Letter to the Editor Intravenous Acetaminophen —an Ineffective Analgesic? To the Editor: Wang et al. reported in the December 2015 issue of P&T 1 that patients after bariatric surgery administered intravenous (IV) acetaminophen required higher doses of opioids in the postoperative period than patients on opioids alone. We would like to comment on two points necessitating a discussion. First, the findings of the presented, small, retrospective study (N = 96) are in conflict with several large meta-analyses, including many prospective randomized trials with thousands of patients.2–4 Possible explanations could include: 1) different bariatric surgical procedures; 2) unchanged opioid prescribing practices after IV acetaminophen was added to the hospital’s formulary; and 3) noncompliance to American Society of Anesthesiologists practice guidelines to schedule acetaminophen and nonsteroidal antiinflammatory drugs around the clock unless contraindicated.5 Second, Wang et al. did not summarize the four retrospective studies presenting data on a similar patient population (morbidly obese patients undergoing bariatric surgery), including approximately 900 patients, all showing a reduction of opioid consumption in the postoperative period with the addition of IV acetaminophen.6–9 We believe that it would be more relevant to try to interpret the study results in light of overwhelming high-quality research. We are interested as to why the results of this small study differ from the results of the prior studies. A possible explanation could be bias and methodological deficiencies that are inevitable in a retrospective analysis. Kangwon Song, PharmD Advanced Addiction Treatment Fellow, South Texas Veterans Healthcare System, San Antonio, Texas; Assistant Professor, University of Texas Health Science Center at San Antonio Isaac Samuel, MD, FRCS, FACS Bariatric, Gastrointestinal, and Minimally Invasive Surgeon; Program Director, Bariatric Surgery Fellowship Program; Director, Obesity Surgery Program; Professor of Surgery—Gastrointestinal, Minimally Invasive, and Bariatric Surgery, all at the University of Iowa Carver College of Medicine, Iowa City, Iowa Patrick Ziemann-Gimmel, MD Assistant Professor, University of Central Florida, Orlando, Florida; Sheridan Healthcare, Sunrise, Florida
REFERENCES 1. 2.
3.
Wang S, Saha R, Shah N, et al. Effect of intravenous acetaminophen on postoperative opioid use in bariatric surgery patients. P T 2015;40(12):847–850. Tzortzopoulou A, McNicol ED, Cepeda MS, et al. Single dose intravenous propacetamol or intravenous paracetamol for postoperative pain. Cochrane Database Syst Rev 2011;(10):CD007126. doi: 10.1002/14651858.CD007126.pub2. Toms L, Derry S, Moore RA, McQuay HJ. Single dose oral
Disclosures: Dr. Ziemann-Gimmel has received speaking fees and honoraria from Cadence (now Mallinckrodt Pharmaceuticals) and Baxter, and is a shareholder in Johnson & Johnson. The other authors report no commercial or financial interests in regard to this letter.
4.
5.
6. 7.
8.
9.
paracetamol (acetaminophen) with codeine for postoperative pain in adults. Cochrane Database Syst Rev 2009;(1):CD001547. doi: 10.1002/14651858.CD001547.pub2. McDaid C, Maund E, Rice S, et al. Paracetamol and selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) for the reduction of morphine-related side effects after major surgery: a systematic review. Health Technol Assess Winch Engl 2010;14(17):1–153, iii—iv. doi: 10.3310/hta14170. American Society of Anesthesiologists. Standards & guidelines. Available at: www.asahq.org/quality-and-practice-management/standards-and-guidelines/search?q=+@audience==%22Physician%20 Anesthesiologist%22+@category==%22Postanesthetic%20Care%22. Accessed January 20, 2016. Gonzalez AM, Romero RJ, Ojeda-Vaz MM, Rabaza JR. Intravenous acetaminophen in bariatric surgery: effects on opioid requirements. J Surg Res 2015;195(1):99–104. doi: 10.1016/j.jss.2015.01.004. Saurabh S, Smith JK, Pedersen M, et al. Scheduled intravenous acetaminophen reduces postoperative narcotic analgesic demand and requirement after laparoscopic Roux-en-Y gastric bypass. Surg Obes Relat Dis 2015;11(2):424–430. doi: 10.1016/j.soard.2014.09.017. Song K, Melroy MJ, Whipple OC. Optimizing multimodal analgesia with intravenous acetaminophen and opioids in postoperative bariatric patients. Pharmacother J Hum Pharmacol Drug Ther 2014;34(suppl 1):S14–S21. doi: 10.1002/phar.1517. Ziemann-Gimmel P, Hensel P, Koppman J, Marema R. Multimodal analgesia reduces narcotic requirements and antiemetic rescue medication in laparoscopic Roux-en-Y gastric bypass surgery. Surg Obes Relat Dis Off J Am Soc Bariatr Surg 2013;9(6):975–980. doi: 10.1016/j.soard.2013.02.003.
Authors’ Response
First, it is important to mention that all guidelines were followed during our study. In regard to multimodal techniques for pain management, the American Society of Anesthesiologists guideline states that findings about IV acetaminophen in addition to opioids are equivocal. It is considered category C2 evidence, which means that the number of studies is insufficient and the reports have either not seen significant differences or the findings are inconsistent, which from our research appears to be the case.1 In the 2011 Cochrane review, patients did indeed require 30% less opioids with acetaminophen than without; however, this did not translate to a reduction in opioid- induced adverse events.2 The 2009 Cochrane review features a meta-analysis that does not focus on bariatric patients, has multiple types of acetaminophen delivery, and includes several different types of surgery. This is not to discount their findings, but we focused on IV acetaminophen in gastrointestinal bariatric surgery, and so we sought to publish a paper based on these settings.3 The paper by McDaid et al. did show a statistically significant decrease in 24-hour morphine consumption when acetaminophen was added to patient-controlled analgesia (PCA) morphine, but it was still a small reduction. The author stated that with this small reduction and with the wide confidence intervals for adverse outcomes, there is not a strong case for recommending the routine use of acetaminophen in addition to PCA morphine.4 The paper by Ziemann-Gimmel et al. did show a 73.8% reduction in opioid requirement with use of both IV ketorolac and IV acetaminophen together. However, they did not use IV acetaminophen without using IV ketorolac. For this reason, it is unclear whether these results were due to the IV acetaminophen or IV ketorolac. It is also important to note that in their study, opioid PCA was used in the control group but not in the study group. This could indirectly lead to lower opioid use, since the control group did not have their own access continued on page 387
Vol. 41 No. 6 • June 2016 • P&T 361 ®
Letter to the Editor continued from page 361
to the opioids. It is also important to note that Dr. ZiemannGimmel has been a paid speaker for Cadence, which can lead to potential bias.5 The paper by Gonzalez et al. had not been published when our paper was submitted. It is also important to point out that Dr. Gonzalez has been a paid speaker for Cadence Pharmaceuticals, which can lead to potential bias.6 We also located a trial by Wininger et al. that studied the effects of IV acetaminophen in patients after abdominal laparoscopic surgery. These patients received either 650 mg or 1,000 mg IV acetaminophen or matched placebos. All patients were allowed to ask for rescue medication if the pain was severe. It was reported that a larger percentage of subjects in the matched placebo groups required rescue medication in the first 24 hours; however, the difference was not statistically significant. Placebo groups also had a shorter time to their first rescue dose, but again this was not statistically significant. There were no statistically significant differences between the active-treatment groups and the combined placebo group for the amount of rescue-medication consumption. We will also point out that this study was sponsored by Cadence Pharmaceuticals.7 Overall, while we acknowledge the limitations of our small retrospective trial and the overwhelming evidence on the other side of our conclusion, our results do acknowledge a potential variation in patient population, prescribing practices, and/or management of pain in the bariatric surgery population. Shan Wang, PharmD, RPh Critical Care Pharmacist, Surgical Intensive Care Unit, Winthrop University Hospital, Mineola, New York Neal Shah, PharmD, RPh West Virginia University School of Medicine, Morgantown, West Virginia
REFERENCES 1.
2.
3.
4.
5.
6. 7.
American Society of Anesthesiologists. Standards & guidelines. Available at: www.asahq.org/quality-and-practicemanagement/standards-and-guidelines/search?q=+@ audience==%22Physician%20Anesthesiologist%22+@categor y==%22Postanesthetic%20Care%22. Accessed April 6, 2016. Tzortzopoulou A, McNicol ED, Cepeda MS, et al. Single dose intravenous propacetamol or intravenous paracetamol for postoperative pain. Cochrane Database Syst Rev 2011;(10):CD007126. doi: 10.1002/14651858.CD7126.pub 2. Toms L, Derry S, Moore RA, McQuay HJ. Single dose oral paracetamol (acetaminophen) with codeine for postoperative pain in adults. Cochrane Database Syst Rev 2009;(1):CD001547. doi: 10.1002/14651858.CD001547.pub2. McDaid C, Maund E, Rice S, et al. Paracetamol and selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) for the reduction of morphine-related side effects after major surgery: a systematic review. Health Technol Assess Winch Engl 2010;14(17):1–153, iii–iv. doi: 10.3310/hta14170. Ziemann-Gimmel P, Hensel P, Koppman J, Marema R. Multimodal analgesia reduces narcotic requirements and antiemetic rescue medication in laparoscopic Roux-en-Y gastric bypass surgery. Surg Obes Relat Dis Off J Am Soc Bariatr Surg 2013;9(6):975–980. doi: 10.1016/j.soard.2013.02.003. Gonzalez AM, Romero RJ, Ojeda-Vaz MM, Rabaza JR. Intravenous acetaminophen in bariatric surgery: effects on opioid requirements. J Surg Res 2015;195(1):99–104. doi: 10.1016/j.jss.2015.01.004. Wininger SJ, Miller H, Minkowitz HS, et al. A randomized, doubleblind, placebo-controlled, multicenter, repeat-dose study of two intravenous acetaminophen dosing regimens for the treatment of pain after abdominal laparoscopic surgery. Clin Ther 2010;32(14):2348–2369.
Vol. 41 No. 6 • June 2016 • P&T 387 ®
REFERENCES 1. 2.
3.
Wang S, Saha R, Shah N, et al. Effect of intravenous acetaminophen on postoperative opioid use in bariatric surgery patients. P T 2015;40(12):847–850. Tzortzopoulou A, McNicol ED, Cepeda MS, et al. Single dose intravenous propacetamol or intravenous paracetamol for postoperative pain. Cochrane Database Syst Rev 2011;(10):CD007126. doi: 10.1002/14651858.CD007126.pub2. Toms L, Derry S, Moore RA, McQuay HJ. Single dose oral
Disclosures: Dr. Ziemann-Gimmel has received speaking fees and honoraria from Cadence (now Mallinckrodt Pharmaceuticals) and Baxter, and is a shareholder in Johnson & Johnson. The other authors report no commercial or financial interests in regard to this letter.
4.
5.
6. 7.
8.
9.
paracetamol (acetaminophen) with codeine for postoperative pain in adults. Cochrane Database Syst Rev 2009;(1):CD001547. doi: 10.1002/14651858.CD001547.pub2. McDaid C, Maund E, Rice S, et al. Paracetamol and selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) for the reduction of morphine-related side effects after major surgery: a systematic review. Health Technol Assess Winch Engl 2010;14(17):1–153, iii—iv. doi: 10.3310/hta14170. American Society of Anesthesiologists. Standards & guidelines. Available at: www.asahq.org/quality-and-practice-management/standards-and-guidelines/search?q=+@audience==%22Physician%20 Anesthesiologist%22+@category==%22Postanesthetic%20Care%22. Accessed January 20, 2016. Gonzalez AM, Romero RJ, Ojeda-Vaz MM, Rabaza JR. Intravenous acetaminophen in bariatric surgery: effects on opioid requirements. J Surg Res 2015;195(1):99–104. doi: 10.1016/j.jss.2015.01.004. Saurabh S, Smith JK, Pedersen M, et al. Scheduled intravenous acetaminophen reduces postoperative narcotic analgesic demand and requirement after laparoscopic Roux-en-Y gastric bypass. Surg Obes Relat Dis 2015;11(2):424–430. doi: 10.1016/j.soard.2014.09.017. Song K, Melroy MJ, Whipple OC. Optimizing multimodal analgesia with intravenous acetaminophen and opioids in postoperative bariatric patients. Pharmacother J Hum Pharmacol Drug Ther 2014;34(suppl 1):S14–S21. doi: 10.1002/phar.1517. Ziemann-Gimmel P, Hensel P, Koppman J, Marema R. Multimodal analgesia reduces narcotic requirements and antiemetic rescue medication in laparoscopic Roux-en-Y gastric bypass surgery. Surg Obes Relat Dis Off J Am Soc Bariatr Surg 2013;9(6):975–980. doi: 10.1016/j.soard.2013.02.003.
Authors’ Response
First, it is important to mention that all guidelines were followed during our study. In regard to multimodal techniques for pain management, the American Society of Anesthesiologists guideline states that findings about IV acetaminophen in addition to opioids are equivocal. It is considered category C2 evidence, which means that the number of studies is insufficient and the reports have either not seen significant differences or the findings are inconsistent, which from our research appears to be the case.1 In the 2011 Cochrane review, patients did indeed require 30% less opioids with acetaminophen than without; however, this did not translate to a reduction in opioid- induced adverse events.2 The 2009 Cochrane review features a meta-analysis that does not focus on bariatric patients, has multiple types of acetaminophen delivery, and includes several different types of surgery. This is not to discount their findings, but we focused on IV acetaminophen in gastrointestinal bariatric surgery, and so we sought to publish a paper based on these settings.3 The paper by McDaid et al. did show a statistically significant decrease in 24-hour morphine consumption when acetaminophen was added to patient-controlled analgesia (PCA) morphine, but it was still a small reduction. The author stated that with this small reduction and with the wide confidence intervals for adverse outcomes, there is not a strong case for recommending the routine use of acetaminophen in addition to PCA morphine.4 The paper by Ziemann-Gimmel et al. did show a 73.8% reduction in opioid requirement with use of both IV ketorolac and IV acetaminophen together. However, they did not use IV acetaminophen without using IV ketorolac. For this reason, it is unclear whether these results were due to the IV acetaminophen or IV ketorolac. It is also important to note that in their study, opioid PCA was used in the control group but not in the study group. This could indirectly lead to lower opioid use, since the control group did not have their own access continued on page 387
Vol. 41 No. 6 • June 2016 • P&T 361 ®
Letter to the Editor continued from page 361
to the opioids. It is also important to note that Dr. ZiemannGimmel has been a paid speaker for Cadence, which can lead to potential bias.5 The paper by Gonzalez et al. had not been published when our paper was submitted. It is also important to point out that Dr. Gonzalez has been a paid speaker for Cadence Pharmaceuticals, which can lead to potential bias.6 We also located a trial by Wininger et al. that studied the effects of IV acetaminophen in patients after abdominal laparoscopic surgery. These patients received either 650 mg or 1,000 mg IV acetaminophen or matched placebos. All patients were allowed to ask for rescue medication if the pain was severe. It was reported that a larger percentage of subjects in the matched placebo groups required rescue medication in the first 24 hours; however, the difference was not statistically significant. Placebo groups also had a shorter time to their first rescue dose, but again this was not statistically significant. There were no statistically significant differences between the active-treatment groups and the combined placebo group for the amount of rescue-medication consumption. We will also point out that this study was sponsored by Cadence Pharmaceuticals.7 Overall, while we acknowledge the limitations of our small retrospective trial and the overwhelming evidence on the other side of our conclusion, our results do acknowledge a potential variation in patient population, prescribing practices, and/or management of pain in the bariatric surgery population. Shan Wang, PharmD, RPh Critical Care Pharmacist, Surgical Intensive Care Unit, Winthrop University Hospital, Mineola, New York Neal Shah, PharmD, RPh West Virginia University School of Medicine, Morgantown, West Virginia
REFERENCES 1.
2.
3.
4.
5.
6. 7.
American Society of Anesthesiologists. Standards & guidelines. Available at: www.asahq.org/quality-and-practicemanagement/standards-and-guidelines/search?q=+@ audience==%22Physician%20Anesthesiologist%22+@categor y==%22Postanesthetic%20Care%22. Accessed April 6, 2016. Tzortzopoulou A, McNicol ED, Cepeda MS, et al. Single dose intravenous propacetamol or intravenous paracetamol for postoperative pain. Cochrane Database Syst Rev 2011;(10):CD007126. doi: 10.1002/14651858.CD7126.pub 2. Toms L, Derry S, Moore RA, McQuay HJ. Single dose oral paracetamol (acetaminophen) with codeine for postoperative pain in adults. Cochrane Database Syst Rev 2009;(1):CD001547. doi: 10.1002/14651858.CD001547.pub2. McDaid C, Maund E, Rice S, et al. Paracetamol and selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) for the reduction of morphine-related side effects after major surgery: a systematic review. Health Technol Assess Winch Engl 2010;14(17):1–153, iii–iv. doi: 10.3310/hta14170. Ziemann-Gimmel P, Hensel P, Koppman J, Marema R. Multimodal analgesia reduces narcotic requirements and antiemetic rescue medication in laparoscopic Roux-en-Y gastric bypass surgery. Surg Obes Relat Dis Off J Am Soc Bariatr Surg 2013;9(6):975–980. doi: 10.1016/j.soard.2013.02.003. Gonzalez AM, Romero RJ, Ojeda-Vaz MM, Rabaza JR. Intravenous acetaminophen in bariatric surgery: effects on opioid requirements. J Surg Res 2015;195(1):99–104. doi: 10.1016/j.jss.2015.01.004. Wininger SJ, Miller H, Minkowitz HS, et al. A randomized, doubleblind, placebo-controlled, multicenter, repeat-dose study of two intravenous acetaminophen dosing regimens for the treatment of pain after abdominal laparoscopic surgery. Clin Ther 2010;32(14):2348–2369.
Vol. 41 No. 6 • June 2016 • P&T 387 ®
