This article was downloaded by: [Stockholm University Library] On: 10 August 2015, At: 23:13 Publisher: Taylor & Francis Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: 5 Howick Place, London, SW1P 1WG
Current Medical Research and Opinion Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/icmo20
Effect of nefopam- versus fentanyl-based patientcontrolled analgesia on postoperative nausea and vomiting in patients undergoing gynecological laparoscopic surgery: a prospective double-blind randomized controlled trial a
a
b
ac
Chung-Sik Oh , Eugene Jung , Sun Joo Lee & Seong-Hyop Kim a a
Department of Anesthesiology and Pain Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea b b
Click for updates
Department of Obstetrics and Gynecology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea c c
Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, Korea Published online: 09 Jul 2015.
To cite this article: Chung-Sik Oh, Eugene Jung, Sun Joo Lee & Seong-Hyop Kim (2015): Effect of nefopam- versus fentanylbased patient-controlled analgesia on postoperative nausea and vomiting in patients undergoing gynecological laparoscopic surgery: a prospective double-blind randomized controlled trial, Current Medical Research and Opinion To link to this article: http://dx.doi.org/10.1185/03007995.2015.1058251
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Current Medical Research & Opinion
Downloaded by [Stockholm University Library] at 23:13 10 August 2015
0300-7995 doi:10.1185/03007995.2015.1058251
2015, 1–9
Article ST-0152.R1/1058251 All rights reserved: reproduction in whole or part not permitted
Report Effect of nefopam- versus fentanyl-based patient-controlled analgesia on postoperative nausea and vomiting in patients undergoing gynecological laparoscopic surgery: a prospective double-blind randomized controlled trial
Chung-Sik Oh Eugene Jung Department of Anesthesiology and Pain Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea
Sun Joo Lee Department of Obstetrics and Gynecology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea
Seong-Hyop Kim Department of Anesthesiology and Pain Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, Korea Address for correspondence: Seong-Hyop Kim MD, PhD, Department of Anesthesiology and Pain Medicine, Konkuk University Medical Center, 120-1, Neungdong-ro (Hwayangdong), Gwangjin-gu, Seoul 143-729, Korea. Tel:+82 2-2030-5454; Fax: +82 2-2030-5449; [email protected] Keywords: Fentanyl – Nefopam – Patient-controlled analgesia – Postoperative nausea and vomiting Accepted: 26 May 2015; published online: 6 July 2015 Citation: Curr Med Res Opin 2015; 1–9
! 2015 Informa UK Ltd www.cmrojournal.com
Abstract Objective: This study comparatively evaluated the effect of patient-controlled analgesia (PCA) regimens using equipotent doses of nefopam or fentanyl during laparoscopic gynecological surgery on postoperative nausea and vomiting (PONV). Research design and methods: Patients undergoing gynecological laparoscopic surgery were randomly allocated to receive either nefopam(non-opioid; N group) or fentanyl-based (F group) PCA. PONV and postoperative pain were assessed during the 72 hours following discharge from the post-anesthetic care unit (PACU). The adverse effects of nefopam were also evaluated. Clinical trial registration: Cris.nih.go.kr ID KCT0000783. Results: In total, 94 patients were included in the final analysis. The PONV incidence and scale and the Rhodes index scores were significantly lower in the N group than the F group at all measured times. The N group exhibited a significantly lower incidence of PONV (15/47 [31.9%] vs. 27/47 [57.4%], respectively; P ¼ 0.022) and severity of PONV (0 [1] vs. 1 [2], respectively; P ¼ 0.005) 24 hours after PACU discharge and a significantly lower Rhodes index score (0 [3] vs. 5 [9], respectively; P ¼ 0.002) from 30 minutes after PACU arrival to 24 hours after PACU discharge than did the F group. There was no significant difference in postoperative pain at any time between the two groups. Dry mouth on PACU arrival was significantly more frequent in the N group. However, the frequency of dry mouth decreased after PACU arrival in the N group, resulting in a significantly lower incidence 24 hours after PACU discharge. Conclusions: Use of a PCA regimen with nefopam for analgesia was associated with a similar degree of pain control and superior PONV outcomes 24 hours after PACU discharge and no adverse events compared with a PCA regimen using an equipotent dose of fentanyl.
PONV with nefopam for PCA Oh et al.
1
Current Medical Research & Opinion
2015
Downloaded by [Stockholm University Library] at 23:13 10 August 2015
Introduction Postoperative nausea and vomiting (PONV) and pain are the most distressing adverse events following surgery under general anesthesia. Patient-controlled analgesia (PCA) is among the most popular methods used for postoperative pain control and achieves excellent results. PCA typically involves the administration of an analgesic agent, most commonly an opioid, using a programmed infusion pump1. However, the use of postoperative opioids is associated with delayed recovery from anesthesia and a high incidence of PONV2,3. This has led to the combined use of opioids with other analgesic agents, such as non-steroidal anti-inflammatory drugs, to lower the incidence of PONV. However, this approach is not without problems, such as anticoagulation and gastrointestinal disorders4. Nefopam is a non-opioid analgesic drug in the benzoxazocine class of compounds. It exerts analgesic effects by inhibiting the synaptosomal uptake of noradrenaline, dopamine, and serotonin5,6. Nefopam is thus used in numerous European countries for pain control and as an alternative medication to opioids (by oral and parenteral routes)7. In particular, nefopam is associated with excellent postoperative pain control8–10. However, no studies have evaluated the continuous infusion of nefopam alone for PCA without the use of any adjuvant analgesics to achieve postoperative pain control. Moreover, the difference in PONV associated with nefopam vs. opioid use has not been evaluated. We hypothesized that a PCA regimen using nefopam would confer similar postoperative pain control, but would also reduce PONV, compared with a regimen using equipotent doses of fentanyl because of the well known risk of PONV in association with opioid use. Therefore, this study comparatively evaluated the effect of PCA regimens using equipotent doses of either nefopam or fentanyl for analgesia induction during gynecological laparoscopic surgery on the incidence and severity of PONV.
Patients and methods Study population The study was approved by the Institutional Review Board of Konkuk University Medical Center, Seoul, Korea (KUH1160056) and registered at http://cris.nih.go.kr (KCT0000783). Written informed consent was obtained from all patients, and the study was conducted using a prospective, double-blind, randomized design. Patients undergoing gynecological laparoscopic surgery with intravenous PCA for postoperative pain control were enrolled. All patients had an American Society of Anesthesiologists patient status of I or II and were 19 years of age. The exclusion criteria were as follows: (1) urgent or emergent 2
PONV with nefopam for PCA Oh et al.
case, (2) re-do case, (3) body weight of480 kg, (4) history of drug abuse, (5) currently on medications, (6) undergoing any other concurrent surgery, (7) surgery conducted within 1 h, or (8) discharged from hospital within 72 h. Patients were allocated randomly to receive either nefopam- (non-opioid; N group) or fentanyl-based (F group) PCA for postoperative pain control using sealed envelopes containing the treatment options (N and F) before anesthesia induction. All involved anesthesiologists, surgeons, and nurses were blinded to the study. All data were collected by trained observers who also were blinded and did not participate in patient care.
Anesthetic technique The anesthetic technique was standardized. All patients arrived at the operation room without premedication and had been administered no preanesthetic medications. Anesthesia was induced after establishing routine patient monitoring (pulse oximetry, electrocardiography, noninvasive blood pressure monitoring, and bispectral index determination). The anesthesiologists were requested to anesthetize patients as follows: lidocaine (0.5 mg/kg) was administered to decrease the pain induced by propofol injection, propofol (2 mg/kg) was intravenously administered for anesthesia induction, and remifentanil (5 ng/ml) was administered to a target plasma concentration of 5 ng/ml and maintained until the end of surgery using target-controlled infusion (Orchestra* Base Primea)11. Rocuronium (0.6 mg/kg) was administered for muscle relaxation after loss of consciousness under the guidance of peripheral neuromuscular transmission (NMT) monitoring. Tracheal intubation was performed at a trainof-four count of 0. Anesthesia was maintained with sevoflurane and titrated to maintain a bispectral index of 40 to 60. After anesthesia induction, patients were ventilated with 40% oxygen in air. The tidal volume was 6 ml/kg (lean body mass), and positive end expiratory pressure was not utilized. The respiratory rate was adjusted to maintain the partial pressure of end-tidal carbon dioxide from 35 to 40 mmHg. Additional rocuronium was administered under the guidance of peripheral NMT monitoring. Sevoflurane and target-controlled infusion of remifentanil were stopped at the end of surgery. Residual neuromuscular paralysis was antagonized with neostigmine (0.05 ml/kg) and glycopyrrolate (0.01 ml/kg) under the guidance of peripheral NMT monitoring. After tracheal extubation, patients were transferred to a post-anesthetic care unit (PACU). A Foley catheter was inserted after anesthesia induction and removed at 24 h post-surgery in all patients.
*Orchestra is a registered trade name of Fresenius Vial, Brezins, France.
www.cmrojournal.com ! 2015 Informa UK Ltd
Downloaded by [Stockholm University Library] at 23:13 10 August 2015
Current Medical Research & Opinion
2015
Patient-controlled analgesia (PCA)
Statistical analysis
For analgesia, 20 mg of nefopam is equipotent to 100 mg of fentanyl12,13. Therefore, the PCA (Gemstar* Pump) was set as follows: nefopam at 360 mg for the N group and fentanyl at 1800 mg for the F group to a total volume of 180 ml including normal saline (nefopam, 2 mg/ml; fentanyl, 10 mg/ml). The PCA device was programmed to deliver 0.02 ml/kg/h as a basal infusion rate and 0.01 ml/kg on demand with a 1 h lockout time. All study drugs and PCA pumps were prepared with identical syringes or bags by PACU-registered nurses who were blinded to the study and did not participate in patient care. An intravenous PCA pump was connected at the time of skin closure, and the PCA drugs were intravenously injected at 0.05 ml/kg for postoperative pain control.
The primary outcome was the Rhodes index score from 30 min after PACU arrival to 24 h after PACU discharge; the secondary outcome was the VAS score 30 min after PACU arrival. A pilot study of 10 patients undergoing gynecological laparoscopic surgery yielded a Rhodes index score of 7.1 7.5 in the F group and 2.9 3.4 in the N group, and a VAS score of 41 6 in the F group and 37 5 in the N group. A priori power analysis revealed an effect size of 0.72 and actual power of 0.9 for the Rhodes index, and an effect size of 0.80 and power of 0.9 for the VAS. The calculated sample size for the primary outcome was 47 in each group, compared with 46 in each group for the secondary outcome, with a drop-out rate of 10% and value of 0.05. The data were analyzed using the SPSS for Windows software package (ver. 18.0; SPSS, Chicago, IL, USA). Intergroup differences in PONV and the VAS score over time were analyzed using a Friedman test and analysis of variance for repeated measurements, respectively. If a significant difference was noted, a Mann–Whitney rank-sum test or Student’s t-test was used to compare group differences with application of Bonferroni correction. Categorical variables were analyzed using the chi-squared test or Fisher’s exact test as appropriate. All data are expressed as the number of patients, mean standard deviation, or median [interquartile range]. A value of P50.05 was taken to indicate statistical significance.
Measurements PONV was assessed using a four-point ordinal scale (0 ¼ none, 1 ¼ nausea, 2 ¼ retching, 3 ¼ vomiting)14 upon arrival at the PACU (PACU arrival); at 30 min after PACU arrival (30 min); and at 24 h (24 h), 48 h (48 h), and 72 h after PACU discharge (72 h). Nausea was defined as a subjectively unpleasant sensation associated with awareness of the urge to vomit. Retching was defined as labored, spasmodic, rhythmic contraction of the respiratory muscles without expulsion of gastric contents. Vomiting was defined as the forceful expulsion of gastric contents from the mouth. From 30 min to 24 h, 24 h to 48 h, and 48 h to 72 h, the severity of PONV was evaluated using a modified Rhodes index15. The Rhodes index scores used a numerical scale ranging from 0 to 32, including subjective (degree of severity) and objective (with/without nausea, retching, or vomiting; times of nausea, retching, and vomiting) aspects of PONV. Ondansetron (4 mg) was intravenously administered as a rescue, on-demand anti-emetic treatment, the use of which was recorded. Postoperative pain during coughing or movement was assessed using a visual analogue scale (VAS) ranging from 0 (no pain) to 100 (worst pain imaginable) simultaneous with the PONV severity evaluation. If postoperative pain was sustained even with continuous PCA infusion and on-demand dosage, additional ketorolac (0.5 mg/kg) was administered intravenously as an on-demand rescue analgesic, with the number of ketorolac administrations also recorded. To evaluate the adverse effects of nefopam, patients were asked during the PONV severity evaluation if they had experienced any of the following symptoms: drowsiness, dry mouth, urinary retention, or sweating. Tachycardia, defined as a heart rate of 4120 beats/min for 430 min, was concurrently evaluated. *Gemstar is a registered trade name of Hospira, Lake Forest, IL, USA
! 2015 Informa UK Ltd www.cmrojournal.com
Results In total, 119 patients were eligible for the study from July 2013 to December 2013. Twenty-five patients were excluded for the following reasons: 5 refused to participate, 3 were urgent or emergent cases, 12 were currently receiving medications, 2 underwent other types of concurrent surgery, and 3 had a body weight of 480 kg. Therefore, 94 patients were included in the final analysis (Figure 1). The distribution of patient demographic variables was similar between the two groups (Table 1). The PONV incidence and severity and the Rhodes index scores in the N group were significantly lower than those in the F group at all measured times. Multiple comparison showed that the N group had a significantly lower PONV incidence (15/47 [31.9%] vs. 27/47 [57.4%], respectively; P ¼ 0.022) (Figure 2) and PONV severity (0 [1] vs. 1 [2], respectively; P ¼ 0.005) (Figure 3) 24 h after PACU discharge as well as a significantly lower Rhodes index score (0 [3] vs. 5 [9], respectively; P ¼ 0.002) (Figure 4) from 30 min after PACU arrival to 24 h after PACU discharge than did the F group. No patient in the N group complained of PONV 72 h after PACU discharge. PONV with nefopam for PCA Oh et al.
3
Current Medical Research & Opinion
2015
Enrollment Gynecological laparoscopic surgery with intravenous patient controlled analgesia (PCA) (n = 119)
Downloaded by [Stockholm University Library] at 23:13 10 August 2015
Excluded (n = 25) Refusal of participating the study (n = 5) Urgent or emergent case (n =3) Receiving current medications (n = 12) Concurrent other surgery (n = 2) Body weight over 80 kg (n = 3)
Assessed for eligibility (n = 94)
Allocation
N group (n = 47)
Analysis
F group (n = 47)
Assess Postoperative nausea and vomiting (PONV) incidence, scale and Rhodes index Postoperative visual analogue scale (VAS) Number of rescue anti-emetics use Number of rescue analgesics use PCA on demand use Adverse effect of nefopam (drowsiness, dry mouth, urinary retention, sweating and tachycardia)
Figure 1. CONSORT flow diagram.
Table 1. Demographic data.
Age (years) Height (cm) Weight (kg) Smoking (pack-years) History of motion sickness History of PONV Anesthesia time (min) Sevoflurane (volume%) Min concentration Max concentration Operating time (min) Surgical procedures Ovarian cystectomy Uterine myomectomy Vaginal hysterectomy
N group (n ¼ 47)
F group (n ¼ 47)
P
44 11 157 5 58 9 0.2 1.5 7 1 123 35
44 11 159 6 58 8 0.0 0.0 5 0 125 35
0.667 0.075 0.695 0.323 0.379 0.500 0.809
1.1 0.3 1.8 0.5 97 33
1.2 0.3 1.7 0.3 99 35
0.069 0.809 0.783 0.951
18 4 25
20 4 23
Data are expressed as mean standard deviation or number of patients. N group, nefopam group; F group, fentanyl group; PONV, postoperative nausea and vomiting; Min, minimum; Max, maximum.
4
PONV with nefopam for PCA Oh et al.
Three patients in the F group and no patients in the N group received rescue anti-emetic treatment upon PACU arrival. However, there was no significant difference in the number of rescue anti-emetic treatments given on demand at any point in time between the two groups (Table 2). The PONV incidence and scale and the Rhodes index scores exhibited their highest values 24 h after PACU discharge in both groups, and decreased commensurate with the passage of time after PACU discharge (Figures 2–4). According to the VAS scores, there were no statistically significant differences in the analgesic treatments provided on demand, including PCA, at any time between the two groups (Table 2). Postoperative VAS scores were highest 30 min after PACU arrival and decreased over time thereafter in both groups (Figure 5). Dry mouth on PACU arrival was significantly more frequent in the N group than the F group (Table 3). However, the frequency of dry mouth decreased after PACU arrival in the N group, resulting in a significantly www.cmrojournal.com ! 2015 Informa UK Ltd
Current Medical Research & Opinion
P = 0.022
PONV incidence
30
N group F group
20
∗
10
0 PACU arrival
30 min
48 h
24 h
72 h
Time
Figure 2. Incidence of postoperative nausea and vomiting (PONV) according to time. N group, nefopam group; F group, fentanyl group; PACU arrival, on arrival at the postanesthetic care unit (PACU); 30 min, 30 minutes after PACU arrival; 24 h, 24 hours after PACU discharge; 48 h, 48 hours after PACU discharge; 72 h, 72 hours after PACU discharge. *P50.05 compared with F group. 1.5 N group F group
1 PONV scale
Downloaded by [Stockholm University Library] at 23:13 10 August 2015
2015
P = 0.005
∗
0.5
0 PACU arrival
30 min
24 h
48 h
72 h
Time
Figure 3. Postoperative nausea and vomiting (PONV) scale according to time. Data are expressed as mean with 95% confidence interval. N group, nefopam group; F group, fentanyl group; PACU arrival, on arrival at the postanesthetic care unit (PACU); 30 min, 30 minutes after PACU arrival; 24 h, 24 hours after PACU discharge; 48 h, 48 hours after PACU discharge; 72 h, 72 hours after PACU discharge. *P50.05 compared with F group.
lower incidence 24 h after PACU discharge in the N group than the F group (Table 3).
Discussion The analgesic mechanism of nefopam has not been fully elucidated; however, it appears to mainly involve central ! 2015 Informa UK Ltd www.cmrojournal.com
inhibition of reuptake of neurotransmitters such as serotonin, norepinephrine, and dopamine16,17, and confers anti-hyperalgesic activity through inactivation of the N-methyl-D-aspartic acid (NMDA) receptor7. Therefore, through various analgesic mechanisms, nefopam has been expected to yield, and has demonstrated, excellent pain control18. However, its analgesic effect has been proven only in the context of intermittent administration. PONV with nefopam for PCA Oh et al.
5
Current Medical Research & Opinion
2015
10 N group
Rhodes index
F group
5
P = 0.002
Downloaded by [Stockholm University Library] at 23:13 10 August 2015
∗
0 30 min - 24 h
24 h - 48 h
48 h - 72 h
Time
Figure 4. Postoperative nausea and vomiting (PONV) by measuring Rhodes index according to time. Data are expressed as mean with 95% confidence interval. N group, nefopam group; F group, fentanyl group; PACU arrival, on arrival at the postanesthetic care unit (PACU); 30 min–24 h, from 30 minutes after PACU arrival to 24 hours after PACU discharge; 24–48 h, from 24 hours to 48 hours after PACU discharge; 48–72 h, from 48 hours to 72 hours after PACU discharge. *P50.05 compared with F group.
Table 2. Rescue anti-emetics and analgesics.
Rescue anti-emetics PACU arrival 30 min 24 h 48 h 72 h Rescue analgesics PACU arrival 30 min 24 h 48 h 72 h PCA on demand PACU arrival 30 min 24 h 48 h 72 h
N group (n ¼ 47)
F group (n ¼ 47)
P
0 3 9 1 0
3 7 12 1 1
0.121 0.158 0.311 0.753 0.500
9 10 3 0 0
11 14 5 1 0
0.401 0.239 0.357 0.500 –
0.0 0.0 0.3 0.5 6.9 3.2 4.7 3.1 0.2 0.4
0.0 0.0 0.3 0.4 6.6 3.3 4.0 3.2 0.3 0.4
– 0.818 0.616 0.253 0.631
Data are expressed as number of patients or mean standard deviation. N group, nefopam group; F group, fentanyl group; PACU arrival, on arrival at the postanesthetic care unit (PACU); 30 min, 30 minutes after PACU arrival; 24 h, 24 hours after PACU discharge; 48 h, 48 hours after PACU discharge; 72 h, 72 hours after PACU discharge.
Merle et al.19 reported that continuous infusion of nefopam did not reduce morphine consumption nor ameliorate analgesia during urologic surgery; instead, these authors suggested that the analgesic effect of nefopam might differ according to the type of surgery performed 6
PONV with nefopam for PCA Oh et al.
because of differences in pain intensity, with surgery involving lower postoperative pain associated with a more limited effect of nefopam. In the present study, the patient population underwent gynecological laparoscopic surgery. Because female sex and laparoscopic surgery are well known risk factors for PONV3, a PCA regimen with low PONV risk is especially important in gynecological laparoscopic surgery. However, there have been no clinical trials on nefopam use in patients in the context of this surgical setting. Therefore, we consider that only female patients undergoing gynecological laparoscopic surgery would be acceptable for inclusion in this study. Studies on the effects of nefopam have generally focused on pain and have reported that the use of nefopam use does not achieve PONV reduction despite opioidsparing6,7. Moreover, nefopam shares side effects with opioids, such as nausea (10%–30% incidence) and vomiting6,9. However, our study showed that a PCA regimen using nefopam for analgesia was associated with improved outcomes in terms of PONV 24 h after PACU discharge, with a similar degree of pain control compared with a regimen using an equipotent dose of fentanyl. Mimoz et al.10 reported that nefopam achieved superior pain control and morphine-sparing with a lower incidence of nausea compared with placebo, which represents a superior outcome to that of the present study. These authors suggested that the lower incidence of nausea might have been ascribed to nefopam administration for www.cmrojournal.com ! 2015 Informa UK Ltd
Current Medical Research & Opinion
2015
50 N group
Downloaded by [Stockholm University Library] at 23:13 10 August 2015
VAS
F group
25
0 PACU arrival
30 min
24 h
48 h
72 h
Time
Figure 5. Postoperative pain measured by visual analogue scale (VAS) according to time. Data are expressed as mean with 95% confidence interval. N group, nefopam group; F group, fentanyl group; PACU arrival, on arrival at the postanesthetic care unit (PACU); 30 min, 30 minutes after PACU arrival; 24 h, 24 hours after PACU discharge; 48 h, 48 hours after PACU discharge; 72 h, 72 hours after PACU discharge.
60 min, in contrast to the intravenous administration of nefopam (20 mg) for 15 min used in studies in which nefopam failed to achieve a reduction in PONV despite opioid-sparing. In this study, nefopam at 0.1 mg/kg was followed by PCA at 0.04 mg/kg/h; a longer time period would have been required to administer 20 mg. Therefore, the reduced rate of nefopam administration used in this study may have contributed to PONV reduction. However, there were no significant differences in the PONV frequency upon PACU arrival or 30 min after arrival, suggesting that neither nefopam nor fentanyl reached a level sufficient to influence PONV until 30 min after PACU arrival. Notably, the incidence of dry mouth was higher upon PACU arrival and 24 h after discharge in the N than F group. Nefopam exerts anticholinergic activity with consequent adverse events such as dry mouth, urinary retention, sweating, and tachycardia. Because dry mouth presented alone with no other symptoms, it may be unrelated to the anticholinergic activity associated with nefopam use on PACU arrival. The higher incidence of dry mouth 30 min after PACU arrival in the F group may be associated with dehydration induced by PONV. A final consideration is that in previous studies the majority of adverse events reported occurred mainly in the context of higher nefopam administration rates9,10,20; the less rapid administration of nefopam in the present study appears to be associated with the occurrence of adverse events. ! 2015 Informa UK Ltd www.cmrojournal.com
This study had several limitations. First, our institution uses continuous opioid (fentanyl) administration by intravenous PCA as a standard strategy. In this study, however, the standard opioid dosage was lower and the lock-out time was longer than in our usual institutional strategy. In this study, the continuous administration rate of fentanyl was 0.2 mg/kg/h with a 1 h lock-out time, and the on-demand amount of fentanyl was 0.1 mg/kg. The relatively low dose of fentanyl and long lock-out time were based on the maximum safe daily dose of nefopam that can be used to compare equipotent dosages of nefopam and fentanyl. The maximum safe dosage of nefopam in humans is 120 mg/day 21. Therefore, we set the nefopam infusion as follows: 0.02 ml/kg/h ( ¼ 0.04 mg/kg/h for a maximum of 0.96 mg/kg for 24 h) for the continuous infusion and 0.01 ml/kg ( ¼ 0.02 mg/kg for a maximum of 0.48 mg/kg for 24 h with a 1 h lock-out time) for the on-demand dose. In this setting, the patient’s body weight should not exceed 83 kg (0.96 mg þ 0.48 mg ¼ 1.44 mg; 120 mg/ 1.44 mg/kg ¼ 83 kg) so as not to exceed the allowed nefopam dosage. Therefore, we excluded subjects with body weight of 480 kg from this study. To compare equipotent doses of nefopam and fentanyl (nefopam 20 mg ¼ fentanyl 100 mg), the continuous infusion dose of fentanyl need to be maintained at 0.2 mg/kg/h. In addition, ketorolac (0.5 mg/kg) was administered intravenously as an ondemand rescue analgesic. Although these doses appear to be lower than in the standard PCA setting, they enabled us to achieve optimal postoperative pain control. Second, the PONV with nefopam for PCA Oh et al.
7
Current Medical Research & Opinion
2015
Downloaded by [Stockholm University Library] at 23:13 10 August 2015
Table 3. Postoperative complications.
Drowsiness PACU arrival 30 min 24 h 48 h 72 h Dry mouth PACU arrival 30 min 24 h 48 h 72 h Urinary retention PACU arrival 30 min 24 h 48 h 72 h Sweating PACU arrival 30 min 24 h 48 h 72 h Tachycardia PACU arrival 30 min 24 h 48 h 72 h
Conclusions
N group (n ¼ 47)
F group (n ¼ 47)
P
5 5 0 0 0
10 8 1 0 1
0.130 0.552 0.500 – 0.500
22* 29 4* 0 0
13 30 13 4 0
0.044 0.500 0.015 0.058 –
– – – 0 0
– – – 1 1
– – – 0.500 0.500
1 1 0 0 0
0 1 4 3 0
0.500 0.753 0.058 0.121 –
3 0 1 0 0
1 0 0 0 0
0.308 – 0.500 – –
Data are expressed as number of patients or mean standard deviation. N group, nefopam group; F group, fentanyl group; PACU arrival, on arrival at the postanesthetic care unit (PACU); 30 min, 30 minutes after PACU arrival; 24 h, 24 hours after PACU discharge; 48 h, 48 hours after PACU discharge; 72 h, 72 hours after PACU discharge. *P50.05 compared with F group.
Rhodes index score was not measured on PACU arrival and 30 min after PACU arrival. The Rhodes index score is obtained using a questionnaire method, and it describes the severity of PONV on a numerical scale from 0 to 32, including subjective (severity) and objective (with/without nausea, retching, and vomiting, as well as times of nausea, retching, and vomiting) measures of PONV. All procedures were performed under general anesthesia, and the time of PACU arrival was immediately after emergence from general anesthesia. Considering the condition of the patients immediately after PACU arrival, it was difficult to accurately assess PONV using the Rhodes index score. Therefore, to obtain more exact results for PONV, the Rhodes index score was determined 30 min after PACU arrival (the time required for full awakening). Unlike the Rhodes index, the PONV scale and incidence were relatively easy to assess. Therefore, in this study, the PONV scale and incidence were assessed instead of the Rhodes index upon PACU arrival and 30 min after PACU arrival, and the results were similar in both groups. 8
PONV with nefopam for PCA Oh et al.
In conclusion, a PCA regimen using nefopam for analgesia yielded a similar degree of pain control with a superior outcome in terms of PONV 24 h after PACU discharge and no adverse events compared with a regimen using an equipotent dose of fentanyl.
Transparency Declaration of funding There was no commercial funding for this study. Chung-Sik Oha Eugene Junga Sun Joo Leeb Seong-Hyop Kima,c Declaration of financial/other relationships C.-S.O., E.J., S.J.L., and S.-H.K. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article. CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose. Acknowledgments This study was supported by Konkuk University.
References 1. Walder B, Schafer M, Henzi I, Tramer MR. Efficacy and safety of patientcontrolled opioid analgesia for acute postoperative pain. A quantitative systematic review. Acta Anaesthesiol Scand 2001;45:795-804 2. Choi DH, Ko JS, Ahn HJ, Kim JA. A Korean predictive model for postoperative nausea and vomiting. J Korean Med Sci 2005;20:811-15 3. Gan TJ. Risk factors for postoperative nausea and vomiting. Anesth Analg 2006;102:1884-98 4. Bures J, Rejchrt S, Kopacova M, Siroky M. Effects of nonsteroidal anti-inflammatory agents on the gastrointestinal tract. Cas Lek Cesk 2002;141:673-9 5. Esposito E, Romandini S, Merlo-Pich E, et al. Evidence of the involvement of dopamine in the analgesic effect of nefopam. Eur J Pharmacol 1986;128:157-64 6. Heel RC, Brogden RN, Pakes GE, et al. Nefopam: a review of its pharmacological properties and therapeutic efficacy. Drugs 1980;19:249-67 7. Gray AM, Nevinson MJ, Sewell RD. The involvement of opioidergic and noradrenergic mechanisms in nefopam antinociception. Eur J Pharmacol 1999;365:149-57 8. Du Manoir B, Aubrun F, Langlois M, et al. Randomized prospective study of the analgesic effect of nefopam after orthopaedic surgery. Br J Anaesth 2003;91:836-41 9. Kapfer B, Alfonsi P, Guignard B, et al. Nefopam and ketamine comparably enhance postoperative analgesia. Anesth Analg 2005;100:169-74 10. Mimoz O, Incagnoli P, Josse C, et al. Analgesic efficacy and safety of nefopam vs. propacetamol following hepatic resection. Anaesthesia 2001;56:520-5 11. Minto CF, Schnider TW, Egan TD, et al. Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development. Anesthesiology 1997;86:10-23 12. Sunshine A, Laska E. Nefopam and morphine in man. Clin Pharmacol Ther 1975;18(5 Pt 1):530-4
www.cmrojournal.com ! 2015 Informa UK Ltd
Current Medical Research & Opinion
17. Fuller RW, Snoddy HD. Evaluation of nefopam as a monoamine uptake inhibitor in vivo in mice. Neuropharmacology 1993;32:995-9 18. Evans MS, Lysakowski C, Tramer MR. Nefopam for the prevention of postoperative pain: quantitative systematic review. Br J Anaesth 2008;101:610-17 19. Merle JC, Vandroux D, Odin I, et al. Analgesic effect of continuous intravenous nefopam after urological surgery. Ann Fr Anesth Reanim 2005;24:13-18 20. Beloeil H, Delage N, Negre I, et al. The median effective dose of nefopam and morphine administered intravenously for postoperative pain after minor surgery: a prospective randomized double-blinded isobolographic study of their analgesic action. Anesth Analg 2004;98:395-400 21. Reynolds JEF. Martindale: The Extra Pharmacopoeia, 29th edn. London, UK: The Pharmaceutical Press, 1989:30
Downloaded by [Stockholm University Library] at 23:13 10 August 2015
13. Woodhouse A, Hobbes AF, Mather LE, Gibson M. A comparison of morphine, pethidine and fentanyl in the postsurgical patient-controlled analgesia environment. Pain 1996;64:115-21 14. Gomez-Hernandez J, Orozco-Alatorre AL, Dominguez-Contreras M, et al. Preoperative dexamethasone reduces postoperative pain, nausea and vomiting following mastectomy for breast cancer. BMC Cancer 2010;10:692 15. Rhodes VA, McDaniel RW. The Index of Nausea, Vomiting, and Retching: a new format of the Index of Nausea and Vomiting. Oncol Nurs Forum 1999;26:889-94 16. Rosland JH, Hole K. The effect of nefopam and its enantiomers on the uptake of 5-hydroxytryptamine, noradrenaline and dopamine in crude rat brain synaptosomal preparations. J Pharm Pharmacol 1990;42:437-8
2015
! 2015 Informa UK Ltd www.cmrojournal.com
PONV with nefopam for PCA Oh et al.
9
Current Medical Research and Opinion Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/icmo20
Effect of nefopam- versus fentanyl-based patientcontrolled analgesia on postoperative nausea and vomiting in patients undergoing gynecological laparoscopic surgery: a prospective double-blind randomized controlled trial a
a
b
ac
Chung-Sik Oh , Eugene Jung , Sun Joo Lee & Seong-Hyop Kim a a
Department of Anesthesiology and Pain Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea b b
Click for updates
Department of Obstetrics and Gynecology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea c c
Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, Korea Published online: 09 Jul 2015.
To cite this article: Chung-Sik Oh, Eugene Jung, Sun Joo Lee & Seong-Hyop Kim (2015): Effect of nefopam- versus fentanylbased patient-controlled analgesia on postoperative nausea and vomiting in patients undergoing gynecological laparoscopic surgery: a prospective double-blind randomized controlled trial, Current Medical Research and Opinion To link to this article: http://dx.doi.org/10.1185/03007995.2015.1058251
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Current Medical Research & Opinion
Downloaded by [Stockholm University Library] at 23:13 10 August 2015
0300-7995 doi:10.1185/03007995.2015.1058251
2015, 1–9
Article ST-0152.R1/1058251 All rights reserved: reproduction in whole or part not permitted
Report Effect of nefopam- versus fentanyl-based patient-controlled analgesia on postoperative nausea and vomiting in patients undergoing gynecological laparoscopic surgery: a prospective double-blind randomized controlled trial
Chung-Sik Oh Eugene Jung Department of Anesthesiology and Pain Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea
Sun Joo Lee Department of Obstetrics and Gynecology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea
Seong-Hyop Kim Department of Anesthesiology and Pain Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, Korea Address for correspondence: Seong-Hyop Kim MD, PhD, Department of Anesthesiology and Pain Medicine, Konkuk University Medical Center, 120-1, Neungdong-ro (Hwayangdong), Gwangjin-gu, Seoul 143-729, Korea. Tel:+82 2-2030-5454; Fax: +82 2-2030-5449; [email protected] Keywords: Fentanyl – Nefopam – Patient-controlled analgesia – Postoperative nausea and vomiting Accepted: 26 May 2015; published online: 6 July 2015 Citation: Curr Med Res Opin 2015; 1–9
! 2015 Informa UK Ltd www.cmrojournal.com
Abstract Objective: This study comparatively evaluated the effect of patient-controlled analgesia (PCA) regimens using equipotent doses of nefopam or fentanyl during laparoscopic gynecological surgery on postoperative nausea and vomiting (PONV). Research design and methods: Patients undergoing gynecological laparoscopic surgery were randomly allocated to receive either nefopam(non-opioid; N group) or fentanyl-based (F group) PCA. PONV and postoperative pain were assessed during the 72 hours following discharge from the post-anesthetic care unit (PACU). The adverse effects of nefopam were also evaluated. Clinical trial registration: Cris.nih.go.kr ID KCT0000783. Results: In total, 94 patients were included in the final analysis. The PONV incidence and scale and the Rhodes index scores were significantly lower in the N group than the F group at all measured times. The N group exhibited a significantly lower incidence of PONV (15/47 [31.9%] vs. 27/47 [57.4%], respectively; P ¼ 0.022) and severity of PONV (0 [1] vs. 1 [2], respectively; P ¼ 0.005) 24 hours after PACU discharge and a significantly lower Rhodes index score (0 [3] vs. 5 [9], respectively; P ¼ 0.002) from 30 minutes after PACU arrival to 24 hours after PACU discharge than did the F group. There was no significant difference in postoperative pain at any time between the two groups. Dry mouth on PACU arrival was significantly more frequent in the N group. However, the frequency of dry mouth decreased after PACU arrival in the N group, resulting in a significantly lower incidence 24 hours after PACU discharge. Conclusions: Use of a PCA regimen with nefopam for analgesia was associated with a similar degree of pain control and superior PONV outcomes 24 hours after PACU discharge and no adverse events compared with a PCA regimen using an equipotent dose of fentanyl.
PONV with nefopam for PCA Oh et al.
1
Current Medical Research & Opinion
2015
Downloaded by [Stockholm University Library] at 23:13 10 August 2015
Introduction Postoperative nausea and vomiting (PONV) and pain are the most distressing adverse events following surgery under general anesthesia. Patient-controlled analgesia (PCA) is among the most popular methods used for postoperative pain control and achieves excellent results. PCA typically involves the administration of an analgesic agent, most commonly an opioid, using a programmed infusion pump1. However, the use of postoperative opioids is associated with delayed recovery from anesthesia and a high incidence of PONV2,3. This has led to the combined use of opioids with other analgesic agents, such as non-steroidal anti-inflammatory drugs, to lower the incidence of PONV. However, this approach is not without problems, such as anticoagulation and gastrointestinal disorders4. Nefopam is a non-opioid analgesic drug in the benzoxazocine class of compounds. It exerts analgesic effects by inhibiting the synaptosomal uptake of noradrenaline, dopamine, and serotonin5,6. Nefopam is thus used in numerous European countries for pain control and as an alternative medication to opioids (by oral and parenteral routes)7. In particular, nefopam is associated with excellent postoperative pain control8–10. However, no studies have evaluated the continuous infusion of nefopam alone for PCA without the use of any adjuvant analgesics to achieve postoperative pain control. Moreover, the difference in PONV associated with nefopam vs. opioid use has not been evaluated. We hypothesized that a PCA regimen using nefopam would confer similar postoperative pain control, but would also reduce PONV, compared with a regimen using equipotent doses of fentanyl because of the well known risk of PONV in association with opioid use. Therefore, this study comparatively evaluated the effect of PCA regimens using equipotent doses of either nefopam or fentanyl for analgesia induction during gynecological laparoscopic surgery on the incidence and severity of PONV.
Patients and methods Study population The study was approved by the Institutional Review Board of Konkuk University Medical Center, Seoul, Korea (KUH1160056) and registered at http://cris.nih.go.kr (KCT0000783). Written informed consent was obtained from all patients, and the study was conducted using a prospective, double-blind, randomized design. Patients undergoing gynecological laparoscopic surgery with intravenous PCA for postoperative pain control were enrolled. All patients had an American Society of Anesthesiologists patient status of I or II and were 19 years of age. The exclusion criteria were as follows: (1) urgent or emergent 2
PONV with nefopam for PCA Oh et al.
case, (2) re-do case, (3) body weight of480 kg, (4) history of drug abuse, (5) currently on medications, (6) undergoing any other concurrent surgery, (7) surgery conducted within 1 h, or (8) discharged from hospital within 72 h. Patients were allocated randomly to receive either nefopam- (non-opioid; N group) or fentanyl-based (F group) PCA for postoperative pain control using sealed envelopes containing the treatment options (N and F) before anesthesia induction. All involved anesthesiologists, surgeons, and nurses were blinded to the study. All data were collected by trained observers who also were blinded and did not participate in patient care.
Anesthetic technique The anesthetic technique was standardized. All patients arrived at the operation room without premedication and had been administered no preanesthetic medications. Anesthesia was induced after establishing routine patient monitoring (pulse oximetry, electrocardiography, noninvasive blood pressure monitoring, and bispectral index determination). The anesthesiologists were requested to anesthetize patients as follows: lidocaine (0.5 mg/kg) was administered to decrease the pain induced by propofol injection, propofol (2 mg/kg) was intravenously administered for anesthesia induction, and remifentanil (5 ng/ml) was administered to a target plasma concentration of 5 ng/ml and maintained until the end of surgery using target-controlled infusion (Orchestra* Base Primea)11. Rocuronium (0.6 mg/kg) was administered for muscle relaxation after loss of consciousness under the guidance of peripheral neuromuscular transmission (NMT) monitoring. Tracheal intubation was performed at a trainof-four count of 0. Anesthesia was maintained with sevoflurane and titrated to maintain a bispectral index of 40 to 60. After anesthesia induction, patients were ventilated with 40% oxygen in air. The tidal volume was 6 ml/kg (lean body mass), and positive end expiratory pressure was not utilized. The respiratory rate was adjusted to maintain the partial pressure of end-tidal carbon dioxide from 35 to 40 mmHg. Additional rocuronium was administered under the guidance of peripheral NMT monitoring. Sevoflurane and target-controlled infusion of remifentanil were stopped at the end of surgery. Residual neuromuscular paralysis was antagonized with neostigmine (0.05 ml/kg) and glycopyrrolate (0.01 ml/kg) under the guidance of peripheral NMT monitoring. After tracheal extubation, patients were transferred to a post-anesthetic care unit (PACU). A Foley catheter was inserted after anesthesia induction and removed at 24 h post-surgery in all patients.
*Orchestra is a registered trade name of Fresenius Vial, Brezins, France.
www.cmrojournal.com ! 2015 Informa UK Ltd
Downloaded by [Stockholm University Library] at 23:13 10 August 2015
Current Medical Research & Opinion
2015
Patient-controlled analgesia (PCA)
Statistical analysis
For analgesia, 20 mg of nefopam is equipotent to 100 mg of fentanyl12,13. Therefore, the PCA (Gemstar* Pump) was set as follows: nefopam at 360 mg for the N group and fentanyl at 1800 mg for the F group to a total volume of 180 ml including normal saline (nefopam, 2 mg/ml; fentanyl, 10 mg/ml). The PCA device was programmed to deliver 0.02 ml/kg/h as a basal infusion rate and 0.01 ml/kg on demand with a 1 h lockout time. All study drugs and PCA pumps were prepared with identical syringes or bags by PACU-registered nurses who were blinded to the study and did not participate in patient care. An intravenous PCA pump was connected at the time of skin closure, and the PCA drugs were intravenously injected at 0.05 ml/kg for postoperative pain control.
The primary outcome was the Rhodes index score from 30 min after PACU arrival to 24 h after PACU discharge; the secondary outcome was the VAS score 30 min after PACU arrival. A pilot study of 10 patients undergoing gynecological laparoscopic surgery yielded a Rhodes index score of 7.1 7.5 in the F group and 2.9 3.4 in the N group, and a VAS score of 41 6 in the F group and 37 5 in the N group. A priori power analysis revealed an effect size of 0.72 and actual power of 0.9 for the Rhodes index, and an effect size of 0.80 and power of 0.9 for the VAS. The calculated sample size for the primary outcome was 47 in each group, compared with 46 in each group for the secondary outcome, with a drop-out rate of 10% and value of 0.05. The data were analyzed using the SPSS for Windows software package (ver. 18.0; SPSS, Chicago, IL, USA). Intergroup differences in PONV and the VAS score over time were analyzed using a Friedman test and analysis of variance for repeated measurements, respectively. If a significant difference was noted, a Mann–Whitney rank-sum test or Student’s t-test was used to compare group differences with application of Bonferroni correction. Categorical variables were analyzed using the chi-squared test or Fisher’s exact test as appropriate. All data are expressed as the number of patients, mean standard deviation, or median [interquartile range]. A value of P50.05 was taken to indicate statistical significance.
Measurements PONV was assessed using a four-point ordinal scale (0 ¼ none, 1 ¼ nausea, 2 ¼ retching, 3 ¼ vomiting)14 upon arrival at the PACU (PACU arrival); at 30 min after PACU arrival (30 min); and at 24 h (24 h), 48 h (48 h), and 72 h after PACU discharge (72 h). Nausea was defined as a subjectively unpleasant sensation associated with awareness of the urge to vomit. Retching was defined as labored, spasmodic, rhythmic contraction of the respiratory muscles without expulsion of gastric contents. Vomiting was defined as the forceful expulsion of gastric contents from the mouth. From 30 min to 24 h, 24 h to 48 h, and 48 h to 72 h, the severity of PONV was evaluated using a modified Rhodes index15. The Rhodes index scores used a numerical scale ranging from 0 to 32, including subjective (degree of severity) and objective (with/without nausea, retching, or vomiting; times of nausea, retching, and vomiting) aspects of PONV. Ondansetron (4 mg) was intravenously administered as a rescue, on-demand anti-emetic treatment, the use of which was recorded. Postoperative pain during coughing or movement was assessed using a visual analogue scale (VAS) ranging from 0 (no pain) to 100 (worst pain imaginable) simultaneous with the PONV severity evaluation. If postoperative pain was sustained even with continuous PCA infusion and on-demand dosage, additional ketorolac (0.5 mg/kg) was administered intravenously as an on-demand rescue analgesic, with the number of ketorolac administrations also recorded. To evaluate the adverse effects of nefopam, patients were asked during the PONV severity evaluation if they had experienced any of the following symptoms: drowsiness, dry mouth, urinary retention, or sweating. Tachycardia, defined as a heart rate of 4120 beats/min for 430 min, was concurrently evaluated. *Gemstar is a registered trade name of Hospira, Lake Forest, IL, USA
! 2015 Informa UK Ltd www.cmrojournal.com
Results In total, 119 patients were eligible for the study from July 2013 to December 2013. Twenty-five patients were excluded for the following reasons: 5 refused to participate, 3 were urgent or emergent cases, 12 were currently receiving medications, 2 underwent other types of concurrent surgery, and 3 had a body weight of 480 kg. Therefore, 94 patients were included in the final analysis (Figure 1). The distribution of patient demographic variables was similar between the two groups (Table 1). The PONV incidence and severity and the Rhodes index scores in the N group were significantly lower than those in the F group at all measured times. Multiple comparison showed that the N group had a significantly lower PONV incidence (15/47 [31.9%] vs. 27/47 [57.4%], respectively; P ¼ 0.022) (Figure 2) and PONV severity (0 [1] vs. 1 [2], respectively; P ¼ 0.005) (Figure 3) 24 h after PACU discharge as well as a significantly lower Rhodes index score (0 [3] vs. 5 [9], respectively; P ¼ 0.002) (Figure 4) from 30 min after PACU arrival to 24 h after PACU discharge than did the F group. No patient in the N group complained of PONV 72 h after PACU discharge. PONV with nefopam for PCA Oh et al.
3
Current Medical Research & Opinion
2015
Enrollment Gynecological laparoscopic surgery with intravenous patient controlled analgesia (PCA) (n = 119)
Downloaded by [Stockholm University Library] at 23:13 10 August 2015
Excluded (n = 25) Refusal of participating the study (n = 5) Urgent or emergent case (n =3) Receiving current medications (n = 12) Concurrent other surgery (n = 2) Body weight over 80 kg (n = 3)
Assessed for eligibility (n = 94)
Allocation
N group (n = 47)
Analysis
F group (n = 47)
Assess Postoperative nausea and vomiting (PONV) incidence, scale and Rhodes index Postoperative visual analogue scale (VAS) Number of rescue anti-emetics use Number of rescue analgesics use PCA on demand use Adverse effect of nefopam (drowsiness, dry mouth, urinary retention, sweating and tachycardia)
Figure 1. CONSORT flow diagram.
Table 1. Demographic data.
Age (years) Height (cm) Weight (kg) Smoking (pack-years) History of motion sickness History of PONV Anesthesia time (min) Sevoflurane (volume%) Min concentration Max concentration Operating time (min) Surgical procedures Ovarian cystectomy Uterine myomectomy Vaginal hysterectomy
N group (n ¼ 47)
F group (n ¼ 47)
P
44 11 157 5 58 9 0.2 1.5 7 1 123 35
44 11 159 6 58 8 0.0 0.0 5 0 125 35
0.667 0.075 0.695 0.323 0.379 0.500 0.809
1.1 0.3 1.8 0.5 97 33
1.2 0.3 1.7 0.3 99 35
0.069 0.809 0.783 0.951
18 4 25
20 4 23
Data are expressed as mean standard deviation or number of patients. N group, nefopam group; F group, fentanyl group; PONV, postoperative nausea and vomiting; Min, minimum; Max, maximum.
4
PONV with nefopam for PCA Oh et al.
Three patients in the F group and no patients in the N group received rescue anti-emetic treatment upon PACU arrival. However, there was no significant difference in the number of rescue anti-emetic treatments given on demand at any point in time between the two groups (Table 2). The PONV incidence and scale and the Rhodes index scores exhibited their highest values 24 h after PACU discharge in both groups, and decreased commensurate with the passage of time after PACU discharge (Figures 2–4). According to the VAS scores, there were no statistically significant differences in the analgesic treatments provided on demand, including PCA, at any time between the two groups (Table 2). Postoperative VAS scores were highest 30 min after PACU arrival and decreased over time thereafter in both groups (Figure 5). Dry mouth on PACU arrival was significantly more frequent in the N group than the F group (Table 3). However, the frequency of dry mouth decreased after PACU arrival in the N group, resulting in a significantly www.cmrojournal.com ! 2015 Informa UK Ltd
Current Medical Research & Opinion
P = 0.022
PONV incidence
30
N group F group
20
∗
10
0 PACU arrival
30 min
48 h
24 h
72 h
Time
Figure 2. Incidence of postoperative nausea and vomiting (PONV) according to time. N group, nefopam group; F group, fentanyl group; PACU arrival, on arrival at the postanesthetic care unit (PACU); 30 min, 30 minutes after PACU arrival; 24 h, 24 hours after PACU discharge; 48 h, 48 hours after PACU discharge; 72 h, 72 hours after PACU discharge. *P50.05 compared with F group. 1.5 N group F group
1 PONV scale
Downloaded by [Stockholm University Library] at 23:13 10 August 2015
2015
P = 0.005
∗
0.5
0 PACU arrival
30 min
24 h
48 h
72 h
Time
Figure 3. Postoperative nausea and vomiting (PONV) scale according to time. Data are expressed as mean with 95% confidence interval. N group, nefopam group; F group, fentanyl group; PACU arrival, on arrival at the postanesthetic care unit (PACU); 30 min, 30 minutes after PACU arrival; 24 h, 24 hours after PACU discharge; 48 h, 48 hours after PACU discharge; 72 h, 72 hours after PACU discharge. *P50.05 compared with F group.
lower incidence 24 h after PACU discharge in the N group than the F group (Table 3).
Discussion The analgesic mechanism of nefopam has not been fully elucidated; however, it appears to mainly involve central ! 2015 Informa UK Ltd www.cmrojournal.com
inhibition of reuptake of neurotransmitters such as serotonin, norepinephrine, and dopamine16,17, and confers anti-hyperalgesic activity through inactivation of the N-methyl-D-aspartic acid (NMDA) receptor7. Therefore, through various analgesic mechanisms, nefopam has been expected to yield, and has demonstrated, excellent pain control18. However, its analgesic effect has been proven only in the context of intermittent administration. PONV with nefopam for PCA Oh et al.
5
Current Medical Research & Opinion
2015
10 N group
Rhodes index
F group
5
P = 0.002
Downloaded by [Stockholm University Library] at 23:13 10 August 2015
∗
0 30 min - 24 h
24 h - 48 h
48 h - 72 h
Time
Figure 4. Postoperative nausea and vomiting (PONV) by measuring Rhodes index according to time. Data are expressed as mean with 95% confidence interval. N group, nefopam group; F group, fentanyl group; PACU arrival, on arrival at the postanesthetic care unit (PACU); 30 min–24 h, from 30 minutes after PACU arrival to 24 hours after PACU discharge; 24–48 h, from 24 hours to 48 hours after PACU discharge; 48–72 h, from 48 hours to 72 hours after PACU discharge. *P50.05 compared with F group.
Table 2. Rescue anti-emetics and analgesics.
Rescue anti-emetics PACU arrival 30 min 24 h 48 h 72 h Rescue analgesics PACU arrival 30 min 24 h 48 h 72 h PCA on demand PACU arrival 30 min 24 h 48 h 72 h
N group (n ¼ 47)
F group (n ¼ 47)
P
0 3 9 1 0
3 7 12 1 1
0.121 0.158 0.311 0.753 0.500
9 10 3 0 0
11 14 5 1 0
0.401 0.239 0.357 0.500 –
0.0 0.0 0.3 0.5 6.9 3.2 4.7 3.1 0.2 0.4
0.0 0.0 0.3 0.4 6.6 3.3 4.0 3.2 0.3 0.4
– 0.818 0.616 0.253 0.631
Data are expressed as number of patients or mean standard deviation. N group, nefopam group; F group, fentanyl group; PACU arrival, on arrival at the postanesthetic care unit (PACU); 30 min, 30 minutes after PACU arrival; 24 h, 24 hours after PACU discharge; 48 h, 48 hours after PACU discharge; 72 h, 72 hours after PACU discharge.
Merle et al.19 reported that continuous infusion of nefopam did not reduce morphine consumption nor ameliorate analgesia during urologic surgery; instead, these authors suggested that the analgesic effect of nefopam might differ according to the type of surgery performed 6
PONV with nefopam for PCA Oh et al.
because of differences in pain intensity, with surgery involving lower postoperative pain associated with a more limited effect of nefopam. In the present study, the patient population underwent gynecological laparoscopic surgery. Because female sex and laparoscopic surgery are well known risk factors for PONV3, a PCA regimen with low PONV risk is especially important in gynecological laparoscopic surgery. However, there have been no clinical trials on nefopam use in patients in the context of this surgical setting. Therefore, we consider that only female patients undergoing gynecological laparoscopic surgery would be acceptable for inclusion in this study. Studies on the effects of nefopam have generally focused on pain and have reported that the use of nefopam use does not achieve PONV reduction despite opioidsparing6,7. Moreover, nefopam shares side effects with opioids, such as nausea (10%–30% incidence) and vomiting6,9. However, our study showed that a PCA regimen using nefopam for analgesia was associated with improved outcomes in terms of PONV 24 h after PACU discharge, with a similar degree of pain control compared with a regimen using an equipotent dose of fentanyl. Mimoz et al.10 reported that nefopam achieved superior pain control and morphine-sparing with a lower incidence of nausea compared with placebo, which represents a superior outcome to that of the present study. These authors suggested that the lower incidence of nausea might have been ascribed to nefopam administration for www.cmrojournal.com ! 2015 Informa UK Ltd
Current Medical Research & Opinion
2015
50 N group
Downloaded by [Stockholm University Library] at 23:13 10 August 2015
VAS
F group
25
0 PACU arrival
30 min
24 h
48 h
72 h
Time
Figure 5. Postoperative pain measured by visual analogue scale (VAS) according to time. Data are expressed as mean with 95% confidence interval. N group, nefopam group; F group, fentanyl group; PACU arrival, on arrival at the postanesthetic care unit (PACU); 30 min, 30 minutes after PACU arrival; 24 h, 24 hours after PACU discharge; 48 h, 48 hours after PACU discharge; 72 h, 72 hours after PACU discharge.
60 min, in contrast to the intravenous administration of nefopam (20 mg) for 15 min used in studies in which nefopam failed to achieve a reduction in PONV despite opioid-sparing. In this study, nefopam at 0.1 mg/kg was followed by PCA at 0.04 mg/kg/h; a longer time period would have been required to administer 20 mg. Therefore, the reduced rate of nefopam administration used in this study may have contributed to PONV reduction. However, there were no significant differences in the PONV frequency upon PACU arrival or 30 min after arrival, suggesting that neither nefopam nor fentanyl reached a level sufficient to influence PONV until 30 min after PACU arrival. Notably, the incidence of dry mouth was higher upon PACU arrival and 24 h after discharge in the N than F group. Nefopam exerts anticholinergic activity with consequent adverse events such as dry mouth, urinary retention, sweating, and tachycardia. Because dry mouth presented alone with no other symptoms, it may be unrelated to the anticholinergic activity associated with nefopam use on PACU arrival. The higher incidence of dry mouth 30 min after PACU arrival in the F group may be associated with dehydration induced by PONV. A final consideration is that in previous studies the majority of adverse events reported occurred mainly in the context of higher nefopam administration rates9,10,20; the less rapid administration of nefopam in the present study appears to be associated with the occurrence of adverse events. ! 2015 Informa UK Ltd www.cmrojournal.com
This study had several limitations. First, our institution uses continuous opioid (fentanyl) administration by intravenous PCA as a standard strategy. In this study, however, the standard opioid dosage was lower and the lock-out time was longer than in our usual institutional strategy. In this study, the continuous administration rate of fentanyl was 0.2 mg/kg/h with a 1 h lock-out time, and the on-demand amount of fentanyl was 0.1 mg/kg. The relatively low dose of fentanyl and long lock-out time were based on the maximum safe daily dose of nefopam that can be used to compare equipotent dosages of nefopam and fentanyl. The maximum safe dosage of nefopam in humans is 120 mg/day 21. Therefore, we set the nefopam infusion as follows: 0.02 ml/kg/h ( ¼ 0.04 mg/kg/h for a maximum of 0.96 mg/kg for 24 h) for the continuous infusion and 0.01 ml/kg ( ¼ 0.02 mg/kg for a maximum of 0.48 mg/kg for 24 h with a 1 h lock-out time) for the on-demand dose. In this setting, the patient’s body weight should not exceed 83 kg (0.96 mg þ 0.48 mg ¼ 1.44 mg; 120 mg/ 1.44 mg/kg ¼ 83 kg) so as not to exceed the allowed nefopam dosage. Therefore, we excluded subjects with body weight of 480 kg from this study. To compare equipotent doses of nefopam and fentanyl (nefopam 20 mg ¼ fentanyl 100 mg), the continuous infusion dose of fentanyl need to be maintained at 0.2 mg/kg/h. In addition, ketorolac (0.5 mg/kg) was administered intravenously as an ondemand rescue analgesic. Although these doses appear to be lower than in the standard PCA setting, they enabled us to achieve optimal postoperative pain control. Second, the PONV with nefopam for PCA Oh et al.
7
Current Medical Research & Opinion
2015
Downloaded by [Stockholm University Library] at 23:13 10 August 2015
Table 3. Postoperative complications.
Drowsiness PACU arrival 30 min 24 h 48 h 72 h Dry mouth PACU arrival 30 min 24 h 48 h 72 h Urinary retention PACU arrival 30 min 24 h 48 h 72 h Sweating PACU arrival 30 min 24 h 48 h 72 h Tachycardia PACU arrival 30 min 24 h 48 h 72 h
Conclusions
N group (n ¼ 47)
F group (n ¼ 47)
P
5 5 0 0 0
10 8 1 0 1
0.130 0.552 0.500 – 0.500
22* 29 4* 0 0
13 30 13 4 0
0.044 0.500 0.015 0.058 –
– – – 0 0
– – – 1 1
– – – 0.500 0.500
1 1 0 0 0
0 1 4 3 0
0.500 0.753 0.058 0.121 –
3 0 1 0 0
1 0 0 0 0
0.308 – 0.500 – –
Data are expressed as number of patients or mean standard deviation. N group, nefopam group; F group, fentanyl group; PACU arrival, on arrival at the postanesthetic care unit (PACU); 30 min, 30 minutes after PACU arrival; 24 h, 24 hours after PACU discharge; 48 h, 48 hours after PACU discharge; 72 h, 72 hours after PACU discharge. *P50.05 compared with F group.
Rhodes index score was not measured on PACU arrival and 30 min after PACU arrival. The Rhodes index score is obtained using a questionnaire method, and it describes the severity of PONV on a numerical scale from 0 to 32, including subjective (severity) and objective (with/without nausea, retching, and vomiting, as well as times of nausea, retching, and vomiting) measures of PONV. All procedures were performed under general anesthesia, and the time of PACU arrival was immediately after emergence from general anesthesia. Considering the condition of the patients immediately after PACU arrival, it was difficult to accurately assess PONV using the Rhodes index score. Therefore, to obtain more exact results for PONV, the Rhodes index score was determined 30 min after PACU arrival (the time required for full awakening). Unlike the Rhodes index, the PONV scale and incidence were relatively easy to assess. Therefore, in this study, the PONV scale and incidence were assessed instead of the Rhodes index upon PACU arrival and 30 min after PACU arrival, and the results were similar in both groups. 8
PONV with nefopam for PCA Oh et al.
In conclusion, a PCA regimen using nefopam for analgesia yielded a similar degree of pain control with a superior outcome in terms of PONV 24 h after PACU discharge and no adverse events compared with a regimen using an equipotent dose of fentanyl.
Transparency Declaration of funding There was no commercial funding for this study. Chung-Sik Oha Eugene Junga Sun Joo Leeb Seong-Hyop Kima,c Declaration of financial/other relationships C.-S.O., E.J., S.J.L., and S.-H.K. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article. CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose. Acknowledgments This study was supported by Konkuk University.
References 1. Walder B, Schafer M, Henzi I, Tramer MR. Efficacy and safety of patientcontrolled opioid analgesia for acute postoperative pain. A quantitative systematic review. Acta Anaesthesiol Scand 2001;45:795-804 2. Choi DH, Ko JS, Ahn HJ, Kim JA. A Korean predictive model for postoperative nausea and vomiting. J Korean Med Sci 2005;20:811-15 3. Gan TJ. Risk factors for postoperative nausea and vomiting. Anesth Analg 2006;102:1884-98 4. Bures J, Rejchrt S, Kopacova M, Siroky M. Effects of nonsteroidal anti-inflammatory agents on the gastrointestinal tract. Cas Lek Cesk 2002;141:673-9 5. Esposito E, Romandini S, Merlo-Pich E, et al. Evidence of the involvement of dopamine in the analgesic effect of nefopam. Eur J Pharmacol 1986;128:157-64 6. Heel RC, Brogden RN, Pakes GE, et al. Nefopam: a review of its pharmacological properties and therapeutic efficacy. Drugs 1980;19:249-67 7. Gray AM, Nevinson MJ, Sewell RD. The involvement of opioidergic and noradrenergic mechanisms in nefopam antinociception. Eur J Pharmacol 1999;365:149-57 8. Du Manoir B, Aubrun F, Langlois M, et al. Randomized prospective study of the analgesic effect of nefopam after orthopaedic surgery. Br J Anaesth 2003;91:836-41 9. Kapfer B, Alfonsi P, Guignard B, et al. Nefopam and ketamine comparably enhance postoperative analgesia. Anesth Analg 2005;100:169-74 10. Mimoz O, Incagnoli P, Josse C, et al. Analgesic efficacy and safety of nefopam vs. propacetamol following hepatic resection. Anaesthesia 2001;56:520-5 11. Minto CF, Schnider TW, Egan TD, et al. Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development. Anesthesiology 1997;86:10-23 12. Sunshine A, Laska E. Nefopam and morphine in man. Clin Pharmacol Ther 1975;18(5 Pt 1):530-4
www.cmrojournal.com ! 2015 Informa UK Ltd
Current Medical Research & Opinion
17. Fuller RW, Snoddy HD. Evaluation of nefopam as a monoamine uptake inhibitor in vivo in mice. Neuropharmacology 1993;32:995-9 18. Evans MS, Lysakowski C, Tramer MR. Nefopam for the prevention of postoperative pain: quantitative systematic review. Br J Anaesth 2008;101:610-17 19. Merle JC, Vandroux D, Odin I, et al. Analgesic effect of continuous intravenous nefopam after urological surgery. Ann Fr Anesth Reanim 2005;24:13-18 20. Beloeil H, Delage N, Negre I, et al. The median effective dose of nefopam and morphine administered intravenously for postoperative pain after minor surgery: a prospective randomized double-blinded isobolographic study of their analgesic action. Anesth Analg 2004;98:395-400 21. Reynolds JEF. Martindale: The Extra Pharmacopoeia, 29th edn. London, UK: The Pharmaceutical Press, 1989:30
Downloaded by [Stockholm University Library] at 23:13 10 August 2015
13. Woodhouse A, Hobbes AF, Mather LE, Gibson M. A comparison of morphine, pethidine and fentanyl in the postsurgical patient-controlled analgesia environment. Pain 1996;64:115-21 14. Gomez-Hernandez J, Orozco-Alatorre AL, Dominguez-Contreras M, et al. Preoperative dexamethasone reduces postoperative pain, nausea and vomiting following mastectomy for breast cancer. BMC Cancer 2010;10:692 15. Rhodes VA, McDaniel RW. The Index of Nausea, Vomiting, and Retching: a new format of the Index of Nausea and Vomiting. Oncol Nurs Forum 1999;26:889-94 16. Rosland JH, Hole K. The effect of nefopam and its enantiomers on the uptake of 5-hydroxytryptamine, noradrenaline and dopamine in crude rat brain synaptosomal preparations. J Pharm Pharmacol 1990;42:437-8
2015
! 2015 Informa UK Ltd www.cmrojournal.com
PONV with nefopam for PCA Oh et al.
9
