ISSN : Vol 8 / Issue 2 / May-August Official publication of Pan Arab Federation of Societies of Anesthesiologists

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1 ISSN : Vol 8 / Issue 2 / May-August Official publication of Pan Arab Federation of Societies of Anesthesiologists

2 A E R Editor in Chief : Mohamad Said Maani Takrouri (KSA) Open Access HTML Format For entire Editorial Board visit : Anesthesia: Essays and Researches Original Article Diclofenac is more effective for post operative analgesia in patients undergoing lower abdominal gynecological surgeries: A comparative study Anirban Pal, Jhuma Biswas 1, Purnava Mukhopadhyay, Poushali Sanyal 2, Shyamal Dasgupta 3, Shyamashis Das 4 Departments of Anaesthesiology, Calcutta National Medical College and Hospital, Kolkatta, 1 Obstetrics and Gynecology, Bankura Sammilani Medical College and Hospital, Bankura, 2 Obstetrics and Gynecology, Institute of Postgraduate Medical Education and Research, Kolkatta, 3 Obstetrics and Gynecology, 4 Rheumatology, North Bengal Medical College and Hospital, Darjeeling, West Bengal, India Corresponding author: Dr. Jhuma Biswas, 15P, Roypur Mondal Para Road, Ganguli Bagan, Kolkata , West Bengal, India. E mail: drjhumabiswas@yahoo.in Abstract Aim: The present study aimed to compare the efficacy of injectable diclofenac intramuscularly (IM), injection paracetamol intravenously (IV), or a combination of both to provide post operative analgesia in patients undergoing lower abdominal gynecological surgeries. Materials and Methods: A total of 90 female patients (American Society of Anesthesiologists I and II), aged years, scheduled for elective total abdominal hysterectomy with or without bilateral salpingo oophorectomy were randomized to receive 75 mg diclofenac IM 8 hourly (Group D) or 1 g paracetamol IV 8 hourly (Group P) or a combination of both 8 hourly (Group PD) for 24 h post operative period from the start of surgery. The primary outcome measured was the requirement of rescue analgesic (tramadol), the secondary outcomes measured included visual analog score (VAS) for pain, time until first rescue analgesic administration, patient satisfaction score and any side effects. Results: The requirement of rescue analgesic was significantly lower in Groups D and PD compared to Group P. Mean (standard deviation) tramadol requirement during 24 h was (62.60) mg, (40.68) mg and (40.68) mg in the Groups P, D and PD respectively. Less number of patients in Groups D and PD (20% in both the groups) required rescue analgesic compared to Group P (50%). The VAS showed a significant decrease in Groups D and PD compared to Group P between 4 and 12 h post operatively. However, Group PD showed no significant difference when compared to Group D alone. Conclusion: Injection diclofenac IM is more effective than paracetamol IV in terms of rescue analgesic requirement, but the combination of diclofenac IM and paracetamol IV provides no added advantage over diclofenac IM alone. Key words: Lower abdominal gynecological surgery, post operative analgesia, rescue analgesic Access this article online Website DOI Quick Response Code / INTRODUCTION Management of post operative pain is an important concern after surgery. The lower abdominal gynecological surgery is expected to produce moderate to severe post operative pain. [1] The different classes of analgesics used, exert their effect through different mechanisms. Non opioid analgesics are favored world wide as they 192

3 are devoid of opioid induced side effects and so lesser post operative monitoring is required. A combination of analgesics from different classes may provide additive analgesic effects than a single drug. Non steroidal anti inflammatory drugs (NSAIDS) like diclofenac exert their action via inhibition of prostaglandin (PG) synthesis by inhibiting cyclooxygenase 1 (COX 1) and COX 2 enzymes with relative equipotency [2] while the in vivo effects of paracetamol are similar to those of the selective COX 2 inhibitors. [3] Intramuscular (IM) injection of diclofenac has established its role as an effective post operative analgesic even for major surgeries. [4,5] Intravenous (IV) paracetamol (acetaminophen) is a newer agent gaining worldwide popularity in acute post operative pain relief. [6] There has been a recent trend for combining different NSAIDs with paracetamol for the management of acute post operative pain [7,8] but the therapeutic superiority of any combination remains controversial. [9,10] Since the combination of diclofenac and paracetamol has not been investigated so far, we conducted this trial to compare the analgesic effects of diclofenac, paracetamol and their combination in patients undergoing lower abdominal gynecological surgeries. Our study is intended to help concerned medical personnel or institutions to formulate post operative pain management strategies regarding the use of non opioid analgesics. MATERIALS AND METHODS This prospective, randomized, double blind study was conducted at an Institute of Post Graduate Medical Education and Research (IPGMER), a Teaching Hospital in West Bengal, India and was approved by the Institutional Ethical Committee. After obtaining informed consent from patients, 90 women, in the physiological group American Society of Anaesthesiologists I and II physical status, between 20 and 50 years of age, weighing kg, with height ranging from 5 to 6 feet, with no major systemic disease, undergoing total abdominal hysterectomy with or without bilateral salpingo oophorectomy of duration more than 1 h, but less than 2 h under general anesthesia were randomly allocated into three groups. Patients with any history of allergy to any of the study drugs or any relative contra indications to study drug, were excluded from the study. If the duration of anesthesia exceeded 2 h, the cases were excluded from the study. The study was conducted from June to May Group D received injection diclofenac 75 mg/3 ml IM in the gluteal region, Group P patients received injection paracetamol (1 g/100 ml) IV given over 15 min, and Group PD received both the drugs after starting of surgery and got repeat doses at 8 and 16 h after starting of surgery. The researcher using the different drugs did not make any further participation in the study. The patients are observed for 24 h after starting of surgery. The observer and the patients were blinded to the type of drug used. The pain intensity was judged using a 10 point visual analog score (VAS) scale at time periods 2, 4, 6, 12, 18 and 24 h after the starting of surgery. The pulse, blood pressure, oxygen saturation, urine output, and adverse effect were noted. If a patient reported a VAS pain score of greater than 3, rescue analgesic in the form of IV tramadol 100 mg injection was given. If the patient required tramadol before 2 h from the beginning of surgery, she was excluded from our study. The need of rescue analgesic was recorded in the three groups at time periods 2, 4, 6, 12, 18 and 24 h after starting surgery. A standard anesthetic technique according to the institutional protocol was followed. The patients were premedicated with injection ranitidine 50 mg IV, injection fentanyl 2 mcg/kg IV, injection glycopyrolate 0.2 mg IV, and induced with injection propofol 2 mg/kg and injection rocuronium 0.9 mg/kg. After direct laryngoscopy and endotracheal intubation, anesthesia was maintained with isoflurane % along with nitrous oxide and oxygen in a ratio of 5:3. Injection rocuronium 0.2 mg/kg was repeated as required by using the neuromuscular monitor. Injection fentanyl was chosen deliberately as its duration of action is min and except fentanyl, no long acting analgesic, either opioid or non opioid was used. Reversal of muscle relaxation was achieved by injection neostigmine 0.05 mg/kg and injection glycopyrrolate 0.2 mg/1 mg of neostigmine. The patients were given an injection ondansetron 4 mg, just before completion of surgery and it was repeated 8 hourly over the post operative period. The patients were observed in post anesthesia recovery immediately after reversal and later shifted to ward as per institutional protocol. The primary outcome of our study was the requirement of rescue analgesic in the form of injection tramadol over 24 h. The secondary outcomes measured were VAS till rescue analgesic was administered, time until first rescue analgesic request, patient satisfaction score (PSC) till rescue analgesic was given and adverse events. VAS was measured on a scale from 0 to 10 and rescue analgesic was administered at any score greater than 3. PSC was assessed using a four point rating scale (poor = 0, fair = 1, good = 2 and excellent = 3). [11] Statistical analysis We calculated our sample size on the assumption of a standard deviation (SD) of 0.6 of the expected difference from previous studies, with a power of >80% to detect this difference, using the Tukey Kramer s all pair comparison with type I error (α) of <5%. The calculated sample size came out as 34 in each group. A total of 30 patients in each of the three groups were able to complete the study. Data of rescue analgesic (tramadol) requirement and pain measured by VAS was treated as continuous. Normality was 193

4 confirmed using Kolmogorov Smirnov test. The analysis of continuous data was performed using Tukey Kramer s all pair test. Qualitative data was tested using the Chi square ( 2 ) test followed by Fisher s exact post hoc test in case of significance. P < 0.05 was considered to be statistically significant. Two factorial analysis of variance (ANOVA) (multivariate ANOVA [MANOVA]) was done to evaluate the effect of addition of the two non opioids. The statistical software used was PASW SPSS Statistics for Windows 7 version (SPSS Inc., Chicago, IL ) and GraphPad Prism Instat version 5.0 (GraphPad Software Inc., CA ). RESULTS A total of 102 patients were enrolled for the study of which 90 data sets were included in the final analysis. 12 patients were excluded due to violation of the study protocol. The patient characteristics including age, height, weight and duration of surgery of 30 patients in each Groups P (paracetamol), D (diclofenac) and PD (paracetamol + diclofenac) were similar [Table 1]. The study drugs were given at the start of surgery and at 8 and 16 h after starting of surgery. The PSC and the VAS were recorded post operatively at 2, 4, 6, 12, 18 and 24 h in each of the 3 groups [Table 2] and compared using two factorial ANOVA (MANOVA). While PSC were analyzed for all the 30 patients in each group, VAS were only analyzed for those patients who had not received rescue analgesic at any time during observation as use of rescue analgesic may confound VAS results [Table 2]. Mean (SD) tramadol requirement during 24 h was (62.60) mg in the Group P. In Group D and PD tramadol requirement was significantly reduced to (40.68) mg [Table 1], but Group PD did not have decreased tramadol requirement when compared to the Group D only. Proportion of patients requesting for the rescue analgesic had been significantly more in the Group P when compared to the Group D or PD (P = in both cases). The PSC till administration of rescue analgesic are represented in Table 2 and show no significant difference between the three groups. The VAS showed a significant decrease in Groups D and PD compared to Group P between 4 and 12 h post operatively. However, Group PD showed no significant difference when compared to Group D alone [Table 2]. MANOVA based on total tramadol requirement, percentage of patients requiring rescue analgesic (tramadol) and 24 h VAS indicated that the Group D and Group PD had more analgesic effect when compared to Group P (P = 0.014) [Figure 1]. Side effects such as nausea, vomiting, and allergic bronchospasm occurred in a very small fraction (3.33%) Table 1: Patient characteristics (age, height and weight), duration of surgery, total tramadol requirement and percentage of patients requiring tramadol in each group (n=30), results are represented in mean±sd and percentage format Group P (n=30) Group D (n=30) Group PD (n=30) Age (year) 40.27± ± ±4.715 Height (feet) 5.23± ± ±0.320 Weight (kg) 55.20± ± ±5.610 Duration of surgery (min) ± ± ±7.075 Total tramadol requirement (mg) No. of patients required tramadol (n (%)) 56.67± ±40.684* 20.00±40.684** 15 (50) 6 (20)*** 6 (20)**** *P=0.014 (Group D vs. P), **P=0.014 (Group PD vs. P), ***P=0.016 (Group D vs. P), ****P=0.016 (Group PD vs. P). P = Paracetamol, D = Diclofenac, PD = Paracetamol+ diclofenac, SD = Standard deviation Table 2: PSC and VAS at 2, 4, 6, 12, 18 and 24 h post operatively in mean (±SD) format Group P Group D Group PD PSC_2 h 1.80±0.764 (n=26) 2.27±0.604 (n=26)* 2.11±0.577 (n=27) PSC_4 h 2.00±0.791 (n=18) 2.04±0.624 (n=24) 2.13±0.680 (n=24) PSC_6 h 1.71±0.686 (n=18) 1.71±0.550 (n=24) 1.83±0.565 (n=24) PSC_12 h 1.56±0.629 (n=17) 1.58±0.504 (n=24) 1.75±0.608 (n=24) PSC_18 h 1.53±0.640 (n=16) 1.46±0.509 (n=24) 1.58±0.504 (n=24) PSC_24 h 1.53±0.640 (n=15) 1.46±0.509 (n=24) 1.58±0.504 (n=24) VAS_2 h 1.08±1.129 (n=26) 0.88±0.909 (n=26) 1.15±0.989 (n=27) VAS_4 h 0.94±0.725 (n=18) 0.38±0.576 (n=24)** 0.54±0.588 (n=24)*** VAS_6 h 1.33±0.767 (n=18) 0.50±0.590 (n=24)**** 0.63±0.576 (n=24) $ VAS_12 h 0.76±0.831 (n=17) 0.42±0.504 (n=24) $$ 0.38±0.495 (n=24) # VAS_18 h 0.63±0.885 (n=16) 0.50±0.511 (n=24) 0.42±0.504 (n=24) VAS_24 h 0.93±0.704 (n=15) 0.54±0.658 (n=24) ## 0.38±0.576 (n=24) Remarks: Number of patients compared for PSC and VAS progressively decreased in paracetamol group from 26 to 15 as 4 patients required tramadol within 2 h, 8 patients required tramadol within 4 h, 1 patient required tramadol within 12, 18 and 24 h respectively. Whereas only 6 patients required tramadol in the other two groups within 4 h and were left out of comparison. P = Paracetamol, D = Diclofenac, PD = Paracetamol+diclofenac, PSC = Patient satisfaction score, VAS = Visual analogue score, SD = Standard deviation. *P=0.018 (Group D vs. P), **P=0.003 (Group D vs. P), ***P=0.045 (Group PD vs. P), ****P=0.003 (Group D vs. P), $ P=0.001 (Group PD vs. P), $$ P=0.049 (Group D vs. P), # P=0.048 (Group PD vs. P). ## P=0.048 (Group D vs. P), P=0.01 (Group D vs. P) of patients who were administered these drugs. These side effects, their frequency in each group and the P values obtained by comparing the frequency of adverse effects between the Group P versus Group D, Group D versus Group PD and Group P versus Group PD are depicted in Table 3. The Mc Nemar s 2 P values came out to be and which were not significant. Hence, in the three groups, there was no significant difference in minor side effects. No major adverse reactions to the drugs were noted in our study. 194

5 Table 3: Adverse effects in different groups Adverse effects Group D (%) Group P (%) Group PD (%) P value (Group P vs. D) P value (Group D vs. PD) P value (Group P vs. PD) Nausea 1 (3.33) 1 (3.33) 1 (3.33) Vomiting 1 (3.33) 0 (0) 1 (3.33) Bronchospasm 0 (0) 1 (3.33) 1 (3.33) P = Paracetamol, D = Diclofenac, PD = Paracetamol+diclofenac Figure 1: Requirement of rescue medicine (tramadol in mg) in Groups P, D and PD. The bars indicate 95% confidence interval of mean and the red squares in the center indicate mean (*indicates P < 0.05) DISCUSSION The use of non opioid analgesics for post operative analgesia is a standard practice worldwide as it reduces the opioid induced side effects. [12,13] The combination of two non opioid analgesics may produce an increased benefit if an additive effect is achieved. [14] We conducted this study to compare the effectiveness of these preparations as post operative analgesics. To the best of our knowledge, this is the first study which has compared the use of parenteral paracetamol and diclofenac and their combination together. The mechanism of action of diclofenac goes beyond COX inhibition and includes inhibition of thromboxane prostanoid receptor, affecting arachidonic acid release and uptake, inhibition of lipoxygenase enzymes and activation of the nitric oxide cyclic guanosine monophosphate anti nociceptive pathway. [2] Whereas, action of paracetamol is due to inhibition of COX 2 dependent pathways that are proceeding at low rates. The analgesic effect of paracetamol is central and is due to activation of descending serotonergic pathways, but its primary action may be inhibition of PG synthesis. [3] In our study, in the diclofenac group and the combination of paracetamol and diclofenac group, the requirement of rescue analgesic was significantly lower compared to paracetamol alone group. The combined group was not superior to diclofenac alone, indicating that the combination does not result in an additional benefit in aspect of post operative analgesia. Regarding the secondary outcomes, the VAS scores, time since first rescue analgesic requirement and PSC were comparable between the groups. Hynes et al, in their study of 120 patients undergoing total hip arthroplasty, compared 2 doses of 1g intravenous proparacetamol and 75 mg intramascular diclofenac and found no significant difference over the 10 hour study period. [15] Tuzuner et al, studied the effect of 1 g intravenous paracetamol, 75 mg intramascular diclofenac and 8 mg intravenous lornoxicam in 60 patients undergoing surgical removal of third molar and found the pain scores to be comparable in all the groups. [16] 30 patients undergoing bimaxillary osteotomy were given 1 g paracetamol intravenously and 75 mg diclofenac intramuscularly, by Oncul et al, and the intensity of post operative pain was comparable in both the groups. [17] A study by Munishanker et al, where 78 patients undergoing elective caesarean section under spinal anaesthesia were given oral paracetamol, diclofenac or a combination of both and morphine as rescue analgesic, found the combination group used 38% less morphine than the paracetamol group. [18] Hyllested et al, in their review article commented that further studies are required to come to a conclusion that whether addition of paracetamol to NSAID is helpful with no potential of increased side effects from their combined use. [19] In our study, in patients undergoing lower abdominal gynaecological surgery, we found that Intramuscular Diclofenac appears to be a superior post-operative analgesic compared to intravenous paracetamol, in terms of rescue analgesic requirements (20% vs 50% respectively). Diclofenac IM may be a better analgesic option if no relative or absolute contra indications to its use exist and paracetamol IV may be considered in patients where its relative safety profile is of importance. Combination is not favored as it may increase side effects and cost and with no additional benefit. However further research works with larger sample size are suggested to draw definitive conclusions and influence formulation of post operative pain management strategy. Limitations of this study are the following: Rescue analgesic was administered based on a particular VAS score, which may vary with subjective experience of the patient and interpretation of the observer 195

6 VAS scores are measured at fixed time points so length of analgesic effect of study drugs could not be investigated Primary outcome of our study was rescue analgesic requirement which may not truly reflect the efficacy of study drugs as analgesics The sample size of this study was small, hence it might be difficult to generalize the results. CONCLUSION Hence, from our study, it can be concluded that IM diclofenac appears to be a superior post operative analgesic compared to IV paracetamol, with no added advantage of their combination over IM diclofenac, in terms of rescue analgesic requirements, in patients undergoing lower abdominal gynecological surgery. ACKNOWLEDGMENTS The authors would like to thank Professor Tarun Kumar Ghosh, Ex Head, Department of Obstetrics and Gynecology, IPGMER, Kolkata, during whose tenure the study took place. The authors would also like to thank all the clients who participated in the study. REFERENCES 1. Loan WB, Dundee JW. The value of the study of postoperative pain in the assessment of analgesics. Br J Anaesth 1967;39: Gan TJ. Diclofenac: An update on its mechanism of action and safety profile. Curr Med Res Opin 2010;26: Graham GG, Scott KF. Mechanism of action of paracetamol. Am J Ther 2005;12: Al Waili NS. Efficacy and safety of repeated postoperative administration of intramuscular diclofenac sodium in the treatment of post cesarean section pain: A double blind study. Arch Med Res 2001;32: Ng P, Kam CW, Yau HH. A comparison of ketoprofen and diclofenac for acute musculoskeletal pain relief: A prospective randomised clinical trial. Hong Kong J Emerg Med 2001;8: McNicol ED, Tzortzopoulou A, Cepeda MS, Francia MB, Farhat T, Schumann R. Single dose intravenous paracetamol or propacetamol for prevention or treatment of postoperative pain: A systematic review and meta analysis. Br J Anaesth 2011;106: Merry A, Power I. Perioperative NSAIDs: Towards greater safety. Pain Rev 1995;2: Rømsing J, Møiniche S, Dahl JB. Rectal and parenteral paracetamol, and paracetamol in combination with NSAIDs, for postoperative analgesia. Br J Anaesth 2002;88: Ong CK, Seymour RA. An evidence based update of the use of analgesics in dentistry. Periodontol ;46: Ong CK, Lirk P, Tan CH, Seymour RA. An evidence based update on nonsteroidal anti inflammatory drugs. Clin Med Res 2007;5: Elseify ZA, El Khattab SO, Khattab AM, Atta EM, Ajjoub LF. Combined parecoxib and I.V. paracetamol provides additional analgesic effect with better postoperative satisfaction in patients undergoing anterior cruciate ligament reconstruction. Saudi J Anaesth 2011;5: Ng A, Parker J, Toogood L, Cotton BR, Smith G. Does the opioid sparing effect of rectal diclofenac following total abdominal hysterectomy benefit the patient? Br J Anaesth 2002;88: Iohom G, Walsh M, Higgins G, Shorten G. Effect of perioperative administration of dexketoprofen on opioid requirements and inflammatory response following elective hip arthroplasty. Br J Anaesth 2002;88: Bjune K, Stubhaug A, Dodgson MS, Breivik H. Additive analgesic effect of codeine and paracetamol can be detected in strong, but not moderate, pain after caesarean section. Baseline pain intensity is a determinant of assay sensitivity in a postoperative analgesic trial. Acta Anaesthesiol Scand 1996;40: Kim H, Xu M, Lin Y, Cousins MJ, Eckstein RP, Jordan V, et al. Renal dysfunction associated with the perioperative use of diclofenac. Anesth Analg 1999;89: Hynes D, McCarroll M, Hiesse Provost O. Analgesic efficacy of parenteral paracetamol (propacetamol) and diclofenac in post operative orthopaedic pain. Acta Anaesthesiol Scand 2006;50: Tuzuner Oncul AM, Yazicioglu D, Alanoglu Z, Demiralp S, Ozturk A, Ucok C. Postoperative analgesia in impacted third molar surgery: The role of preoperative diclofenac sodium, paracetamol and lornoxicam. Med Princ Pract 2011;20: Oncül AM, Cimen E, Küçükyavuz Z, Cambazoğlu M. Postoperative analgesia in orthognathic surgery patients: Diclofenac sodium or paracetamol? Br J Oral Maxillofac Surg 2011;49: Munishankar B, Fettes P, Moore C, McLeod GA. A double blind randomised controlled trial of paracetamol, diclofenac or the combination for pain relief after caesarean section. Int J Obstet Anesth 2008;17:9 14. How to cite this article: Pal A, Biswas J, Mukhopadhyay P, Sanyal P, Dasgupta S, Das S. Diclofenac is more effective for post-operative analgesia in patients undergoing lower abdominal gynecological surgeries: A comparative study. Anesth Essays Res 2014;8: Source of Support: Nil, Conflict of Interest: None declared. 196