Published in American Journal of Therapeutics: January/February 2015 – Volume 22 – Issue 1 – p 2–10
Authors: Singla, Neil K. MD et al
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.
Total hip arthroplasties are among the most common musculoskeletal surgeries. In these procedures, postoperative pain management is often difficult to manage safely because patients are typically elderly and frequently suffer comorbid conditions, such as hypertension, ischemic heart disease, renal dysfunction, obstructive pulmonary disease, vascular disease, diabetes, and obesity. In some total hip arthroplasty studies, a quarter to a half of patients report persistent postsurgical pain. Failure to manage pain adequately in these patients can have serious negative consequences on patient rehabilitation.
Opioids continue to play a dominant role in postoperative pain management after total hip arthroplasty; however, the use of opioids is associated with well-known dose-dependent adverse events (AEs) and negative postoperative outcomes, which has been directly linked to increased healthcare costs. Multimodal analgesia regimens, including the use of nonopioid analgesics such as acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), are increasingly being used to minimize these negative outcomes and reduce the costs associated with opioid-related AEs.
NSAIDs are sometimes avoided after orthopedic surgery because of potential effects on bone healing, upper gastrointestinal tract bleeding, and renal toxicity. In contrast, acetaminophen is not associated with these AEs. Intravenous (IV) acetaminophen, or its prodrug IV propacetamol, has been widely used in Europe for the management of acute pain for more than 20 years. The intravenous form of acetaminophen (OFIRMEV; Cadence Pharmaceuticals, Inc., San Diego, CA), which was approved in the United States in 2010, has been described as an element of multimodal analgesia in total hip or joint arthroplasty. Intravenous acetaminophen may be the preferred route of administration for treating acute pain in the perioperative setting over other acetaminophen dosage forms (oral and rectal) because of its more rapid onset, reduced intrapatient variability in plasma levels, and earlier and greater cerebrospinal fluid penetration.
This report describes the results of 2 separate studies run concurrently in comparable study populations and with similar objectives. Although both studies were stopped prematurely, there was considerable overlap in patient populations, study design, and methodologies in the single-dose phase of these studies that allowed for an analysis of their results to be presented concurrently in this report.
MATERIALS AND METHODS
We analyzed 2 previously conducted parallel-group, multicenter, double-blind, randomized, placebo-controlled trials funded by Bristol-Myers Squibb that comprised a total of 130 male and female patients [study 1: protocol 136-01-03, n = 69, 11 clinical sites in the United States (IV acetaminophen, n = 35; placebo, n = 34); and study 2: protocol 136-02-03, clinicaltrials.gov NCT00344045, n = 61, 16 clinical sites in the United States (IV acetaminophen, n = 30; placebo, n = 31)] undergoing primary unilateral total hip arthroplasty. Study 1 was a single-dose efficacy, pharmacokinetic (PK), and safety study. Study 2 was a repeated-dose efficacy and safety study. In both studies, patients were adults classified as American Society of Anesthesiology (ASA) I to III enrolled from November 2003 through September 2004.
Other entry criteria included a body mass index ≥19 and ≤40 kg/m2, the ability to operate an IV patient-controlled analgesia (PCA) device, and an understanding of pain scales with an ability to use them effectively. Patients who had a contraindication to the study drugs, excipients, or the rescue medication and those with impaired liver function (alanine aminotransferase and aspartate aminotransferase) and bilirubin ≥1.25 times the upper limit of normal (ULN) or renal function (creatinine >2.0 mg/dL) were excluded. Exclusion criteria also included patients who had received NSAIDs and analgesics within 12 hours or corticosteroids within 7 days before administration of study medication.
Both studies were conducted in accordance with Good Clinical Practice and the Declaration of Helsinki and were approved by an independent institutional review board for each clinical center. All participating patients provided written informed consent.
Both studies were stopped prematurely in response to reports of particulate matter and altered pH only in the placebo vials. Vials containing IV acetaminophen did not contain particulate matter or altered pH and remained within specification throughout the course of the studies. As such, early termination resulted in these studies being relatively underpowered compared with the original design, leading to the modified intent-to-treat (mITT) populations of 69 patients in study 1 (out of a planned enrollment of 140 patients) and 61 patients in study 2 (out of a planned enrollment of 230 patients).
Patient demographics are listed in Table 1 and appeared similar across treatment groups for both studies (130 patients total included in the mITT population and analyzed for efficacy and safety). Five patients (7.7%) withdrew from the IV acetaminophen groups, 2 patients in study 1 and 3 patients in study 2; and 6 patients (9.2%) from the placebo group, none from study 1 and 6 from study 2. Two patients (3.1%) from the IV acetaminophen groups and 3 patients (4.6%) from the placebo groups withdrew because of AEs; the remaining 6 patients withdrew their consent. There were no statistically significant differences in withdrawal frequencies between the IV acetaminophen and placebo groups.
Study design and methods
During the screening visit of both studies, which was within 21 days before the administration of study drug, informed consent and medical history were obtained, physical examination and laboratory testing were performed, and training on the use of the PCA device and pain scales was provided to patients.
In both studies, patients received general, spinal, or epidural anesthesia during their surgical procedures and did not receive local anesthetic wound infiltration, continuous neuraxial local anesthetic infusions, or neuraxial opioids in combination with the epidural or spinal anesthetic. In the postanesthesia care unit, a morphine PCA pump was started once the patient was able to use the device and was programmed to deliver morphine 1 mg of boluses with a 6-minute lockout interval and a 40 mg 4-hour maximum dose. In cases of inadequate pain relief (PAR) with the PCA, additional 2 mg of morphine rescue boluses were administered via the pump or by IV push. The PCA was interrupted approximately 16 hours after surgery to allow the patient’s pain intensity to reach at least moderate intensity on a 4-point categorical scale (0 = none; 1 = mild; 2 = moderate; and 3 = severe) and at least a score of 45 mm on a 100-mm visual analog scale, at which point the patient received the blinded study drug as a 15-minute infusion. Patients were randomized to 100 mL of IV acetaminophen (1 g/100 mL) or 100 mL of saline (placebo), with the start time of the infusion designated as T0. Both patients and investigators were masked to study drug. Patients were encouraged to wait at least 30 minutes after administration of study drug before self-administering IV PCA morphine for inadequate PAR.
After the administration of study drug, investigators in both studies collected pain responses at identical time points up to 4 hours with assessments performed at 15 minutes (T0.25), 30 minutes (T0.5), 45 minutes (T0.75), 1 hour (T1), 2 hours (T2), 3 hours (T3), and 4 hours (T4). Study 1 examined the single-dose efficacy of IV acetaminophen, with assessment time points over the course of 6 hours (T6) and included a PK analysis of plasma acetaminophen levels. Study 2 included repeated-dose efficacy endpoints (patients received additional study drug doses at T4, T10, and T16). This analysis focused on first dose endpoints, and as such, formal presentation of the data from the 2 studies is limited to the common first-dose efficacy parameters collected in the first 4 (T4, study 2) to 6 hours (T6, study 1) after study drug administration.
In both studies, safety assessments (vital signs, physical examinations, AEs, and concomitant medications) were monitored; AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA).
Efficacy and safety endpoints
The primary efficacy endpoint for each study was the pain intensity difference (PID) as measured using a 4-point categorical scale (0 = none, 1 = mild, 2 = moderate, 3 = severe) from baseline through T6 hour for study 1 and through T4 hour for study 2. Secondary efficacy outcome measures included PAR measured using a 5-point categorical scale (0 = none, 1 = a little, 2 = some, 3 = a lot, 4 = complete), PID at T0.25, T0.5, and T0.75 hour postdose, sum of PID, maximum PID (MAXPID), maximum PAR (MAXPAR), time to MAXPID (T-MAXPID), weighted sum of PAR scores (TOTPAR), time to MAXPAR (T-MAXPAR), and minimal clinically important difference (MCID; defined as PAR ≥2 between T0 and T4). Responder was defined as a subject whose pain intensity was reduced to mild or none calculated at each posttreatment scheduled time point. The time to onset of effect was evaluated as time to meaningful PAR using a double stopwatch method. The duration of effect was analyzed as time to first rescue medication request among those with onset of effect. The primary safety outcome measures were the type, number, and severity of AEs spontaneously reported.
Each study was analyzed independently. Analyses of efficacy were based on the mITT population, which was defined as all randomized patients who took at least 1 dose of study drug and who had at least 1 post-baseline efficacy assessment. The safety population was defined as all randomized patients who took any portion of a dose of study drug. All statistical tests were 2 sided and conducted at the 0.05 level of significance. An analysis of covariance model using treatment effect, site, and baseline pain intensity was used to analyze all pain intensity–derived and PAR-derived measures. Two-sided 95% confidence interval calculations for the treatment effect used the least square means and root mean square error from the analysis of covariance model. Survival distribution of time-to-event variables models were used to analyze onset and duration measures. Safety outcome measures were compared across treatment groups using Fisher exact test. In both studies, a sample size of 60 subjects per treatment group was calculated to provide at least 90% power to detect a difference of 0.5 PID units, assuming a standard deviation of 0.8 units (α = 0.05, 2 tailed). In study 2, the sample size was increased to 100 subjects per group to obtain a more robust estimate of the adequacy of the proposed dosing interval.
Patient demographics seemed to be similar across treatment groups for both studies (Table 1). IV acetaminophen was effective in treating moderate-to-severe pain after total hip arthroplasty. Mean PID were consistently higher for IV acetaminophen than for placebo, with significant (P < 0.05) differences between treatment arms at every time point from T0.25 to T5 (study 1) and T0.5 to T4. Secondary PID measures significantly favored IV acetaminophen over placebo in both studies.
Pain relief scores for IV acetaminophen were consistently better than placebo starting at T0.25 in study 1 and T0.5 in study 2, and superior until T4. Percentage of patients achieving MCID in both studies was significantly higher for IV acetaminophen starting at T0.5 to T6 (88.6% vs. 38.2% for placebo, P < 0.001) in study 1 and T0.25 up to T4 (90.0% vs. 38.7% for placebo, P < 0.001) in study 2 (Figure 3). Onset of PAR for IV acetaminophen was rapid in both studies, with median time to MCID of T0.5 in both studies versus T6 (study 1) and T4 (study 2) in the placebo groups.
IV acetaminophen groups achieved a significantly higher number of responders at every time point in relevant study periods in both studies. By T1, ≥80% of all patients receiving IV acetaminophen and ≤42% of all patients receiving placebo were classified as responders (P < 0.001). A small proportion of patients in the placebo arm (≤8.8%) achieved pain-free status during the studies, whereas up to 40% of IV acetaminophen patients achieved a pain-free state (P ≤ 0.002).
Use of IV acetaminophen reduced the need for rescue opioid consumption up to 6 hours in study 1 and up to 4 hours in study 2 (Figure 4). Median time to first rescue favored IV acetaminophen, with the first rescue request occurring at 1.4 and 1.25 hours for placebo and at 4.72 and >4 hours for acetaminophen injection, respectively, in study 1 and study 2 (P ≤ 0.001 for both). Patients receiving IV acetaminophen consumed less than half the mean consumption of rescue medication compared with patients receiving placebo (study 1: 4.5 vs. 9.6 mg, P = 0.017; study 2: 1.9 vs. 5.1 mg, P = 0.006).
In both studies, reports of treatment-emergent adverse events (TEAEs) were similar in the IV acetaminophen and placebo groups with few TEAEs designated as related to study medication. TEAEs were reported by 49 (75%) of 65 in the IV acetaminophen group (study 1, 29/35; study 2, 20/30) and by 51 (78%) of 65 in the placebo group (study 1, 20/30; study 2, 26/31). The most common TEAEs in both studies were anemia, tachycardia, constipation, and nausea.
Serious AEs were reported in 4 IV acetaminophen patients and 8 placebo patients. All serious AEs resolved quickly and uneventfully. No new or unexpected AEs, deaths, or vital sign abnormalities were reported in the studies. Tolerability was similar in both arms. No patients were administered placebo product with particulate matter.
Despite modern day advances in analgesic techniques, total hip arthroplasty is still associated with moderate-to-severe postoperative pain. Opioids are still mainstay analgesics in major joint surgery but are associated with adverse effects. The use of opioid-sparing or opioid-replacement multimodal techniques may have overall clinical and cost advantages over using opioids alone.
IV acetaminophen is an important component of this multimodal analgesic approach. Compared with other routes of administration, IV delivery of acetaminophen achieves higher Cmax and earlier Tmax than oral and rectal acetaminophen with less interpatient plasma variability. In a small study, Singla et al demonstrated higher mean plasma Cmax values for IV acetaminophen (21.6 μg/mL) compared with oral (PO) (12.3 μg/mL) and rectal (PR) (6.1 μg/mL), and 75% greater central nervous system (CNS) penetration with mean area under the curve (AUC0–6) for IV acetaminophen (24.9 μg·h/mL) compared with PO (14.2 μg·h/mL) and 142% compared with PR (10.3 μg·h/mL). These PK differences may explain the differential efficacy seen between IV and PO acetaminophen in a study in which Pettersson et al studied patients following cardiothoracic surgery and observed a 21% reduction in opioid consumption in the IV acetaminophen group compared with the PO acetaminophen group (17.4 vs. 22.1 mg, P = 0.016).
These 2 studies separately and collectively demonstrated the efficacy and safety of IV acetaminophen when used to treat postoperative pain after total hip arthroplasty. In nearly all primary and secondary efficacy endpoints, IV acetaminophen demonstrated statistically significant differences with improved analgesia, rapid onset of action, and opioid consumption decreases of more than 50% when compared with placebo. These reductions are comparable with the opioid consumption reduction observed in other studies examining IV acetaminophen or IV propacetamol in postoperative pain after orthopedic surgery. The results seen in these 2 studies are consistent with other postoperative hip arthroplasty trials studying the efficacy of IV acetaminophen. Sinatra et al included 151 patients who underwent major orthopedic surgery [total hip (n = 86) or knee (n = 65) replacement] and were randomized to receive repeated doses of IV acetaminophen (1000 mg), propacetamol (2000 mg), or placebo every 6 hours for 24 hours in a double-blind study. The IV acetaminophen and propacetamol groups had significantly better PAR (5-point verbal scale) from 15 minutes to 6 hours (P < 0.05). Treatment groups had significantly reduced morphine consumption over the 24-hour period [33% less (19 mg) in the IV acetaminophen group and 29% less (17 mg) in the IV propacetamol group] and decreased median time to morphine rescue (3 hours, 2.6 hours, and 0.8 hours for IV acetaminophen, IV propacetamol, and placebo groups, respectively). The benefit of IV acetaminophen over placebo was also reflected in the number of rescue requests and overall consumption of rescue opioids.
There were no new or unexpected AEs reported in the current studies nor were any clinically meaningful changes in vital signs, laboratory assessments or physical examinations reported by the investigators. The AE profile of the IV acetaminophen and placebo arms of these studies were comparable.
These 2 studies dosed IV acetaminophen the day after surgery to minimize variability caused by anesthetic technique. A more practical consideration would be to administer IV acetaminophen before or during surgery and maintain IV therapy for at least 24 hours to cover the maximal pain period. Using this approach may minimize opioid consumption and opioid-related AEs with improvement of patient outcomes. Limitations of these studies include the small sample sizes in each treatment group and the limited collection of samples (up to T6 in the single-dose study 1 and T4 in repeated-dose study 2).