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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 32  |  Issue : 1  |  Page : 46-50

Comparison of efficacy and safety of transdermal buprenorphine patch applied 48 versus 72 hours preoperatively in providing adequate postoperative analgesia following major abdominal surgeries


Department of Anaesthesiology, Amrita Institute of Medical Sciences, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India

Date of Web Publication30-Apr-2018

Correspondence Address:
Dr. Sunil Rajan
Department of Anaesthesiology, Amrita Institute of Medical Sciences, Kochi, Kerala 682041
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpn.ijpn_4_18

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  Abstract 

Introduction: A transdermal drug delivery system provides steady and continuous drug delivery. As the onset of action is delayed, it has to be applied preoperatively to provide optimal postoperative analgesia. Aim: To compare the efficacy and safety of transdermal buprenorphine patches applied 48 and 72 h preoperatively in providing adequate postoperative analgesia following major abdominal surgeries and the incidence of side effects. Materials and Methods: This prospective randomized, double-blinded study was conducted in a tertiary care institution. Thirty patients undergoing laparotomy were recruited. Group A (n = 15) received a transdermal buprenorphine 10 mg patch with a delivery rate of 10 μg/h, which was applied approximately 48 h before surgery, whereas in group B (n = 15) buprenorphine 10 mg patch was applied 72 h preoperatively. All patients received general anesthesia following standardized protocol. Postoperative pain was assessed using numerical rating scale (NRS). The Mann–Whitney U test and independent t-test were used for statistical analysis. Results: NRS was significantly high in group A for up to 30 h postoperatively as compared to group B. From 36 to 48 h, it was comparable. The need for rescue analgesia was significantly high in group A as compared to group B. Significant number of patients in group B experienced nausea and vomiting (53.33% vs. 26.67%) and sedation (20% vs. 13.33%) in the preoperative period. Conclusion: Transdermal buprenorphine patch applied 72 h preoperatively provided better analgesia than the one applied 48 h before surgery. However, its preoperative use in patients without painful conditions predisposes them to develop side effects.

Keywords: Analgesia, buprenorphine, postoperative, sedation, transdermal


How to cite this article:
Kadapamannil D, Rajan S, Tosh P, Kumar L. Comparison of efficacy and safety of transdermal buprenorphine patch applied 48 versus 72 hours preoperatively in providing adequate postoperative analgesia following major abdominal surgeries. Indian J Pain 2018;32:46-50

How to cite this URL:
Kadapamannil D, Rajan S, Tosh P, Kumar L. Comparison of efficacy and safety of transdermal buprenorphine patch applied 48 versus 72 hours preoperatively in providing adequate postoperative analgesia following major abdominal surgeries. Indian J Pain [serial online] 2018 [cited 2019 Sep 17];32:46-50. Available from: http://www.indianjpain.org/text.asp?2018/32/1/46/231506


  Introduction Top


Epidural analgesia is a time-tested method for the management of postoperative pain, but as it is an invasive technique, patient acceptability could be less. Transdermal drug delivery system has the advantage of providing steady and continuous drug delivery resulting in constant plasma concentrations. This may overcome situations when the patient has to demand pain relief after experiencing pain. Though used extensively for chronic pain management, its utility in postoperative pain management is not yet fully investigated. As drug absorption from transdermal patch is delayed, it has to be applied preoperatively to have optimal drug concentrations in the postoperative period. However, use of it as a preemptive analgesic could lead on to the development of adverse effects in the absence of painful stimuli such as in the preoperative period.

The primary objective of this study was to assess whether transdermal buprenorphine patch applied 48 or 72 h preoperatively provided optimal postoperative analgesia in patients undergoing major abdominal surgeries. Secondary objectives included comparing the analgesic efficacy and safety as assessed with the occurrence of side effects such as sedation, respiratory depression, nausea, and vomiting in the preoperative and postoperative periods.


  Materials and Methods Top


This study was a prospective, randomized, double-blinded study conducted after obtaining Institutional Ethical Committee clearance and the patients' consent. As no such similar studies were published in the past, this study was initiated as a pilot study, which was conducted on 20 patients. Considering the percentage of patients with pain score of >4 at 6 h postoperatively as primary outcome (62.7% vs. 20.1%), with 95% confidence interval and 80% power, sample size per group was estimated to be 15.

The study was conducted during the period from July 2016 to December 2017. We recruited 30 patients with American Society of Anesthesiologist (ASA) physical status 1–3, aged between 18 and 70 years, and undergoing laparotomy with incision extending up to epigastrium. Those who were allergic to test drug, with severe hepatic impairment or opioid dependence, were excluded.

The patients were randomized equally into two groups (A and B) using computer-generated random sequence of numbers. Allocation concealment was ensured using sequentially numbered, opaque, sealed envelopes. The patients belonging to group A received a transdermal buprenorphine 10 mg patch with a delivery rate of 10 μg/h, which was applied 48 h before the surgery. In group B, a transdermal buprenorphine 10 mg patch was applied 72 h preoperatively. Occurrence of excessive sedation, local erythema, nausea, or vomiting in the preoperative period were noted.

All the patients were kept fasting for 6 h for solids and 2 h for clear fluids before surgery, and they received general anesthesia following a standardized protocol. The patients were induced with propofol, muscle relaxation was provided with vecuronium, and after intubation, anesthesia was maintained with oxygen, air (1:2) and isoflurane 1% with mechanical ventilation. Intravenous fentanyl (2 μg/kg) was given during induction, followed by 20 μg boluses every second hour of procedure. Additional analgesia was provided with intravenous paracetamol (1 g), which was repeated 8 hourly into the postoperative period for 2 days. Intraoperative tachycardia and hypertension was initially treated by increasing isoflurane concentration from 1% to 1.5%. Additional doses of fentanyl were given if unresponsive. At the end of surgery, the patients were extubated on table following reversal of neuromuscular blockade.

The efficacy of pain relief was checked using the numerical rating scale (NRS), with 0 being no pain and 10 being worst pain, and the two groups were compared at 6 hourly intervals for 48 h. The NRS of 4 or more was treated with intravenous fentanyl 20 μg boluses in both the groups. Rescue analgesic consumption and the number of times it was required were documented. The sedation levels were scored using Ramsay sedation score. The incidence of adverse effects such as sedation, nausea and vomiting, itching, and respiratory depression in the postoperative period was observed in both the groups.

The Mann–Whitney U test was used to compare the NRS, sedation score, and rescue analgesia among the groups. Independent t-test was used to compare age, height, weight, intraoperative fentanyl consumption, and duration of surgery. Statistical analysis was carried out using IBM SPSS Statistics, version 20 for Windows (SPSS, Chicago, USA).


  Results Top


Thirty patients were recruited for the study [Figure 1]. The demographic variables and distribution of the ASA status were comparable among the groups. The NRS was significantly high in group A at 0, 6, 12, 18, 24, and 30 h as compared to that in group B (P< 0.05). However, it became comparable at 36, 42, and 48 h [Table 1], [Figure 2]. Sedation score was significantly low in group A at 0 h. There was no significant difference with group B at any other time points between 6 and 48 h [Table 2]. The need for rescue analgesia was significantly high in group A as compared to group B (P< 0.001) [Figure 3]. The duration of surgery was comparable in both the groups; however, intraoperative fentanyl consumption was found to be significantly high in group A (188 ± 33.4 mg vs. 131.3 ± 40.9 mg, P< 0.001) [Table 3]. Compared to group A, a significant number of patients in group B experienced nausea and vomiting (26.67% vs. 53.33%) and complained of sedation (13.33% vs. 20%) in the preoperative period, which were statistically significant (P< 0.05) [Table 3]. A total of 20% of patients in both the groups had postoperative nausea and vomiting.
Figure 1: CONSORT flow diagram

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Table 1: Comparison of numerical rating scale

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Figure 2: Comparison of mean postoperative NRS

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Table 2: Comparison of Ramsay sedation score

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Figure 3: Number of rescue analgesic requirement

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Table 3: Comparison of need for rescue analgesia, intraoperative opioid consumption, duration of surgery, incidence of pre-op sedation, nausea, and vomiting

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  Discussion Top


In this study, it was observed that patients who received transdermal buprenorphine patch 72 h preoperatively had better postoperative pain relief as compared to that applied 48 h preoperatively. But earlier application of buprenorphine patch led to the development of side effects such as sedation, nausea, and vomiting in the preoperative period.

Postoperative pain contributes significantly to patient morbidity and mortality. Experiencing pain has been the most common concern among surgical patients, and it has been estimated that 80% of patients experience acute pain after surgery, despite an increased focus on pain management systems and improved awareness. Among these patients, 86% had moderate, severe, or intense pain.[1] The primary analgesic agent of choice for severe pain still continues to be opioids, though the routes of administration and dosing regimen have undergone changes over decades.

Following major abdominal surgeries, though various routes of analgesic administration had been tried, epidural analgesia was found to provide optimal results. Local anesthetic agents and opioids [2] are commonly used for this purpose, but the development of hypotension with the use of local anesthetics was a cause of concern. Reducing the concentration of local anesthetic with the addition of opioid has helped to overcome this problem to a certain extent. As epidural is an invasive procedure, patient acceptability can be poor.

Unless given as an infusion, even epidural analgesia may not provide constant and uniform pain relief. Bolus drug administration carries a risk of excessive therapeutic plasma concentration soon after administration, and later, the drug levels gradually drop to a subtherapeutic level leading to development of pain. Blanket administration of epidural boluses at fixed intervals carries risk of overdosing. Safe and optimal analgesia could be provided by administering the drug as an infusion. But need of infusion pumps for this purpose limits its regular use.

An alternative approach to epidural infusion is transdermal administration, which provides a steady-state plasma concentration of the desired drug. It has the added advantage of lesser chances of inaccurate drug doses. Human skin acts as a physiochemical barrier preventing free passage of drugs across it. Transdermal drug delivery systems, otherwise known as “patches,” are dosage forms designed to deliver a predetermined amount of drug across skin. For drug passage to occur via the skin, the drug should be one with adequate lipophilicity and have a molecular weight of <500 Da.[3] Transdermal route of administration is quite common for management of cancer pain with good efficacy.[4],[5] However, it has not found many takers as postoperative analgesic.

Buprenorphine, a semisynthetic opioid, has been used commonly for postoperative epidural analgesia with an advantage of it being 25 times more potent than morphine. It acts as a partial agonist on the μ-opioid receptors, antagonist on the κ-opioid receptors, agonist on the δ-opioid receptors, and partial agonist on opioid receptor-like (ORL-1) receptors. ORL-1 receptors are similar in structure to opioid receptors and may be involved in central modulation of pain.[6] Epidural buprenorphine has shown to significantly reduce postoperative pain [7] and increase the quality of analgesia with a longer duration of action, and is suggested as a better alternative to butorphanol [8] and epidural tramadol.[9]

Transdermal buprenorphine patches are now increasingly being used for the management of chronic cancer as well as nonmalignant pain.[4],[5],[10],[11],[12],[13] There are five buprenorphine patch strengths available now: 5, 7.5, 10, 15, and 20 μg/h. Each transdermal patch usually contains 5 mg of buprenorphine in 6.25 cm2 area releasing 5 μg of buprenorphine per hour over a period of 7 days. Patches with higher strengths have proportionately larger areas. After application, these are usually kept for 7 days. More than one patch may be applied depending on the need, but the total dosage should not exceed 20 μg/h.

In a recent study,[14] transdermal buprenorphine was found to be superior to oral tramadol in postoperative pain relief in surgery for hip fracture. Seven days of application of buprenorphine patch at 5–20 μg/h had been suggested for pain relief in elderly patients with osteoarthritis, with close monitoring of the development of side effects, in whom surgery was not feasible.[15] Transdermal buprenorphine has low incidence of central nervous system adverse events and constipation. It is safe for use in severe renal dysfunction without a need for dose adjustment. So transdermal buprenorphine is recommended in diabetics, elderly and in those undergoing hemodialysis.[16]

In our study, group A did not have adequate analgesia in the initial 30 h of the postoperative period. This could be because adequate plasma levels of buprenorphine were not attained by 48 h. In our study, though patients in both the groups experienced nausea and vomiting and complained of sedation in the preoperative period itself, these were found to be more significant in group B. Earlier patch placement in the absence of pain stimulus has many implications, as it might expose the patient to greater risk of excessive sedation, respiratory depression, nausea, and vomiting. Therefore, if the patches are to be applied 72 h before surgery, the patient should be under careful monitoring for early detection of any side effects. The reason for the significantly lower intraoperative opioid consumption in group B could be because they might have had higher plasma buprenorphine concentration intraoperatively as it was applied 72 h before surgery. We applied the patches at 48 and 72 h preoperatively, as it was reported that the onset of peak action following transdermal application of buprenorphine could take 48–72 h. Lower incidence of side effects in the postoperative period could be explained by the presence of pain-negating sedative effects and the use of antiemetics for controlling nausea and vomiting.

Another concern of using a transdermal patch for postoperative pain relief is that it maintains constant plasma drug concentration, whereas pain is not of same intensity throughout the postoperative period. It is of maximum intensity in the initial 24–48 h, and then the pain gradually comes down. So the dose that provided optimal analgesia initially might become excessive on a later postoperative day, exposing patients to complications of opioid overdosing. If used for chronic pain management, as in patients with cancer, no such risk exists. Another concern in postoperative period is fever, which is mostly due to tissue inflammatory reactions or infection. Cutaneous vasodilatation associated with increased body temperature could further enhance transdermal absorption resulting in excessive plasma levels.

One of the major drawbacks of the study was that that we relied entirely on numerical rating score for the assessment of efficacy of analgesia, which had subjective variations in pain perception. Periodic estimation of plasma concentration of buprenorphine could have given a definite idea regarding the efficacy of drug absorption following transdermal administration of the drug. Future research with assessment of plasma drug levels might reveal the actual potential and safety of transdermal buprenorphine for the control of postoperative pain.


  Conclusion Top


Transdermal buprenorphine patch applied 72 h preoperatively provided better postoperative analgesia than the one applied 48 h preoperatively. However, its preoperative application in patients with none of the associated painful conditions, predispose them to develop side effects such as sedation, nausea, and vomiting.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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Apfelbaum JL, Chen C, Mehta SS, Gan TJ. Postoperative pain experience: results from a national survey suggest postoperative pain continues to be undermanaged. Anesth Analg 2003;97:534-40, table of contents.  Back to cited text no. 1
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Singh B, Nihlani S. Postoperative analgesia: a comparative study of epidural butorphanol and epidural tramadol. J Adv Res Biol Sci 2011;3:86-9.  Back to cited text no. 2
    
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Brown MB, Martin GP, Jones SA, Akomeah FK. Dermal and transdermal drug delivery systems: current and future prospects. Drug Deliv 2006;13:175-87.  Back to cited text no. 3
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Likar R, Kayser H, Sittl R. Long-term management of chronic pain with transdermal buprenorphine: a multicenter, open-label, follow-up study in patients from three short-term clinical trials. Clin Ther 2006;28:943-52.  Back to cited text no. 4
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Böhme K, Likar R. Efficacy and tolerability of a new opioid analgesic formulation, buprenorphine transdermal therapeutic system (TDS), in the treatment of patients with chronic pain. A randomised, double-blind, placebo-controlled study. Pain Clinic 2003;15:193-202.  Back to cited text no. 5
    
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Ipe S, Korula S, Varma S, George GM, Abraham SP, Koshy LR. A comparative study of intrathecal and epidural buprenorphine using combined spinal-epidural technique for caesarean section. Indian J Anaesth 2010;54:205-9.  Back to cited text no. 7
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Jose DE, Ganapathi P, Anish Sharma NG, Shankaranarayana P, Aiyappa DS, Nazim M. Postoperative pain relief with epidural buprenorphine versus epidural butorphanol in laparoscopic hysterectomies: a comparative study. Anesth Essays Res 2016;10: 82-7.  Back to cited text no. 8
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Griessinger N, Sittl R, Likar R. Transdermal buprenorphine in clinical practice—a post-marketing surveillance study in 13,179 patients. Curr Med Res Opin 2005;21:1147-56.  Back to cited text no. 11
    
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Steiner DJ, Sitar S, Wen W, Sawyerr G, Munera C, Ripa SR, et al. Efficacy and safety of the seven-day buprenorphine transdermal system in opioid-naïve patients with moderate to severe chronic low back pain: an enriched, randomized, double-blind, placebo-controlled study. J Pain Symptom Manage 2011;42:903-17.  Back to cited text no. 12
    
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Desai SN, Badiger SV, Tokur SB, Naik PA. Safety and efficacy of transdermal buprenorphine versus oral tramadol for the treatment of post-operative pain following surgery for fracture neck of femur: a prospective, randomised clinical study. Indian J Anaesth 2017;61:225-9.  Back to cited text no. 14
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Breivik H, Ljosaa TM, Pedersen KS, Persson J, Aro H, Villumsen J, et al. A 6-months, randomised, placebo-controlled evaluation of efficacy and tolerability of a low-dose 7-day buprenorphine transdermal patch in osteoarthritis patients naïve to potent opioid. Scand J Pain 2010;1:122-41.  Back to cited text no. 15
    
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    Tables

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