Postoperative pain and side effects after thyroidectomy: randomized double blind study comparing nefopam and ketorolac

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1 Anesth Pain Med 2014; 9: Clinical Research Postoperative pain and side effects after thyroidectomy: randomized double blind study comparing nefopam and ketorolac Department of Anesthesia and Pain Medicine, Pusan National University Hospital, Busan, Korea Bora Yoo, Jae-Young Kwon, Boo-Young Hwang, Jung-Min Hong, Tae-Kyun Kim, and Hae-Kyu Kim Background: Nefopam is a centrally acting, non-opioid analgesic drug used to reduce opioid consumption and so reduce the prevalence of postoperative nausea and vomiting (PONV). This study compared and assessed the effects of nefopam and ketorolac on postoperative pain and PONV after thyroid surgery. Methods: Two hundred patients underwent total thyroidectomy with central compartment neck dissection in our hospital during a 5 month enrollment period. and was administered nefopam 20 mg and ketorolac 30 mg, respectively, during the last 30 minutes of surgery. Pain was measured using a 10-point numerical rating scale. Pain scores and PONV were assessed 30 min, 1, 6, and 24 h postoperatively. Results: Pain scores and episodes of vomiting and shivering did not differ significantly between the two groups. patients experienced fewer episodes of nausea at 30 min, 1 h and 6 h after the operation. Conclusions: Nefopam and ketorolac are similarly effective in reducing postoperative pain after thyroid surgery. Postoperative nausea was less in patients within 6 h postoperatively, especially 1 h. Nefopam is favored for pain management after thyroidectomy. (Anesth Pain Med 2014; 9: ) Key Words: Ketorolac, Nausea, Nefopam, Postoperative pain, Vomiting. INTRODUCTION Most patients who undergo total thyroidectomy may suffer from postoperative pain, nausea, and vomiting (PONV) [1,2]. Thyroid surgery induces brief postoperative pain caused by several mechanisms [1]. The management of postoperative pain is a critical component of patient care and is associated with Received: January 9, Revised: 1st, January 24, 2014; 2nd, February 19, Accepted: March 11, Corresponding author: Jae-Young Kwon, M.D., Ph.D., Department of Anesthesia and Pain Medicine, Pusan National University Hospital, 10, Ami-dong 1-ga, Seo-gu, Busan , Korea. Tel: , Fax: , jykwon@pusan.ac.kr patient satisfaction and postoperative outcomes in thyroid surgery [3,4]. Non-steroidal anti-inflammatory drugs (NSAIDs) and opioids are typically administrated to reduce postoperative pain. The use of NSAIDs does not increase cervical bleeding after thyroid and parathyroid surgery [1]. PONV are common problems following general anesthesia, occurring in 20 30% in all patients and in up to 80% of high-risk patients including those undergoing thyroid surgery [5]. The incidence of PONV is an important cause of delayed discharge from the recovery room and decreased patient satisfaction [6,7]. Nefopam is a centrally acting non-opioid analgesic benzoxazocine [8,9]. The action mechanism of nefopam is not well understood, although inhibition of serotonin, dopamine, and norepinephrine re-uptake is thought to be involved in its analgesic effects; other modes of action may involve histamine H 3 receptors and glutamate [10,11]. In clinical practice, the administration of nefopam has been reported to reduce the use of opioid analgesics, which reduces the prevalence of PONV [12]. A comparison between nefopam and ketorolac has not been reported. This study compared and assessed the effects of nefopam and ketorolac on the postoperative pain and side-effects, such as nausea, vomiting, shivering, and cervical bleeding, after thyroid surgery. MATERIALS AND METHODS Patients This study was approved by the Institutional Review Board of our hospital, and written informed consent for participation was obtained from all patients. Two hundred patients between 18 and 70 years of age with American Society of 110

2 Bora Yoo, et al:nefopam and ketorolac after thyroidectomy 111 Anesthesiologists physical status classification I II who were scheduled for elective total thyroidectomy were enrolled. The exclusion criteria were gastrointestinal bleeding disorders; allergy or sensitivity to ketorolac, aspirin, or other NSAIDs; severe cardiac disease; renal or hepatic insufficiency; coagulopathy; severe bronchial asthma; administration of monoamine oxidase inhibitor; glaucoma; seizure; and epilepsy. Patients who did not provide informed consent or who could not use the numerical rating scale (NRS) were excluded. Treatments Premedication, induction, and maintenance of general anesthesia were standardized. Patients were fasted from midnight prior to the surgery. During the preoperative anesthetic examination, the NRS was explained to the patients. The NRS ranged from 0 (no pain) to 10 (worst pain imaginable). All drugs were discontinued except for antihypertensive drugs. Patients were randomly assigned to two groups. received nefopam 20 mg mixed with 100 ml normal saline and group T received ketorolac 30 mg mixed with 100 ml normal saline. Both drugs were infused for the last 30 min of surgery. All patients were premedicated with a intramuscular injection of glycopyrrolate 0.2 mg. Anesthesia was induced with a combination of propofol 2 mg/kg, rocuronium 0.8 mg/kg, and remifentanil 0.2 mg/h. After tracheal intubation, anesthesia was maintained using desflurane, which was managed with Bispectral index (BIS, XP version 4.1; Aspect Medical Systems, Newton, MA, USA) targeting a value of 40 to 50. The BIS was measured every 5 min from beginning to infusion of nefopam 20 mg or ketorolac 30 mg. Desflurane concentration was unchanged after the start of nefopam or ketorolac infusion. After the end of surgery, all patients were injected intravenously with pyridostigmine 10 mg and glycopyrrolate 0.4 mg. The remifentanil infusion was stopped at the end of surgery. After desflurane and remifentanil were discontinued, the elapsed time to eye opening, recovery of tidal volume above 6 ml/kg, and extubation were measured. No preventive antiemetics were administered. All patients were extubated when BIS value was above 80 and tidal volume was recovered above 6 ml/kg in the operating room. Outcomes The primary outcome of this study was the effects of nefopam and ketorolac on postoperative pain measured using the NRS and patient recounted type, location, and intensity of the pain at 30 min, 1, 6, and 24 h after surgery. Pain rated as above 8 points on NRS prompted intravenous administration of ketorolac 30 mg as a rescue analgesic. Secondary outcomes were the incidence of side effects including shivering, nausea, vomiting, and postoperative bleeding. The incidence of nausea and the number of vomiting episodes were estimated at 1, 6, and 24 h after the operation. Severe nausea and episodes of vomiting prompted intravenous administration of ramosetron 0.3 mg as a rescue antiemetic. Patient satisfaction was gauged in an interview (1: very dissatisfied, 2: dissatisfied, 3: mildly satisfied, 4: moderately satisfied, 5: very satisfied) at 24 h postoperatively. Adverse events, such as sedation, shivering, and postoperative bleeding were recorded for the first 24 h postoperatively. Statistical analyses The demographic data of patients and anesthetic characteristics were compared using the Student s t-test and chi-square test. BIS was compared using two-way repeated measures ANOVA. Pain scores were compared using two-way repeated measures ANOVA at each time point. Side effects and the type and location of the pain were compared between two groups using chi-square test or Fisher s exact test. Fisher's exact test was used to compare the satisfaction scores of two groups. Table 1. Demographic Data Age (yr) Sex (F/M) Height (cm) Weight (kg) RESULTS There was no significant difference in patients characteristics between two groups (Table 1). No significant difference was found in BIS scores after the administration of nefopam and ketorolac between both groups. Emergence profiles between two groups showed no significant difference between 52.1 ± / ± ± ± / ± ± Data are expressed as mean ± SD or number (%). (n = 100) was infused 20 mg of nefopam, and was infused 30 mg of ketorolac during the 30 minutes before the end of surgery. There was no significant difference between two groups.

3 112 Anesth Pain Med Vol. 9, No. 2, 2014 Table 2. Emergence Profiles of Each Group TV recovery time (sec) Eye opening time (sec) Extubation time (sec) ± ± ± ± ± ± Data are expressed as mean ± SD. was infused 20 mg of nefopam, and was infused with 30 mg of ketorolac during the 30 minutes before the end of surgery. There was no significant difference between two groups. TV: Tidal Volume. Table 3. Type and Location of the Pain after Total Thyroidectomy with Central Compartment Neck Dissection in Each Group Type Dullness Sharp Tearing Tingling Location Incision lesion Shoulder pain Headache Rescue drug Ketorolac 68 (68) 11 (11) 23 (23) 96 (96) 4 (4) 15 (15) 24 (24) 69 (69) 15 (15) 6 (6) 21 (21) 98 (98) 7 (7) 12 (12) 25 (25) Data are expressed as number (%). was infused with 20 mg of nefopam, and was infused with 30 mg of ketorolac during 30 minutes before the end of surgery. There was no significant difference in the type and location of pain and rescue drug between two groups. Table 4. Incidence of Post-operative Side Effects Fig. 1. Numerical rating scale at 30 min, 1, 6, and 24 h after the end of the surgery. Data are expressed as mean ± SD. was infused with 20 mg of nefopam, and was infused with 30 mg of ketorolac during the 30 minutes before the end of surgery. There was no significant difference between two groups. Both groups showed decrease in pain with time. two groups (Table 2). There was no significant difference in NRS at 30 min, 1, 6, and 24 h after the operation between both groups, and NRS scores decreased with time (Fig. 1). There was no significant difference in the type and location of pain and numbers of rescue analgesics prescription between both groups (Table 3). No significant difference was found in the incidences of side effects including shivering, vomiting, and postoperative bleeding between both groups. One patient had postoperative bleeding in, and underwent emergency surgery for hemostasis. The incidence of nausea of group N within 1 h (10%) and 1 h to 6 h (3%) after operation was significantly lower than those in group T (32 and 12%, respectively; P < and P = 0.016, respectively) (Table 4). However, there was no significant difference in the incidence of nausea from 6 h after operation between two groups. The incidence of rescue Nausea <1 h 1 6 h <6 h Rescue antiemetics Ramosetron Vomiting Shivering Bleeding 10 (10) 2 (2) 5 (5) 32 (32) 12 (12) 7 (7) < Data are expressed as number (%). was infused with 20 mg of nefopam, and was infused with 30 mg of ketorolac during 30 minutes before the end of surgery. The incidence of nausea within 6 h after the end of surgery was less in nefopam group, compared to that of ketorolac group. The number of rescue antiemetics (ramosetron 0.3 mg) use of was significantly greater than that of. antiemetics (ramosetron 0.3 mg) use of group T (3%) was significantly greater than that (0%) of group N (P = 0.013, Table 4). patients reported greater satisfaction (P = 0.041, Table 5). DISCUSSION After thyroid surgery, most patients suffer from minor

4 Bora Yoo, et al:nefopam and ketorolac after thyroidectomy 113 Table 5. Patient Satisfaction Satisfaction level (4) 20 (20) 50 (50) 26 (26) 2 (2) 38 (38) 39 (39) 21 (21) Data are expressed as number (%). was infused with 20 mg of nefopam, and was infused with 30 mg of ketorolac during 30 minutes before the end of surgery. Satisfaction level was divided into five levels (1: very dissatisfied, 2: dissatisfied 3: mildly satisfied, 4: moderately satisfied, 5: very satisfied). The patients in showed higher satisfaction level than the patients in at 24 hours after operation (P = 0.041). postoperative discomforts from complex mechanisms. Cervicotomy itself, orotracheal intubation, and the cervical hyperextension position can induce postoperative discomfort, neck pain, and shoulder pain. Most patients who undergo thyroidectomy do not use patient-controlled analgesia, because the postoperative pain does not usually last for a long time. Basto et al. [1] showed that the pain scores fell markedly between 24 and 36 h after an operation. In this study, the pain intensity was also decreased at 24 h after operation. However, the mean NRS exceeded 5 at 30 min after operation, and about 25% of patients needed rescue analgesics. This result suggests that the increased dose of analgesics may be needed during the early postoperative period. Ketorolac was used as a rescue analgesic in both groups. The use of ketorolac as a rescue analgesic after nefopam or ketorolac treatment might have affected the results. Combination therapy of nefopam and ketorolac may be needed in the future. The incidence of PONV in group T patients was similar to that of a recently reported study [13] that investigated the incidence of PONV in endoscopic thyroidectomy. That study reported rates of nausea of 35.9 and 23.5% at 0 2 hour and 2 6 hour after surgery, respectively. The present and prior study differed concerning the endoscopic procedure and the use of meperidine as first choice of postoperative pain control, which seemed to be attributable to a marginally higher incidence of nausea in the previous study [13]. Ketorolac is a heterocyclic acetic acid derivative NSAID that is used as an analgesic. It acts by inhibiting the bodily synthesis of prostaglandins. The primary mechanism of action responsible for ketorolac's anti-inflammatory, antipyretic, and analgesic effects is the inhibition of prostaglandin synthesis by competitive blocking of the enzyme cyclooxygenase. NSAIDs are not usually recommended for coadministration with other NSAIDs, because of the potential side effects. NSAIDs carry the risk of systemic side effects such as bleeding, gastroduodenal bleeding, and kidney damage [14]. One report described inhibited spinal fusion [15]. NSAIDs also inhibit platelet aggregation and may be associated with an increased risk of bleeding [16]. In thyroid surgery, ketorolac might have a risk for postoperative bleeding, and postoperative bleeding after thyroidectomy can induce dyspnea and decreased saturation. Patients who undergo cervicofacial surgery are at high risk of nausea and vomiting due to edema and inflammation on the neck tissue and parasympathetic impact through vagus, recurrent laryngeal, and glossopharyngeal nerves to the vomiting center [17,18]. In particular, women have a high incidence of nausea and vomiting [2]. Postoperative nausea and vomiting in patients with thyroid surgery are very important, because they lead to cough or movement inducing postoperative bleeding. Therefore, we seldom used an opioid after thyroidectomy, and had to find other medications to reduce postoperative pain and emesis [2]. The action mechanism of nefopam has not been discovered completely yet. Serotonin reuptake inhibition involves nefopam's analgesic action. Serotonin reuptake inhibition can induce nausea and vomiting by 5HT 3 receptor involvement. Lu et al. [19] used ondansetron as an antiemetic with nefopam; ondansetron did not inhibit nefopam's analgesic effect. The authors suggested that nefopam involves specific serotonin receptor subtypes. The action mechanism of nefopam on decreased nausea is unclear. Nefopam has previously been associated with a 15 30% incidence of minor side effects, especially nausea, dizziness, and sweating [9]. However, the incidences of the minor adverse events of nefopam and placebo groups with morphine PCA were similar [20]. In another study, the incidence of postoperative nausea was lower in the nefopam 20 mg group than the placebo and nefopam 40 mg group [12]. We did not evaluate the dose-dependent effect of nefopam on the incidence of nausea. A small dose change of nefopam may lead to an altered incidence or severity of nausea. In this study, nefopam 20 mg infusion significantly reduced the incidence of nausea compared to ketorolac within 6 h after thyroidectomy. We checked the incidence of nausea divided into within 1 h, within 6 h, and after 6 h, because the nausea within 6 h might be influenced by the

5 114 Anesth Pain Med Vol. 9, No. 2, 2014 anesthesia or surgical factors, such as inhalation agents and the operation itself. In this study, most of nausea symptoms subsided quickly after intravenous administration of ramosetron 0.3 mg, although the severity of nausea was not evaluated. As the knowledge of the effect of nefopam on PONV is still limited, it should be further investigated in terms of benefit and side effects according to the dose, interaction between other analgesics or opioids, and the influence of anesthetics (inhalation vs intravenous). In conclusion, nefopam showed similar analgesic effects compared to ketorolac. Since nefopam more effectively reduced the incidence of postoperative nausea within 6 h after the operation, it is suggested as another effective choice to reduce pain and nausea after total thyroidectomy. REFERENCES 1. Basto ER, Waintrop C, Mourey FD, Landru JP, Eurin BG, Jacob LP. Intravenous ketoprofen in thyroid and parathyroid surgery. Anesth Analg 2001; 92: Sonner JM, Hynson JM, Clark O, Katz JA. Nausea and vomiting following thyroid and parathyroid surgery. J Clin Anesth 1997; 9: Chung JW, Lui JC. Postoperative pain management: study of patients' level of pain and satisfaction with health care providers' responsiveness to their reports of pain. Nurs Health Sci 2003; 5: Song YK, Lee C. Effects of ramosetron and dexamethasone on postoperative nausea, vomiting, pain, and shivering in female patients undergoing thyroid surgery. J Anesth 2013; 27: Kim SI, Kim SC, Baek YH, Ok SY, Kim SH. Comparison of ramosetron with ondansetron for prevention of postoperative nausea and vomiting in patients undergoing gynaecological surgery. Br J Anaesth 2009; 103: Fujii Y. The benefits and risks of different therapies in preventing postoperative nausea and vomiting in patients undergoing thyroid surgery. Curr Drug Saf 2008; 3: Kim YY, Song DU, Lee KH, Lee IJ, Song JW, Lim JH. Comparison of palonosetron with ondansetron in preventing postoperative nausea and vomiting after thyroidectomy during a 48-hour period. Anesth Pain Med 2012; 7: Kapfer B, Alfonsi P, Guignard B, Sessler DI, Chauvin M. Nefopam and ketamine comparably enhance postoperative analgesia. Anesth Analg 2005; 100: Heel RC, Brogden RN, Pakes GE, Speight TM, Avery GS. Nefopam: a review of its pharmacological properties and therapeutic efficacy. Drugs 1980; 19: Fuller RW, Snoddy HD. Evaluation of nefopam as a monoamine uptake inhibitor in vivo in mice. Neuropharmacology 1993; 32: 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: Lee JH, Kim JH, Cheong YK. The analgesic effect of nefopam with fentanyl at the end of laparoscopic cholecystectomy. Korean J Pain 2013; 26: Kim GH, Ahn HJ, Kim HS, Bang SR, Cho HS, Yang M, et al. Postoperative nausea and vomiting after endoscopic thyroidectomy: Total intravenous vs. balanced anesthesia. Korean J Anesthesiol 2011; 60: Camu F, Lauwers MH, Vanlersberghe C. Side effects of NSAIDs and dosing recommendations for ketorolac. Acta Anaesthesiol Belg 1996; 47: Lumawig JM, Yamazaki A, Watanabe K. Dose-dependent inhibition of diclofenac sodium on posterior lumbar interbody fusion rates. Spine J 2009; 9: Stichtenoth DO, Tsikas D, Gutzki FM, Frolich JC. Effects of ketoprofen and ibuprofen on platelet aggregation and prostanoid formation in man. Eur J Clin Pharmacol 1996; 51: Fukuda H, Koga T. Stimulation of glossopharyngeal and laryngeal nerve afferents induces expulsion only when it is applied during retching in paralyzed decerebrate dogs. Neurosci Lett 1995; 193: Grelot L, Barillot JC, Bianchi AL. Activity of respiratory-related oropharyngeal and laryngeal motoneurones during fictive vomiting in the decerebrate cat. Brain Res 1990; 513: Lu KZ, Shen H, Chen Y, Li MG, Tian GP, Chen J. Ondansetron does not attenuate the analgesic efficacy of nefopam. Int J Med Sci 2013; 10: Du Manoir B, Aubrun F, Langlois M, Le Guern ME, Alquier C, Chauvin M, et al. Randomized prospective study of the analgesic effect of nefopam after orthopaedic surgery. Br J Anaesth 2003; 91: