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The effect of ondansetron on analgesic efficacy of acetaminophen after hysterectomy: A randomized double blinded placebo controlled trial
Journal of Clinical Anesthesia 40 (2017) 78–83
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Journal of Clinical Anesthesia
Original Contribution
The effect of ondansetron on analgesic efficacy of acetaminophen after hysterectomy: A randomized double blinded placebo controlled trial☆ Onur Koyuncu, MD a,⁎, Steve Leung, MD e, Jing You, MS d, Menekse Oksar, MD b, Selim Turhanoglu, MD b, Cagla Akkurt, MD b, Kenan Dolapcioglu, MD c, Hanifi Sahin, MD c, Daniel I. Sessler, MD e, Alparslan Turan, MD e a
Department of Anesthesiology, Department of Outcomes Research, Anesthesiology Institute, Mustafa Kemal University Tayfur Ata Sokmen Medicine Faculty, Hatay, Turkey Department of Anesthesiology, Mustafa Kemal University Tayfur Ata Sokmen Medicine Faculty, Hatay, Turkey c Department of Obstetrics and Gynecology, Mustafa Kemal University Tayfur Ata Sokmen Medicine Faculty, Hatay, Turkey d Departments of Quantitative Health Sciences and Outcomes Research, Anesthesiology Institute, Cleveland Clinic, Cleveland, United States e Department of Outcomes Research, Anesthesiology Institute, Cleveland Clinic, Cleveland, United States b
a r t i c l e
i n f o
Article history: Received 20 January 2017 Received in revised form 6 March 2017 Accepted 31 March 2017 Keywords: Anesthesia Acetaminophen Abdominal hysterectomy Serotonergic pathway Postoperative pain
a b s t r a c t Objectives: To determine that perioperative ondansetron reduces the analgesic efficacy of acetaminophen. Design: Randomized, double-blinded study. Patients: 120 patients ASA I-II who underwent abdominal hysterectomy. Interventions: All the patients were given 1 g acetaminophen at skin closure. Patients were divided into two groups; ondansetron HCl (8 mg, 2 ml IV) (Group I, N = 60) and saline (2 ml IV) (Group II, N = 60) at the skin closure. Measurement: Postoperative pain scores (VAS) while resting in bed and sitting, total opioid consumption were noted. Main results: Patients randomized to ondansetron had significantly worse pain scores upon arrival to the recovery unit [by 1.7 (99.7% CI: 0.75, 2.59) cm] and at 1 h [by 1.3 (0.5, 2.1) cm] while resting in bed. Pain scores while sitting were also significantly greater in ondansetron group at arrival in PACU by 0.6 (99.7% CI: 0.1, 1.0) cm. Thereafter, pain scores did not differ significantly. Median total opioid (tramadol) consumption was 441 [Q1, Q3: 280, 578] mg in the ondansetron group and 412 [309, 574] mg in the placebo group, P = 0.95. Conclusions: Ondansetron significantly decreased the analgesic effect of acetaminophen during the initial postoperative period. Our results thus confirm that acetaminophen analgesia is partially mediated by serotonin receptors. However, the reduction was of marginal clinical importance and short-lived. © 2017 Elsevier Inc. All rights reserved.
1. Introduction Control of postoperative pain and nausea-vomiting (PONV) are key components of quality of recovery after surgery [1]. Multimodal analgesia has become routine for postoperative pain. Acetaminophen is frequently added to multimodal analgesia, and its use has increased because of its effective opioid sparing resulting in reduction of opioidrelated side effects [2]. Acetaminophen exerts its analgesic effects by multiple pathways including inhibition of COX-2-dependent ☆ Received from Mustafa Kemal University Department of Anesthesiology; and the Department of Outcomes Research, Anesthesiology Institute, Cleveland Clinic.Supported by internal funds only. The Department of Outcomes Research receives research support from Mallinckrodt unrelated to this project. None of the authors has a personal financial interest in this research. ⁎ Corresponding author at: Department of Anesthesiology, Mustafa Kemal University Tayfur Ata Sokmen Medicine Faculty, Serinyol, Hatay, Turkey. E-mail address: [email protected] (O. Koyuncu).
http://dx.doi.org/10.1016/j.jclinane.2017.03.049 0952-8180/© 2017 Elsevier Inc. All rights reserved.
prostaglandin E2 synthesis [3], indirectly activating cannabinoid CB1 receptors and inhibition of nitric oxide system through involvement of Nmethyl-D-aspartate and substance-P [4]. The analgesic effect of acetaminophen may be primarily mediated by stimulation of descending serotonergic pathways which inhibits nociceptive signal transmission in the spinal cord [5–8]. Serotonin 5-Hydroxytryptamine (5-HT3) receptor antagonists, such as ondansetron, are generally considered to be the first-line antiemetics due to their effectiveness at preventing PONV and rare side effects [9]. Ondansetron primarily acts at the chemoreceptor trigger zone in the medulla oblongata, but it also interacts with 5-HT3 receptors within the spinal cord which modulate transmission of pain signals [10]. Ondansetron may therefore antagonize acetaminophen because the two drugs have opposite effects on 5-HT3 pathways [11,12]. The potential interaction between 5-HT3 receptors antagonists and acetaminophen has prompted studies to evaluate the of 5-HT3 receptors antagonism on analgesic efficacy of acetaminophen. Animal work
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shows that intrathecal administration of a 5-HT3 antagonist abolishes the analgesic effect of acetaminophen [6], and that blocking 5-HT3 receptors in the dorsal horn of the spinal cord by ondansetron is pro-nociceptive [13]. As might thus be expected, Arcioni et al. demonstrated that ondansetron inhibits the analgesic effects of tramadol, a central analgesic that activates descending serotonergic pathway [14]. Some human studies report that 5-HT3 antagonists decrease the analgesic efficacy of acetaminophen [7,11,12,15], while others failed to identify an association [16–18]. However, existing studies are limited by reliance on experimental pain models and relatively small sample sizes. Furthermore, existing studies mostly tested tropisetron which is not a commonly used 5-HT3 antagonist. There is scarce data about the interaction of acetaminophen and ondansetron, although these are often co-administered. We thus postulated that ondansetron attenuates acetaminophen-induced analgesia, presumably by directing interfering with serotonin transmission in the spinal cord. We therefore tested the primary hypothesis that ondansetron administration increases pain scores in patients given acetaminophen. Our secondary hypothesis was that ondansetron administration reduces opioid postoperative requirements. 2. Materials and methods This single-center, randomized, double-blinded study was conducted at Mustafa Kemal University Hospital. Ethics Committee approval (March 2012, Approval number 5) was obtained from the institution and written consent was obtained from participating patients. The study was registered at ClinicalTrials.gov (NCT02296333). We enrolled 120 American Society of Anesthesiologists Physical Status I-II women 18–80 years old who were scheduled for hysterectomy with general anesthesia from May through December 2014. The study was restricted to hysterectomies with horizontal abdominal skin incision, and to patients who were able to operate a patient-controlled analgesia (PCA) device. We excluded emergency procedures; women with pre-existing chronic pain at any site requiring opioid analgesia; women who had a history of significant Axis I psychiatric disease (major depressive disorder, bipolar disorder, schizophrenia, etc.); women with significant hepatic (ALT or AST N 2 times normal) or renal (serum creatinine N 2 mg/dl) impairment; and those reporting allergies to acetaminophen or ondansetron. 3. Protocol Participating women were premedicated with 1–2 mg intravenous (IV) midazolam per preference of the attending anesthesiologist. Anesthesia was induced with propofol (2 mg/kg IV); intubation was facilitated by rocuronium (0.6 mg/kg IV); and anesthesia was maintained by sevoflurane in combination with nitrous oxide 50% in oxygen. Fentanyl (2 μg/kg IV) was given 3–5 min before the surgical incision. After endotracheal intubation, patients' lungs were mechanically ventilated to maintain the end-expiratory CO2 partial pressure between 34 and 36 mm Hg. A Pfannenstiel approach was used in each patient, with the same surgeon similarly conducting all operations. All the patients were given 1 g acetaminophen at skin closure, and an additional 1 g every 6 h for 24 h. All patients were also given tramadol HCl (0.5 mg/kg IV) at skin closure. Randomization 1:1 without stratification was web-based using computer-generated codes. The system was accessed shortly before induction of anesthesia to mask allocation until the last practical moment. Drugs were covered by opaque plastic to keep the surgical team and anesthesiologists blinded to treatment. Patients assigned to ondansetron were given ondansetron HCl (8 mg, 2 ml IV) at closure of the skin incision. Patients assigned to placebo were given 2 ml saline IV, also at skin closure.
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After return of spontaneous ventilation and tracheal extubation, patients were transferred to the post anesthesia care unit (PACU). Patients were connected to a patient-controlled analgesia (PCA) device and postoperative analgesia was provided by 20-mg intravenous bolus injections of tramadol HCl at a lockout interval of 15 min and with a maximum 4-h limit of 150 mg. The PCA device was discontinued when patients made no demands for the opioid analgesic in the preceding 4-h interval or at a maximum of 24 h after surgery. When pain exceeded 4 cm on a visual analogue scale (VAS), a rescue dose of 75 mg diclofenac sodium was given intramuscularly. If systolic arterial pressure (SAP) decreased to b90 mm Hg or mean arterial pressure to b50 mm Hg, ephedrine HCl (5 mg IV) was given. If the heart rate decreased to b50 beats/min, atropine sulfate (0.5 mg IV) was given. When patients sustained nausea or vomiting lasting longer than 5 min, metoclopramide HCl (10 mg IV) was given. 4. Measurements All postoperative measurements were conducted by a research assistant who was blinded to group allocation. All patients were educated preoperatively at anesthesia clinic about how to use VAS tool consisting of a 10-cm-long ruler and a marker that the patient moved to a point indicating their intensity; 0 cm was designated no pain, and 10 cm as the worst imaginable pain. Postoperative pain was recorded separately with patients (who remained blinded to treatment) resting in bed and while sitting upon arrival at PACU and 1, 2, 4, 8, 12, 16, 20, and 24 thereafter. Sedation was assessed using the Ramsey sedation scale [19]. Heart rate, blood pressure, oxygen saturation (SpO2), respiratory rate, pain, sedation, opioid usage, cumulative analgesic consumption, and antiemetic use were assessed upon arrival in the PACU, and then 1, 4, 8, 12, 16, 20, and 24 h thereafter while awake. After the 4th postoperative hour, postoperative pain management was additionally assessed as 1 = unsatisfied, 2 = slightly satisfied, 3 = mostly satisfied, 4 = completely satisfied [20]. Hospital anxiety and depression surveys [21] were evaluated before discharge from the hospital. Postoperative side effects including nausea-vomiting, bradycardia (heart rate lower than 50 beats per minute), hypotension (decrease in systolic arterial pressure of N10 mm Hg from baseline), itching, headache, and respiratory depression (respiratory rate b 10) were recorded at intervals specified above. We recorded time to first flatus, initial ambulation, and first oral intake of solid food. The total amounts of opioid (tramadol) administration, rescue analgesics, antiemetics for 24 h were recorded. 5. Statistical analysis The two randomized groups were compared for balance on demographics and baseline characteristics using standard summary statistics and the absolute standardized difference (ASD), defined as the absolute difference in means or proportions divided by the pooled standard deviation. Any variable with an ASD N 0.20 was considered imbalanced, and was adjusted for in all analyses. The analgesic effect of acetaminophen with ondansetron or placebo on the VAS pain scores while resting in bed and while sitting was evaluated using separate multivariable regression models. The overall mean difference between the two randomized groups in the pain scores while resting in bed was not evaluated (treatment-by-time interaction P b 0.001) but in the VAS while sitting was evaluated (treatment-by-time interaction P = 0.59) using a mixed effect model with repeated measurements. The corresponding confidence interval was appropriately adjusted for multiple comparisons with a Bonferroni correction. We assessed the analgesic effect of acetaminophen with ondansetron on total opioid consumption (after logarithm transformation) during the first 24 h after arrival at PACU, using a multivariable
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Table 1 Patient characteristics. Factor
Ondansetron (N = 60)
Placebo (N = 60)
ASDa
Age, years BMI, kg/m2 ASA Physical Status II (vs. I), no. (%) Anesthesia duration, hours Surgery duration, hours
51 [46, 54] 29.4 [25.8, 31.3] 52 (87)
49 [44, 57] 29.4 [26.8, 33.2] 48 (80)
0.01 0.18 0.18
1.7 [1.4, 2.3] 1.4 [1.1, 2.0]
2.2 [1.9, 2.6] 1.9 [1.7, 2.3]
0.66 0.70
ASA = American Society of Anesthesiologists; ASD = absolute standardized difference. a Absolute difference in means or proportions divided by the pooled standard deviation. Any variable with an ASD N 0.20 was considered imbalanced, and was adjusted for in all analyses.
regression model. The ratio of median total opioids consumption was estimated by back transformation. For informational purposes, we also summarized Ramsey sedation scale, heart rate, blood pressure, oxygen saturation, respiratory rate, postoperative nausea vomiting, rescue analgesics, antiemetics during the first 24 h in PACU. Student t or Fisher's exact Chi-square tests were used to compare the two groups, as appropriate. With 60 patients per group, the study was planned to have 90% power at the 0.025 significance level to detect a difference of 1.0 cm or more in the mean Verbal Analog Scale (VAS) pain score at each condition between the two randomized groups (i.e., while resting in bed and while sitting). We assumed a SD of 1.5 for VAS (based on clinical experience and literature). SAS software version 9.4 for Windows (SAS Institute, Cary, NC, USA) was used for analyses.
thereafter. The estimated mean difference was 1.7 (99.7% CI: 0.8, 2.6) cm upon arrival in the PACU and 1.3 (0.5, 2.1) cm 1 h later. Thereafter, pain score remained greater in patients given ondansetron, but not significantly so. The analgesic effect of acetaminophen plus ondansetron on VAS pain scores while resting in bed depended on the measurement time (treatment-by-time interaction P b 0.001). Thus, the overall mean difference between the two randomized groups was not evaluated. Pain scores while sitting were significantly greater in ondansetron patients than those given placebo upon arrival in PACU. The estimated mean difference was 0.6 (99.7% CI: 0.1, 1.0). There was no difference between the two groups at any other measurement times thereafter. The overall mean difference between the two randomized groups was 0.3 (97.5% CI: − 0.3, 1.0) for ondansetron minus placebo, P = 0.55 (Table 2) (Fig. 1). 6.2. Secondary analysis Median total opioid (tramadol) consumption was 441 [Q1, Q3: 280, 578] mg in the ondansetron group and 412 [309, 574] mg in the placebo group. No difference was observed between the two groups; the estimated ratio of median total opioids consumption was 0.99 (95% CI: 0.81, 1.11) for ondansetron vs. placebo, P = 0.95. The two groups did not differ on heart rate, blood pressure, oxygen saturation, or respiratory rate during the first 24 h in the PACU (Table 3). Ramsey sedation scores differed significantly, but not by clinically meaningful amounts. The ondansetron group was more likely to receive rescue analgesics, but less likely to experience complications, receive antiemetics, or experience PONV (Table 3).
6. Results 7. Discussion The two randomized groups were poorly balanced on duration of anesthesia and duration of surgery, with absolute standardized differences of 0.66 and 0.70, respectively (Table 1). We thus adjusted for each when comparing the two groups on outcomes. 6.1. Primary analysis The ondansetron group had significantly higher pain scores than the placebo group while resting in bed upon arrival in PACU and 1 h
Coadministration of ondansetron and acetaminophen increased acute pain scores while patients rested supine by about 1.7 cm (on a 10-cm scale) upon arrival to the PACU, and pain scores remained about 1.3 cm greater after the initial hour of recovery. Differences while sitting were smaller, only 0.6 cm, and restricted to PACU arrival. After the first hour of recovery, there were no further significant differences in pain scores either resting in bed or sitting. That the inhibitory effect of ondansetron was restricted to one postoperative hour
Table 2 Primary results – comparison on VAS pain score over the first 24 h in the PACU. VAS pain score Resting in the bed Arrival in the PACU 1 h thereafter 4 h thereafter 8 h thereafter 12 h thereafter 16 h thereafter 20 h thereafter 24 h thereafter Overall effecta While sitting Arrival in the PACU 1 h thereafter 4 h thereafter 8 h thereafter 12 h thereafter 16 h thereafter 20 h thereafter 24 h thereafter Overall effecta
Ondansetron (N = 60)
Placebo (N = 60)
Mean difference (99.7% CI)b (groups 1–2)
5.6 ± 1.7 5.1 ± 1.6 3.7 ± 1.2 3.2 ± 1.2 2.7 ± 1.0 2.0 ± 0.9 1.6 ± 1.0 0.8 ± 0.7
3.8 ± 1.6 3.7 ± 1.2 3.0 ± 1.3 2.5 ± 1.1 2.2 ± 1.0 1.8 ± 1.0 1.1 ± 1.0 0.5 ± 0.7
1.67 (0.75, 2.59) 1.31 (0.50, 2.11) 0.65 (−0.07, 1.38) 0.63 (−0.05, 1.31) 0.46 (−0.10, 1.02) 0.13 (−0.40, 0.66) 0.48 (−0.11, 1.07) 0.34 (−0.10, 0.77) –
b0.001c 0.01 0.01 0.01 0.46 0.02 0.02 –
9.8 ± 0.6 8.8 ± 1.1 7.5 ± 1.4 6.3 ± 1.6 5.4 ± 1.7 4.1 ± 1.6 3.2 ± 1.5 2.0 ± 1.3
9.1 ± 0.9 8.6 ± 1.0 7.5 ± 1.4 6.1 ± 1.8 5.1 ± 1.7 4.2 ± 2.0 3.1 ± 1.7 1.7 ± 1.2
0.57 (0.14, 1.00) 0.07 (−0.52, 0.66) −0.03 (−0.84, 0.78) 0.11 (−0.87, 1.08) 0.14 (−0.84, 1.11) −0.27 (−1.28, 0.73) 0.05 (−0.88, 0.97) 0.32 (−0.40, 1.04) 0.34 (97.5% CI: −0.32, 1.00)
b0.001c 0.71 0.91 0.74 0.67 0.41 0.88 0.18 0.55
P value b0.001c
a The overall mean difference between the two randomized groups in the VAS resting in bed was not evaluated (treatment-by-time interaction P b 0.001) but in the VAS while sitting was evaluated (treatment-by-time interaction P = 0.59). b The corresponding confidence interval was adjusted for multiple comparisons appropriately by Bonferroni correction; the 97.5% CI was reported for the overall effect and 99.7% CI was reported at each assessment time (i.e., 0.025/8). c Statistically significant.
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presumably resulted from single-dose administration of a drug with a half-life of 3–4 h and unknown central nervous system clearance [22]. Our findings are also supported by several animal [23–25] and human studies [12,15,26]. Ramirez et al. examined coadministration of ondansetron and acetaminophen in pediatric patients having tonsillectomies. Children given acetaminophen were nearly three times as likely to require morphine (57% vs 21%) to achieve similar PACU pain scores [15]. In pediatrics, opioid consumption was been suggested as a more accurate indicator of pain level [27,28]. Pickering and colleagues compared the efficacy of acetaminophen analgesia in patients having ear surgery who were given tropisetron or placebo [17]. Postoperative pain scores were 30% greater in the
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Table 3 Summary of hemodynamics and complications during the first 24 h of PACU. Factor
Ondansetron (N = 60)
Placebo (N = 60)
P value
Average of heart rate, beats/min Average of systolic BP, mm Hg Average of diastolic BP, mm Hg Average of MAP, mm Hg Average of oxygen saturation, % Average of respiratory rate Average of Ramsey sedation scale Number of rescue analgesics, no. (%) 0 1 2 3 4 5 6 Number of complications, no. (%) 0 1 2 3 4 Number of antiemetics, no. (%) 0 1 2 3 4 PONV, no (%) None Mild Moderate Severe
81 ± 8 128 ± 15 75 ± 7 93 ± 9 98 ± 2 16 ± 2 1.87 ± 0.12
83 ± 5 125 ± 14 74 ± 4 91 ± 7 99 ± 2 16 ± 2 1.93 ± 0.10
0.12 0.23 0.19 0.13 0.24 0.67 0.005 0.003
3 (5) 7 (12) 18 (30) 14 (23) 10 (17) 8 (13) 0 (0)
7 (12) 27 (45) 11 (18) 5 (8) 6 (10) 3 (5) 1 (2)
51 (85) 7 (12) 2 (3) 0 (0) 0 (0)
31 (52) 22 (37) 5 (8) 1 (2) 1 (2)
45 (75) 11 (18) 3 (5) 0 (0) 1 (2)
26 (43) 24 (40) 7 (12) 2 (3) 1 (2)
45 (75) 11 (18) 2 (3) 2 (3)
26 (43) 21 (35) 5 (8) 8 (13)
0.006
0.004
0.003
Student t or Fisher's exact Chi-square tests were used.
Fig. 1. Boxplots of (A) VAS resting in bed and (B) VAS while sitting over the first 24 h in the PACU (N = 120). The first quartile, median, and third quartile comprise the boxes; whiskers extend to the most extreme observations within 1.5 times the interquartile range of the first and third quartiles, respectively.
tropisetron patients which is consistent with our hypothesis. However, the difference was not statistically significant because inter-individual variability was greater than the investigators anticipated. Their result should thus be considered under-powered rather than truly negative. A further consideration is that while tropisetron is similar to ondansetron, 5-HT3 antagonists differ their anti-serotonergic potential [29,30]. The same authors in a different study used an electrical stimulus as pain model to evaluate pain in healthy volunteers and reported that 5-HT3 antagonists (tropisteron and granisetron) decrease the analgesia of acetaminophen when coadministered [7]. However, our results contrast with several other clinical studies that evaluated similar drug interactions [16,17]. Jokela et al., for example, reported that a single dose of ondansetron did not reduce the analgesic efficacy of acetaminophen in patients recovering from laparoscopic hysterectomy [16]. A plausible explanation relates to their selection of surgical model and methodology. Postoperative pain after laparoscopic procedures is usually short-lived and mild. It is reasonable to assume that acetaminophen, even with its efficacy reduced by ondansetron, nonetheless provided adequate analgesia for the typically mild pain after laparoscopic surgery, thus minimizing possible difference. Another explanation might be the timing of acetaminophen administration and the dose of ondansetron used. In contrast to our study, acetaminophen was given at induction and ondansetron was given at the end of surgery; furthermore, most of their hysterectomies lasted longer than 2 h. The time between acetaminophen and ondansetron might also have been excessive, allowing substantial elimination of acetaminophen before ondansetron was given and thus limiting the drug-drug interaction [16]. This explanation seems consistent with the short-lived effect we observed. And finally, Jokela et al. gave 4 mg ondansetron which is presumably less effective at blocking 5-HT3 receptors than the 8 mg dose we used.
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A natural consequence of evaluating hysterectomies is that we enrolled only women. Although sex differences in pharmacokinetics and pharmacodynamics might affect the interaction of ondansetron and acetaminophen [31], it seems likely that our results will largely apply to men. Bandschapp et al. previously showed that coadministration of acetaminophen and tropisetron led to lower plasma concentration of acetaminophen, suggesting a potential pharmacokinetic interaction as both drugs are primarily metabolized by the liver [12]. However, we did not measure the plasma concentrations of our drugs and thus cannot rule out a pharmacokinetic effect rather than the drug interaction we postulate. In summary, ondansetron significantly decreased the analgesic effect of acetaminophen in the initial postoperative period. Our results thus confirm that acetaminophen analgesia is partially mediated by serotonin receptors. However, the reduction was of marginal clinical importance and short-lived. Clinicians can thus use the combination without anticipating much analgesic impairment. Author contributions 1. Onur Koyuncu, MD a. Role: This author helped design the study, conduct the study, and write the manuscript b. Attestation: This author has seen the original study data, reviewed the analysis of the data, and approved the final manuscript 2. Steve Leung, MD a. Role: This author helped conduct the study, and write the manuscript b. Attestation: This author reviewed the analysis of the data and approved the final manuscript 3. Jing You, MS a. Role: This author helped analyze the data and write the manuscript b. Attestation: This author has seen the original study data, reviewed the analysis of the data, and approved the final manuscript 4. Menekse Oksar a. Role: This author helped conduct the study, and write the manuscript b. Attestation: This author reviewed the analysis of the data and approved the final manuscript 5. Selim Turhanoglu a. Role: This author helped conduct the study, and write the manuscript b. Attestation: This author reviewed the analysis of the data and approved the final manuscript 6. Cagla Akkurt a. Role: This author helped analyze the data and write the manuscript b. Attestation: This author has seen the original study data, reviewed the analysis of the data, and approved the final manuscript 7. Kenan Dolapcioglu, MD a. Role: This author helped conduct the study, and write the manuscript b. Attestation: This author reviewed the analysis of the data and approved the final manuscript 8. Hanifi Sahin, MD a. Role: This author helped design the study, conduct the study, and write the manuscript b. Attestation: This author reviewed the analysis of the data and approved the final manuscript
9. Daniel I Sessler, MD a. Role: This author helped conduct the study, and write the manuscript b. Attestation: This author reviewed the analysis of the data and approved the final manuscript. 10. Alparslan Turan, MD a. Role: This author helped conduct the study, and write the manuscript b. Attestation: This author reviewed the analysis of the data and approved the final manuscript Acknowledgments Dr. Onur Koyuncu was supported by a grant for life expenses from TUBITAK: Technology and Innovation Support Programs, Directorate of the Scientific and Research Council of Turkey. The work was presented in part at the American Society of Anesthesiologists Annual Meeting, October 12 2015, San Diego. References [1] Haller G, Stoelwinder J, Myles PS, McNeil J. Quality and safety indicators in anesthesia: a systematic review. Anesthesiology May 2009;110(5):1158–75. [2] Apfel CC, Turan A, Souza K, Pergolizzi J, Hornuss C. Intravenous acetaminophen reduces postoperative nausea and vomiting: a systematic review and meta-analysis. Pain May 2013;154(5):677–89. [3] Smith HS. Perioperative intravenous acetaminophen and NSAIDs. Pain Med Jun 2011;12(6):961–81. [4] Bjorkman R. Central antinociceptive effects of non-steroidal anti-inflammatory drugs and paracetamol. Experimental studies in the rat. Acta Anaesthesiol Scand Suppl 1995;103:1–44. [5] Tjolsen A, Lund A, Hole K. Antinociceptive effect of paracetamol in rats is partly dependent on spinal serotonergic systems. Eur J Pharmacol Feb 7 1991;193(2): 193–201. [6] Pelissier T, Alloui A, Caussade F, Dubray C, Cloarec A, Lavarenne J, et al. Paracetamol exerts a spinal antinociceptive effect involving an indirect interaction with 5-hydroxytryptamine3 receptors: in vivo and in vitro evidence. J Pharmacol Exp Ther Jul 1996;278(1):8–14. [7] Pickering G, Esteve V, Loriot MA, Eschalier A, Dubray C. Acetaminophen reinforces descending inhibitory pain pathways. Clin Pharmacol Ther Jul 2008;84(1):47–51. [8] Courade JP, Chassaing C, Bardin L, Alloui A, Eschalier A. 5-HT receptor subtypes involved in the spinal antinociceptive effect of acetaminophen in rats. Eur J Pharmacol Nov 30 2001;432(1):1–7. [9] Apfel CC, Korttila K, Abdalla M, Kerger H, Turan A, Vedder I, et al. A factorial trial of six interventions for the prevention of postoperative nausea and vomiting. N Engl J Med Jun 10 2004;350(24):2441–51. [10] McCleane GJ, Suzuki R, Dickenson AH. Does a single intravenous injection of the 5HT3 receptor antagonist ondansetron have an analgesic effect in neuropathic pain? A double-blinded, placebo-controlled cross-over study. Anesth Analg Nov 2003;97(5):1474–8. [11] Pickering G, Loriot MA, Libert F, Eschalier A, Beaune P, Dubray C. Analgesic effect of acetaminophen in humans: first evidence of a central serotonergic mechanism. Clin Pharmacol Ther Apr 2006;79(4):371–8. [12] Bandschapp O, Filitz J, Urwyler A, Koppert W, Ruppen W. Tropisetron blocks analgesic action of acetaminophen: a human pain model study. Pain Jun 2011;152(6): 1304–10. [13] Peng YB, Lin Q, Willis WD. The role of 5-HT3 receptors in periaqueductal gray-induced inhibition of nociceptive dorsal horn neurons in rats. J Pharmacol Exp Ther Jan 1996;276(1):116–24. [14] Arcioni R, della Rocca M, Romano S, Romano R, Pietropaoli P, Gasparetto A. Ondansetron inhibits the analgesic effects of tramadol: a possible 5-HT(3) spinal receptor involvement in acute pain in humans. Anesth Analg Jun 2002;94(6):1553–7 (table of contents). [15] Ramirez L, Cros J, Marin B, Boulogne P, Bergeron A, de Lafont GE, et al. Analgesic interaction between ondansetron and acetaminophen after tonsillectomy in children: the Paratron randomized, controlled trial. Eur J Pain May 2015;19(5):661–8. [16] Jokela R, Ahonen J, Seitsonen E, Marjakangas P, Korttila K. The influence of ondansetron on the analgesic effect of acetaminophen after laparoscopic hysterectomy. Clin Pharmacol Ther Jun 2010;87(6):672–8. [17] Pickering G, Faure M, Commun F, de Boissy EC, Roche G, Mom T, et al. Tropisetron and paracetamol association in post-operative patients. Fundam Clin Pharmacol Jun 2012;26(3):432–7. [18] Tiippana E, Hamunen K, Kontinen V, Kalso E. The effect of paracetamol and tropisetron on pain: experimental studies and a review of published data. Basic Clin Pharmacol Toxicol Feb 2013;112(2):124–31. [19] Gentili M, Huu PC, Enel D, Hollande J, Bonnet F. Sedation depends on the level of sensory block induced by spinal anaesthesia. Br J Anaesth Dec 1998;81(6):970–1.
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Contents lists available at ScienceDirect
Journal of Clinical Anesthesia
Original Contribution
The effect of ondansetron on analgesic efficacy of acetaminophen after hysterectomy: A randomized double blinded placebo controlled trial☆ Onur Koyuncu, MD a,⁎, Steve Leung, MD e, Jing You, MS d, Menekse Oksar, MD b, Selim Turhanoglu, MD b, Cagla Akkurt, MD b, Kenan Dolapcioglu, MD c, Hanifi Sahin, MD c, Daniel I. Sessler, MD e, Alparslan Turan, MD e a
Department of Anesthesiology, Department of Outcomes Research, Anesthesiology Institute, Mustafa Kemal University Tayfur Ata Sokmen Medicine Faculty, Hatay, Turkey Department of Anesthesiology, Mustafa Kemal University Tayfur Ata Sokmen Medicine Faculty, Hatay, Turkey c Department of Obstetrics and Gynecology, Mustafa Kemal University Tayfur Ata Sokmen Medicine Faculty, Hatay, Turkey d Departments of Quantitative Health Sciences and Outcomes Research, Anesthesiology Institute, Cleveland Clinic, Cleveland, United States e Department of Outcomes Research, Anesthesiology Institute, Cleveland Clinic, Cleveland, United States b
a r t i c l e
i n f o
Article history: Received 20 January 2017 Received in revised form 6 March 2017 Accepted 31 March 2017 Keywords: Anesthesia Acetaminophen Abdominal hysterectomy Serotonergic pathway Postoperative pain
a b s t r a c t Objectives: To determine that perioperative ondansetron reduces the analgesic efficacy of acetaminophen. Design: Randomized, double-blinded study. Patients: 120 patients ASA I-II who underwent abdominal hysterectomy. Interventions: All the patients were given 1 g acetaminophen at skin closure. Patients were divided into two groups; ondansetron HCl (8 mg, 2 ml IV) (Group I, N = 60) and saline (2 ml IV) (Group II, N = 60) at the skin closure. Measurement: Postoperative pain scores (VAS) while resting in bed and sitting, total opioid consumption were noted. Main results: Patients randomized to ondansetron had significantly worse pain scores upon arrival to the recovery unit [by 1.7 (99.7% CI: 0.75, 2.59) cm] and at 1 h [by 1.3 (0.5, 2.1) cm] while resting in bed. Pain scores while sitting were also significantly greater in ondansetron group at arrival in PACU by 0.6 (99.7% CI: 0.1, 1.0) cm. Thereafter, pain scores did not differ significantly. Median total opioid (tramadol) consumption was 441 [Q1, Q3: 280, 578] mg in the ondansetron group and 412 [309, 574] mg in the placebo group, P = 0.95. Conclusions: Ondansetron significantly decreased the analgesic effect of acetaminophen during the initial postoperative period. Our results thus confirm that acetaminophen analgesia is partially mediated by serotonin receptors. However, the reduction was of marginal clinical importance and short-lived. © 2017 Elsevier Inc. All rights reserved.
1. Introduction Control of postoperative pain and nausea-vomiting (PONV) are key components of quality of recovery after surgery [1]. Multimodal analgesia has become routine for postoperative pain. Acetaminophen is frequently added to multimodal analgesia, and its use has increased because of its effective opioid sparing resulting in reduction of opioidrelated side effects [2]. Acetaminophen exerts its analgesic effects by multiple pathways including inhibition of COX-2-dependent ☆ Received from Mustafa Kemal University Department of Anesthesiology; and the Department of Outcomes Research, Anesthesiology Institute, Cleveland Clinic.Supported by internal funds only. The Department of Outcomes Research receives research support from Mallinckrodt unrelated to this project. None of the authors has a personal financial interest in this research. ⁎ Corresponding author at: Department of Anesthesiology, Mustafa Kemal University Tayfur Ata Sokmen Medicine Faculty, Serinyol, Hatay, Turkey. E-mail address: [email protected] (O. Koyuncu).
http://dx.doi.org/10.1016/j.jclinane.2017.03.049 0952-8180/© 2017 Elsevier Inc. All rights reserved.
prostaglandin E2 synthesis [3], indirectly activating cannabinoid CB1 receptors and inhibition of nitric oxide system through involvement of Nmethyl-D-aspartate and substance-P [4]. The analgesic effect of acetaminophen may be primarily mediated by stimulation of descending serotonergic pathways which inhibits nociceptive signal transmission in the spinal cord [5–8]. Serotonin 5-Hydroxytryptamine (5-HT3) receptor antagonists, such as ondansetron, are generally considered to be the first-line antiemetics due to their effectiveness at preventing PONV and rare side effects [9]. Ondansetron primarily acts at the chemoreceptor trigger zone in the medulla oblongata, but it also interacts with 5-HT3 receptors within the spinal cord which modulate transmission of pain signals [10]. Ondansetron may therefore antagonize acetaminophen because the two drugs have opposite effects on 5-HT3 pathways [11,12]. The potential interaction between 5-HT3 receptors antagonists and acetaminophen has prompted studies to evaluate the of 5-HT3 receptors antagonism on analgesic efficacy of acetaminophen. Animal work
O. Koyuncu et al. / Journal of Clinical Anesthesia 40 (2017) 78–83
shows that intrathecal administration of a 5-HT3 antagonist abolishes the analgesic effect of acetaminophen [6], and that blocking 5-HT3 receptors in the dorsal horn of the spinal cord by ondansetron is pro-nociceptive [13]. As might thus be expected, Arcioni et al. demonstrated that ondansetron inhibits the analgesic effects of tramadol, a central analgesic that activates descending serotonergic pathway [14]. Some human studies report that 5-HT3 antagonists decrease the analgesic efficacy of acetaminophen [7,11,12,15], while others failed to identify an association [16–18]. However, existing studies are limited by reliance on experimental pain models and relatively small sample sizes. Furthermore, existing studies mostly tested tropisetron which is not a commonly used 5-HT3 antagonist. There is scarce data about the interaction of acetaminophen and ondansetron, although these are often co-administered. We thus postulated that ondansetron attenuates acetaminophen-induced analgesia, presumably by directing interfering with serotonin transmission in the spinal cord. We therefore tested the primary hypothesis that ondansetron administration increases pain scores in patients given acetaminophen. Our secondary hypothesis was that ondansetron administration reduces opioid postoperative requirements. 2. Materials and methods This single-center, randomized, double-blinded study was conducted at Mustafa Kemal University Hospital. Ethics Committee approval (March 2012, Approval number 5) was obtained from the institution and written consent was obtained from participating patients. The study was registered at ClinicalTrials.gov (NCT02296333). We enrolled 120 American Society of Anesthesiologists Physical Status I-II women 18–80 years old who were scheduled for hysterectomy with general anesthesia from May through December 2014. The study was restricted to hysterectomies with horizontal abdominal skin incision, and to patients who were able to operate a patient-controlled analgesia (PCA) device. We excluded emergency procedures; women with pre-existing chronic pain at any site requiring opioid analgesia; women who had a history of significant Axis I psychiatric disease (major depressive disorder, bipolar disorder, schizophrenia, etc.); women with significant hepatic (ALT or AST N 2 times normal) or renal (serum creatinine N 2 mg/dl) impairment; and those reporting allergies to acetaminophen or ondansetron. 3. Protocol Participating women were premedicated with 1–2 mg intravenous (IV) midazolam per preference of the attending anesthesiologist. Anesthesia was induced with propofol (2 mg/kg IV); intubation was facilitated by rocuronium (0.6 mg/kg IV); and anesthesia was maintained by sevoflurane in combination with nitrous oxide 50% in oxygen. Fentanyl (2 μg/kg IV) was given 3–5 min before the surgical incision. After endotracheal intubation, patients' lungs were mechanically ventilated to maintain the end-expiratory CO2 partial pressure between 34 and 36 mm Hg. A Pfannenstiel approach was used in each patient, with the same surgeon similarly conducting all operations. All the patients were given 1 g acetaminophen at skin closure, and an additional 1 g every 6 h for 24 h. All patients were also given tramadol HCl (0.5 mg/kg IV) at skin closure. Randomization 1:1 without stratification was web-based using computer-generated codes. The system was accessed shortly before induction of anesthesia to mask allocation until the last practical moment. Drugs were covered by opaque plastic to keep the surgical team and anesthesiologists blinded to treatment. Patients assigned to ondansetron were given ondansetron HCl (8 mg, 2 ml IV) at closure of the skin incision. Patients assigned to placebo were given 2 ml saline IV, also at skin closure.
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After return of spontaneous ventilation and tracheal extubation, patients were transferred to the post anesthesia care unit (PACU). Patients were connected to a patient-controlled analgesia (PCA) device and postoperative analgesia was provided by 20-mg intravenous bolus injections of tramadol HCl at a lockout interval of 15 min and with a maximum 4-h limit of 150 mg. The PCA device was discontinued when patients made no demands for the opioid analgesic in the preceding 4-h interval or at a maximum of 24 h after surgery. When pain exceeded 4 cm on a visual analogue scale (VAS), a rescue dose of 75 mg diclofenac sodium was given intramuscularly. If systolic arterial pressure (SAP) decreased to b90 mm Hg or mean arterial pressure to b50 mm Hg, ephedrine HCl (5 mg IV) was given. If the heart rate decreased to b50 beats/min, atropine sulfate (0.5 mg IV) was given. When patients sustained nausea or vomiting lasting longer than 5 min, metoclopramide HCl (10 mg IV) was given. 4. Measurements All postoperative measurements were conducted by a research assistant who was blinded to group allocation. All patients were educated preoperatively at anesthesia clinic about how to use VAS tool consisting of a 10-cm-long ruler and a marker that the patient moved to a point indicating their intensity; 0 cm was designated no pain, and 10 cm as the worst imaginable pain. Postoperative pain was recorded separately with patients (who remained blinded to treatment) resting in bed and while sitting upon arrival at PACU and 1, 2, 4, 8, 12, 16, 20, and 24 thereafter. Sedation was assessed using the Ramsey sedation scale [19]. Heart rate, blood pressure, oxygen saturation (SpO2), respiratory rate, pain, sedation, opioid usage, cumulative analgesic consumption, and antiemetic use were assessed upon arrival in the PACU, and then 1, 4, 8, 12, 16, 20, and 24 h thereafter while awake. After the 4th postoperative hour, postoperative pain management was additionally assessed as 1 = unsatisfied, 2 = slightly satisfied, 3 = mostly satisfied, 4 = completely satisfied [20]. Hospital anxiety and depression surveys [21] were evaluated before discharge from the hospital. Postoperative side effects including nausea-vomiting, bradycardia (heart rate lower than 50 beats per minute), hypotension (decrease in systolic arterial pressure of N10 mm Hg from baseline), itching, headache, and respiratory depression (respiratory rate b 10) were recorded at intervals specified above. We recorded time to first flatus, initial ambulation, and first oral intake of solid food. The total amounts of opioid (tramadol) administration, rescue analgesics, antiemetics for 24 h were recorded. 5. Statistical analysis The two randomized groups were compared for balance on demographics and baseline characteristics using standard summary statistics and the absolute standardized difference (ASD), defined as the absolute difference in means or proportions divided by the pooled standard deviation. Any variable with an ASD N 0.20 was considered imbalanced, and was adjusted for in all analyses. The analgesic effect of acetaminophen with ondansetron or placebo on the VAS pain scores while resting in bed and while sitting was evaluated using separate multivariable regression models. The overall mean difference between the two randomized groups in the pain scores while resting in bed was not evaluated (treatment-by-time interaction P b 0.001) but in the VAS while sitting was evaluated (treatment-by-time interaction P = 0.59) using a mixed effect model with repeated measurements. The corresponding confidence interval was appropriately adjusted for multiple comparisons with a Bonferroni correction. We assessed the analgesic effect of acetaminophen with ondansetron on total opioid consumption (after logarithm transformation) during the first 24 h after arrival at PACU, using a multivariable
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Table 1 Patient characteristics. Factor
Ondansetron (N = 60)
Placebo (N = 60)
ASDa
Age, years BMI, kg/m2 ASA Physical Status II (vs. I), no. (%) Anesthesia duration, hours Surgery duration, hours
51 [46, 54] 29.4 [25.8, 31.3] 52 (87)
49 [44, 57] 29.4 [26.8, 33.2] 48 (80)
0.01 0.18 0.18
1.7 [1.4, 2.3] 1.4 [1.1, 2.0]
2.2 [1.9, 2.6] 1.9 [1.7, 2.3]
0.66 0.70
ASA = American Society of Anesthesiologists; ASD = absolute standardized difference. a Absolute difference in means or proportions divided by the pooled standard deviation. Any variable with an ASD N 0.20 was considered imbalanced, and was adjusted for in all analyses.
regression model. The ratio of median total opioids consumption was estimated by back transformation. For informational purposes, we also summarized Ramsey sedation scale, heart rate, blood pressure, oxygen saturation, respiratory rate, postoperative nausea vomiting, rescue analgesics, antiemetics during the first 24 h in PACU. Student t or Fisher's exact Chi-square tests were used to compare the two groups, as appropriate. With 60 patients per group, the study was planned to have 90% power at the 0.025 significance level to detect a difference of 1.0 cm or more in the mean Verbal Analog Scale (VAS) pain score at each condition between the two randomized groups (i.e., while resting in bed and while sitting). We assumed a SD of 1.5 for VAS (based on clinical experience and literature). SAS software version 9.4 for Windows (SAS Institute, Cary, NC, USA) was used for analyses.
thereafter. The estimated mean difference was 1.7 (99.7% CI: 0.8, 2.6) cm upon arrival in the PACU and 1.3 (0.5, 2.1) cm 1 h later. Thereafter, pain score remained greater in patients given ondansetron, but not significantly so. The analgesic effect of acetaminophen plus ondansetron on VAS pain scores while resting in bed depended on the measurement time (treatment-by-time interaction P b 0.001). Thus, the overall mean difference between the two randomized groups was not evaluated. Pain scores while sitting were significantly greater in ondansetron patients than those given placebo upon arrival in PACU. The estimated mean difference was 0.6 (99.7% CI: 0.1, 1.0). There was no difference between the two groups at any other measurement times thereafter. The overall mean difference between the two randomized groups was 0.3 (97.5% CI: − 0.3, 1.0) for ondansetron minus placebo, P = 0.55 (Table 2) (Fig. 1). 6.2. Secondary analysis Median total opioid (tramadol) consumption was 441 [Q1, Q3: 280, 578] mg in the ondansetron group and 412 [309, 574] mg in the placebo group. No difference was observed between the two groups; the estimated ratio of median total opioids consumption was 0.99 (95% CI: 0.81, 1.11) for ondansetron vs. placebo, P = 0.95. The two groups did not differ on heart rate, blood pressure, oxygen saturation, or respiratory rate during the first 24 h in the PACU (Table 3). Ramsey sedation scores differed significantly, but not by clinically meaningful amounts. The ondansetron group was more likely to receive rescue analgesics, but less likely to experience complications, receive antiemetics, or experience PONV (Table 3).
6. Results 7. Discussion The two randomized groups were poorly balanced on duration of anesthesia and duration of surgery, with absolute standardized differences of 0.66 and 0.70, respectively (Table 1). We thus adjusted for each when comparing the two groups on outcomes. 6.1. Primary analysis The ondansetron group had significantly higher pain scores than the placebo group while resting in bed upon arrival in PACU and 1 h
Coadministration of ondansetron and acetaminophen increased acute pain scores while patients rested supine by about 1.7 cm (on a 10-cm scale) upon arrival to the PACU, and pain scores remained about 1.3 cm greater after the initial hour of recovery. Differences while sitting were smaller, only 0.6 cm, and restricted to PACU arrival. After the first hour of recovery, there were no further significant differences in pain scores either resting in bed or sitting. That the inhibitory effect of ondansetron was restricted to one postoperative hour
Table 2 Primary results – comparison on VAS pain score over the first 24 h in the PACU. VAS pain score Resting in the bed Arrival in the PACU 1 h thereafter 4 h thereafter 8 h thereafter 12 h thereafter 16 h thereafter 20 h thereafter 24 h thereafter Overall effecta While sitting Arrival in the PACU 1 h thereafter 4 h thereafter 8 h thereafter 12 h thereafter 16 h thereafter 20 h thereafter 24 h thereafter Overall effecta
Ondansetron (N = 60)
Placebo (N = 60)
Mean difference (99.7% CI)b (groups 1–2)
5.6 ± 1.7 5.1 ± 1.6 3.7 ± 1.2 3.2 ± 1.2 2.7 ± 1.0 2.0 ± 0.9 1.6 ± 1.0 0.8 ± 0.7
3.8 ± 1.6 3.7 ± 1.2 3.0 ± 1.3 2.5 ± 1.1 2.2 ± 1.0 1.8 ± 1.0 1.1 ± 1.0 0.5 ± 0.7
1.67 (0.75, 2.59) 1.31 (0.50, 2.11) 0.65 (−0.07, 1.38) 0.63 (−0.05, 1.31) 0.46 (−0.10, 1.02) 0.13 (−0.40, 0.66) 0.48 (−0.11, 1.07) 0.34 (−0.10, 0.77) –
b0.001c 0.01 0.01 0.01 0.46 0.02 0.02 –
9.8 ± 0.6 8.8 ± 1.1 7.5 ± 1.4 6.3 ± 1.6 5.4 ± 1.7 4.1 ± 1.6 3.2 ± 1.5 2.0 ± 1.3
9.1 ± 0.9 8.6 ± 1.0 7.5 ± 1.4 6.1 ± 1.8 5.1 ± 1.7 4.2 ± 2.0 3.1 ± 1.7 1.7 ± 1.2
0.57 (0.14, 1.00) 0.07 (−0.52, 0.66) −0.03 (−0.84, 0.78) 0.11 (−0.87, 1.08) 0.14 (−0.84, 1.11) −0.27 (−1.28, 0.73) 0.05 (−0.88, 0.97) 0.32 (−0.40, 1.04) 0.34 (97.5% CI: −0.32, 1.00)
b0.001c 0.71 0.91 0.74 0.67 0.41 0.88 0.18 0.55
P value b0.001c
a The overall mean difference between the two randomized groups in the VAS resting in bed was not evaluated (treatment-by-time interaction P b 0.001) but in the VAS while sitting was evaluated (treatment-by-time interaction P = 0.59). b The corresponding confidence interval was adjusted for multiple comparisons appropriately by Bonferroni correction; the 97.5% CI was reported for the overall effect and 99.7% CI was reported at each assessment time (i.e., 0.025/8). c Statistically significant.
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presumably resulted from single-dose administration of a drug with a half-life of 3–4 h and unknown central nervous system clearance [22]. Our findings are also supported by several animal [23–25] and human studies [12,15,26]. Ramirez et al. examined coadministration of ondansetron and acetaminophen in pediatric patients having tonsillectomies. Children given acetaminophen were nearly three times as likely to require morphine (57% vs 21%) to achieve similar PACU pain scores [15]. In pediatrics, opioid consumption was been suggested as a more accurate indicator of pain level [27,28]. Pickering and colleagues compared the efficacy of acetaminophen analgesia in patients having ear surgery who were given tropisetron or placebo [17]. Postoperative pain scores were 30% greater in the
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Table 3 Summary of hemodynamics and complications during the first 24 h of PACU. Factor
Ondansetron (N = 60)
Placebo (N = 60)
P value
Average of heart rate, beats/min Average of systolic BP, mm Hg Average of diastolic BP, mm Hg Average of MAP, mm Hg Average of oxygen saturation, % Average of respiratory rate Average of Ramsey sedation scale Number of rescue analgesics, no. (%) 0 1 2 3 4 5 6 Number of complications, no. (%) 0 1 2 3 4 Number of antiemetics, no. (%) 0 1 2 3 4 PONV, no (%) None Mild Moderate Severe
81 ± 8 128 ± 15 75 ± 7 93 ± 9 98 ± 2 16 ± 2 1.87 ± 0.12
83 ± 5 125 ± 14 74 ± 4 91 ± 7 99 ± 2 16 ± 2 1.93 ± 0.10
0.12 0.23 0.19 0.13 0.24 0.67 0.005 0.003
3 (5) 7 (12) 18 (30) 14 (23) 10 (17) 8 (13) 0 (0)
7 (12) 27 (45) 11 (18) 5 (8) 6 (10) 3 (5) 1 (2)
51 (85) 7 (12) 2 (3) 0 (0) 0 (0)
31 (52) 22 (37) 5 (8) 1 (2) 1 (2)
45 (75) 11 (18) 3 (5) 0 (0) 1 (2)
26 (43) 24 (40) 7 (12) 2 (3) 1 (2)
45 (75) 11 (18) 2 (3) 2 (3)
26 (43) 21 (35) 5 (8) 8 (13)
0.006
0.004
0.003
Student t or Fisher's exact Chi-square tests were used.
Fig. 1. Boxplots of (A) VAS resting in bed and (B) VAS while sitting over the first 24 h in the PACU (N = 120). The first quartile, median, and third quartile comprise the boxes; whiskers extend to the most extreme observations within 1.5 times the interquartile range of the first and third quartiles, respectively.
tropisetron patients which is consistent with our hypothesis. However, the difference was not statistically significant because inter-individual variability was greater than the investigators anticipated. Their result should thus be considered under-powered rather than truly negative. A further consideration is that while tropisetron is similar to ondansetron, 5-HT3 antagonists differ their anti-serotonergic potential [29,30]. The same authors in a different study used an electrical stimulus as pain model to evaluate pain in healthy volunteers and reported that 5-HT3 antagonists (tropisteron and granisetron) decrease the analgesia of acetaminophen when coadministered [7]. However, our results contrast with several other clinical studies that evaluated similar drug interactions [16,17]. Jokela et al., for example, reported that a single dose of ondansetron did not reduce the analgesic efficacy of acetaminophen in patients recovering from laparoscopic hysterectomy [16]. A plausible explanation relates to their selection of surgical model and methodology. Postoperative pain after laparoscopic procedures is usually short-lived and mild. It is reasonable to assume that acetaminophen, even with its efficacy reduced by ondansetron, nonetheless provided adequate analgesia for the typically mild pain after laparoscopic surgery, thus minimizing possible difference. Another explanation might be the timing of acetaminophen administration and the dose of ondansetron used. In contrast to our study, acetaminophen was given at induction and ondansetron was given at the end of surgery; furthermore, most of their hysterectomies lasted longer than 2 h. The time between acetaminophen and ondansetron might also have been excessive, allowing substantial elimination of acetaminophen before ondansetron was given and thus limiting the drug-drug interaction [16]. This explanation seems consistent with the short-lived effect we observed. And finally, Jokela et al. gave 4 mg ondansetron which is presumably less effective at blocking 5-HT3 receptors than the 8 mg dose we used.
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A natural consequence of evaluating hysterectomies is that we enrolled only women. Although sex differences in pharmacokinetics and pharmacodynamics might affect the interaction of ondansetron and acetaminophen [31], it seems likely that our results will largely apply to men. Bandschapp et al. previously showed that coadministration of acetaminophen and tropisetron led to lower plasma concentration of acetaminophen, suggesting a potential pharmacokinetic interaction as both drugs are primarily metabolized by the liver [12]. However, we did not measure the plasma concentrations of our drugs and thus cannot rule out a pharmacokinetic effect rather than the drug interaction we postulate. In summary, ondansetron significantly decreased the analgesic effect of acetaminophen in the initial postoperative period. Our results thus confirm that acetaminophen analgesia is partially mediated by serotonin receptors. However, the reduction was of marginal clinical importance and short-lived. Clinicians can thus use the combination without anticipating much analgesic impairment. Author contributions 1. Onur Koyuncu, MD a. Role: This author helped design the study, conduct the study, and write the manuscript b. Attestation: This author has seen the original study data, reviewed the analysis of the data, and approved the final manuscript 2. Steve Leung, MD a. Role: This author helped conduct the study, and write the manuscript b. Attestation: This author reviewed the analysis of the data and approved the final manuscript 3. Jing You, MS a. Role: This author helped analyze the data and write the manuscript b. Attestation: This author has seen the original study data, reviewed the analysis of the data, and approved the final manuscript 4. Menekse Oksar a. Role: This author helped conduct the study, and write the manuscript b. Attestation: This author reviewed the analysis of the data and approved the final manuscript 5. Selim Turhanoglu a. Role: This author helped conduct the study, and write the manuscript b. Attestation: This author reviewed the analysis of the data and approved the final manuscript 6. Cagla Akkurt a. Role: This author helped analyze the data and write the manuscript b. Attestation: This author has seen the original study data, reviewed the analysis of the data, and approved the final manuscript 7. Kenan Dolapcioglu, MD a. Role: This author helped conduct the study, and write the manuscript b. Attestation: This author reviewed the analysis of the data and approved the final manuscript 8. Hanifi Sahin, MD a. Role: This author helped design the study, conduct the study, and write the manuscript b. Attestation: This author reviewed the analysis of the data and approved the final manuscript
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