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.▪

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 patient's 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 microg 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.

Relative analgesic potency of fentanyl and sufentanil during intermediate-term infusions in patients after long-term opioid treatment for chronic pain.

Sufentanil, a potent mu-opioid agonist, historically has not been been given systemically to treat chronic pain. An implantable, fixed-rate osmotic pump that delivers sufentanil subcutaneously is being developed for this purpose. In that transdermal fentanyl may be a useful intermediary to estimate the appropriate sufentanil dose before implant, accurate information is needed about the relative analgesic potency of sufentanil and fentanyl during continuous infusion. To determine this relative potency, we administered these drugs to opioid-treated chronic pain patients using a target-controlled infusion (TCI). Sixty-three patients with stable chronic pain and daily oral opioid requirements equivalent to 100-1000 mg of morphine received TCI of fentanyl and sufentanil, each for a minimum of 16 h. Drug administration was double-blind and the order of administration was randomly assigned. Target concentration was changed until the patient reported that analgesia was adequate (defined as a pain level equal to or better than baseline). Seven patients did not complete the infusion and protocol violations invalidated data for 15 patients. For the remaining 41 patients, target concentrations associated with adequate analgesia were achieved for both sufentanil and fentanyl. The median value for the equianalgesic concentration ratio (steady-state fentanyl infusion to steady-state sufentanil infusion) was 7.5; mean potency ratio was 7.44 (95% confidence interval 6.8-8.2). During titrated, intermediate-term infusions in patients previously treated with opioids for chronic pain, sufentanil is approximately 7.5 times as potent as fentanyl.

The COX-2 specific inhibitor, valdecoxib, is an effective, opioid-sparing analgesic in patients undergoing total knee arthroplasty.

This multicenter, randomized, double-blind, placebo-controlled study evaluated the analgesic efficacy and opioid-sparing effects of valdecoxib, a potent COX-2 specific inhibitor, in patients undergoing knee replacement. Patients received morphine by patient-controlled analgesia (PCA), and valdecoxib 40 mg or 80 mg daily, or placebo, for up to two days. Efficacy was assessed by the cumulative amount of morphine administered over 48 hours, pain intensity and patient's evaluation of medication. Morphine consumption over 48 hours by patients receiving valdecoxib 40 mg or 80 mg daily plus morphine was 83.7% and 75.8% (P < 0.05) of the total amount consumed by patients receiving morphine alone. Patients receiving valdecoxib 40 mg and 80 mg daily experienced significantly lower maximum pain intensity on Day 2 (P < 0.05), and rated their study medication significantly higher than patients receiving morphine alone. Valdecoxib plus morphine was well tolerated. Thus, valdecoxib in combination with morphine provides multi-modal analgesia that reduces pain and opioid use and increases patient satisfaction following knee replacement surgery.

Patient-controlled transdermal fentanyl hydrochloride vs intravenous morphine pump for postoperative pain: a randomized controlled trial.

CONTEXT: Patient-controlled analgesia (PCA) with morphine is commonly used to provide acute postoperative pain control after major surgery. The fentanyl hydrochloride patient-controlled transdermal system eliminates the need for venous access and complicated programming of pumps. OBJECTIVE: To assess the efficacy and safety of an investigational patient-controlled iontophoretic transdermal system using fentanyl hydrochloride compared with a standard intravenous morphine patient-controlled pump. DESIGN, SETTING, AND PATIENTS: Prospective randomized controlled parallel-group trial conducted between September 2000 and March 2001 at 33 North American hospitals, enrolling 636 adult patients who had just undergone major surgery. INTERVENTIONS: In surgical recovery rooms, patients were randomly assigned to intravenous morphine (1-mg bolus every 5 minutes; maximum of 10 mg/h) by a patient-controlled analgesia pump (n = 320) or iontophoretic fentanyl hydrochloride (40- microg infusion over 10 minutes) by a patient-controlled transdermal system (n = 316). Supplemental analgesia (morphine or fentanyl intravenous boluses) was administered as needed before and for the first 3 hours after activation of the PCA treatments. Patients then used the PCA treatments without additional analgesics for up to 72 hours. MAIN OUTCOME MEASURES: The primary efficacy variable was patient global assessment of the method of pain control during the first 24 hours. Additional efficacy measures were the proportion of patients discontinuing the study because of inadequate analgesia for any reason, patient-reported pain intensity scores on a 100-mm visual analog scale (VAS), and patient global assessments at 48 and 72 hours. Adverse effects were also recorded. RESULTS: Ratings of good or excellent after 24 hours of treatment for the method of pain control were given by 73.7% of patients (233/316) who used transdermal fentanyl PCA and 76.9% of patients (246/320) who used intravenous morphine PCA; treatment difference was -3.2% (95% confidence interval, -9.9% to 3.5%; P =.36). Early patient discontinuations (25.9% fentanyl vs 25.0% morphine; P =.78) and last pain intensity scores (32.7 fentanyl vs 31.1 morphine on the VAS; P =.45) were not different between the 2 treatments. With continued treatment for up to 48 or 72 hours, more than 80% of patient assessments in each treatment group were good or excellent. The incidence of opioid-related adverse events was similar between the groups. CONCLUSION: An investigational PCA transdermal system using iontophoresis to deliver fentanyl provided postsurgical pain control equivalent to that of a standard intravenous morphine regimen delivered by a PCA pump.

Efficacy and safety of fentanyl sublingual spray for the treatment of breakthrough cancer pain: a randomized, double-blind, placebo-controlled study.

BACKGROUND AND OBJECTIVES: A number of transmucosal fentanyl formulations have been developed for the management of breakthrough cancer pain (BTCP). Sublingual delivery of fentanyl, formulated as fentanyl sublingual spray, offers the potential for more rapid and greater absorption of fentanyl and associated onset of analgesic effect compared with other formulations. The objective of this study was to assess the efficacy and safety of fentanyl sublingual spray for the treatment of BTCP. RESEARCH DESIGN AND METHODS: This was a randomized, double-blind, placebo-controlled phase III trial conducted in opioid-tolerant patients with BTCP. An open-label titration period was followed by a double-blind treatment period during which patients received fentanyl sublingual spray (100-1600 mcg) or placebo. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT00538850. MAIN OUTCOME MEASURES: The primary efficacy measure was summed pain intensity difference at 30 minutes (SPID(30)). Secondary efficacy measures included total pain relief at 30 minutes (TOTPAR(30)) and patient global evaluation of study medication at 30 minutes. Efficacy measures were also assessed at various time points from 5-60 minutes postdose. Adverse events were monitored throughout the study. RESULTS: A total of 130 patients were treated during the titration period, of whom 98 (75.4%) entered the double-blind period. Relative to placebo, fentanyl sublingual spray significantly improved mean SPID scores from 5 minutes (p = 0.0219) through 60 minutes (p < 0.0001), including the primary endpoint at 30 minutes (p < 0.0001). Fentanyl sublingual spray produced significantly greater pain relief (expressed in terms of TOTPAR) from 5 through 60 minutes (p < 0.0001), and significantly greater global evaluation of treatment effectiveness (p < 0.0001), compared with placebo. During double-blind treatment, the most frequently reported adverse events were nausea (7.1%), hyperhidrosis (5.1%), and peripheral edema (5.1%). Serious adverse events occurred in seven patients (5.4%) during titration and six (6.1%) during double-blind treatment; none were considered related to treatment. CONCLUSIONS: These findings indicate that treatment with fentanyl sublingual spray results in effective relief of BTCP, with a rapid onset of action, and is well tolerated.

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.

Epidural and intrathecal analgesia for cancer pain.

The three-step analgesic ladder approach developed by the World Health Organization works well in treating the vast majority (70-90%) of patients suffering from pain related to cancer. In those patients who do not get pain relief by this three-step approach, intraspinal agents can be a fourth step in managing pain of malignant origin. Although morphine is the only opioid approved by the US Food and Drug Administration for intraspinal use, many different opioid analgesics are used intraspinally, including hydromorphone, fentanyl, sufentanil, meperidine and methadone in the treatment of cancer pain. Many non-opioid agents have also been used intraspinally either alone or in combination with opioids in the treatment of intractable cancer pain. This chapter summarizes the clinical use of these agents with some practical points.