days). The primary efficacy endpoint was time to gastrointestinal (GI) recovery (measured by toleration of solid food and passage of flatus/stool; GI-3). Secondary endpoints included time to GI-2 recovery (toleration of solid food and passage of stool) and hospital discharge order written (DCO).ResultsAlvimopan did not significantly accelerate GI-3 compared with placebo [6 mg: hazard ratio (HR) = 1.20, p = 0.080; 12 mg: HR = 1.24, p = 0.038). However, after adjustment for significant covariates (sex/surgical duration), benefits were significant for both doses (6 mg: HR = 1.24, p = 0.037; 12 mg: HR = 1.26, p = 0.028). Alvimopan also significantly accelerated time to GI-2 (6 mg: HR = 1.37, p = 0.008; 12 mg: HR = 1.33, p = 0.018) and DCO (6 mg: HR = 1.31, p = 0.008; 12 mg: HR = 1.28, p = 0.015). Adverse events were similar between groups.ConclusionsAlvimopan (6 or 12 mg) accelerates GI recovery and is well tolerated in patients undergoing open laparotomy.

Acute Post-Surgical Pain Management: A Critical Appraisal of Current Practice

The Acute Pain Summit 2005 was convened to critically examine the perceptions of physicians about current methods used to control postoperative pain and to compare those perceptions with the available scientific evidence. Clinicians with expertise in treatment of postsurgical pain were asked to evaluate 10 practice-based statements. The statements were written to reflect areas within the field of acute-pain management, where significant questions remain regarding everyday practice. Each statement made a specific claim about the usefulness of a specific therapy (eg, PCA or epidural analgesia) or the use of pain-control modalities in specific patient populations (eg, epidural analgesia after colon resection). Members of the American Society of Regional Anesthesia and Pain Medicine (ASRA) were asked, via a Web-based survey, to rate their degree of agreement with each of the 10 statements; 22.8% (n = 632) of members responded. In preparation for the pain summit, a panel member independently conducted a literature search and summarized the available evidence relevant to each statement. Summit participants convened in December 2005. The assigned panel member presented the available evidence, and workshop participants then assigned a category for the level of evidence and recommendation for each statement. All participants then voted about each statement by use of the same accept/reject scale used earlier by ASRA members. This manuscript details those opinions and presents a critical analysis of the existing evidence supporting new and emerging techniques used to control postsurgical pain.

Alvimopan, for postoperative ileus following bowel resection: a pooled analysis of phase III studies.

Objective:To obtain further analysis regarding specific outcomes and alvimopan doses in bowel resection (BR) patients. Summary Background Data:Although postoperative ileus (POI) is common after BR, there is currently no recognized treatment or prevention available. Alvimopan, a novel, peripherally active mu-opioid receptor antagonist, accelerated GI recovery after BR or hysterectomy in 3 phase III trials. Methods:A pooled retrospective subset analysis of BR patients in alvimopan phase III trials was performed. Randomized BR patients received alvimopan 6 mg (n = 397), 12 mg (n = 413), or placebo (n = 402) ≥2 hours before surgery and twice daily until hospital discharge for ≤7 days. The primary endpoint of each trial was time to recovery of GI function. Hospital discharge order (DCO) written, readmission, and morbidities were also assessed. Cox proportional hazard models were used to analyze treatment effects on time-to-event endpoints. Results:Alvimopan (6 or 12 mg) significantly accelerated GI recovery (GI-3; hazard ratio = 1.28 and 1.38, respectively; P ≤ 0.001 for both). Alvimopan significantly accelerated time to DCO written by 16 hours for 6 mg and 18 hours for 12 mg (P < 0.001 for both) from a mean of 147 hours for placebo. Alvimopan-treated patients had reduced postoperative morbidity compared with placebo, and incidence of prolonged hospital stay or readmission was significantly reduced (P < 0.001). Tolerability profiles were similar among groups. Conclusions:Alvimopan significantly accelerated GI recovery in BR patients. A 12-mg dose provided more consistent benefits across both sexes and all ages. Postoperative morbidity rates, prolonged hospital stay, and rates of hospital readmission were significantly reduced. Alvimopan reduces the consequences of POI after BR.

An iontophoretic fentanyl patient-activated analgesic delivery system for postoperative pain: a double-blind, placebo-controlled trial.

An iontophoretic fentanyl HCl patient-activated transdermal system (fentanyl HCl PATS) is under development for the treatment of acute postoperative pain. The fentanyl HCl PATS is a needle-free, credit card-sized, preprogrammed system that is applied to the patients upper outer arm or chest. The fentanyl HCl PATS was demonstrated to be superior to placebo in a previous trial; however, the randomization scheme used and the lack of control of entry pain level may have contributed to the lack of robust findings. We compared the fentanyl HCl PATS with placebo for acute postoperative pain management in a larger trial that addressed the limitations of the previous study. Adult patients admitted to the postanesthesia care unit after major surgery were titrated to comfort with opioids and randomized 1:1 to receive the fentanyl HCl PATS 40 &mgr;g or placebo for 24 hours. Supplemental IV fentanyl was available to patients upon request in both treatment groups for the first 3 hours after enrollment. The primary efficacy end-point was the percentage of patients who discontinued participation in the study because of inadequate analgesia. Pain intensity scores, patient global assessments (PGA), and investigator global assessments (IGA) were collected. Four-hundred-eighty-four patients (PATS, n = 244; placebo, n = 240) were enrolled. Fewer patients receiving the fentanyl HCl PATS discontinued because of inadequate analgesia compared with placebo (28.7% versus 60.0%; P < 0.0001). Mean last pain intensity scores were 3.5 and 5.4 for the fentanyl HCl PATS and placebo groups, respectively. Patients (73.4%, PGA) and investigators (72.1%, IGA) considered the fentanyl HCl PATS a good or excellent method of pain control. Treatment-related adverse events were similar between groups. This study demonstrated the superiority of the iontophoretic fentanyl HCl PATS over placebo for acute postoperative pain management.

Forty-eight hours of postoperative pain relief after total hip arthroplasty with a novel, extended-release epidural morphine formulation

Background: Epidural morphine has proven analgesic efficacy in the postoperative period and is widely used. This study evaluated the efficacy of extended-release epidural morphine (EREM; DepoDur; Endo Pharmaceuticals Inc., Chadds Ford, PA; SkyePharma, Inc., San Diego, CA) in providing pain relief for 48 h after surgery. Methods: Patients (n = 200) scheduled to undergo total hip arthroplasty were randomized to receive a single dose of 15, 20, or 25 mg EREM or placebo. After surgery and after asking for pain medication, patients had access to intravenous patient-controlled analgesia fentanyl for breakthrough pain as needed. Postoperative intravenous patient-controlled analgesia fentanyl use, time to first postoperative fentanyl use, pain intensity at rest and with activity, patient and surgeon ratings of pain control, and adverse events were recorded. Results: All EREM dosages reduced the mean (± SD) fentanyl use versus placebo (510 ± 708 vs. 2,091 ± 1,803 &mgr;g; P < 0.0001) and delayed the median time to first dose of fentanyl (21.3 vs. 3.6 h; P < 0.0001). All EREM groups had significantly improved pain control at rest through 48 h postdose (area under the curve [0–48 h]) compared with placebo (P < 0.0005). More EREM-treated patients rated their pain control as good or very good compared with placebo (at 24 h: 90 vs. 65%, P < 0.0001; at 48 h: 83 vs. 67%, P < 0.05). No supplemental analgesia was needed in 25% of EREM-treated patients and 2% of placebo-treated patients at 48 h (P < 0.05). The safety profile of EREM was consistent with that of other epidurally administered opioid analgesics. Conclusions: EREM provided significant postoperative pain relief over a 48-h period after hip surgery, without the need for indwelling epidural catheters.

Effective treatment of laparoscopic cholecystectomy pain with intravenous followed by oral COX-2 specific inhibitor

In this multicenter, double-blinded, randomized, placebo-controlled study we evaluated the analgesic and opioid-sparing efficacy of a preoperative dose of IV parecoxib followed by oral valdecoxib in treating pain associated with elective laparoscopic cholecystectomy. Patients were randomized to receive a single IV dose of parecoxib 40 mg (n = 134) or placebo (n = 129) 30–45 min before induction of anesthesia. Six to 12 h after the IV dose, the parecoxib group received a single oral dose of valdecoxib 40 mg, followed by valdecoxib 40 mg qd on postoperative days 1–4, then 40 mg qd prn days 5–7. The placebo IV group received oral placebo on an identical schedule. All patients were allowed supplemental IV fentanyl as needed during the first 4 h postoperatively (T0–240 min) followed by hydrocodone 5 mg/acetaminophen 500 mg (Vicodin®; 1–2 tablets orally every 4–6 h as needed). Patients taking parecoxib used 21% less fentanyl than those receiving placebo (P = 0.011). The mean area under the curve of pain intensity (PI) scores over time from T0–240 min was 55.2 for parecoxib and 61.2 for placebo (P = 0.083). At T180 and T240 min, mean PI score was 7.0 and 7.6 points lower in the parecoxib group, respectively (P < 0.02). Fewer patients on valdecoxib required supplemental analgesics (P < 0.05) after discharge. At T240 min and at day 7, Patient’s and Physician’s/Nurse’s Global Evaluations were significantly better in the parecoxib/valdecoxib group (P < 0.05). Incidences of adverse events, adverse events causing withdrawal, and serious adverse events were less for parecoxib/valdecoxib than for placebo. The authors conclude that preoperative parecoxib is a valuable opioid-sparing adjunct to the standard of care for treating pain after laparoscopic cholecystectomy, and subsequent treatment with oral valdecoxib extends this clinical benefit.

Preoperative parenteral parecoxib and follow-up oral valdecoxib reduce length of stay and improve quality of patient recovery after laparoscopic cholecystectomy surgery.

In this randomized, double-blinded, placebo-controlled study, we evaluated the effects of preoperative IV parecoxib sodium (parecoxib) followed by postoperative oral valdecoxib on length of stay, resource utilization, opioid-related side effects, and patient recovery after elective laparoscopic cholecystectomy. Patients were randomized to receive a single IV dose of parecoxib 40 mg (n = 134) or placebo (n = 129) 30–45 min before the induction of anesthesia. Six to 12 h after the IV dose, the parecoxib group received a single oral dose of valdecoxib 40 mg, followed by valdecoxib 40 mg once daily on postoperative Days 1–4 and then 40 mg once daily as needed on Days 5–7. Patients in the parecoxib/valdecoxib group had a shorter length of stay in the postanesthesia care unit (78 ± 47 min) compared with those taking placebo (90 ± 49 min; P < 0.05). Patients in the parecoxib/valdecoxib group also had reduced pain intensity and, after discharge, experienced a significant reduction in vomiting in the first 24 h, slept better, returned to normal activity earlier, and expressed greater satisfaction than placebo patients (P < 0.05). Preoperative parecoxib followed by postoperative valdecoxib is a valuable adjunct for treating pain and improving patient outcome after laparoscopic cholecystectomy.

Patient-controlled drug delivery for acute postoperative pain management: a review of current and emerging technologies.

Postoperative pain management has dramatically improved with the advent of patient‐controlled analgesia (PCA) delivery. The optimal PCA system would encompass several key characteristics, including consistent efficacy across a number of surgeries; safety of both the analgesic drug delivered and the delivery system; ease of setup, maintenance, and administration; patient comfort during analgesic delivery; avoidance of analgesic gaps; minimal invasiveness; and it would be associated with high patient satisfaction. Existing PCA modalities (using intravenous or epidural routes) encompass some of these characteristics (e.g., they have demonstrated efficacy across a number of surgeries); however, they are limited by the need for an indwelling catheter and the time and resources required for system setup and use. Device programming‐related medication errors by hospital staff are an unfortunate risk, and could lead to significant harm. New PCA technologies are on the horizon that address some of the limitations to existing modalities; however, the added complexity of these newer systems are a concern, and their benefits and drawbacks remain to be assessed. These technologies include “smart” intravenous PCA infusion pumps to improve the safety of analgesic administration; needle‐free options, such as the fentanyl HCl iontophoretic transdermal system for transdermal delivery; and a number of PCA devices for intranasal delivery, as well as several new options for patient‐controlled regional analgesia. This review will discuss the benefits and drawbacks of both existing and emerging PCA modalities in the context of the ideal PCA system, and provide a critical evaluation of their use in postoperative settings.