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Patient Satisfaction With Intravenous Acetaminophen: A Pooled Analysis of Five Randomized, Placebo-Controlled Studies in the Acute Postoperative Setting

Apfel, Christian C.; Souza, Kimberly; Portillo, Juan; Dalal, Poorvi; Bergese, Sergio D.

The Journal for Healthcare Quality (JHQ): May/June 2015 - Volume 37 - Issue 3 - p 155–162
doi: 10.1111/jhq.12062
Original Article
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Abstract: Intravenous (IV) acetaminophen has been shown to reduce postoperative pain and opioid consumption, which may lead to increased patient satisfaction. To determine the effect IV acetaminophen has on patient satisfaction, a pooled analysis from methodologically homogenous studies was conducted. We obtained patient-level data from five randomized, placebo-controlled studies in adults undergoing elective surgery in which patient satisfaction was measured using a 4-point categorical rating scale. The primary endpoint was “excellent” satisfaction and the secondary endpoint was “good” or “excellent” satisfaction at 24 hr after first study drug administration. Bivariate analyses were conducted using the chi-square test and Student's t-test and multivariable analyses were conducted using logistic regression analysis. Patients receiving IV acetaminophen were more than twice as likely as those who received placebo to report “excellent” patient satisfaction ratings (32.3% vs. 15.9%, respectively). Of all variables that remained statistically significant in the multivariable analysis (i.e., type of surgery, duration of anesthesia, last pain rating, and opioid consumption), IV acetaminophen had the strongest positive effect on “excellent” patient satisfaction with an odds ratio of 2.76 (95% CI 1.81–4.23). Results for “excellent” or “good” satisfaction were similar. When given as part of a perioperative analgesic regimen, IV acetaminophen was associated with significantly improved patient satisfaction.

For more information on this article, contact Christian C. Apfel at capfelmd@sagemedic.com and Christian.apfel@ucsf.edu.

The authors declare no conflict of interest.

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Background

It is widely accepted that integrating patient perspective and satisfaction into clinical practice can help to improve overall healthcare in the United States (Wu, 2001). Within the past 5 years, national standardized surveys have been instituted to measure patient satisfaction and the results are being used to dictate reimbursement at risk, which is the portion of the Medicare reimbursement allocation to hospitals that could potentially be reduced by poor performance outcomes (National Association of Public Hospitals and Health Systems [NAPH], 2008). Studies have demonstrated a strong positive correlation between global patient satisfaction ratings and magnitude of pain relief (Stahmer, 1998) or maximum possible pain relief (Collins, 2001), with other studies suggesting that global patient satisfaction ratings may be more sensitive to the effects of treatment than serial evaluations of pain intensity (Fischer, 1999). Due to these correlations, patient satisfaction is a pertinent piece of information that should be considered when evaluating the effectiveness of new analgesic drugs.

Intravenous (IV) administration of acetaminophen was introduced as a new option for postoperative pain control in the United States in January 2011; the wholesale acquisition cost as of the date of this article is $11.40 (Jahr, 2013). IV acetaminophen has been reported to reduce the consumption of opioids in the postoperative setting compared to the oral administration of acetaminophen (Pettersson, 2005). Furthermore, IV acetaminophen is associated with significantly higher plasma and effect site concentrations than equivalent doses of oral or rectal formulations, resulting in greater central nervous system penetration (Singla, 2012). Recent systematic reviews and meta-analyses have demonstrated its significant effect in reducing opioid consumption (McNicol, 2011; Tzortzopoulou, 2011). We sought to determine if the established reduction in pain and opioid requirements translated to higher patient satisfaction. This review is the first pooled analysis of patient-level data to quantify the effects of IV acetaminophen on patient satisfaction as an additional analgesic to the current standard opioid regimen.

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Methods

The standard approach to synthesize and quantify all available evidence regarding the putative effect of IV acetaminophen on patient satisfaction would be to conduct a systematic review and meta-analysis. However, whether such an effect would still be present when reduction in postoperative pain and/or opioid consumption is taken into account would require a meta-regression. A more rigorous methodology would be to conduct a pooled analysis of individual patient data from randomized controlled trials (RCTs) with consistent design and methodology. Thus, we contacted the manufacturer of IV acetaminophen (OFIRMEV®, Cadence Pharmaceuticals, Inc., San Diego, CA) and obtained patient level data of five double-blind, randomized, placebo-controlled trials in adults in which patient satisfaction was measured in patients receiving IV acetaminophen or IV saline (placebo; Table 1; Candiotti et al., 2008; Gimbel et al., 2008; Minkowitz et al., 2008; Sinatra et al., 2005; Wininger et al., 2010). In these studies, IV acetaminophen or placebo was given in addition to the standard opioid regimen. Studies by Candiotti et al. and Winninger et al. were sponsored by Cadence Pharmaceuticals, Inc, and studies by Gimbel et al., Minkowitz et al., and Sinatra et al. were sponsored by Bristol-Myers Squibb, Inc. (New York, NY).

Table 1

Table 1

All studies included in this analysis were double-blind, randomized, placebo-controlled trials conducted in human adult inpatients in the postsurgical setting. The treatment group received 1 g boluses of acetaminophen intravenously immediately after surgery and at fixed intervals throughout the first 24 hr postsurgery, while the control group received placebo according to the same dosing schedule (Table 1). All patients, irrespective of grouping, had IV patient-controlled analgesia (PCA) available, allowing them to receive opioid treatment as per the hospital's standard of care.

The primary endpoint was “excellent” patient satisfaction and the secondary endpoint was “excellent” or “good” satisfaction measured at 24 hr after first study drug administration on a scale of 0–3 (0 = poor; 1 = fair; 2 = good; 3 = excellent). In the studies reported by Gimbel et al. (2008) and Minkowitz et al. (2008), patients were asked “How would you rate your overall satisfaction with the study treatments?” whereas, in the studies reported by Candiotti et al. (2008), Sinatra et al. (2005), and Wininger et al. (2010), patients were asked “Overall, how would you rate the study treatments?” Additionally, we collected data on and performed a multivariable analysis to assess the effects of age, gender, height (cm), weight (kg), type of surgery, duration of anesthesia (hours), last pain rating before satisfaction measurement, and opioid consumption on patient satisfaction outcomes. Pain intensity was measured on (1) a 4-point Likert categorical scale (0 = none; 1 = mild; 2 = moderate; 3 = severe) and (2) a 100 mm visual analog scale (VAS). Opioid consumption was defined as the total amount of rescue medication consumed, measured as 10 mg morphine equivalents, during the first 24 hr postsurgery.

Bivariate analyses on the effects of IV acetaminophen as well as other collected variables were conducted using the chi-square test and Student's t-test. Multivariable analyses using logistic regression were conducted of all collected variables and only significant variables with p < .05 were considered to be statistically significant and remained in the model. All results are reported as odds ratios and 95% confidence intervals, unless otherwise stated. Statistical analyses were conducted using JMP (SAS, Inc, Cary, NC) and SPSS (IBM, Corporation, Armonk, NY). As each of the individual studies had received institutional review board approval no additional approval was necessary for this analysis.

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Results

Patient Characteristics

The raw data were analyzed from five double-blind RCTs in which patient satisfaction was collected at 24 hr for patients receiving scheduled doses of IV acetaminophen (n = 356) or placebo (n = 370). Demographics (age and gender) and baseline characteristics such as surgery type and pain intensity were similar between both IV acetaminophen and placebo groups (Table 2). Approximately 86% of total patients were under 65 years of age, 83% were female, and 78% underwent abdominal or gynecological surgery. Baseline pain intensity was classified as moderate in 66% of the patients and severe in 27%. Satisfaction data were missing for a total of nine patients enrolled in the included trials (five from the IV acetaminophen group and four from the placebo group) and therefore excluded from the analysis, leaving a total of 717 patients with satisfaction data to be analyzed (IV acetaminophen n = 351, placebo n = 366).

Table 2

Table 2

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Excellent Satisfaction

In bivariate analysis, IV acetaminophen increased incidence of “excellent” patient satisfaction with an odds ratio of 2.52 (95% confidence interval of 1.76–3.59; p < .001; Table 3; Figure 1). When multivariable logistic regression was performed, IV acetaminophen had the strongest positive effect on “excellent” patient satisfaction (OR 2.76, 95% CI 1.81–4.23; Table 3). Additionally, type of surgery, duration of anesthesia (OR 0.76, 95% CI 0.63–0.91), last pain rating (OR 0.59, 95% CI 0.46–0.75), and opioid consumption (OR 0.89, 95% CI 0.82–0.96) also significantly affected “excellent” patient satisfaction (Table 3). Arthroplasties were associated with less favorable outcomes compared to abdominal and gynecological surgery, particularly knee arthroplasty, which can be an extremely painful procedure (OR 0.08, 95% CI 0.01–0.60; Table 3). Of note, according to our interaction analyses, the increase in patient satisfaction with IV acetaminophen was independent of the type of surgery, duration of anesthesia, postoperative opioid consumption, and postsurgical pain, that is, none of the tested interactions between IV acetaminophen and the other variables were statistically significant.

Table 3

Table 3

Figure 1

Figure 1

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“Excellent” or “Good” Satisfaction

Results for “excellent” or “good” satisfaction were similar to those for “excellent” satisfaction with IV acetaminophen increasing “good to excellent” satisfaction with an odds ratio of 2.10 (95% CI 1.93–2.27, p < .001) in bivariate analysis. IV acetaminophen treatment remained significant in multivariable analysis (OR 2.54, 95% CI 2.33–2.75; p < .001), with opioid consumption, type of surgery, and last pain rating also significantly affecting incidence of “good to excellent” satisfaction. Interestingly, in contrast to results for “excellent” satisfaction, duration of anesthesia did not affect incidence of “excellent” or “good” satisfaction (p = .126).

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Additional Outcomes

Across the five studies, less total rescue medication (in morphine equivalents) was required in patients receiving 1 g of IV acetaminophen every 6 hr for 24 hr (mean 32.1 ± 30.0 mg) versus placebo (mean 38.7 ± 34.8 mg; p = .01). Additionally, last pain rating before measurement of patient satisfaction was similar in both IV acetaminophen and placebo groups (mean 1.39 ± 0.78 and mean 1.40 ± 0.77 on a scale of 0–3, respectively, p = .904).

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Individual Studies

The results of the individual studies conducted by Sinatra et al. (2005), Candiotti et al. (2008), and Gimbel et al. (2008) demonstrated overall better global satisfaction scores (p < .01, p = .0079, and p = .0003, respectively) with IV acetaminophen. The trials by Minkowitz et al. (2008) and Wininger et al. (2010) showed no statistically significant difference between IV acetaminophen and placebo; however, upon pooled analysis of patient level data from all five studies, an overall improved patient satisfaction was observed in the IV acetaminophen group compared to placebo (p < .001, Table 4).

Table 4

Table 4

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Discussion

In this pooled analysis of five randomized, placebo-controlled trials, a postoperative analgesic regimen including IV acetaminophen resulted in a statistically significant and clinically relevant improvement in patient satisfaction at 24 hr postsurgery compared to placebo. Specifically, patients receiving IV acetaminophen had more than double the incidence of “excellent” patient satisfaction ratings compared to those who received placebo. The impressive positive results of this analysis reconcile the varied results of the individual trials and suggest that the lack of statistical significance in individual trials may be due to differences in baseline incidences of “excellent” satisfaction in the populations studied or small sample sizes in the individual studies. To explore the methods through which IV acetaminophen increases patient satisfaction and gain further insight into other factors that may affect satisfaction, we performed multivariable analysis. We found that IV acetaminophen was the strongest modifiable factor for “excellent” patient satisfaction, independent of surgery type, the duration of anesthesia, postoperative opioid consumption, and last postsurgical pain rating, all of which significantly affected satisfaction. These results are similar with previous studies that have analyzed the various factors that influence global patient satisfaction (Jensen et al., 2004).

Patients receiving IV acetaminophen required less opioid rescue medication via the PCA pump than those who received placebo while maintaining similar pain control. Although we did not analyze whether IV acetaminophen's opioid-reducing effect led to a reduction in opioid-related side effects, such as nausea, vomiting, constipation, urinary retention, respiratory depression, and sedation (Benyamin et al., 2008), any such reduction could positively affect patient satisfaction. However, while we found that opioid consumption significantly affected patient satisfaction, based on the logistic regression results we can conclude that IV acetaminophen's effect on patient satisfaction was independent of the amount opioids consumed.

The principal strength of this pooled analysis is the common methodology found in these five randomized, placebo-controlled studies, allowing for a robust, patient-level evaluation of the impact of scheduled doses of IV acetaminophen in the first 24 hr for postoperative pain intensity on patient satisfaction. All included studies had comparable overall designs and similar primary and secondary endpoints. These study results do relate to the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey and Value-Based Purchasing program. However, as the questions in our data were phrased slightly differently from the questions in the HCAHPS survey, the actual impact might differ.

A possible limitation of this analysis is that patients underwent different types of surgery, which may affect optimal analgesic regimen. However, while the type of surgery has a very strong effect on patient satisfaction, the significant increase in patient satisfaction with IV acetaminophen remains after type of surgery is accounted for in the multivariable analysis.

In conclusion, as patient satisfaction will affect Centers of Medicare and Medicaid Services reimbursement in the hospital setting, it is becoming an increasingly important outcome when considering postoperative analgesic drug regimens. In addition to its efficacy in controlling pain and reducing opioid consumption, when given as part of a perioperative analgesic regimen, IV acetaminophen was also associated with significantly improved patient satisfaction. Based on these results, it appears wise to consider integration of IV acetaminophen into multimodal postoperative analgesic regimens.

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Acknowledgments

The authors wish to thank Donna Simcoe at Cadence Pharmaceuticals, Inc. for providing patient-level satisfaction data from the five clinical trials provided at the authors’ request. Furthermore, the authors thank Christine Pan (CPAN Statistical Consulting) for her preliminary statistical analyses, funded by Cadence Pharmaceuticals, Inc.

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References

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Conflict of Interest

Christian Apfel, MD, PhD, was a former Associate Professor of the Department of Anesthesia and Perioperative Clinical Research Care and the Department of Biostatistics and Epidemiology at University of California, San Francisco and a former employee of Cadence Pharmaceuticals, Inc. Dr. Apfel is currently an Adjunct Associate Professor, Department of Epidemiology & Biostatistics, University of California, San Francisco and a consultant for Cadence Pharmaceuticals, Inc. Kimberly Souza performed this research when she was a member of the Department of Anesthesia & Perioperative Care, University of California, San Francisco. Ms. Souza is now a student at Stanford School of Medicine, Stanford, CA. Ms. Dalal was a former Clinical Research Assistant with the Department of Anesthesiology, but is now a first-year resident with the Department of Internal Medicine at The Ohio State University Wexner Medical Center.

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Authors' Biographies

Christian C. Apfel, MD, PhD, is an Adjunct Associate Professor at the Department of Epidemiology & Biostatistics, University of California, San Francisco. Dr. Apfel is focused on clinical research on a wide range of outcomes, including but not limited to postoperative nausea, vomiting, pain, and tumor response and survival in cancer research, etc. In collaboration with other colleagues he performs evidence-based quantitative systematic reviews, epidemiological research, and controlled clinical single- and multicenter investigator-initiated or registration trials.

Kimberly Souza, BS, is an MD Candidate, Stanford School of Medicine, Stanford, CA. Ms. Souza performed this research when she was a member of the Department of Anesthesia & Perioperative Care, University of California, San Francisco.

Juan Portillo, MD, is a Postdoctoral Researcher in the Department of Anesthesiology at The Ohio State University Wexner Medical Center. Dr. Portillo has research experience with sponsored and principal investigator initiated research trials, as well as with oral and poster presentations at scientific research meetings.

Poorvi Dalal, DO, is a first-year resident with the Department of Internal Medicine at The Ohio State University Wexner Medical Center. Dr. Dalal performed this research when she was a Clinical Research Assistant with the Department of Anesthesiology at The Ohio State University Wexner Medical Center.

Sergio D. Bergese, MD, is Associate Professor of the Department of Anesthesiology and Neurological Surgery, The Ohio State University Wexner Medical Center. Dr. Bergese's areas of interest are in postoperative pain, postoperative nausea and vomiting, postoperative delirium, and patient monitoring devices.

Keywords:

intravenous acetaminophen; patient satisfaction; perioperative analgesia; postoperative outcomes

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