A comparison of opioid-related adverse events with fentanyl iontophoretic transdermal system versus morphine intravenous patient-controlled analgesia in acute postoperative pain.

OBJECTIVE: This analysis compared opioid-related adverse events (ORADEs) observed with fentanyl iontophoretic transdermal system (ITS) versus morphine intravenous (iv.) patient-controlled analgesia (PCA) in the management of postoperative pain. METHODS: Safety data from four Phase IIIB randomized, active-comparator trials were pooled for this analysis (n = 1288 fentanyl ITS and 1313 morphine iv. PCA patients). Treatment-emergent adverse events were collected via spontaneous report. In this post hoc analysis, ORADEs were defined as apnea, confusion, constipation, dyspnea, hypotension, hypoventilation, hypoxia, ileus, nausea, pruritus, somnolence, tachycardia, urinary retention and vomiting. Odds ratios (OR) and 95% CI were calculated for all ORADEs and p-values were based on logistic regression with treatment as effect. RESULTS: There were fewer patients in the fentanyl ITS group compared with the morphine iv. PCA group who experienced at least one ORADE (52.7 vs 59.1%, respectively; OR: 0.772: 95% CI: 0.661-0.901; p = 0.0011). The ORADEs that occurred less frequently in the fentanyl ITS group than in the morphine iv. PCA group included hypotension (3.7 vs 5.5%, respectively; OR: 0.667; 95% CI: 0.459-0.969; p = 0.0338), hypoventilation (0.9 vs 1.9%, respectively; OR: 0.444; 95% CI: 0.217-0.906; p = 0.0256), nausea (40.3 vs 44.5%, respectively; OR: 0.842; 95% CI: 0.721-0.984; p = 0.0310), pruritus (5.5 vs 9.4%, respectively; OR: 0.559; 95% CI: 0.413-0.757; p = 0.0002) and tachycardia (1.6 vs 2.8%, respectively; OR: 0.489; 95% CI: 0.277-0.863; p = 0.0136). No ORADEs occurred more frequently in the fentanyl ITS group compared with the morphine iv. PCA group. CONCLUSION: Fentanyl ITS, in the management of acute postoperative pain, offered safety advantages in terms of ORADEs compared with morphine iv. PCA.

Meta-analysis of the efficacy of the fentanyl iontophoretic transdermal system versus intravenous patient-controlled analgesia in postoperative pain management.

OBJECTIVE: This meta-analysis was conducted to analyze and compare the efficacy outcomes associated with the fentanyl iontophoretic transdermal system (ITS) and morphine intravenous (IV) patient-controlled analgesia (PCA) in the management of postoperative pain. RESEARCH DESIGN AND METHODS: This meta-analysis assessed the efficacy of the fentanyl ITS versus morphine IV PCA using data from four randomized, active-controlled trials (n = 1271 fentanyl ITS and 1298 morphine IV PCA patients). Main outcome measures were patient global assessment (PGA) of the method of pain control at 24 h. RESULTS: Fentanyl ITS and morphine IV PCA did not significantly differ regarding 'good' and 'excellent' ratings on the PGA of the method of pain control at 24 h (odds ratio = 0.95, p = 0.66), however, fentanyl ITS was superior in terms of 'excellent' PGA ratings at that time point (odds ratio = 1.53, p < 0.0001). No significant differences were found in weighted mean pain intensity scores at 24, 48 and 72 h. CONCLUSIONS: In this meta-analysis, fentanyl ITS was as efficacious as morphine IV PCA and may offer additional benefits as demonstrated by its 'excellent' PGA ratings.

Pharmacokinetic characteristics of fentanyl iontophoretic trandermal system over a range of applied current.

OBJECTIVE: To evaluate the pharmacokinetic (PK) characteristics of a modified fentanyl iontophoretic transdermal system (ITS). RESEARCH DESIGN AND METHODS: This was a prospective, open-label, single-center, randomized, 3-period, 5-treatment, 6-sequence study. Each subject was randomly assigned to receive three treatments in a sequence consisting of intravenous fentanyl citrate, fentanyl ITS at 170 µA, and then one of three other fentanyl ITS treatments at 140, 200 or 230 µA. MAIN OUTCOME MEASURES: The following PK parameters were determined: Cmax, tmax, t1/2, AUC23 - 25 and amount of fentanyl absorbed into systemic circulation (i.e., Dose Absorbed). RESULTS: Fifty-two subjects received at least one fentanyl treatment. Serum exposure (Cmax and AUC23 - 25) and Dose Absorbed increased with increasing current. The median tmax ranged from 23.0 to 23.2 h across the 4 ITS groups. Mean t1/2 values ranged from 11.0 to 13.0 h. The Dose Absorbed from the fentanyl ITS at 170 µA met bioequivalence criteria when compared to data from an earlier version of the fentanyl ITS. CONCLUSIONS: Exposure of fentanyl and the amount of fentanyl absorbed increased with the magnitude of applied current with the ITS. The fentanyl ITS at 170 µA is bioequivalent to an earlier version of the system.

Perioperative pain management in hip and knee replacement surgery.

Many patients who undergo hip or knee replacement surgery today experience high levels of postoperative pain. Data from clinical studies and analyses of hospital records have demonstrated that severe postoperative pain is associated with an increased risk for complications, slowing of the rehabilitation process, delayed return to normal functioning, progression to persistent pain states, prolonged length of hospital stay, elevated rates of readmission, and higher overall costs. Orthopedic surgeons may now play a more active role in reducing the severity of pain following surgery, decreasing both opioid use and the incidence of opioid-related adverse events, and eliminating breakthrough pain and analgesic gaps. The benefits of multimodal regimens that include a combination of agents acting synergistically have been established unequivocally, and many analgesic and anesthetic agents are now available, as well as treatment options that differ according to route of administration. It is therefore possible to individualize treatment based on the type of procedure and patient need. One exciting advance that offers effective, safe, and efficient analgesia for many kinds of surgical procedures is the introduction of an extended-release local anesthetic (liposomal bupivacaine) for infiltration. This new option, which can be administered directly into the knee or hip by an orthopedic surgeon, is an example of the changing paradigm in perioperative analgesia, where commitment, communication, and coordination across all members of the clinical care team- including the surgeon, anesthesiologist, pharmacist, physical therapist, and nursing staff-are fundamental elements of an improved standard of care. An Expert Working Group on Anesthesia and Orthopaedics: Critical Issues in Hip and Knee Replacement Arthroplasty (April 13, 2013; Dallas, Texas) evaluated current approaches to perioperative pain management and proposed new regimens to help achieve optimal outcomes in these procedures.

Defining new directions for more effective management of surgical pain in the United States: highlights of the inaugural Surgical Pain Congress™.

Despite advances in pharmacologic options for the management of surgical pain, there appears to have been little or no overall improvement over the last two decades in the level of pain experienced by patients. The importance of adequate and effective surgical pain management, however, is clear, because inadequate pain control 1) has a wide range of undesirable physiologic and immunologic effects; 2) is associated with poor surgical outcomes; 3) has increased probability of readmission; and 4) adversely affects the overall cost of care as well as patient satisfaction. There is a clear unmet need for a national surgical pain management consensus task force to raise awareness and develop best practice guidelines for improving surgical pain management, patient safety, patient satisfaction, rapid postsurgical recovery, and health economic outcomes. To comprehensively address this need, the multidisciplinary Surgical Pain Congress™ has been established. The inaugural meeting of this Congress (March 8 to 10, 2013, Celebration, Florida) evaluated the current surgical pain management paradigm and identified key components of best practices.

The safety of liposome bupivacaine, a novel local analgesic formulation.

OBJECTIVE: Pooled safety data from 10 randomized, double-blind studies of liposome bupivacaine, a novel local analgesic formulation, were examined. METHODS: Eight hundred twenty-three patients received liposome bupivacaine (dose, 66 to 532 mg) given locally at the surgical site in 5 different settings (hemorrhoidectomy, bunionectomy, breast augmentation, total knee arthroplasty, and hernia repair); 446 received bupivacaine HCl (dose, 75 to 200 mg) and 190 received placebo. Adverse events (AEs) were monitored for up to 36 days after administration. RESULTS: Overall, 48% of patients were men and 21% were 65 years and older. Incidence of AEs was 62% for patients receiving liposome bupivacaine, versus 75% and 43% for patients receiving bupivacaine HCl and placebo, respectively. The most common AEs (incidence >10%) in the liposome bupivacaine arms were nausea, constipation, and vomiting. One death was reported in the liposome bupivacaine group and 1 in the bupivacaine HCl group; both deemed unrelated to study drug. Serious AEs were reported in 2.7% of patients receiving liposome bupivacaine, versus 5.4% and 1.1% of those receiving bupivacaine HCl and placebo, respectively. In both the liposome bupivacaine and bupivacaine HCl groups, 6% of patients experienced a cardiac AE; these were primarily tachycardia (4% vs. 5%, respectively) and bradycardia (2% vs. 1%, respectively). Overall incidence of treatment-related cardiac AEs was <1%; all were associated with liposome bupivacaine. All of these events were assessed by investigators as possibly related to study drug; all were mild or moderate in severity, and none required therapeutic intervention. DISCUSSION: Liposome bupivacaine exhibited acceptable tolerability across 823 patient exposures.

Patient considerations in the use of tapentadol for moderate to severe pain.

Poorly controlled acute and chronic pain can increase morbidity, impair quality of life and prolong disability. Over 80 percent of post surgical patients report moderate to severe uncontrolled postoperative pain. Over-reliance on potent opioid agonists can lead to several opioid related side effects such as gastrointestinal intolerability, respiratory depression and cognitive impairment. A recently approved dual acting central analgesic tapentadol may offer improved tolerability over traditional opioid agonists while having multimodal opioid and nonopioid analgesic benefits. Tapentadol, classified by the US Food and Drug Administration as a class 2 opioid, is currently marketed in the United States as immediate release (IR) NUCYNTA® for moderate to severe acute pain in tablets of 50 mg, 75 mg, and 100 mg, and as extended release (ER) NUCYNTA ER® for the treatment of chronic moderate to severe pain in tablets of 50 mg, 100 mg, 150 mg, 200 mg, and 250 mg. Tapentadol is a low affinity mu opioid receptor agonist and a norepinephrine reuptake inhibitor. Tapentadol has no active metabolites and this property makes it useful in patients with hepatic and renal failure. Clinical trials with tapentadol IR showed that there was improved gastrointestinal tolerability and similar pain relief as compared to oxycodone IR. Tapentadol ER allows for twice daily dosing. Clinical trials showed that tapentadol ER could effectively relieve moderate to severe chronic pain and was associated with significantly fewer gastrointestinal adverse effects as compared to oxycodone controlled release. Tapentadol ER is indicated and has Food and Drug Administration approval for the treatment of chronic painful diabetic neuropathy. The most common side effects of tapentadol are nausea (30%), vomiting (18%), dizziness (24%), and somnolence (15%). Tapentadol, due to its potential synergistic effects on norepinephrine levels, is contraindicated in patients who have taken monoamine oxidase inhibitors within the last 14 days. Caution has to be exercised with the use of tapentadol IR and tapentadol ER in the presence of other central nervous system depressants such as neuroleptics, opioids, illicit drugs, muscle relaxants, sedatives, and anxiolytics.

Bupivacaine liposome injectable suspension compared with bupivacaine HCl for the reduction of opioid burden in the postsurgical setting.

OBJECTIVE: Assess comparative efficacy of liposome bupivacaine administered at doses ≤266 mg and bupivacaine HCl administered at doses ≤200 mg for postsurgical analgesia. RESEARCH DESIGN AND METHODS: Analysis of pooled efficacy and safety data from nine double-blind, placebo or active (bupivacaine HCl) controlled multimodal analgesia studies using a single dose of liposome bupivacaine or comparator, given via administration into the surgical site before end of surgery (i.e., inguinal hernia repair, total knee arthroplasty, hemorrhoidectomy, breast augmentation, or bunionectomy). Data from study arms that received liposome bupivacaine doses ≤266 mg were included. CLINICAL TRIAL REGISTRATION: Pooled data analysis includes nine studies: Study 1 - NCT01203644; Study 2 - NCT00485433; Study 3 - NCT00485693; Study 4 - NCT00529126; Study 5 - NCT00745290; Study 6 - NCT00744848; Study 7 - NCT00813111; Study 8 - NCT00890721; Study 9 - NCT00890682. MAIN OUTCOME MEASURES: Outcome measures included area under the curve (AUC) of pain intensity scores assessed by numeric rating scale (NRS) through 72 h postsurgery, time to first use of rescue opioid medications, total amount (mg) of opioid medications used, and occurrence of opioid-related adverse events (ORAEs). Incidence of overall AEs was also assessed. RESULTS: Mean cumulative pain score (AUC of NRS through 72 h) was significantly lower with liposome bupivacaine (283) compared with bupivacaine HCl (329, p = 0.039). Median time from administration of study drug to first use of opioid rescue medication was significantly longer for liposome bupivacaine (10 h vs 3 h, p < 0.0001). Liposome bupivacaine was associated with a significant reduction in opioid use (12 mg vs 19 mg; p < 0.0001) and incidence of ORAEs (20% vs 36%; p < 0.0001), compared with bupivacaine HCl. CONCLUSIONS: In this pooled analysis from nine studies representing five different surgical procedures, liposome bupivacaine administered at doses ≤266 mg in a multimodal setting was associated with statistically significant and clinically meaningful lower cumulative pain score at 72 h, delayed and less consumption of opioids, and fewer ORAEs than bupivacaine HCl.

Intravenous acetaminophen for pain after major orthopedic surgery: an expanded analysis.

BACKGROUND AND METHODS: From the time that Sinatra et al. (Anesthesiology. 2005;102:822) was published to FDA apaproval of intravenous (IV) acetaminophen, an expanded analysis of the original raw study data became necessary for the regulatory submission. The following analyses were conducted: (1) sum of pain intensity differences over 24 hours (SPID24) using currently accepted imputation methods to account for both missing data and the effects of rescue; (2) efficacy results after the first 6 hours; (3) effects of gender, race/ethnicity, age, weight, surgical site, ASA Class, and serotonin antagonists; and (4) a stepwise regression analysis of why adverse events of nausea and vomiting were numerically (although not statistically) higher in the IV acetaminophen group compared with placebo. RESULTS: Sum of pain intensity differences over 24 hours using a 0- to 100-mm visual analog scale was statistically significantly (P < 0.001) in favor of IV acetaminophen (n = 49) compared with placebo (n = 52). Time to rescue was found to be 3.9 and 2.1 hours, respectively, for total hip and knee arthroplasty compared with 0.8 hours for the placebo group. Rescue medication consumption, requests, and actual administration were all significantly lower in the IV acetaminophen group compared with placebo for each dosing interval, except in the 6- to 12-hours interval where a numerical trend was observed. Analysis of various subset variables demonstrated similar efficacy for each variable. A stepwise regression analysis demonstrated that AE reports of nausea and vomiting were most likely due to prerandomization events, particularly opioid consumption and presence of nausea prior to randomization. CONCLUSION: Repeated-dose 24-hours end points were found to be as robust as previously published results. IV acetaminophen efficacy and safety appeared to be unaffected by specific subset variables.▪

Tapentadol extended-release for treatment of chronic pain: a review.

Tapentadol is a centrally acting analgesic with a dual mechanism of action of mu receptor agonism and norepinephrine reuptake inhibition. Tapentadol immediate-release is approved by the US Food and Drug Administration for the management of moderate-to-severe acute pain. It was developed to decrease the intolerability issue associated with opioids. Tapentadol extended-release has a 12-hour duration of effect, and has recently been evaluated for pain in patients with chronic osteoarthritis, low back pain, and pain associated with diabetic peripheral neuropathy. Tapentadol extended-release was found to provide safe and highly effective analgesia for the treatment of chronic pain conditions, including moderate-to-severe chronic osteoarthritis pain and low back pain. Initial trials demonstrating efficacy in neuropathic pain suggest that tapentadol has comparable analgesic effectiveness and better gastrointestinal tolerability than opioid comparators, and demonstrates effectiveness in settings of inflammatory, somatic, and neuropathic pain. Gastrointestinal intolerance and central nervous system effects were the major adverse events noted. Tapentadol will need to be rigorously tested in chronic neuropathic pain, cancer-related pain, and cancer-related neuropathic pain.

Causes and consequences of inadequate management of acute pain.

CONTEXT: Intense acute pain afflicts millions of patients each year. Despite the recently increased focus on the importance of pain control, management of acute pain has remained suboptimal. OBJECTIVE: The objective of this study was to identify through a review of recent literature the barriers to effective treatment of acute pain and the potential consequences of inadequate pain management. DESIGN: A comprehensive literature review was conducted to identify articles relevant to the management of acute pain. Information regarding the underlying causes of inadequate pain management, as well as the sequelae associated with undermanaged pain was extracted and summarized. RESULTS: Studies indicate that treatment of acute pain remains suboptimal due to attitudes and educational barriers on the part of both physicians and patients, as well as the intrinsic limitations of available therapies. Inadequate management of acute pain negatively impacts numerous aspects of patient health, and may increase the risk of developing chronic pain. Although opioids are the preferred treatment for most moderate to severe acute pain, their side effects can impede their use, and thus, their clinical effectiveness. Analgesic regimens with an improved efficacy/tolerability balance have the potential to improve acute pain management, and thus reduce the incidence of chronic pain. Studies examining the use of multiple analgesics with different mechanisms of action suggest that multimodal therapies may offer an improved efficacy/tolerability balance over single agent regimens. CONCLUSIONS: There exists a significant need for effective, well-tolerated analgesic therapies to limit the negative consequences of undermanaged acute pain. The use of multimodal therapy has demonstrated increasing promise and is supported by current practice guidelines.

A severe inflammatory cutaneous reaction after continuous epidural analgesia.

A very rare, but important, risk factor in placement of epidural catheters is skin reactions to the antiseptic solution, adhesive tape, or the catheter itself. We describe a case of a severe inflammatory cutaneous reaction after continuous epidural analgesia used after an abdominal perineal resection. We highlight the importance of making the proper diagnosis and initiating timely therapy.

Acute post-surgical pain management: a critical appraisal of current practice, December 2-4, 2005.

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.

Peripherally acting mu-opioid-receptor antagonists and the connection between postoperative ileus and pain management: The anesthesiologist's view and beyond.

The adverse effects of opioids are well documented. Because opioid receptors have a wide-ranging anatomic distribution, the effects subsequent to opioid binding, both good and bad, occur centrally and in the periphery. Postoperative strategies to reduce opioid burden, therefore, are in the patient's best interest. Multimodal analgesia is the key towards balancing the need for opioids while simultaneously reducing their burden. Alternative anesthesia and analgesia options such as regional anesthesia, nonsteroidal anti-inflammatory drugs, or cyclooxygenase-2 enzyme inhibitors should be considered part of multimodal protocols. Familiarity of where these drugs are active in the body and how they can be employed is imperative for all surgical team members. Optimal implementation of multimodal approaches can reduce hospital stay and improve clinical outcomes, including patient satisfaction. Finally, strategies that may help reduce rates of hospital readmission also contribute to overall improved outcome. New peripherally acting mu-opioid-receptor antagonists represent significant progress in the ability of perianesthesia nurses to play an even greater role in achieving these goals. In contrast to older opioid-receptor antagonists, these agents specifically target an important aspect of the multifactorial etiology of postoperative ileus (POI), mu-opioid-receptor-mediated activity in the GI tract. In addition, they do not pass the blood-brain barrier or diminish opioid-mediated analgesia. Advanced clinical trials have already demonstrated the ability of one of these agents, alvimopan, to reduce POI and improve other postoperative outcomes while maintaining adequate analgesia. Combined with other options aimed at reducing opioid burden, alvimopan and similar drugs in development hold promise as part of multimodal protocols to optimize pain management while minimizing postoperative morbidities.

Opioid analgesics in primary care: challenges and new advances in the management of noncancer pain.

Primary care attitudes affecting the use of strong opioids in pain management have changed considerably in the last 3 decades. Forces that have shaped current attitudes and trends in opioid prescribing include historical influences, regulatory factors, and technologic and scientific advances. The article identifies for primary care physicians the current challenges and issues surrounding the use of opioid analgesics for noncancer pain and examines how new technology and expanding knowledge have been applied to existing opioids such as morphine, oxymorphone, and fentanyl to address continuing challenges in pain management.

Evaluation of the effect of perioperative rofecoxib treatment on pain control and clinical outcomes in patients recovering from gynecologic abdominal surgery: a randomized, double-blind, placebo-controlled clinical study.

BACKGROUND AND OBJECTIVES: In this randomized, placebo-controlled, double-blind study, the efficacy and safety of rofecoxib 50 mg was evaluated in patients undergoing major abdominal gynecologic surgery. METHODS: Patients were randomized to receive rofecoxib 50 mg (n = 81) or placebo (n = 83) approximately 2 hours before total abdominal hysterectomy or myomectomy and once daily over the ensuing 4 days. Clinical measurements included average daily opioid use over the 5-day period (primary endpoint), pain intensity on movement, and opioid-related side effects. RESULTS: Patients receiving rofecoxib required 32% less (P = .001) intravenous and oral opioids to relieve their postoperative pain from days 1 to 5 (primary endpoint), used 21% less (P = .011) on day 1, and 42% less (P < .001) from days 2 to 5. The rofecoxib group experienced less pain upon movement (P < .001), less sedation (P = .007), and a 24% reduction in the rate of antiemetic intake (P = .037) over the first 72 hours postsurgery. Earlier mean times to first flatus (-10.1 hours, P = .001), first bowel movement (-14.1 hours, P = .037), and time to hospital discharge (-10.9 hours; 95% confidence interval, -17.1 to -4.7) occurred in the rofecoxib group. There were no significant intergroup differences in blood loss, wound healing, or overall adverse experiences. CONCLUSIONS: Compared with placebo, perioperative administration of rofecoxib 50 mg provided significant opioid sparing, significantly better pain control, improved clinical outcomes, and was well tolerated.

The fentanyl HCl patient-controlled transdermal system (PCTS): an alternative to intravenous patient-controlled analgesia in the postoperative setting.

Inadequate pain control in the postoperative period not only contributes to patient discomfort, but also causes physiological changes that may result in increased risk of myocardial ischaemia, deep vein thrombosis and pulmonary embolism. These events complicate postoperative recovery and may lead to longer hospital stays as well as increased healthcare costs. Patient-controlled analgesia (PCA) has emerged as an effective way for patients to manage their pain, allowing self-administration of small doses of analgesics to maintain a certain level of pain control. PCA is most commonly delivered via an intravenous (IV) or epidural route, and while patient satisfaction is higher with PCA than with conventional methods of analgesic administration, the invasiveness, costs and risk of errors associated with currently available modalities may limit their utility. These systems also require significant healthcare resources, as nurses must manually program the pumps to deliver the correct amount of medication. Several new PCA modalities are being developed to address these limitations. These systems deliver drug through a variety of routes, including nasal transmucosal and transdermal. Most notably, a self-contained, credit card-sized, transdermal PCA system is currently in the final stages of development. The fentanyl HCl patient-controlled transdermal system (PCTS; IONSYS, Ortho-McNeil Pharmaceutical, Inc., Raritan, NJ) uses an imperceptible, low-intensity direct current to transfer fentanyl on demand across the skin into the systemic circulation. This compact system is patient-activated, can be applied to the patient's upper arm or chest, and is designed to manage moderate-to-severe pain requiring opioid analgesia. The system delivers a preprogrammed amount of fentanyl HCI over 10 minutes, for a total of 80 doses, or for 24 hours, whichever occurs first. The on-demand dosing and pharmacokinetics of this system differentiate it from the passive transdermal formulation of fentanyl designed for the management of chronic pain. Clinical studies have shown that the fentanyl HCl PCTS is effective in the management of acute postoperative pain. These studies have also demonstrated that the system is safe and well tolerated by patients.

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.