SPINE Volume 39, Number 9, pp E543-E549 ©2014, Lippincott Williams & Wilkins
RANDOMIZED TRIAL
Efficacy of Palonosetron Versus Ramosetron on Preventing Opioid-Based Analgesia-Related Nausea and Vomiting After Lumbar Spinal Surgery A Prospective, Randomized, and Double-Blind Trial Go Un Roh, MD,* So Young Yang, MD,† Jae Kwang Shim, MD, PhD,* and Young Lan Kwak, MD, PhD*
Study Design. A prospective, randomized, and double-blind study. Objective. To compare the efficacy of ramosetron and palonosetron on preventing postoperative nausea and vomiting (PONV) associated with opioid-based intravenous patient-controlled analgesia (IV-PCAopioid) after lumbar spinal surgery. Summary of Background Data. IV-PCAopioid, an effective method to control pain after lumbar spinal surgery, accompanies PONV. Ramosetron and palonosetron are novel 5-hydroxytryptamine 3 antagonists known to have longer action duration and higher receptor affinity than their congeners, whereas their relative efficacy has not been validated yet. Methods. One hundred ninety-six patients were randomly and evenly allocated to receive either 0.3 mg of ramosetron or 0.075 mg of palonosetron 10 minutes before the end of operation. Ramosetron or palonosetron were also added to the IV-PCAopioid, which was continuously infused for 48 hours postoperatively. The incidence and intensity of PONV were serially assessed for 72 hours postoperatively. Intensity of pain, volume of IV-PCAopioid consumption, use of rescue analgesics and antiemetics, and adverse events were also assessed. Results. The overall incidence of PONV was lower in the ramosetron group than the palonosetron group (50% vs. 67%, P = 0.014) without any intergroup difference in the incidence of vomiting. Nausea intensity scores were also lower until 6 (P = 0.041) and 24 hour (P = 0.026) postoperatively in the ramosetron group From the *Department of Anesthesiology and Pain Medicine and Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, South Korea; and †Department of Anesthesiology and Pain Medicine, Choong-Ang University College of Medicine, Seoul, South Korea. Acknowledgment date: November 11, 2013. Revision date: December 24, 2013. Acceptance date: January 9, 2014. The manuscript submitted does not contain information about medical device(s)/drug(s). No funds were received in support of this work. No relevant financial activities outside the submitted work. Address correspondence and reprint requests to Young Lan Kwak, MD, PhD, Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Severance Biomedical Science Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, South Korea, 120752; E-mail: [email protected] DOI: 10.1097/BRS.0000000000000236 Spine
than the palonosetron group. Pain intensity scores were significantly lower in the ramosetron group than the palonosetron group for 72 hours postoperatively. Conclusion. Ramosetron was superior to palonosetron in term of reducing the incidence and severity of nausea associated with IV-PCAopioid after lumbar spinal surgery. This favorable influence of ramosetron on PONV was translated to significant postoperative pain reduction compared with palonosetron. Key words: analgesia, patient-controlled, anti-emetics, palonosetron, anti-emetics, ramosetron, postoperative nausea and vomiting. Level of Evidence: 1 Spine 2014;39:E543–E549
A
dequate pain control after lumbar spinal surgery is a prerequisite to patients’ well-being as well as early recovery and rehabilitation.1 Currently, opioid-based intravenous patient-controlled analgesia (IV-PCAopioid) is one of the most effective ways to control postoperative pain,2–5 yet it accompanies unpleasant adverse effects occurring at a considerable incidence. The use of IV-PCAopioid inevitably increases the incidence of postoperative nausea and vomiting (PONV), a vexing adverse event, reported to be as high as 80% in patients with multiple risk factors.6,7 Accordingly, there have been consistent efforts to reduce the incidence of PONV with multimodal therapies such as risk stratification, modification, and preventive use of antiemetics.4,8 Among the available antiemetics, 5-hydroxytryptamine (5-HT3) receptor antagonists are most commonly used and extensively studied regarding PONV reduction.8 Their efficacies, however, are not quite satisfactory when it comes to PONV associated with IV-PCAopioid, especially in case of ondansetron.9–11 Newer generations of 5-HT3 receptor antagonists were developed with higher receptor affinity and longer action duration, such as ramosetron, which has been shown to exert more potent and sustained antiemetic efficacy than the first generation.12,13 Palonosetron, the latest 5-HT3 antagonist, has a unique allosteric binding property to the 5-HT3 receptor and thus, it is segregated from previous 5-HT3 antagonists www.spinejournal.com
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RANDOMIZED TRIAL in terms of higher receptor binding affinity, longer duration of action and longer elimination half-time.14,15 However, evidences are not enough to suggest palonosetron as the most efficient 5-HT3 antagonists for PONV. Through previous studies, the superior efficacy of ramosetron and palonosetron over ondansetron in reducing PONV associated with IV-PCAopioid has been validated separately.10–14,16 Yet, direct comparison between ramosetron and palonosetron regarding their preventive effects on IV-PCAopioid–related PONV has not been addressed heretofore. In this prospective, randomized, and double-blind study, we evaluated whether palonosetron would be superior to ramosetron in preventing PONV in patients receiving IV-PCAopioid after lumbar spinal surgery.
MATERIALS AND METHODS After approval of institutional review board and obtaining patients’ written informed consent, 196 patients (20–65 yr) scheduled for lumbar spinal surgery in prone position between August 2011 and July 2012 were screened and enrolled. All patients were treated with IV-PCAopioid postoperatively for pain control. Patients with the following profiles were excluded: gastrointestinal disease; renal or hepatic dysfunction; diabetes mellitus on insulin; pregnancy; use of steroid, opioid, or antiemetics 1 day before surgery; inability to understand verbal rating scale; inability to use PCA device. After enrollment, patients were randomly allocated into either ramosetron or palonosetron group by a computerized randomization table. The code of the assigned group was enclosed in the opaque envelope. Patients’ demographic profiles and medical histories including motion sickness, PONV, and smoking state were recorded. Anesthesia was induced with 1.5 to 2.5 mg/kg of propofol, 0.5 to 1.5 μg/kg of Remifentanil, and 0.06 mg/kg of Rocuronium, and maintained with 1.5% to 2.5% of Sevoflurane (50:50 mixture of oxygen and air) and 0.1 to 0.3 μg/kg/min of remifentanil. Ten minutes before the end of surgery, 2 mL of medication containing either 0.3 mg of ramosetron or 0.075 mg palonosetron was injected, then IV-PCAopioid was introduced. IV-PCAopioid consisted of 25 μg/kg of fentanyl, 120 mg of ketorolac, and either 0.3 mg of ramosetron or 0.075 mg of palonosetron according to the group allocation (total volume of 100 mL including 0.9% normal saline, basal rate 2 mL/hr, bolus 0.5 mL, lockout time 15 min). The costs of ramosetron and palonosetron per patient in Korea were approximately $54 and $59, respectively. An unblinded anesthesiologist not involved in patient management and assessment received the opaque envelope containing the code of assigned group, prepared all the medications in the same syringes and PCA devices without labeling according to the group allocation, and handed over to the blinded anesthesiologists who managed the studied patients. Rescue antiemetic (10 mg of metoclopramide, IV) or analgesic (30 mg of ketorolac, IV) was administered according to the decision of blinded neurosurgeons in charge of postoperative care in wards or upon patient’s request. Serial postoperative assessments were E544
Antiemetic Efficacy of Ramosetron and Palonsetron • Roh et al
performed according to the schedule by one physician blinded to the group allocation. The primary end point of this study was to compare the overall incidence of PONV between the groups. The incidences of PONV were assessed in postanesthesia care unit and at intervals of 0 to 6, 6 to 24, 24 to 48, and 48 to 72 hours postoperatively. Nausea was defined as a subjectively unpleasant sensation with concomitant awareness of the urge to vomit. Vomiting was defined as the forceful expulsion of gastric contents through the mouth. Retching, the labored spasmodic rhythmic contractions of the respiratory muscles without the expulsion of the gastric contents, was also regarded as vomiting.17 Secondary end points were to compare the intensities of nausea (verbal rating scale, 0 = no nausea, 10 = worst nausea imaginable) and pain (verbal rating scale, 0 = no pain, 10 = worst pain imaginable). Additionally, cumulative volume of IV-PCAopioid administered during each observation period, rescue analgesics and antiemetic requirements, discontinuation of IV-PCAopioid ahead of time, and adverse events (dizziness, drowsiness, headache, constipation, urinary retention, and pruritus) were assessed. On the basis of the reported efficacy of palonosetron in a previous study,10 98 patients were needed for each group to detect a 33% decrease of the incidence of PONV with a power of 80% and type I error of 0.05, when the incidence of PONV would be 60% in this study. SAS (version 9.2, SAS Institute Inc., Cary, NC) was used for the data analysis. To compare the data of groups, the Student t test, Mann-Whitney U test, χ2 test, or Fisher exact test were used as appropriate. For the analysis of repeatedly measured data, linear mixed model and logistic regression with generalized estimating equation method were performed as appropriate. After correction with Bonferroni method, P values less than 0.05 were considered to be statistically significant. The results were presented as number with percentage, mean with standard deviation, or median with interquartile range according to the normality of their distribution.
RESULTS Among the 248 patients assessed for eligibility, 196 patients who met the inclusion criteria consented to participate in this study and completed (Figure 1). A total of 7 patients requested discontinuation of IV-PCAopioid infusion before completion due to negligible pain (ramosetron group: 4, palonosetron group: 3) on the second postoperative day. The data of these patients were included in the analysis according to the intendto-treat principle. The patients’ characteristics, operative, and anesthetic data were comparable, except greater body mass index in the ramosetron group (Table 1). The overall incidence of PONV during the study period was significantly higher in the palonosetron group than in the ramosetron group (67% vs. 50%, P = 0.014). In detail, palonosetron group showed significantly higher incidence of PONV than the ramosetron group during the first postoperative 6 hours (50% vs. 32%, P = 0.009). The overall incidence of nausea was significantly greater in the palonosetron group than the ramosetron group (67% vs. 49%, P = 0.009), which
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Enrollment
Antiemetic Efficacy of Ramosetron and Palonsetron • Roh et al
Assessed for eligibility (n = 248) Excluded (n = 52) ♦ Not meeting inclusion criteria (n = 40) ♦ Older than 65 years (n = 31) ♦ Diabetes mellitus on insulin (n = 8) ♦ Use of opioid within 1 day before surgery (n = 1) ♦ ♦
Declined to participate (n = 12) Other reasons (n = 0)
Randomization 1:1 (n = 196)
Allocation Allocated to intervention (n = 98) ♦ Received allocated intervention (n = 98)
Allocated to intervention (n = 98) ♦ Received allocated intervention (n = 98)
Follow-Up Lost to follow-up (give reasons) (n = 0)
Lost to follow-up (give reasons) (n = 0)
Discontinued intervention (give reasons) (n = 0)
Discontinued intervention (give reasons) (n = 0)
Analysis Analyzed (n = 98) ♦ Excluded from analysis (give reasons) (n = 0)
Analyzed (n = 98) ♦ Excluded from analysis (give reasons) (n = 0)
Figure 1. CONSORT diagram showing the flow of participants.
was also more evident during the first postoperative 6 hours (48% vs. 32%, P = 0.02). The intensity of nausea was significantly greater in the palonosetron group than the ramosetron group until the first postoperative 24 hours (0–6 hr, P = 0.041 and 6–24 hr, 0.026). The overall incidence of vomiting was not significantly different between the groups. The numbers of patients requiring rescue antiemetics and discontinuing IV-PCAopioid infusion due to PONV were similar between the groups (Table 2). The pain intensities were significantly greater in the palonosetron group than the ramosetron group during the entire study period, except during the stay at postanesthesia care unit (Table 3). The cumulative volumes of consumed IV-PCAopioid and the number of patients requiring rescue analgesics at each observation period were not different throughout the study period between the groups (Table 4). The incidences of adverse events were similar between the groups (Table 5).
DISCUSSION In this prospective, randomized, double-blind trial, ramosetron showed superior efficacy to palonosetron in terms of Spine
mitigating the incidence and severity of PONV associated with IV-PCAopioid after lumbar spinal surgery, especially during the early postoperative period (0–24 hr). In addition, this favorable influence of ramosetron was translated to significant reduction in postoperative pain intensity compared with the palonosetron group for 72 hours. Lumbar spinal surgery confers severe postoperative pain, which is a major concern to both patients and physicians.1 Appropriate pain control with IV-PCAopioid facilitates early ambulation, reduces the length of hospital stay, and improves postoperative outcome.2,5,18 At the same time, however, it is frequently accompanied by critical complications, PONV.6 PONV induces dehydration, increased perception of pain, dehiscence of surgical wound, delayed recovery and worsened patient satisfaction, which could negate all the advantages of IV-PCAopioid.19,20 Currently, 5-HT3 antagonists are most widely used agents for PONV. Despite their shared mechanism of action, they have distinguished chemical structures and demonstrate variable receptor binding affinity, duration of action, and dose response. Among the 5-HT3 antagonists, ramosetron, and palonosetron have been proven to possess higher affinity for 5-HT3 receptor and a much longer plasma half-life, which www.spinejournal.com
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Antiemetic Efficacy of Ramosetron and Palonsetron • Roh et al
TABLE 1. Patient Characteristics Ramosetron (n = 98)
Palonosetron (n = 98)
P
Age (yr)
49 ± 13
49 ± 14
0.909
Sex (female)
41 (42)
48 (49)
0.315
BMI (kg/m2)
24.5 ± 3.2
23.3 ± 2.8
0.005
18
19
0.855
28 (29)
18 (18)
0.092
1.9 ± 0.6
1.9 ± 0.7
0.825
PONV, motion sickness Smoking Risk factors Operation Discectomy
0.099 4 (4)
4 (4)
Laminectomy
59 (60)
49 (50)
Fusion, 1 level
16 (17)
19 (20)
Fusion, ≥2 level
14 (14)
10 (10)
5 (5)
16 (16)
Duration of anesthesia (min)
170 ± 71
168 ± 66
0.866
Duration of operation (min)
124 ± 66
127 ± 59
0.745
Tumor removal
Values are mean ± SD or number of patients (percentage). Risk factors including female sex, nonsmoking state, history of postoperative nausea, and vomiting, history of motion sickness, postoperative use of opioid. PONV indicates postoperative nausea and vomiting; BMI, body mass index; SD, standard deviation.
provide longer duration of action and greater potency than previous 5-HT3 antagonists.12,14 In particular, palonosetron, the latest 5-HT3 antagonist, has characteristic binding property with the 5-HT3 receptor. It binds at the allosteric site of the 5-HT3 receptor, allowing the most potent receptor affinity among the 5-HT3 antagonists with an elimination halflife of 40 hours.14,15 Palonosetron is being considered to be the most effective 5-HT3 receptor antagonist on preventing nausea and vomiting in patients receiving chemotherapy.21 As yet, evidence regarding its comparative efficacy to other 5-HT3 antagonists is limited, especially in patients receiving IV-PCAopioid. Thus, we compared the effect of palonosetron on PONV in patients receiving IV-PCAopioid with ramosetron, which has been already shown to exert superior antiemetic efficacy than ondansetron, the most widely studied 5-HT3 receptor antagonist in various clinical scenarios. Contrary to our expectations, prophylactic effect of palonosetron on PONV associated with IV-PCAopioid was less than that of ramosetron in this study, despite its pharmacological advantages. The overall incidence of PONV, mainly nausea, was greater in the palonosetron group compared with the ramosetron group. The difference was prominent during the early postoperative period with concomitantly greater intensities of nausea in the palonosetron group. Although palonosetron resulted in lower incidence of vomiting during the early postoperative period (0–6 hr) compared with ramosetron in a previous study involving gynecological laparoscopic surgical patients,22 the incidence of vomiting was higher in the palonosetron group without statistical significance in this study. E546
The most distinguishable feature of this study compared with previous studies addressing palonosetron is the use of continuous infusion of fentanyl (25 μg/kg) to control pain after lumbar spinal surgery.22,23 In two studies demonstrating superior efficacy of palonosetron on PONV to other 5-HT3 receptor antagonists,22,23 the amounts of fentanyl used during postoperative period were markedly lower than that of this study, possibly due to differences in the nature of surgeryinduced pain. Instrumentation in the lumbar spine induces far greater pain than laparoscopic surgeries, requiring higher dose of opioids. As opioids increase the incidence of nausea in a dose-related manner,8 the need for surgery-specific analgesic and antiemetic prophylaxis is evident. Thus, difficulties exist to make direct comparisons among studies addressing the antiemetic efficacies of palonosetron. Other plausible explanations for the observed results are differences in the metabolism and continuous infusion of the studied 5-HT3 receptor antagonists. Palonosetron is primarily metabolized by CYP2D6 system, which is subject to remarkable genetic polymorphism, whereas ramosetron is primarily metabolized by much less polymorphic CYP1A2 system.15 In patients with three or more normally functioning CYP2D6 alleles (ultrametabolizer), drugs metabolized by CYP2D6 undergo ultrarapid metabolism resulting in reduced efficacy.24 Although the accurate prevalence of ultrametabolizer in the Korean population is unknown, its presence could mitigate the effect of palonosetron on PONV. In this study, both agents were used by combined manner of bolus injection and addition to the IV-PCAopioid since
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Antiemetic Efficacy of Ramosetron and Palonsetron • Roh et al
TABLE 2. Complete Response Rate, Intensity of Nausea, Number of Rescue Antiemetic Use, and
Discontinuation of PCA
Ramosetron (n = 98)
Palonosetron (n = 98)
P
PACU
14 (14)
18 (18)
0.440
0–6 hr
31 (32)
49 (50)
0.009
6–24 hr
31 (32)
39 (40)
0.232
24–48 hr
21 (22)
29 (30)
0.218
48–72 hr
10 (11)
5 (5)
0.159
0–72 hr
49 (50)
66 (67)
0.014
PACU
14 (14)/ 3 (2–4)
18 (18)/2 (2–5)
0.440/0.984
0–6 hr
31 (32)/ 2 (1–4)
47 (48)/3 (2–5)
0.020/0.041
6–24 hr
30 (31)/ 2 (1–5)
38 (39)/4 (2–5)
0.229/0.026
24–48 hr
21 (22)/ 3 (2–6)
29 (30)/4 (2–5)
0.218/0.611
48–72 hr
10 (11)/ 2 (1–4)
5 (5)/2 (1–7)
0.159/0.921
0–72 hr
49 (50)
66 (67)
0.014
PACU
0 (0)/1 (1)
0 (0)/2 (2)
1.000/0.568
0–6 hr
0 (0)/5 (5)
5 (5)/9 (9)
0.059/0.274
6–24 hr
1 (1)/7 (7)
3 (3)/8 (8)
0.621/0.790
24–48 hr
2 (2)/6 (6)
2 (2)/10 (11)
1.000/0.354
48–72 hr
0 (0)/2 (2)
1 (1)/2 (2)
1.000/0.883
0–72 hr
3 (3)/16 (16)
10 (10)/17 (17)
0.082/0.849
7 (7)
11 (11)
0.459
PONV
Nausea (incidence/severity*)
Vomiting/antiemetics
Discontinuation
Values are number of patients (percentage) or median (interquartile range). *Severity of nausea expressed as verbal numerical rating scale from 0 to 10. PONV indicates postoperative nausea and vomiting; PCA, patient-controlled analgesia; PACU, postanesthesia care unit.
continuous infusion of antiemetics was regarded to be beneficial to prevent prolonged PONV.25 Receptor occupancy of ramosetron dropped to 50% at 24 hours after injection, whereas it could be maintained around 80% with additional dosing,13,26 and ramosetron mixed to PCA produced prolonged antiemetic effect.27 Furthermore, a single bolus of 0.075 mg palonosetron failed to attenuate the incidence of PONV after 24 hours postoperatively compared with placebo despite its known long elimination half time (40 hr).28,29 As both 5-HT3 receptor antagonists were continuously infused for 48 hours in this study, the pharmacological advantage of palonosetron over ramosetron in terms of longer elimination half-life would have been eliminated in this setting. In terms of patient’s satisfaction, the intensities of nausea should be more critical than the development of nausea per se. In this study, the severity of nausea as well as the incidence of PONV were significantly higher in the palonosetron Spine
group, especially during the early postoperative period. Another significant finding of this study is that the intensities of pain were significantly greater in the palonosetron group during the entire observation period. PONV is well known to increase the perception of pain, and at the same time, pain itself is a risk factor for PONV.12,30 Therefore, higher incidence and greater intensity of nausea in the palonosetron group might have resulted in escalation of pain intensities. In this study, the absolute and relative incidences of nausea were lessened in ramosetron group by 18% and 27%, respectively. It may be arguable that the nature of surgical procedure as well as the number of levels treated, and the individual variability in opioid susceptibility may confound the observed results. However, the types of surgical procedures and the number of levels treated were similar between the groups (Table 1). Moreover, this study included fairly large www.spinejournal.com
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Antiemetic Efficacy of Ramosetron and Palonsetron • Roh et al
TABLE 3. Pain Intensities Ramosetron (n = 98)
Palonosetron (n = 98)
P
PACU
3.1 ± 1.6
3.0 ± 1.5
0.583
0–6 hr
5.3 ± 1.9
6.0 ± 1.8
0.008
6–24 hr
4.0 ± 1.9
4.7 ± 2.0
0.003
24–48 hr
3.7 ± 1.8
4.4 ± 2.0
0.015
48–72 hr
3.7 ± 2.0
4.5 ± 1.8
0.002
Values are mean ± SD. PACU indicates postanesthesia care unit; SD, standard deviation.
number of patients for each group and this large number of patients could improve the reliability of comparison and the risk reduction rate was quite relevant for clinical implication according to the recommendation.31 Limitations of the study are follows. First, to evaluate the current practice-based relative efficacy, the doses of ramosetron and palonosetron were decided based on the currently known optimal dose for PONV prevention but not their pharmacological potency. Also, FDA approved 0.075 mg of palonosetron as the minimum effective dose for PONV prophylaxis, whereas the optimal dose of palonosetron for opioid-related PONV is not known, as well as the equipotent doses of ramosetron and palonosetron under the circumstance. Second, patients in the ramosetron group weighed
more than those in the palonosetron group. Obesity was reported to increase the incidence of nausea.17 However, none of the studied patients had a BMI >28 kg/m2 and considering the lower incidence of PONV in the ramosetron group, its confounding influence should be negligible. Third, as this study was designed to address the incidence of PONV, we cannot provide information regarding the translation of our results to actual clinical outcome. We can only refer to previous studies showing close relations between PONV and hospital discharge.3,4
CONCLUSION Despite its theoretical advantages in terms of receptor affinity and action duration, palonosetron was inferior to ramosetron
TABLE 4. Cumulative Volume of PCA Consumed and Number of Patients Using Rescue Analgesics Ramosetron (n = 98)
Palonosetron (n = 98)
P
PACU (mL)
1.5 ± 0.9/19 (19)
1.5 ± 0.8/11(11)
0.983/0.112
∼6 hr (mL)
12.6 ± 5.5/70 (71)
13.7 ± 5.4/73 (75)
0.655/0.629
∼24 hr (mL)
47.2 ± 13.3/29 (30)
47.1 ± 13.3/41 (42)
0.968/0.074
∼48 hr (mL)
84.8 ± 23.1/27 (28)
85.2 ± 24.7/33 (34)
0.832/0.352
∼72 hr (mL)
91.3 ± 22.3/29 (30)
89.9 ± 23.5/41(42)
0.541/0.074
Values are mean ± SD or number of patients (percentage). PACU indicates postanesthesia care unit; PCA, patient-controlled analgesia; SD, standard deviation.
TABLE 5. Adverse Events Over 72 Hours Ramosetron (n = 98)
Palonosetron (n = 98)
P
Adverse events
39 (40)
31 (32)
0.233
Dizziness
18 (18)
16 (16)
0.706
Somnolence
24 (25)
19 (19)
0.388
Headache
12 (12)
12 (12)
1.000
Constipation, urinary retention
4 (4)
6 (6)
0.516
Pruritus
1 (1)
1 (1)
1.000
Values are number of patients (percentage).
E548
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RANDOMIZED TRIAL in preventing PONV in patients receiving IV-PCAopioid after lumbar spinal surgery. In addition, increased PONV was translated to increased intensities of postoperative pain in the palonosetron group favoring the use of ramosetron for antiemetic prophylaxis in patients receiving opioid-based analgesia after lumbar spinal surgery.
Antiemetic Efficacy of Ramosetron and Palonsetron • Roh et al
12. 13.
14.
➢ Key Points Opioid-based intravenous patient-controlled analgesia (IV-PCAopioid) after lumbar spinal surgery is associated with a high incidence of PONV. Ramosetron and palonosetron are novel 5-hydroxytryptamine 3 antagonists known to have longer action duration and higher receptor affinity than their congeners. Ramosetron showed better efficacy to reduce the incidence and severity of nausea associated with IV-PCAopioid after lumbar spinal surgery. The favorable influence of ramosetron was associated with significant reduction in the severity of postoperative pain.
Acknowledgments
15. 16.
17. 18.
19.
20.
21.
Go Un Roh and So Young Yang contributed equally to the article.
References
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27. 28.
29. 30. 31.
in patients undergoing gynaecological surgery. Br J Anaesth 2009;103:549–53. Rabasseda X. Ramosetron, a 5-HT3 receptor antagonist for the control of nausea and vomiting. Drugs Today (Barc) 2002;38: 75–89. Ogata A, Yamada Y, Sugiura M, et al. Analysis of 5-HT3 receptor antagonist, ramosetron hydrochloride, based on receptor occupancy considering its active metabolite. Yakugaku Zasshi 2001;121: 793–8. Yang LP, Scott LJ. Palonosetron: in the prevention of nausea and vomiting. Drugs 2009;69:2257–78. Muchatuta NA, Paech MJ. Management of postoperative nausea and vomiting: focus on palonosetron. Ther Clin Risk Manage 2009;5:21–34. Candiotti KA, Kovac AL, Melson TI, et al. A randomized, doubleblind study to evaluate the efficacy and safety of three different doses of palonosetron versus placebo for preventing postoperative nausea and vomiting. Anesth Analg 2008;107:445–51. Watcha MF, White PF. Postoperative nausea and vomiting. Its etiology, treatment, and prevention. Anesthesiology 1992;77:162–84. Walder B, Schafer M, Henzi I, et al. Efficacy and safety of patientcontrolled opioid analgesia for acute postoperative pain. A quantitative systematic review. Acta Anaesthesiol Scand 2001;45: 795–804. Tramer MR. A rational approach to the control of postoperative nausea and vomiting: evidence from systematic reviews. Part I. Efficacy and harm of antiemetic interventions, and methodological issues. Acta Anaesthesiol Scand 2001;45:4–13. Choi YS, Shim JK, Yoon do H, et al. Effect of ramosetron on patientcontrolled analgesia-related nausea and vomiting after spine surgery in highly susceptible patients: comparison with ondansetron. Spine 2008;33:E602–6. Gralla R, Lichinitser M, Van Der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol 2003;14:1570–7. Park SK, Cho EJ. A randomized, double-blind trial of palonosetron compared with ondansetron in preventing postoperative nausea and vomiting after gynaecological laparoscopic surgery. J Int Med Res 2011;39:399–407. Kranke P, Eberhart LH, Apfel CC, et al. Tropisetron for prevention of postoperative nausea and vomiting: a quantitative systematic review. Der Anaesthesist 2002;51:805–14. Kovac AL, Eberhart L, Kotarski J, et al. A randomized, double-blind study to evaluate the efficacy and safety of three different doses of palonosetron versus placebo in preventing postoperative nausea and vomiting over a 72-hour period. Anesth Analg 2008;107: 439–44. Roewer N, Apfel CC. New facts on the risks of aspiration?. Anasthesiol Intensivmed Notfallmed Schmerzther 2002;37:509–11. Ito H, Akuzawa S, Tsutsumi R, et al. Comparative study of the affinities of the 5-HT3 receptor antagonists, YM060, YM114 (KAE-393), Granisetron and Ondansetron in rat vagus nerve and cerebral cortex. Neuropharmacology 1995;34:631–7. Choi DK, Chin JH, Lee EH, et al. Prophylactic control of postoperative nausea and vomiting using ondansetron and ramosetron after cardiac surgery. Acta Anaesthesiol Scand 2010;54:962–9. Apfel CC, Kranke P, Katz MH, et al. Volatile anaesthetics may be the main cause of early but not delayed postoperative vomiting: a randomized controlled trial of factorial design. Br J Anaesth 2002;88:659–68. Durila M, Bronsky J, Harustiak T, et al. Early diagnostic markers of sepsis after oesophagectomy (including thromboelastography). BMC Anesthesiol 2012;12:12. Chia YY, Kuo MC, Liu K, et al. Does postoperative pain induce emesis? Clin J Pain 2002;18:317–23. Rosenstock CV, Thogersen B, Afshari A, et al. Awake fiberoptic or awake video laryngoscopic tracheal intubation in patients with anticipated difficult airway management: a randomized clinical trial. Anesthesiology 2012;116:1210–6. www.spinejournal.com
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Efficacy of Palonosetron Versus Ramosetron on Preventing Opioid-Based Analgesia-Related Nausea and Vomiting After Lumbar Spinal Surgery A Prospective, Randomized, and Double-Blind Trial Go Un Roh, MD,* So Young Yang, MD,† Jae Kwang Shim, MD, PhD,* and Young Lan Kwak, MD, PhD*
Study Design. A prospective, randomized, and double-blind study. Objective. To compare the efficacy of ramosetron and palonosetron on preventing postoperative nausea and vomiting (PONV) associated with opioid-based intravenous patient-controlled analgesia (IV-PCAopioid) after lumbar spinal surgery. Summary of Background Data. IV-PCAopioid, an effective method to control pain after lumbar spinal surgery, accompanies PONV. Ramosetron and palonosetron are novel 5-hydroxytryptamine 3 antagonists known to have longer action duration and higher receptor affinity than their congeners, whereas their relative efficacy has not been validated yet. Methods. One hundred ninety-six patients were randomly and evenly allocated to receive either 0.3 mg of ramosetron or 0.075 mg of palonosetron 10 minutes before the end of operation. Ramosetron or palonosetron were also added to the IV-PCAopioid, which was continuously infused for 48 hours postoperatively. The incidence and intensity of PONV were serially assessed for 72 hours postoperatively. Intensity of pain, volume of IV-PCAopioid consumption, use of rescue analgesics and antiemetics, and adverse events were also assessed. Results. The overall incidence of PONV was lower in the ramosetron group than the palonosetron group (50% vs. 67%, P = 0.014) without any intergroup difference in the incidence of vomiting. Nausea intensity scores were also lower until 6 (P = 0.041) and 24 hour (P = 0.026) postoperatively in the ramosetron group From the *Department of Anesthesiology and Pain Medicine and Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, South Korea; and †Department of Anesthesiology and Pain Medicine, Choong-Ang University College of Medicine, Seoul, South Korea. Acknowledgment date: November 11, 2013. Revision date: December 24, 2013. Acceptance date: January 9, 2014. The manuscript submitted does not contain information about medical device(s)/drug(s). No funds were received in support of this work. No relevant financial activities outside the submitted work. Address correspondence and reprint requests to Young Lan Kwak, MD, PhD, Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Severance Biomedical Science Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, South Korea, 120752; E-mail: [email protected] DOI: 10.1097/BRS.0000000000000236 Spine
than the palonosetron group. Pain intensity scores were significantly lower in the ramosetron group than the palonosetron group for 72 hours postoperatively. Conclusion. Ramosetron was superior to palonosetron in term of reducing the incidence and severity of nausea associated with IV-PCAopioid after lumbar spinal surgery. This favorable influence of ramosetron on PONV was translated to significant postoperative pain reduction compared with palonosetron. Key words: analgesia, patient-controlled, anti-emetics, palonosetron, anti-emetics, ramosetron, postoperative nausea and vomiting. Level of Evidence: 1 Spine 2014;39:E543–E549
A
dequate pain control after lumbar spinal surgery is a prerequisite to patients’ well-being as well as early recovery and rehabilitation.1 Currently, opioid-based intravenous patient-controlled analgesia (IV-PCAopioid) is one of the most effective ways to control postoperative pain,2–5 yet it accompanies unpleasant adverse effects occurring at a considerable incidence. The use of IV-PCAopioid inevitably increases the incidence of postoperative nausea and vomiting (PONV), a vexing adverse event, reported to be as high as 80% in patients with multiple risk factors.6,7 Accordingly, there have been consistent efforts to reduce the incidence of PONV with multimodal therapies such as risk stratification, modification, and preventive use of antiemetics.4,8 Among the available antiemetics, 5-hydroxytryptamine (5-HT3) receptor antagonists are most commonly used and extensively studied regarding PONV reduction.8 Their efficacies, however, are not quite satisfactory when it comes to PONV associated with IV-PCAopioid, especially in case of ondansetron.9–11 Newer generations of 5-HT3 receptor antagonists were developed with higher receptor affinity and longer action duration, such as ramosetron, which has been shown to exert more potent and sustained antiemetic efficacy than the first generation.12,13 Palonosetron, the latest 5-HT3 antagonist, has a unique allosteric binding property to the 5-HT3 receptor and thus, it is segregated from previous 5-HT3 antagonists www.spinejournal.com
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RANDOMIZED TRIAL in terms of higher receptor binding affinity, longer duration of action and longer elimination half-time.14,15 However, evidences are not enough to suggest palonosetron as the most efficient 5-HT3 antagonists for PONV. Through previous studies, the superior efficacy of ramosetron and palonosetron over ondansetron in reducing PONV associated with IV-PCAopioid has been validated separately.10–14,16 Yet, direct comparison between ramosetron and palonosetron regarding their preventive effects on IV-PCAopioid–related PONV has not been addressed heretofore. In this prospective, randomized, and double-blind study, we evaluated whether palonosetron would be superior to ramosetron in preventing PONV in patients receiving IV-PCAopioid after lumbar spinal surgery.
MATERIALS AND METHODS After approval of institutional review board and obtaining patients’ written informed consent, 196 patients (20–65 yr) scheduled for lumbar spinal surgery in prone position between August 2011 and July 2012 were screened and enrolled. All patients were treated with IV-PCAopioid postoperatively for pain control. Patients with the following profiles were excluded: gastrointestinal disease; renal or hepatic dysfunction; diabetes mellitus on insulin; pregnancy; use of steroid, opioid, or antiemetics 1 day before surgery; inability to understand verbal rating scale; inability to use PCA device. After enrollment, patients were randomly allocated into either ramosetron or palonosetron group by a computerized randomization table. The code of the assigned group was enclosed in the opaque envelope. Patients’ demographic profiles and medical histories including motion sickness, PONV, and smoking state were recorded. Anesthesia was induced with 1.5 to 2.5 mg/kg of propofol, 0.5 to 1.5 μg/kg of Remifentanil, and 0.06 mg/kg of Rocuronium, and maintained with 1.5% to 2.5% of Sevoflurane (50:50 mixture of oxygen and air) and 0.1 to 0.3 μg/kg/min of remifentanil. Ten minutes before the end of surgery, 2 mL of medication containing either 0.3 mg of ramosetron or 0.075 mg palonosetron was injected, then IV-PCAopioid was introduced. IV-PCAopioid consisted of 25 μg/kg of fentanyl, 120 mg of ketorolac, and either 0.3 mg of ramosetron or 0.075 mg of palonosetron according to the group allocation (total volume of 100 mL including 0.9% normal saline, basal rate 2 mL/hr, bolus 0.5 mL, lockout time 15 min). The costs of ramosetron and palonosetron per patient in Korea were approximately $54 and $59, respectively. An unblinded anesthesiologist not involved in patient management and assessment received the opaque envelope containing the code of assigned group, prepared all the medications in the same syringes and PCA devices without labeling according to the group allocation, and handed over to the blinded anesthesiologists who managed the studied patients. Rescue antiemetic (10 mg of metoclopramide, IV) or analgesic (30 mg of ketorolac, IV) was administered according to the decision of blinded neurosurgeons in charge of postoperative care in wards or upon patient’s request. Serial postoperative assessments were E544
Antiemetic Efficacy of Ramosetron and Palonsetron • Roh et al
performed according to the schedule by one physician blinded to the group allocation. The primary end point of this study was to compare the overall incidence of PONV between the groups. The incidences of PONV were assessed in postanesthesia care unit and at intervals of 0 to 6, 6 to 24, 24 to 48, and 48 to 72 hours postoperatively. Nausea was defined as a subjectively unpleasant sensation with concomitant awareness of the urge to vomit. Vomiting was defined as the forceful expulsion of gastric contents through the mouth. Retching, the labored spasmodic rhythmic contractions of the respiratory muscles without the expulsion of the gastric contents, was also regarded as vomiting.17 Secondary end points were to compare the intensities of nausea (verbal rating scale, 0 = no nausea, 10 = worst nausea imaginable) and pain (verbal rating scale, 0 = no pain, 10 = worst pain imaginable). Additionally, cumulative volume of IV-PCAopioid administered during each observation period, rescue analgesics and antiemetic requirements, discontinuation of IV-PCAopioid ahead of time, and adverse events (dizziness, drowsiness, headache, constipation, urinary retention, and pruritus) were assessed. On the basis of the reported efficacy of palonosetron in a previous study,10 98 patients were needed for each group to detect a 33% decrease of the incidence of PONV with a power of 80% and type I error of 0.05, when the incidence of PONV would be 60% in this study. SAS (version 9.2, SAS Institute Inc., Cary, NC) was used for the data analysis. To compare the data of groups, the Student t test, Mann-Whitney U test, χ2 test, or Fisher exact test were used as appropriate. For the analysis of repeatedly measured data, linear mixed model and logistic regression with generalized estimating equation method were performed as appropriate. After correction with Bonferroni method, P values less than 0.05 were considered to be statistically significant. The results were presented as number with percentage, mean with standard deviation, or median with interquartile range according to the normality of their distribution.
RESULTS Among the 248 patients assessed for eligibility, 196 patients who met the inclusion criteria consented to participate in this study and completed (Figure 1). A total of 7 patients requested discontinuation of IV-PCAopioid infusion before completion due to negligible pain (ramosetron group: 4, palonosetron group: 3) on the second postoperative day. The data of these patients were included in the analysis according to the intendto-treat principle. The patients’ characteristics, operative, and anesthetic data were comparable, except greater body mass index in the ramosetron group (Table 1). The overall incidence of PONV during the study period was significantly higher in the palonosetron group than in the ramosetron group (67% vs. 50%, P = 0.014). In detail, palonosetron group showed significantly higher incidence of PONV than the ramosetron group during the first postoperative 6 hours (50% vs. 32%, P = 0.009). The overall incidence of nausea was significantly greater in the palonosetron group than the ramosetron group (67% vs. 49%, P = 0.009), which
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Enrollment
Antiemetic Efficacy of Ramosetron and Palonsetron • Roh et al
Assessed for eligibility (n = 248) Excluded (n = 52) ♦ Not meeting inclusion criteria (n = 40) ♦ Older than 65 years (n = 31) ♦ Diabetes mellitus on insulin (n = 8) ♦ Use of opioid within 1 day before surgery (n = 1) ♦ ♦
Declined to participate (n = 12) Other reasons (n = 0)
Randomization 1:1 (n = 196)
Allocation Allocated to intervention (n = 98) ♦ Received allocated intervention (n = 98)
Allocated to intervention (n = 98) ♦ Received allocated intervention (n = 98)
Follow-Up Lost to follow-up (give reasons) (n = 0)
Lost to follow-up (give reasons) (n = 0)
Discontinued intervention (give reasons) (n = 0)
Discontinued intervention (give reasons) (n = 0)
Analysis Analyzed (n = 98) ♦ Excluded from analysis (give reasons) (n = 0)
Analyzed (n = 98) ♦ Excluded from analysis (give reasons) (n = 0)
Figure 1. CONSORT diagram showing the flow of participants.
was also more evident during the first postoperative 6 hours (48% vs. 32%, P = 0.02). The intensity of nausea was significantly greater in the palonosetron group than the ramosetron group until the first postoperative 24 hours (0–6 hr, P = 0.041 and 6–24 hr, 0.026). The overall incidence of vomiting was not significantly different between the groups. The numbers of patients requiring rescue antiemetics and discontinuing IV-PCAopioid infusion due to PONV were similar between the groups (Table 2). The pain intensities were significantly greater in the palonosetron group than the ramosetron group during the entire study period, except during the stay at postanesthesia care unit (Table 3). The cumulative volumes of consumed IV-PCAopioid and the number of patients requiring rescue analgesics at each observation period were not different throughout the study period between the groups (Table 4). The incidences of adverse events were similar between the groups (Table 5).
DISCUSSION In this prospective, randomized, double-blind trial, ramosetron showed superior efficacy to palonosetron in terms of Spine
mitigating the incidence and severity of PONV associated with IV-PCAopioid after lumbar spinal surgery, especially during the early postoperative period (0–24 hr). In addition, this favorable influence of ramosetron was translated to significant reduction in postoperative pain intensity compared with the palonosetron group for 72 hours. Lumbar spinal surgery confers severe postoperative pain, which is a major concern to both patients and physicians.1 Appropriate pain control with IV-PCAopioid facilitates early ambulation, reduces the length of hospital stay, and improves postoperative outcome.2,5,18 At the same time, however, it is frequently accompanied by critical complications, PONV.6 PONV induces dehydration, increased perception of pain, dehiscence of surgical wound, delayed recovery and worsened patient satisfaction, which could negate all the advantages of IV-PCAopioid.19,20 Currently, 5-HT3 antagonists are most widely used agents for PONV. Despite their shared mechanism of action, they have distinguished chemical structures and demonstrate variable receptor binding affinity, duration of action, and dose response. Among the 5-HT3 antagonists, ramosetron, and palonosetron have been proven to possess higher affinity for 5-HT3 receptor and a much longer plasma half-life, which www.spinejournal.com
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Antiemetic Efficacy of Ramosetron and Palonsetron • Roh et al
TABLE 1. Patient Characteristics Ramosetron (n = 98)
Palonosetron (n = 98)
P
Age (yr)
49 ± 13
49 ± 14
0.909
Sex (female)
41 (42)
48 (49)
0.315
BMI (kg/m2)
24.5 ± 3.2
23.3 ± 2.8
0.005
18
19
0.855
28 (29)
18 (18)
0.092
1.9 ± 0.6
1.9 ± 0.7
0.825
PONV, motion sickness Smoking Risk factors Operation Discectomy
0.099 4 (4)
4 (4)
Laminectomy
59 (60)
49 (50)
Fusion, 1 level
16 (17)
19 (20)
Fusion, ≥2 level
14 (14)
10 (10)
5 (5)
16 (16)
Duration of anesthesia (min)
170 ± 71
168 ± 66
0.866
Duration of operation (min)
124 ± 66
127 ± 59
0.745
Tumor removal
Values are mean ± SD or number of patients (percentage). Risk factors including female sex, nonsmoking state, history of postoperative nausea, and vomiting, history of motion sickness, postoperative use of opioid. PONV indicates postoperative nausea and vomiting; BMI, body mass index; SD, standard deviation.
provide longer duration of action and greater potency than previous 5-HT3 antagonists.12,14 In particular, palonosetron, the latest 5-HT3 antagonist, has characteristic binding property with the 5-HT3 receptor. It binds at the allosteric site of the 5-HT3 receptor, allowing the most potent receptor affinity among the 5-HT3 antagonists with an elimination halflife of 40 hours.14,15 Palonosetron is being considered to be the most effective 5-HT3 receptor antagonist on preventing nausea and vomiting in patients receiving chemotherapy.21 As yet, evidence regarding its comparative efficacy to other 5-HT3 antagonists is limited, especially in patients receiving IV-PCAopioid. Thus, we compared the effect of palonosetron on PONV in patients receiving IV-PCAopioid with ramosetron, which has been already shown to exert superior antiemetic efficacy than ondansetron, the most widely studied 5-HT3 receptor antagonist in various clinical scenarios. Contrary to our expectations, prophylactic effect of palonosetron on PONV associated with IV-PCAopioid was less than that of ramosetron in this study, despite its pharmacological advantages. The overall incidence of PONV, mainly nausea, was greater in the palonosetron group compared with the ramosetron group. The difference was prominent during the early postoperative period with concomitantly greater intensities of nausea in the palonosetron group. Although palonosetron resulted in lower incidence of vomiting during the early postoperative period (0–6 hr) compared with ramosetron in a previous study involving gynecological laparoscopic surgical patients,22 the incidence of vomiting was higher in the palonosetron group without statistical significance in this study. E546
The most distinguishable feature of this study compared with previous studies addressing palonosetron is the use of continuous infusion of fentanyl (25 μg/kg) to control pain after lumbar spinal surgery.22,23 In two studies demonstrating superior efficacy of palonosetron on PONV to other 5-HT3 receptor antagonists,22,23 the amounts of fentanyl used during postoperative period were markedly lower than that of this study, possibly due to differences in the nature of surgeryinduced pain. Instrumentation in the lumbar spine induces far greater pain than laparoscopic surgeries, requiring higher dose of opioids. As opioids increase the incidence of nausea in a dose-related manner,8 the need for surgery-specific analgesic and antiemetic prophylaxis is evident. Thus, difficulties exist to make direct comparisons among studies addressing the antiemetic efficacies of palonosetron. Other plausible explanations for the observed results are differences in the metabolism and continuous infusion of the studied 5-HT3 receptor antagonists. Palonosetron is primarily metabolized by CYP2D6 system, which is subject to remarkable genetic polymorphism, whereas ramosetron is primarily metabolized by much less polymorphic CYP1A2 system.15 In patients with three or more normally functioning CYP2D6 alleles (ultrametabolizer), drugs metabolized by CYP2D6 undergo ultrarapid metabolism resulting in reduced efficacy.24 Although the accurate prevalence of ultrametabolizer in the Korean population is unknown, its presence could mitigate the effect of palonosetron on PONV. In this study, both agents were used by combined manner of bolus injection and addition to the IV-PCAopioid since
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Antiemetic Efficacy of Ramosetron and Palonsetron • Roh et al
TABLE 2. Complete Response Rate, Intensity of Nausea, Number of Rescue Antiemetic Use, and
Discontinuation of PCA
Ramosetron (n = 98)
Palonosetron (n = 98)
P
PACU
14 (14)
18 (18)
0.440
0–6 hr
31 (32)
49 (50)
0.009
6–24 hr
31 (32)
39 (40)
0.232
24–48 hr
21 (22)
29 (30)
0.218
48–72 hr
10 (11)
5 (5)
0.159
0–72 hr
49 (50)
66 (67)
0.014
PACU
14 (14)/ 3 (2–4)
18 (18)/2 (2–5)
0.440/0.984
0–6 hr
31 (32)/ 2 (1–4)
47 (48)/3 (2–5)
0.020/0.041
6–24 hr
30 (31)/ 2 (1–5)
38 (39)/4 (2–5)
0.229/0.026
24–48 hr
21 (22)/ 3 (2–6)
29 (30)/4 (2–5)
0.218/0.611
48–72 hr
10 (11)/ 2 (1–4)
5 (5)/2 (1–7)
0.159/0.921
0–72 hr
49 (50)
66 (67)
0.014
PACU
0 (0)/1 (1)
0 (0)/2 (2)
1.000/0.568
0–6 hr
0 (0)/5 (5)
5 (5)/9 (9)
0.059/0.274
6–24 hr
1 (1)/7 (7)
3 (3)/8 (8)
0.621/0.790
24–48 hr
2 (2)/6 (6)
2 (2)/10 (11)
1.000/0.354
48–72 hr
0 (0)/2 (2)
1 (1)/2 (2)
1.000/0.883
0–72 hr
3 (3)/16 (16)
10 (10)/17 (17)
0.082/0.849
7 (7)
11 (11)
0.459
PONV
Nausea (incidence/severity*)
Vomiting/antiemetics
Discontinuation
Values are number of patients (percentage) or median (interquartile range). *Severity of nausea expressed as verbal numerical rating scale from 0 to 10. PONV indicates postoperative nausea and vomiting; PCA, patient-controlled analgesia; PACU, postanesthesia care unit.
continuous infusion of antiemetics was regarded to be beneficial to prevent prolonged PONV.25 Receptor occupancy of ramosetron dropped to 50% at 24 hours after injection, whereas it could be maintained around 80% with additional dosing,13,26 and ramosetron mixed to PCA produced prolonged antiemetic effect.27 Furthermore, a single bolus of 0.075 mg palonosetron failed to attenuate the incidence of PONV after 24 hours postoperatively compared with placebo despite its known long elimination half time (40 hr).28,29 As both 5-HT3 receptor antagonists were continuously infused for 48 hours in this study, the pharmacological advantage of palonosetron over ramosetron in terms of longer elimination half-life would have been eliminated in this setting. In terms of patient’s satisfaction, the intensities of nausea should be more critical than the development of nausea per se. In this study, the severity of nausea as well as the incidence of PONV were significantly higher in the palonosetron Spine
group, especially during the early postoperative period. Another significant finding of this study is that the intensities of pain were significantly greater in the palonosetron group during the entire observation period. PONV is well known to increase the perception of pain, and at the same time, pain itself is a risk factor for PONV.12,30 Therefore, higher incidence and greater intensity of nausea in the palonosetron group might have resulted in escalation of pain intensities. In this study, the absolute and relative incidences of nausea were lessened in ramosetron group by 18% and 27%, respectively. It may be arguable that the nature of surgical procedure as well as the number of levels treated, and the individual variability in opioid susceptibility may confound the observed results. However, the types of surgical procedures and the number of levels treated were similar between the groups (Table 1). Moreover, this study included fairly large www.spinejournal.com
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Antiemetic Efficacy of Ramosetron and Palonsetron • Roh et al
TABLE 3. Pain Intensities Ramosetron (n = 98)
Palonosetron (n = 98)
P
PACU
3.1 ± 1.6
3.0 ± 1.5
0.583
0–6 hr
5.3 ± 1.9
6.0 ± 1.8
0.008
6–24 hr
4.0 ± 1.9
4.7 ± 2.0
0.003
24–48 hr
3.7 ± 1.8
4.4 ± 2.0
0.015
48–72 hr
3.7 ± 2.0
4.5 ± 1.8
0.002
Values are mean ± SD. PACU indicates postanesthesia care unit; SD, standard deviation.
number of patients for each group and this large number of patients could improve the reliability of comparison and the risk reduction rate was quite relevant for clinical implication according to the recommendation.31 Limitations of the study are follows. First, to evaluate the current practice-based relative efficacy, the doses of ramosetron and palonosetron were decided based on the currently known optimal dose for PONV prevention but not their pharmacological potency. Also, FDA approved 0.075 mg of palonosetron as the minimum effective dose for PONV prophylaxis, whereas the optimal dose of palonosetron for opioid-related PONV is not known, as well as the equipotent doses of ramosetron and palonosetron under the circumstance. Second, patients in the ramosetron group weighed
more than those in the palonosetron group. Obesity was reported to increase the incidence of nausea.17 However, none of the studied patients had a BMI >28 kg/m2 and considering the lower incidence of PONV in the ramosetron group, its confounding influence should be negligible. Third, as this study was designed to address the incidence of PONV, we cannot provide information regarding the translation of our results to actual clinical outcome. We can only refer to previous studies showing close relations between PONV and hospital discharge.3,4
CONCLUSION Despite its theoretical advantages in terms of receptor affinity and action duration, palonosetron was inferior to ramosetron
TABLE 4. Cumulative Volume of PCA Consumed and Number of Patients Using Rescue Analgesics Ramosetron (n = 98)
Palonosetron (n = 98)
P
PACU (mL)
1.5 ± 0.9/19 (19)
1.5 ± 0.8/11(11)
0.983/0.112
∼6 hr (mL)
12.6 ± 5.5/70 (71)
13.7 ± 5.4/73 (75)
0.655/0.629
∼24 hr (mL)
47.2 ± 13.3/29 (30)
47.1 ± 13.3/41 (42)
0.968/0.074
∼48 hr (mL)
84.8 ± 23.1/27 (28)
85.2 ± 24.7/33 (34)
0.832/0.352
∼72 hr (mL)
91.3 ± 22.3/29 (30)
89.9 ± 23.5/41(42)
0.541/0.074
Values are mean ± SD or number of patients (percentage). PACU indicates postanesthesia care unit; PCA, patient-controlled analgesia; SD, standard deviation.
TABLE 5. Adverse Events Over 72 Hours Ramosetron (n = 98)
Palonosetron (n = 98)
P
Adverse events
39 (40)
31 (32)
0.233
Dizziness
18 (18)
16 (16)
0.706
Somnolence
24 (25)
19 (19)
0.388
Headache
12 (12)
12 (12)
1.000
Constipation, urinary retention
4 (4)
6 (6)
0.516
Pruritus
1 (1)
1 (1)
1.000
Values are number of patients (percentage).
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RANDOMIZED TRIAL in preventing PONV in patients receiving IV-PCAopioid after lumbar spinal surgery. In addition, increased PONV was translated to increased intensities of postoperative pain in the palonosetron group favoring the use of ramosetron for antiemetic prophylaxis in patients receiving opioid-based analgesia after lumbar spinal surgery.
Antiemetic Efficacy of Ramosetron and Palonsetron • Roh et al
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➢ Key Points Opioid-based intravenous patient-controlled analgesia (IV-PCAopioid) after lumbar spinal surgery is associated with a high incidence of PONV. Ramosetron and palonosetron are novel 5-hydroxytryptamine 3 antagonists known to have longer action duration and higher receptor affinity than their congeners. Ramosetron showed better efficacy to reduce the incidence and severity of nausea associated with IV-PCAopioid after lumbar spinal surgery. The favorable influence of ramosetron was associated with significant reduction in the severity of postoperative pain.
Acknowledgments
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Go Un Roh and So Young Yang contributed equally to the article.
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