A COMPARATIVE STUDY OF TRANSDERMAL BUPRENORPHINE WITH TRANSDERMAL FENTANYL FOR POSTOPERATIVE ANALGESIA IN PATIENTS UNDERGOING POSTERIOR STABILIZATION OF LUMBAR SPINE

Dr. Kishan Shetty MD 1 and Dr. Seena Marene Solomon MD 2 . 1. Associate Professor, Dept. of Anaesthesiology, Father Muller Medical College, Mangalore-575002 India. 2. Senior Resident, Dept. of Anaesthesiology, St. Johns Medical College and Hospital, Bangalore-560034 India. ...................................................................................................................... Manuscript Info Abstract ......................... ........................................................................ Manuscript History Received: 08 August 2019 Final Accepted: 10 September 2019 Published: October 2019

1. To compare the analgesic efficacy, adverse effects and need for rescue analgesics while using transdermal buprenorphine versus transdermal fentanyl for postoperative pain in patients undergoing posterior stabilization of lumbar spine. 2. To determine if there is a significant difference between the two study groups allowing consideration towards better analgesia for the patient Review of literature:-Transdermal drug delivery system: Transdermal drug delivery system refers to the administration of therapeutic agents through intact skin for systemic effect. It has emerged as one of the most rapidly advancing areas of novel drug delivery system by improving the therapeutic efficacy and safety. It maintains a steady state of the drugs in plasma by releasing the drug at a predetermined and controlled rate. It also overcomes significant drawbacks of the conventional oral dosage forms and parenteral preparations.
Transdermal delivery of lipophilic drugs like buprenorphine and fentanyl is facilitated by diffusion through blood, lymphatics and interstitial transport to deep tissues. (7) The zero-order (constant rate of delivery) kinetics of transdermal delivery has been one of the cornerstones in the development of transdermal systems. (8) From a global perspective, advances in transdermal delivery systems can be categorized as undergoing three generations of development from the first generation of systems that produced many of today's patches by judicious selection of drugs that can cross the skin at therapeutic rates with little or no enhancement; through the second generation that has yielded additional advances for small molecule delivery by increasing skin permeability and driving forces for transdermal transport; to the third generation that will enable transdermal delivery of small molecule drugs, macromolecules (including proteins and DNA) and virus-based/other vaccines through targeted permeabilization of the skin's stratum corneum.
329 The first-generation approach to transdermal delivery is limited primarily by the barrier posed by skin's outermost layer called stratum corneum, which is 10 to 20 µm thick (Fig 2.). Underneath this layer is the viable epidermis, which measures 50 to 100 µm and is avascular. Deeper still is the dermis, which is 1-2 mm thick and contains a rich capillary bed for systemic drug absorption just below the dermal-epidermal junction. Drug transport across the stratum corneum typically involves diffusion through the intercellular lipids via a path that winds tortuously around 330 corneocytes, where hydrophilic molecules travel through the lipid head group regions and lipophilic molecules travel through the lipid tails. This transport pathway is highly constrained by the structural and solubility requirements for solution and diffusion within stratum corneum lipid bilayers. (9) Pharmacology: Buprenorphine: It is a semisynthetic derivative of thebaine, a morphine alkaloid. It is a safe and potent analgesic. Buprenorphine is a highly lipophilic drug that is a non-selective mixed agonist-antagonist opioid receptor modulator, acting as a partial agonist of the μ receptor, an antagonist of the κ and the δ-receptors, but with very low affinity to the δ-receptor. Its active metabolite norbuprenorphine, acts as a strong agonist at the δ-receptors. Buprenorphine is a partial agonist at the μ-opioid receptor and an antagonist at the kappa-opioid receptors, an agonist at delta-opioid receptors and a partial agonist at nociception receptors. Buprenorphine interacts predominately with the opioid μ-receptor. These μ-binding sites are discretely distributed in the human brain, spinal cord and other tissues. In clinical settings, buprenorphine exerts its principal pharmacologic effects on the central nervous system. Its primary actions of therapeutic value are analgesia and sedation.

Absorption:
Each buprenorphine patch is designed to deliver the drug for a period of seven days. Steady state is achieved by the third day. Application of heat directly to the patch can cause a 26-55% increase in blood concentration of buprenorphine and the levels came down within 5 hours after the heat was removed. Fever may increase the permeability of the skin hence febrile patients must be monitored closely for adverse effects. Patients receiving opioid transdermal patches must be educated regarding life threatening respiratory depression, methods of disposal of the patch and risk of accidental exposure in children. They should be informed about drug interactions and how to recognize emergencies such as anaphylactic reactions. Patients need to be warned regarding 332 the potential for temperature dependent increases in opioid release from the patch which could result in an overdose. Using buprenorphine patch may impair their ability to drive or operate heavy machinery. The graph below (Fig. 5) compares the measured plasma concentration for buprenorphine and fentanyl at various time intervals. It can be observed that the maximum plasma concentration of fentanyl was attained between 12-24 hours and for buprenorphine it was around 72 hours.

Fentanyl:
Fentanyl was first synthesized as an intravenous anaesthetic by Paul Janssen in 1960. It is a potent agonist of the μopioid receptor which is responsible for its analgesic and sedative properties. It is almost 100 times more potent than morphine and has a relatively wide therapeutic index, which makes it a very safe anaesthetic drug when monitored carefully.
The transdermal patch containing fentanyl was introduced in the mid-1990s. Fentanyl is now on the WHO's list of essential medicines, the most effective and safe medicines needed in a health system (10). It bypasses first pass metabolism and hence has high bioavailability. Due to its highly lipophilic action, it achieves a large volume of distribution. Fentanyl selectively binds to the μ-receptor in the central nervous system (CNS) thereby mimicking the effects of endogenous opiates. Stimulation of the μ-subtype opioid receptor stimulates the exchange of GTP for GDP on the G-protein complex and subsequently inhibits adenylate cyclase. This results in a decrease in intracellular cAMP and leads to a reduction in the release of neurotransmitters such as substance P, GABA, dopamine, acetylcholine and noradrenaline. The analgesic effect of fentanyl is likely due to its metabolites, which induce opening of G-protein-coupled inwardly rectifying potassium channels and blocks the opening of Ntype voltage-gated calcium channels, thereby resulting in hyperpolarization and reduced neuronal excitability. (11) Pharmacokinetics:(12) pKa-8.4 Plasma protein bound-84% Terminal half-life-3.5 hours 333 Clearance-0.8-1.0 ml/min/kg Volume of distribution-3-5 L/Kg Bioavailability of transdermal patch-92%

Absorption:
Fentanyl is released from the adhesive matrix at a nearly constant amount per unit time. The skin under the system absorbs fentanyl and a depot of fentanyl concentrates in the upper skin layers. The concentration gradient existing between the matrix and the lower concentration in the skin drives the drug release. Fentanyl then becomes available to the systemic circulation. Serum fentanyl concentrations increase gradually following initial patch application, generally levelling off between 12-24 hours and remaining relatively constant, with some fluctuation, for the remainder of the 72-hour application period. Peak serum concentrations of fentanyl generally occurred between 20 and 72 hours after initial application. (13) Studies have shown that the application of heat over the Fentanyl Transdermal System increased mean overall fentanyl exposure by 120% and average maximum fentanyl level by 61%.  Fentanyl plasma protein binding capacity decreases with increasing ionization of the drug. Alterations in pH may affect its distribution between plasma and the central nervous system. Fentanyl accumulates in the skeletal muscle and fat and is released slowly into the blood.

Elimination:
Fentanyl is metabolized primarily via cytochrome P450 3A4 isoenzyme to undergo oxidative N-dealkylation to norfentanyl and other inactive metabolites. Within 72 hours of administration, approximately 75% of the dose is excreted in the urine and about 9% in faeces. (6) Pharmacodynamics: 1. Effect on the central nervous system: Fentanyl produces respiratory depression and subsequent hypoventilation by direct action on the brainstem respiratory centres which maybe resistant to carbon dioxide retention. 2. Fentanyl causes miosis, even in total darkness. 3. Effect on gastrointestinal system and other smooth muscles: Fentanyl causes reduction in motility and an increase in the smooth muscle tone of the stomach antrum. Digestion is delayed and the propulsive peristaltic waves in the colon is decreased resulting in constipation. Other opioid induced effects may include spasm of sphincter of Oddi and reduced biliary and pancreatic secretions. 4. Effects on the cardiovascular system: Fentanyl produces peripheral vasodilation leading to orthostatic hypotension/syncope. Clinically significant histamine release rarely occurs with fentanyl administration. 5. Effects on endocrine system: Opioids inhibit secretion of adrenocorticotropic hormone (ACTH), cortisol and luteinizing hormone (LH). They stimulate prolactin, growth hormone (GH) secretion and pancreatic secretion of insulin and glucagon. Chronic use may influence hypothalamo-pituitary-gonadal axis which may manifest as low libido, impotence, erectile dysfunction, amenorrhoea and infertility. 6. Effects on immune system: In animal models, opioids appear to be modestly immunosuppressive.

Precaution:
1. -Cardiac disease: Fentanyl may produce bradycardia and hence it should be administered with caution to patients with bradycardia. 2. -Hepatic or renal disease: Fentanyl is dependent on the liver for metabolism and kidneys for excretion and hence doses should be accordingly adjusted in those with deranged hepatic and renal parameters. 3. -Paediatric use: Transdermal fentanyl is not studied or recommended in children under two years of age. 4. -Pregnancy and lactation: TDF belongs to category C for teratogenic effects. No epidemiological studies of congenital anomalies in infants born to women treated with fentanyl during pregnancy have been reported. Fentanyl is excreted in human milk and hence is not recommended for nursing women. 5. -Geriatric use: A study conducted with the fentanyl transdermal system in elderly patients demonstrated that fentanyl pharmacokinetics did not differ significantly from young adult subjects, although peak serum concentrations tended to be lower and mean half-life values were prolonged to approximately 34 hours. Respiratory depression is the chief hazard in elderly or debilitated patients, usually following large initial doses in non-tolerant patients or when opioids are given in conjunction with other agents that depress respiration.
Fentanyl transdermal system should be used with caution in elderly, cachectic or debilitated patients as they may have altered pharmacokinetics due to poor fat stores, muscle wasting or altered clearance.

Physical dependence:
Physical dependence is a state of adaptation that is manifested by an opioid specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood concentration of the drug, and/or administration of an antagonist. The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, piloerection, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhoea, or increased blood pressure, respiratory rate, or heart rate. In general, opioids should not be abruptly discontinued.

Ambulatory patients:
Patients who have been given fentanyl transdermal system should not drive or operate dangerous machinery unless they are tolerant to the effects of the drug as strong opioid impair mental or physical abilities required for performing these tasks.

Drug interactions:
Concomitant use of fentanyl with all cytochrome P450 3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice and verapamil) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression.
Using fentanyl along with other central nervous system depressants, including but not limited to other opioids, sedatives, hypnotics, anxiolytics (e.g., benzodiazepines), general anesthetics, phenothiazines, skeletal muscle relaxants and alcohol, may cause respiratory depression, hypotension and profound sedation or potentially result in coma or death. When such combined therapy is contemplated, the dose of one or both agents should be significantly reduced.
Special instructions to the patients and care-takers: Patients receiving fentanyl patch should be counselled regarding its addiction, abuse and misuse potential. Also, they must be educated regarding life threatening respiratory depression, methods of disposal of the patch and risk of accidental exposure in children. They should be informed about drug interactions and how to recognize emergencies such as allergic reactions. Patients need to be warned regarding the potential for temperature dependent increases in 335 fentanyl release from the patch which could result in an overdose. Fentanyl may impair their ability to drive or operate heavy machinery.  Katz et al (1996) followed up thirty patients who had under gone thoracotomy with an aim to identify predictors of long term post-thoracotomy pain by measuring the VAS scores at rest and on movement, Mc Gill Pain Questionnaire, patient controlled morphine consumption and pain threshold to pressure applied on the rib contralateral to thoracotomy incision. They found that 52% of patients reported long term pain and that early postoperative pain was the only factor that significantly predicted this. Hence, aggressive management of early postoperative pain may reduce the likelihood of long term post thoracotomy pain.(2) 3. Lehman LJ et al (1997) conducted a placebo-controlled study on 40 individuals posted for abdominal surgery under general anaesthesia with an aim to determine the safety and effectiveness of TDF for postoperative pain relief. He divided the subjects randomly into two groups of twenty each. The test group received TDF (0.16mg/cm 2 ) depending on their body weight i.e. for <60 kgs, a 30cm 2 patch and for >60kgs, a 40cm 2 patch respectively while the control group received placebo patches approximately 60 minutes before induction of anesthesia. Patients were followed up in the postoperative ward for 36 hours to assess pain levels and rescue analgesia was administered accordingly. During the observation period, 30 doses of 30 mg ketorolac and 14 doses of 1.3 g acetaminophen were administered to 13 patients in the placebo group and 18 doses of ketorolac and 8 doses of acetaminophen were given to 16 in the fentanyl group. Hence it can be deduced that the differences in postoperative analgesic requirement were significant. Also, in the fentanyl group, 12 patients experienced nausea vs 5 patients in the control group. TDF 50-75mcg/h, did not depress the respiratory rate or oxygen saturation. Hence, if used properly, the TDS can be effective in providing a background of analgesia and thereby assist in the management of acute postoperative pain. (  hydromorphone, TDF and TDB on nausea, emesis and constipation. They found that the incidence of constipation was significantly higher with TD opioids (22% with TDF, 21% with TDB, 2% with hydromorphone PO; p=0.003). The mean NRS for nausea (TDF-1.3, TDB-1.2, oral hydromorphone-1.5; p=0.6) and the consumption of antiemetics (TDF-42%, TDB-33%, oral hydromorphone-36%; p=0.6) did not differ significantly in contrast to the score for emesis (TDF-16%, TDB-13%, oral hydromorphone-33%; p=0.02).(29) 13. Nelson et al (2009) reviewed multiple data to evaluate the underlying pharmacological safety and misuse/abuse potential of TDF and they found that TDF is an extremely high potency opioid that maintains a steady serum 337 concentration, thereby improving efficacy and compliance. But its use can also complicate the drugs safety due to improper application or prescription. It is also prone to abuse potential and can carry a high risk of morbidity. Hence, physician awareness and education in this matter will result in fewer poor outcomes.(6) 14. Andresen et al (2011) described the tissue differentiated analgesic effects between TDB and TDF. TDB  significantly attenuated the bone pain, heat pain, nerve growth factor-induced soreness and cold pressor pain  while fentanyl significantly decreased the cold pressor

338
Haemodynamic and analgesic effects were compared using ANOVA & Turkeys post hoc test and side effects were compared using the chi square test. They found that haemodynamic changes were comparable in all 3 groups and the VAS score of group A subjects was significantly higher (4.93±0.98) as compared to Group B (1.73±0.64) and Group C (1.40±0.50). On second postoperative day, no pain was reported by the Group C patients and on 4th day after surgery, no pain was reported by Group B patients. Hence it was concluded that TDB 20 mg was effective in attenuating postoperative pain, maintaining haemodynamic stability requiring no rescue analgesia while fewer postoperative rescue analgesic requirements were seen in the TDB 10mg group.(38) 25. Conaghan P et al (2016) conducted an observational study on patients affected with osteoarthritis in the UK and found that those who were treated with TDB were more satisfied and compliant with their medication and reported a higher quality of life than those treated with paracetamol-codeine combination or tramadol.(39) 26. Pergolizzi et al (2017) evaluated the safety of TDB in the management of chronic pain in older adults by conducting a retrospective analysis of 16 placebo and active controlled and uncontrolled studies (N=6566) and found that the incidence of adverse events was similar in the >65year old and <65year old patient (63.8% and 61%, respectively). TDB appeared to be a viable option for the management of pain in the age group of 65-98 years but the benefits need to be tempered by potential risks among the older adults.  Sample size and sampling procedure: Sample size was 60 and it comprised of men and women in more or less equal proportion.

Study procedure:
Group B: 30 patients who received transdermal buprenorphine 10µg/hour Group F: 30 patients who received transdermal fentanyl 25µg/hour.
After institutional ethical committee clearance, patients falling within the inclusion criteria were selected for the study after a pre-anaesthetic evaluation was carried out and an informed consent taken. Patients were randomly allotted into the two groups mentioned above using sealed envelope technique. They were premedicated with Tab. Ranitidine 150mg on the night before the surgery and on the morning of the surgery. The transdermal patch was applied onto a clean, hairless portion of the skin (the upper back or chest of the patient) on the previous night of the surgery and the patients vitals were monitored closely. Patients were educated regarding the transdermal patch with an information leaflet and they were familiarized with the visual analog scale (VAS) for pain assessment (0 being no pain and 10 being the worst possible pain).

Pre-operatively:
A baseline recording of the vital parameters-heart rate (HR), non-invasive blood pressure (NIBP), respiratory rate (RR) and oxygen saturation (SpO 2 ) was done.

Intra-operatively:
On the day of the surgery, in the operation theatre, patient was connected to the monitors using pulse-oximeter, ECG leads and blood pressure cuff. An 18G intravenous cannula was secured on the upper limb. Patient was induced for general anaesthesia with injections morphine (0.1mg/kg), propofol (2mg/kg) and vecuronium (0.1mg/kg) and intubated with an armoured endotracheal tube; maintained with inhalational anaesthetic, nitrous oxide and oxygen. Patient was positioned prone and care was taken to pad the pressure points. Hemodynamic parameters, respiration and SpO 2 were monitored.
Half an hour before the surgery was completed, all the patients received paracetamol infusion (15mg/kg) over 15 minutes. Once the surgery was completed, patients were repositioned, reversed, extubated and shifted to the postoperative unit where he/she was monitored every second hourly for 24 hours to assess the severity of pain (VAS), vitals, adverse effects and use of rescue analgesia.
The patients received intravenous analgesics in the form of continuous morphine infusion (1mg/hour) for the first post-operative day. If the patient experienced any breakthrough pain (VAS >4), rescue drugs such as injection ketorolac (0.5 mg/kg) or injection diclofenac (1.5 mg/kg) was administered immediately and time was noted. Oxygen saturation was continuously monitored using a pulse-oximeter and the respiratory rate was also kept track of. In case of severe bradypnoea (RR<8/min), injection Naloxone (0.4-2mg/kg) was kept ready. The patients were asked to report pain and three of the most frequent adverse effects (nausea, drowsiness and local irritation due to the patch) every two hours on the first day and thereafter every four hours for the second and third days. In case of nausea, they were treated with ondansetron (0.1mg/kg). The patch was discontinued in case of local irritation or drowsiness.
Patients were asked to rate their adverse effects with either 1nothing, 2light feeling, 3moderate feeling and 4 intolerable feeling. All other adverse effects reported spontaneously by the subjects were recorded and rated in the same way.
Using the visual analog scale (VAS), the severity of pain was assessed and compared between both the groups. Also the demand for rescue drugs was monitored and compared between the two groups.
Modified Ramsay sedation score (RSS) (41) was used to assess the degree of sedation. 1. Paralyzed; unable to evaluate 2. Awake 3. Lightly sedated 4. Moderately sedated, follows simple commands 5. Deeply sedated, responds to non-painful stimuli 6. Deeply sedated, responds to painful stimuli 7. Deeply sedated, unresponsive to painful stimuli 340 Results:-Statistical analysis: Power analysis from similar studies suggest that a sample size of 30 patients/group is required to get the power of study to 80 %, with 0.05 level of significance. All the data was fed into the IBM SPSS software, mean and standard deviation was used for continuous data and median for non-parametric data. Age, weight and hemodynamic parameters were compared using students' t-test. Sedation and VAS scores were compared using independent t-test. The mean age in group B was 43.97+/-12.34 and in group F was 41.67+/-13.797. With a p-value of 0.4, these groups were comparable in terms of age. The mean weight in group B was 54.27+/-6.3 and in group F was 58.4+/-6.32. P-value was 0.014 and this means that there was statistically significant higher weight in the fentanyl group when compared to the buprenorphine group.   Comparison of the HR between both the groups was overall statistically and clinically insignificant.

Fig 13:-Comparison of SpO2 between the two groups
There was statistically significant higher SpO2 in group B when compared to group F. however there was no clinically significant respiratory depression in group F. Comparison of RR between the two groups showed that there was statistically significant lower respiratory rate in group B (p <0.001). It should be noted that this was not clinically significant as all the patients in group B had RR >12/min. Group B showed lower VAS scores that were statistically significant in the 2 nd and 6 th hours of POD-1. However, after the 8 th hour of POD-1, both groups had comparable VAS scores. From POD-2 onwards, VAS scores were significantly lower in group F.

Discussion:-
The goal of this study was to compare the analgesic efficacy and adverse effects, if any, between transdermal buprenorphine and transdermal fentanyl in the post-operative period in patients who underwent posterior stabilization of lumbar spine.
The dosage of each drug was decided after careful review of the various studies which use different doses of both buprenorphine and fentanyl by transdermal route and the effects of the different doses, as mentioned in the review of literature.
It was observed that 10 of transdermal buprenorphine and 25µg/hour of transdermal fentanyl had equianalgesic potency when compared to the standard drug morphine.
A total of 60 patients who were posted for elective posterior stabilization of lumbar spine and who gave their informed consent, were enrolled in the study. The patients were allotted into two groups by sealed envelope technique. Since it was a single blinded study, only the patient did not know which group they belonged to. Depending on the envelope they picked, they were During the pre-anaesthetic evaluation, all the patients were taught the visual analogue scale (VAS) and how to identify adverse reactions/emergencies, if any occurred. The respective patch was then applied onto a clean, hairless, dry area on the upper chest/back. If there was no area free of hair, then the hair over the chest was 1clipped with scissors and the patch was firmly held over the skin for 30 seconds. Patients were educated on the care to be taken while on the patch and a patient information leaflet was also provided.
Comparison of the age between the two groups shows that the age was higher in group B which was statistically not significant and hence, the groups were comparable.
Comparison of weight between the two groups shows that weight was higher in group F which was statistically significant. The increase in weight may demand a higher need for analgesia as the volume of distribution increases with weight.
Comparison of duration of surgery among the two groups shows that group B had longer surgeries which was statistically not significant. Hence the two groups are comparable with respect to duration of surgery and it can be established that the procedure was more or less similar in both groups.
The comparison of the postoperative VAS scores was done every 2 hours on the first postoperative day and was statistically significant with group F having higher VA scores at the 2 nd and 6 th hours. On the second and third postoperative days, there was a statistically significant difference in the VAS scores with group B having relatively higher scores throughout the day. This leads us to the understanding that transdermal fentanyl takes around 16-18 hours to reach maximum serum concentrations and has better analgesic effect when compared to buprenorphine which may have an earlier onset of action but is less potent than fentanyl.
Comparison of the RSS between the two groups showed that there was no statistically significant change or drop in RSS except for 4 hours postoperatively there was a statistically significant increase in Group B, which was transient and not associated with adverse effects. All patients in both groups were calm, comfortable and easily arousable throughout the study and none of them showed excessive sedation.
However, one patient in the buprenorphine group had an episode of giddiness after the second postoperative day and hence the patch was discontinued.
Comparison of the oxygen saturation postoperatively shows that on all three postoperative days, the saturation was higher in group B and was statistically significant 95% of the time, which indicates that group F causes relatively more respiratory depression than group B, although not life threatening.
Comparison of respiratory rate between the two groups shows that on the first postoperative day, RR is higher in group F which is statistically significant On the second postoperative day, the RR was higher in group B although not statistically significant. There however was no clinically significant bradypnoea in either groups.
Comparison of the SBP and DBP shows no statistically significant difference between the two groups B & F. This shows that transdermal patches as such have no significant impact on the blood pressure.
Comparison of the heart rate between the two groups show that group F had a higher heart rate although it was statistically significant only 10% of the time. It should be noted that the heart rate remained within acceptable limits of 75-80 beats per minute.
T test was used for comparing oxygen saturation between the two groups, Comparison of the SBP, HR, RR, RSS and VAS was done using independent t test. Comparison of DBP was done using student t test.
All the 60 patients showed VAS <4 in the first 2-4 hours after surgery. At 12 th and 22 nd hour, two patients in group B experienced VAS >4 and were administered the rescue analgesic. On the second postoperative day, eight patients from group B required rescue analgesic compared to two in group F. On postoperative day three, seven patients in