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ORIGINAL ARTICLE
Year : 2020  |  Volume : 14  |  Issue : 3  |  Page : 428-433  

Comparative evaluation of efficacy of preventive analgesia with diclofenac and buprenorphine patch versus single diclofenac patch for postoperative pain following general anesthesia for laparoscopic cholecystectomy


Department of Anaesthesia, ESIC Medical College and Hospital, Hyderabad, Telangana, India

Date of Submission09-Dec-2020
Date of Decision11-Jan-2021
Date of Acceptance20-Jan-2021
Date of Web Publication22-Mar-2021

Correspondence Address:
Dr. Ananya Nanda
C/O Department of Anesthesia, ESIC Medical College and Hospital, Sanathnagar, Hyderabad - 500 038, Telangana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aer.AER_109_20

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   Abstract 

Background: Acute postoperative pain is managed with parenteral and oral medications requiring skilled personnel for administration and vigilance. Previous studies have been done either with transdermal buprenorphine or diclofenac patch separately in mitigating postoperative pain. Aims: The primary aim was to compare pain scores and rescue analgesia requirement. The secondary aims were comparison of side effects, time to mobilization and oral intake start, sedation scores, and satisfaction scores of surgeons and patients receiving transdermal patches of buprenorphine and diclofenac versus placebo and diclofenac patches following laparoscopic cholecystectomy. Settings and Design: This is a randomized double-blinded (1:1), case–control study. Materials and Methods: One hundred patients undergoing laparoscopic cholecystectomies were enrolled for the study. Patients were allocated into two groups by computer-generated randomization: those receiving dual patch of buprenorphine and diclofenac (DP) and those receiving patches of diclofenac and placebo (SP). Outcomes were measured after extubation and at 4, 8, 12, 24, 36, and 48 h after surgery. Statistics: Analysis was done using the Statistical Package for the Social Sciences version 22.0, R environment 3.2.2 for data analysis, and Microsoft Excel to generate graphs and tables. Results: The pain scores and rescue analgesia requirements were significantly higher in group SP compared to group DP. Patient satisfaction scores were better with group DP. No significant difference was found in both the groups concerning sedation scores, side effects, and time to patient mobilization and start of oral intake. Conclusions: Concomitant use of transdermal patches of buprenorphine and diclofenac for postoperative pain in laparoscopic cholecystectomy provides adequate analgesia and patient satisfaction without compromising postoperative recovery.

Keywords: Acute postoperative pain, buprenorphine, diclofenac, laparoscopic, transdermal


How to cite this article:
Nanda A, Sangineni KS, Pakhare V, Ramchandran G. Comparative evaluation of efficacy of preventive analgesia with diclofenac and buprenorphine patch versus single diclofenac patch for postoperative pain following general anesthesia for laparoscopic cholecystectomy. Anesth Essays Res 2020;14:428-33

How to cite this URL:
Nanda A, Sangineni KS, Pakhare V, Ramchandran G. Comparative evaluation of efficacy of preventive analgesia with diclofenac and buprenorphine patch versus single diclofenac patch for postoperative pain following general anesthesia for laparoscopic cholecystectomy. Anesth Essays Res [serial online] 2020 [cited 2021 Apr 20];14:428-33. Available from: https://www.aeronline.org/text.asp?2020/14/3/428/311708


   Introduction Top


Alleviation of pain after surgery is a humanitarian right and basic need. Inadequate control causes delayed recovery, increased hospital stay, and mortality.[1],[2] Parenteral administration of opioids and nonsteroidal anti-inflammatory drugs (NSAIDS), the mainstay of the anesthesiologist's pain armamentarium, requires skilled personnel and vigilance.

Transdermal patches for NSAIDS and opioids offer the advantage of sustained drug delivery, bioavailability, and avoidance of first-pass metabolism which reduces systemic effects. They have a one-time application, reduce workload on health-care workers, and prevent waxing-waning of analgesia due to diminishing blood levels.[3] Studies have been done to assess the efficacy of transdermal buprenorphine or diclofenac separately for spinal and dental surgeries with consistent results.

Incorporating the idea of multimodal analgesia into transdermal patch application, we conducted this study to evaluate the effectiveness of dual patches of diclofenac and buprenorphine for postoperative pain control in comparison to a single diclofenac patch for patients undergoing laparoscopic cholecystectomies. The primary aim was to compare pain scores and rescue analgesia requirement. The secondary aims were comparison of side effects, time to mobilization and start of oral intake, sedation scores, and surgeon and patient satisfaction scores.


   Materials and Methods Top


After approval from the institutional ethical committee with number ESICMC/SNR/IEC-F067/9/2018, this double-blinded, prospective randomized, interventional, case–control study was registered in the Clinical Trials Registry India and conducted from March 1 to December 31, 2019, according to principles of the Declaration of Helsinki. Written informed consent was obtained from all participants during preanesthetic check.

One hundred and eighteen patients (59 in each group) were enrolled for the study [Figure 1]. Inclusion criteria were American Society of Anesthesiologists I, II patients aged 18–58 years of either sex and patients posted for laparoscopic cholecystectomy under general anesthesia. Out of these, 100 patients (50 from each group) met the inclusion criteria successfully.
Figure 1: CONSORT diagram

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Figure 2: Buprenorphine and diclofenac patches

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Exclusions criteria were as follows – (1) known allergy to study drugs; (2) patients with cardiac, renal, liver, or coagulation disorders; (3) opioid dependents; (4) pregnant and lactating mothers; and (5) if surgery was converted to open laparotomy.

Buprenorphine patches are available in three different strengths such as 5, 10, and 20 μg.h-1, and diclofenac comes in 100 and 200 mg patches. Based on previous studies, we selected 10 μg.h-1 buprenorphine and diclofenac 100 mg patches for evaluation of pain relief in our study [Figure 2]. Diclofenac has onset within 3–5 h[4] whereas Buprenorphine patch of 10 mg has an onset of action between 12 and 24 h,[5] post application prompting us to apply the buprenorphine patch the evening before surgery and the diclofenac patch on the morning of surgery.

The study was double blinded with the surgeon, patient, and personnel involved in administering the patches and data collection being unaware of the patient's group. Patients were allocated into two groups by computer-generated randomization.

  • Group DP – Buprenorphine 10 mg patch was placed on the evening before surgery (18–20 h before incision) on upper one-third of the lateral arm (any side). The Next day's operative list was finalized on the previous day afternoon, and the patch was placed in the evening, giving reasonable time till 11.00 a.m. when the patient would go on table. The patch was conserved for 7 days with clear instructions to the patient regarding care of the patch. For the same patient, preoperatively, a diclofenac patch 100 mg was applied on the left or right flank which was replaced after 24 h
  • Group SP – A placebo patch was placed in the evening before surgery on the upper third of the lateral arm (any side) and kept for 7 days. Preoperatively, a diclofenac patch of 100 mg was applied on the left or right lateral flank which was replaced after 24 h.


All patients underwent preanesthetic checkup before surgery. Linear Numeric Rating Scale (NRS) to determine the level of pain was explained day before surgery with a 10-cm line marked on paper, with 0 meaning no pain and 10 denoting maximum pain. Pain scores were interpreted as: 1–3 cm – mild pain; 4–6 cm – moderate pain; and 7–10 cm – severe pain.

In the operation theater, the baseline parameters electrocardiograph (ECG), noninvasive blood pressure (NIBP), oxygen saturation (SpO2), and sedation scores were recorded. Intraoperatively, EtCO2 was also monitored. After preoxygenation, anesthesia was induced with intravenous (i.v.) propofol (2–3 mg.kg−1), fentanyl 100 μg, lignocaine (1.5 mg.kg−1), and vecuronium (0.1 mg.kg−1) to facilitate intubation. Anesthesia was maintained with air and oxygen along with sevoflurane (1 MAC) and muscle relaxation with vecuronium 1 mg as needed. Paracetamol 1 g intravenously was given intraoperatively. At the end of surgery (mean duration – 168 min ± 36 min), residual neuromuscular blockade was reversed with i.v. neostigmine (0.05 mg.kg−1) and glycopyrrolate (0.01 mg.kg−1). After adequate recovery and extubation, patients were shifted to the postanesthetic care unit for observation in propped up position with oxygen supplementation for 8 h with monitoring of ECG, NIBP, SpO2, respiratory rate, pain score at rest, and sedation scores. Postoperatively, all patients received i.v. paracetamol 1 g thrice a day. Patients having moderate-to-severe pain (>4/10) received rescue analgesia with i.v. tramadol 100 mg.

Pain measurement was done by a nurse blinded to the study and noted immediately after extubation and 4, 8, 12, 24, 36, and 48 h after surgery. Ramsay's sedation score was used to assess sedation.[6]

Adverse effects such as rash, itching, application site reactions, pruritus, gastritis, nausea, vomiting, sedation, and respiratory depression (<8/min) which could be either be due to diclofenac or buprenorphine were noted. Rescue analgesia with tramadol 100 mg i.v. was given whenever the pain score was >4, and the total doses of rescue analgesics at 48 h were recorded. The time to first ingestion of clear fluid without vomiting and the mobilization of the patient was recorded. The ability to comfortably stand and take few steps under close observation was considered as adequate mobilization. In addition, all patients and the surgeons were asked to grade their satisfaction of the pain service as “good,” “fair,” and “unsatisfactory” before discharge on the 3rd day.

Statistical analysis

Results on continuous measurements were presented on mean ± standard deviation (SD) and categorical measurements were in number (%). Mann–Whitney U-test (two-tailed, independent) was used to find the significance of study parameters on continuous scale. Chi-square was in nonparametric setting for qualitative data analysis. For sample size derivation, the effect size (d) was calculated using the SD of Visual Analog Scale score taken from a previous study.[7] Using the formula for calculation of sample sizes for two independent samples of continuous outcome with power of 99%, and enrollment ratio of 1:1,



where n = sample per group, r = enrollment ratio, Z (1−β) = desired power (2.33), Z (1−α/2) = critical value for level of confidence, σ = SD based on previous study, and d = effect size, 48.5 patients were required for each group which was rounded to 50. Adding a dropout rate of 20%, a total of 118 patients (59 in each group) were enrolled.

The statistical software Statistical Package for the Social Sciences 22.0 (IBM) and R environment version 3.2.2 were used for the analysis of the data and Microsoft Excel to generate graphs and tables.


   Results Top


The patients were equally matched in age and gender. The mean age in group DP was 40 ± 7.5 years and in group SP was 41 ± 8.0 years. Pain scores were similar for the first 4 h after surgery which could be because of the residual effects of general anesthesia [Figure 3]. NRS was significantly higher in group SP at 8, 12, and 24 h postoperatively with P < 0.001 at 12 and 24 h. At 36 and 48 h, the pain scores of both the groups were similar which showed that patients of group DP were as comfortable as those in group SP.
Figure 3: Pain Score: An assessment at different study points in two groups of patients studied

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The rescue analgesia requirements over 48 h in group SP were higher [Figure 4]. The mean tramadol dose of group DP was 150.00 ± 54.39 mg and in group SP was 388.00 ± 93.98 mg which was statistically significant.
Figure 4: Total rescue analgesic in 48-h distribution in two groups of patients studied

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The sedation scores of both the groups were comparable with each other. The highest mean score recorded was 3.20 ± 0.57 in group DP and 2.96 ± 0.70 in group SP at 4 h. The score most commonly observed in group DP and group SP was 3 which translated to the patient being asleep but responding to oral commands which is desirable in a postoperative patient.

In group DP, 88% of the patients described their analgesia as satisfactory and 12% found it fair. In group SP, 58% of the patients described their analgesia as satisfactory, 22% termed it fair, but 20% of the patients found it unsatisfactory [Figure 5].
Figure 5: Patient satisfaction score distribution in two groups of patients studied

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Eighty-two percent of the surgeons of group DP and 84% of the surgeons of group SP were satisfied with the mode of analgesia their patients received which was comparable. Their main concern was regarding constipation in the patients receiving the patches, but only 1 patient in group DP had constipation.

In group DP, 8% of the patients complained of nausea compared to 12% of the patients in group SP [Table 1]. This can be due to increased dose of tramadol as rescue analgesia. The side effects were statistically insignificant.
Table 1: Side effects

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The average time to start of oral intake and time to ambulate the patient were 7.14 ± 0.62 h and 13.12 ± 1.29 h, respectively in group DP, whereas in group SP, they were 7.38 ± 0.7 h and 13.39 ± 1.32 h, respectively, which was statistically comparable [Table 2].
Table 2: Time to mobilization and oral intake in the postoperative period

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   Discussion Top


The incidence of moderate-to-severe postoperative pain is 25%–30% following day-care surgery.[8] Laparoscopic cholecystectomy, in spite of the small incision, registers moderate pain at 65% and severe pain in 23% of the patients.[9] Pain is most intense on the day of surgery and on the following day subsequently declining to low levels by 3–4 days. However, pain remains severe in 13% of the patients throughout the 1st week after surgery which, apart from causing unacceptable suffering, has been associated with an increased incidence of nausea, vomiting, cardiovascular instability, delays in patient mobilization, and increase in patient readmissions.[10] Although many patients experience pain and discomfort after discharge, still 30%–50% do not take adequate analgesia because of insufficient information. Hence, we aimed to provide an analgesic regimen which would last for at least a week and chose buprenorphine for its long duration of action.[11]

Traditional approaches such as epidural analgesia and opioid-based i.v. patient-controlled analgesia (PCA), though associated with superior pain control, fail to translate into improved recovery or reduced morbidity when compared with pain management strategies used within an enhanced recovery after surgery pathway.[12] The requirement for delivery systems and co-administration of i.v. fluids is thought to impede patients reaching the desired state of DrEaMing (DR: drinking, EA: eating, and Ming: Moving).[13]

Opioids have been the cornerstone treatment for moderate and severe acute pain. There is, however, contention between their benefit and threat to optimal recovery. Opioid-related adverse events were associated with an increase in hospital stay of 1.6 days.[14] We used buprenorphine 10 mg.h−1 patch, giving a wide margin of safety and added security of no abuse potential. Each patient received one buprenorphine patch, which was removed on the 7th day, leaving no option for a repeat prescription.

The NSAID used was diclofenac (100 mg), as the number needed to treat of oral diclofenac is 1.9 which suggests a good analgesic profile. Transdermal diclofenac patches are potentially advantageous in having a reduced risk of upper gastrointestinal complications such as gastric and peptic ulcers or dyspepsia.[15],[16] In laparoscopic surgery, the pain is somatic at site of incision as well as visceral due to tissue destruction and pneumoperitoneum, referred pain to the shoulder, is superadded to the existing discomfort.

Previous studies have shown that transdermal application of diclofenac causes a high concentration of the active molecule in the subcutaneous tissues proving the efficacy of transdermal diclofenac for postoperative pain in patients undergoing laparoscopic gynecological surgeries.[17],[18]

Transdermal buprenorphine patch of 10 μg.h−1 has been used effectively in postoperative pain relief for total knee replacements, total hip replacement surgeries, laparoscopic gynecological surgeries, and spinal instrumental surgeries, provided that the patch is applied at least 10–14 h before surgery.[19],[20] Preventive analgesia reduces postoperative pain, and an indirect evidence of this is the reduction in levels of interleukin 6.[21]

The effective pain relief with the combined patches of buprenorphine and diclofenac was conclusively better as seen by the much reduced need for rescue analgesia with tramadol with group DP receiving only 150 ± 54.39 mg and group SP needing 388.00 ± 93.98 mg which was statistically very significant. Addition of a buprenorphine patch reduced the need for rescue analgesia of tramadol by 2.58 times without any increase in the sedation scores or nausea and vomiting. The pain scores were similar in the first 4 h after surgery, but later, scores were significantly higher in group SP at 8, 12, and 24 h postoperatively. At 36 and 48 h, the pain scores of both the groups were similar though patients on single patch were requiring more doses of rescue analgesia. The pain scores after 8 h, though statistically significant, were similar after 24 h in both the groups as the consumption of tramadol increased to maintain patient comfort. These findings were similar to a previous study, where the requirement of rescue analgesia with tramadol in patients undergoing elective spinal instrumentation was 125 mg in those who were on buprenorphine patch, whereas the placebo group required 480 mg of tramadol.[22]

In another study, transdermal fentanyl when used for multimodal analgesia provided adequate postoperative pain relief in abdominal surgeries as reflected in the reduced dose of rescue analgesia. The ease of administration by skin adhesion, reduced risk of infection, easy availability, and nonrequirement of specially trained personnel (as for epidural insertion) was more cost effective than a PCA pump while providing a steady release of the drugs.[23]

The incidence of adverse events and sedation scores were similar between both the groups. None of the patients in our study suffered allergic reactions or skin irritation to the drug patches, however, these problems were noted in other studies.[24] The buprenorphine patch was applied on the lateral aspect of the upper arm as this site is hairless, easily visualized, and would not be displaced by surgical scrubbing.

The satisfaction scores, which reflect the overall effect of comfort, were statistically significant in favor of group DP, with no patient being unhappy, while in group SP, 20% of the patients were still unhappy with the pain relief. The use of dual patches of buprenorphine and diclofenac provided adequate analgesia and reduced the logistics of nursing care, and patients were comfortable. This can also be construed that a single analgesic regimen with only diclofenac even with the standard paracetamol usage does not provide adequate pain relief and increases the demand for more rescue analgesics.

The limitations of our study were that the study population was limited to laparoscopic cholecystectomies only and we could not follow up the patients for beyond 48 h after surgery or measure the plasma levels of the study drugs.

Multimodal analgesia with transdermal patches can be introduced in clinical practice, with reduction in adverse events and better analgesia without any delay in oral intake due to the addition of narcotic.


   Conclusions Top


Multimodal analgesia with transdermal buprenorphine and diclofenac can be a novel yet simple alternative to injectable painkillers while providing good analgesia in postoperative laparoscopic cholecystectomy patients. Opioid free anesthesia is gaining importance but this should not preclude the use of opioids for control of acute pain when done in a supervised, controlled and comprehensive manner.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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