Introduction. Shigemi Matsumoto 1 Kazu Matsumoto

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1 Arch Orthop Trauma Surg (2015) 135: DOI /s z KNEE ARTHROPLASTY Transdermal fentanyl patch improves post-operative pain relief and promotes early functional recovery in patients undergoing primary total knee arthroplasty: a prospective, randomised, controlled trial Shigemi Matsumoto 1 Kazu Matsumoto 2 Hiroki Iida 1 Received: 4 March 2015 / Published online: 26 June 2015 Springer-Verlag Berlin Heidelberg 2015 Abstract Introduction The aim of the present study was to evaluate the efficacy and safety of a 12.5 lg/h transdermal fentanyl patch (TFP). Materials and Methods Fifty-two patients scheduled for primary total knee arthroplasty (TKA) were recruited in the study. They were randomly divided into two groups: patients provided with a transdermal fentanyl patch (Group TFP) and those provided with non-steroid anti-inflammatory drugs (Group NSAID). The patients in the TFP and NSAID groups had mean ages of 70.1 years (range years) and 73.5 years (range years), respectively. Post-operative pain intensity was measured using the visual analogue scale both at rest and during movement (mvas). We also evaluated lower leg functional recovery and adverse events. Results The mean mvas scores were not different between the two groups on post-operative day 4, but were significantly smaller in the TFP group than in the NSAID group on post-operative days 7 (p = ) and 14 (p = 0.007). Muscle strength recovered faster in the TFP group than in the NSAID group, the percentage of preoperative strength being significantly greater in the former Electronic supplementary material The online version of this article (doi: /s z) contains supplementary material, which is available to authorized users. & Hiroki Iida iida@gifu-u.ac.jp 1 2 Department of Anesthesiology and Pain Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu , Japan Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, Gifu, Japan than in the latter on post-operative days 7 (p = 0.027) and 14 (p = 0.047). Furthermore, there were no remarkable adverse events in patients using TFP. Conclusion We conclude that a 12.5 lg/h TFP can improve post-operative pain relief and promotes early functional recovery following total knee arthroplasty. Keywords Transdermal fentanyl patch Post-operative pain Total knee arthroplasty Early functional recovery NSAIDs Introduction Total knee arthroplasty (TKA) is one of the most important orthopaedic procedures for improving the quality of life and restoring patients to a higher level of function with less pain [1 3]. Pain is known to compromise the early outcome of TKA by increasing the risk of post-operative complications, and affecting patient ambulation and compliance with physical therapy. Moreover, inadequate pain control lengthens hospital stay, increases the cost of care, and is associated with venous thromboembolism, coronary ischaemia, myocardial infarction, pneumonia, insomnia, cognitive dysfunction, poor wound healing, and delayed overall recovery [4 8]. Severe pain during the post-operative period causes patient dissatisfaction and may lead to chronic persistent pain, even when the TKA has been otherwise successful [9, 10]. For these reasons, management of pain in the immediate post-operative period is one of the most critical issues encountered in orthopaedic surgery, including TKA. Various techniques and medications have been used to achieve good pain relief and early mobilisation after TKA. At present, analgesic modalities include epidural analgesia, intravenous opioids, patient-controlled analgesia (PCA),

2 1292 Arch Orthop Trauma Surg (2015) 135: peripheral nerve block, and local intra-articular or periarticular analgesic injection [11 18]. Many studies on periarticular injection have reported good results in terms of reduction in post-operative pain and increased patient satisfaction [12, 13, 19, 20]. These studies focused on the acute pain experienced in the early post-operative period. To date, control of sub acute pain following TKA remains imperfect, and this is especially true of post-operative pain management. In previous studies [21 23], a single transdermal fentanyl patch (TFP) was placed before surgery for post-operative pain management only. In the present study, it was examined whether fitting a TFP, which provides a steady concentration of fentanyl, may aid post-operative pain management with NSAIDs in patients undergoing TKA. Simultaneously, lower leg functional recovery and adverse events (including nausea, vomiting, and constipation) were evaluated in the both groups. Methods Participants Fifty-two patients were prospectively studied. Primary total knee arthroplasty (TKA) was performed by a single surgeon in our university hospital. Ethical approval for this study (Ethical Committee No ) was provided by the Ethical Committee of Gifu University School of Medicine, Gifu, Japan (Chairman Prof. M. Seishima) on 2nd May All patients provided written, informed consent for participation in the study. The study was conducted using the sealed-envelope technique. Subjects offered enrolment included adults (32 86 years) scheduled for primary total knee arthroplasty (TKA) via a cm midline skin incision and a parapatellar approach. Exclusion criteria included the presence of allergy or sensitivity, or other contraindications to a TFP or morphine, as well as neuromuscular disease, dementia, major organ disease, pregnancy, history of substance or alcohol abuse, and tolerance to or dependence on opioids. Peri-operative procedures One hour and a half before arrival in the operating room (OR), all patients were orally pre-medicated with clonidine 3 lg/kg and ranitidine 150 mg. After arrival in the OR, standard monitoring and peripheral venous access was obtained. An epidural catheter was placed, before general anaesthesia, through the interspace between the second and third lumbar vertebral bodies, using a loss of resistance to saline for confirmation. The tip was directed 5 cm cephalad in all subjects. Intravascular or intrathecal catheter placement was excluded with a test dose of 3 ml lidocaine (1.5 %) plus 1:200,000 epinephrine. After confirming the correct placement of the catheter and providing effective analgesia, general anaesthesia was induced with thiopental 4 mg/kg, remifentanil 0.5 lg/kg/min, and rocuronium 0.6 mg/kg. Following tracheal intubation, anaesthesia was maintained with sevoflurane ( %: end-tidal) and remifentanil ( lg/kg/min). Infusion of 0.3 % ropivacaine was provided at a rate of 5 ml/h throughout surgery. An epidural infusion pump set to deliver ropivacaine 0.2 % (2 ml/h) and morphine (3 mg/day) was provided for two post-operative days, starting just before the end of surgery. All patients received oral loxoprofen 60 mg every 8 h for 14 postoperative days. Additionally, because a fentanyl patch should be used by patients who have already received opioid therapy and demonstrated opioid tolerance, patients who were to be fitted with a transdermal fentanyl patch received codeine 20 mg every 8 h for 2 days as a prior opioid drug beginning on post-operative day 2. In such patients, a single transdermal fentanyl patch 12.5 lg/h was placed on the anterior or lateral chest wall on post-operative day 4. This was replaced with a fresh one on post-operative day 7. The second TFP was removed on post-operative day 10. Intravenous flurbiprofen or diclofenac sodium suppository was provided to 27 patients who required additional analgesic drugs. Randomization Before surgery, participating patients were randomly assigned to one of the two treatment groups (Group NSAID or Group TFP) using a sealed-envelope technique. Patients in Group NSAID received loxoprofen 60 mg every 8 h for 14 post-operative days. Patients in Group TFP received one TFP (Durotep 12.5 lg/h, Janssen-Cliag) on post-operative day 4 and another on post-operative day 7, as well as loxoprofen 60 mg every 8 h for 14 post-operative days. In addition, we gave rescue NSAIDs as necessary in both groups. Outcome measurements Post-operative pain intensity was measured and recorded (by physical therapists who were not aware of the treatment group) using a 100 mm visual analogue scale (VAS), where 0 = no pain and 100 = worst imaginable pain. This was done at rest (rvas) and during movement (mvas) for 14 post-operative days. They also evaluated lower leg functional recovery by assessing both the range of motion of the knee and the muscle strength of the quadriceps. To measure the manual muscle force of the quadriceps, a muscle tester (Isoforce, OG GIKEN, Japan), which uses the same method as the Manual Muscle Test (MMT), was used on the last pre-operative day and on post-operative days 4,

3 Arch Orthop Trauma Surg (2015) 135: , and 14 (Table 1). Post-operative muscle strength was expressed as a percentage of the pre-operative value. The physical therapists measured outcome independently of each other. Adverse events and rescue dose Adverse events (including nausea, vomiting, constipation, drowsiness, dizziness, confusion, fatigue, itchiness, and headache) were examined. Patients with post-operative nausea and vomiting were treated with metoclopramide 10 mg as necessary. Patients with post-operative pain received relief via intravenous flurbiprofen 50 mg or diclofenac sodium suppository 25 mg. The number of times that a given patient received rescue drugs for pain or nausea was recorded for 14 post-operative days. Statistical methods A power analysis (two-tailed a error of 5 % and b error of 20 %) was performed before the study. The calculation of the required sample size was based on the quadriceps strength measured in a previous study during inpatient rehabilitation, following unilateral TKA with controlledrelease oxycodone (13.7 ± 6.2 Ib) or placebo (8.8 ± 4.0 Ib). Nineteen patients per group were required to reveal a statistically significant difference between the two groups. Group data were compared using the Mann Whitney U test for quantitative data and the Chi-square test for qualitative data. Statistical analysis was performed using the Prism 5.0 software. A value of p \ 0.05 was regarded as significant. Data are presented as mean ± SD. Results Demographic and clinical data Twenty-six patients from each group completed the study. The overall study population in the TFP and NSAID groups had mean ages of 70.1 years (range years) and 73.5 years (range years), respectively. The mean BMI was 25.7 kg/m 2 (range kg/m 2 ) in Group TFP and 25.1 kg/m 2 (range kg/m 2 ) in Group Table 1 Postoperative pain control protocol after TKA Group TFP Group NSAID Preoperative Operation day POD1 NSAIDs or acetaminofen if needed Epidural analgesia 2 Codeine 60mg/day FTP 12.5mg/hour FTP 12.5mg/hour

4 1294 Arch Orthop Trauma Surg (2015) 135: NSAID. Surgery time was min (range min) in Group TFP and min (range min) in Group NSAID. Intraoperative blood loss was 62.1 ml (range ml) in Group TFP and 37.5 ml (range ml) in Group NSAID. There were no differences in age (p = 0.28), BMI (p = 0.67), surgery time (p = 0.22), or intraoperative blood loss (p = 0.37) between the two groups (Table 2). Post-operative pain Post-operative pain intensity was measured (using a 100 mm VAS scale) at rest (rvas) and during movement (mvas). Mean rvas scores did not differ significantly between the two groups throughout the 14-day post-operative period (Fig. 1a). Mean mvas scores were not different on post-operative day 4, but were significantly smaller in the TFP group than in the NSAID group on postoperative days 7 (p = ) and 14 (p = 0.007) (Fig. 1b). These results suggest that TFP was effective, especially for post-operative pain during movement. Post-operative functional recovery Lower leg functional recovery was evaluated by examining range of motion (ROM) and muscle strength using a muscle tester. ROM did not differ between the two groups throughout the post-operative period (Table 3). However, muscle strength recovered faster in the TFP group than in the NSAID group, the percentage of pre-operative strength being significantly greater in the former than in the latter on post-operative days 7 (p = 0.027) and 14 (p = 0.047) (Fig. 2). These results indicate that TFP effectively promoted early post-operative recovery of muscle strength. Adverse events Summary of adverse events were shown in Table 4. Nausea was the most frequent side effect in each group. All the affected patients had nausea until post-operative day 2 [for nausea: Group TFP, N = 13/26 (50.0 %); Group NSAID, N = 9/26 (34.6 %); (p = )]. On or after post-operative day 3, no patient complained of nausea or vomiting in Table 2 Baseline patient characteristics and preoperative, intraoperative data Variables Group TFP Group NSAID p value N Age 70.1 ± ± Weight (kg) 58.5 ± ± Height (cm) ± ± Body Mass Index (kg/m 2 ) 25.7 ± ± Sex (M/F) 3/24 6/20 Side of surgery (R/L) 14/13 16/10 Surgery time (min) ± ± Intraoperative blood loss (ml) 62.1 ± ± Diagnosis (osteoarthritis/necrosis) 25/1 25/1 Fig. 1 a rvas. b mvas. VAS at rest (rvas) was comparable between Group TFP (transdermal fentanyl patch) and Group NSAID (non-steroid antiinflammatory drug), and in each group, the values were less than 30 mm throughout the study period. VAS during movement (mvas) was significantly smaller in Group TFP than in Group NSAID on postoperative days 7 and 14

5 Arch Orthop Trauma Surg (2015) 135: Table 3 Range of motion (ROM) Group TFP Group NSAID Pre-op ± ± 3.6 POD ± ± 4.8 POD ± ± 2.9 POD ± ± 2.8 Fig. 2 % muscle strength. Patients in Group TFP showed significantly faster recovery of lower leg muscle strength than those in Group NSAID on postoperative days 7 and 14 Table 4 Postoperative side effects, presented as number and percentage Side effects Group TFP N = 26 (%) Group NSAID N = 26 (%) p value Nausea 13 (50.0) 9 (34.6) 0.23 Vomiting 0 (0) 0 (0) Constipation 8 (30.8) 5 (19.2) 0.41 Drowsiness 0 (0) 0 (0) Dizziness 0 (0) 0 (0) Confusion 0 (0) 0 (0) Fatigue 0 (0) 0 (0) Itchiness 0 (0) 0 (0) Headache 0 (0) 0 (0) either group. The number of times a rescue drug for postoperative pain was given was significantly smaller in Group TFP than in Group NSAID (0.38 ± 0.15 vs 2.05 ± 0.58, p = ). The number of times an anti-constipation drug was needed did not differ between the groups (TFP group: 0.73 ± 0.23 vs NSAID group: 1.18 ± 0.73, p = 0.27). There were no instances of drowsiness, dizziness, confusion, fatigue, itchiness, or headache in either group after post-operative day 3. Discussion For improving the quality of life and restoring patients to a higher level of function with less pain, TKA is one of the most reliable orthopaedic procedures. Inadequate pain control during the post-operative period can lead to patient dissatisfaction and may result in chronic pain syndrome [9, 10]. As such, pain management in the immediate postoperative period is a particularly critical issue in orthopaedic surgery, including TKA. We opted to examine the post-operative pain management effect of a transdermal fentanyl patch (TFP) in patients who had undergone TKA. We found that TFP was effective for such post-operative pain management without any remarkable adverse events. Furthermore, the TKA patients treated with TFP exhibited early recovery of muscle strength. The transdermal fentanyl patch was originally described by Sebel et al. in 1987 [24], and indeed fentanyl was the first opioid commercially available for transdermal delivery. The Food and Drug Administration has granted limited approval for its use in patients with chronic cancer pain [21, 25 29]. In the 1990s, many authors reported that transdermal fentanyl was efficacious in the treatment of post-operative pain. Among them were Gourlay et al. [25] who noted the efficacy of transdermal fentanyl in the treatment of pain following abdominal surgery. Subsequently, Lehmann et al. [26] found that patients who were treated with transdermal fentanyl after major urological operations required significantly less additional fentanyl and reported less pain than patients in the placebo group. In the present study, patients treated by means of transdermal fentanyl patches had significantly less pain during movement and less requirement for rescue doses of analgesic drugs. These results indicate that the transdermal fentanyl patch is an effective form of post-operative pain management following total knee arthroplasty. Management of pain in the immediate post-operative period is critical for a speedy rehabilitation and for a reduced risk of post-operative complications. Cheville et al. [5] reported that pre-emptive use of controlled-release oxycodone during rehabilitation following unilateral total knee arthroplasty, led to improved pain control and also to a more rapid functional recovery. They concluded that a better constant-level analgesia would reduce the development of aberrant biomechanical patterns and facilitate the recovery of normal movement. Van Bastelaere et al. [21] detected stable plasma fentanyl concentrations in patients in their 75 lg/h TFP group. Furthermore, transdermal fentanyl patches are convenient because each patch can be left in place for 3 days. For these reasons, we selected the transdermal fentanyl patch for this study of post-operative pain management after TKA.

6 1296 Arch Orthop Trauma Surg (2015) 135: No previous reports have examined the efficacy of the transdermal fentanyl patch for muscle strength recovery. Our data indicate that patients treated with such patches displayed early recovery of muscle strength. Judging from these results, the TFP is effective not only in alleviating post-operative pain, but also in facilitating muscle strength recovery after total knee arthroplasty. Despite several other studies having been conducted in the field of orthopaedics, our study is unique with respect to the amount of fentanyl delivered and the timing of the transdermal fentanyl patch treatment. For example, Van Bastelaere et al. [21] reported that a 75 lg/h TFP used preoperatively resulted in post-operative pain relief and decreased morphine consumption following orthopaedic surgeries. Also, Minville et al. [22] showed that a 50 lg/h TFP, placed 10 h before the induction of general anaesthesia, was effective for 24 h in decreasing both the severity of pain and the consumption of rescue morphine in patients undergoing total hip arthroplasty. Recently, Abrisham et al. [23] reported that two 25 lg/h TFPs, which were placed simultaneously on the lateral chest wall approximately 12 h before the induction of general anaesthesia, provided effective pain relief and decreased the total rescue morphine consumption during the first 72 h after TKA surgery without adverse side effects. In our study, we used 12.5 lg/h TFP patches placed sequentially on the chest wall from post-operative day 4 to 10; therefore, the amount of TFP delivered per hour was one-fourth or less than half that mentioned in previous reports. Thus, our study indicates that even this amount of TFP is effective in providing post-operative pain relief and early functional recovery, without adverse events. A power analysis was conducted but several limitations still exist. In this study, we could not use other opioids, including oxycodone. It may be interesting to examine the effects of other narcotics and compare them with those of fentanyl. Ip et al. noted that pre-operative psychological factors affected the post-operative pain intensity and analgesic consumption [30]; therefore, further studies that take into consideration pre-operative psychological factors, such as anxiety or catastrophizing, may be helpful in evaluating patients in need of TFP. Other studies [21, 31] have shown that we need to pay attention to the adverse events associated with the use of the transdermal fentanyl patch. Sandler et al. [31] reported that a 50 or 75 lg/h TFP was associated with a high incidence of respiratory depression, requiring intensive monitoring and oxygen supplementation in patients undergoing abdominal hysterectomy. Van Bastelaere et al. [21], whilst noting the efficacy of transdermal fentanyl for post-operative pain relief, reported that intense respiratory depression was sometimes seen in patients following orthopaedic surgery. In this study, we did not observe significantly more adverse events, such as respiratory depression, constipation, and nausea in Group TFP than in Group NSAID. However, nausea did occur in some of our patients until post-operative day 2. According to Apfel et al. [32], post-operative nausea and vomiting (PONV) is mainly triggered by perioperative administration of emetogenic stimuli, such as volatile anaesthetics and post-operative opioids. The incidence of nausea in the present study may be related to the anaesthetic drugs and/or to the post-operative morphine administered via the epidural catheter before the first transdermal fentanyl patch was applied. The crucial difference between previous reports and the present study, with respect to the occurrence of adverse events, may be attributed to the amount of fentanyl (50 75 vs lg/h) administered. In addition, our patients sensitivity to opioid, for the induction of nausea, may have been reduced because of the repeated use of opioid during surgery. Finally, the present study has shown that a 12.5 lg/h TFP can improve post-operative pain relief and hasten functional recovery in patients who undergo total knee arthroplasty. Mobilisation may be limited for orthopaedic patients because of uncontrolled movement-evoked pain in the early post-operative period. Adequate pain relief during motion because of the TFP (vs. NSAID alone), for around 10 days post-operatively, may have contributed to the pain relief observed on the 14th post-operative day (Fig. 1b). Judging from these results, patients undergoing TKA may benefit from the use of a 12.5 lg/h TFP; however, larger studies are necessary to prove these points. For even better post-operative pain management, this treatment may be combined with effective alternative analgesia, including peri-articular analgesic injection [17, 18] or regional nerve blockade. Conflict of interest References None. 1. Hawker G, Wright J, Coyte P et al (1998) Health-related quality of life after knee replacement. J Bone Joint Surg Am 80(2): Meding JB, Meding LK, Ritter MA et al (2012) Pain relief and functional improvement remain 20 years after knee arthroplasty. Clin Orthop Relat Res 470(1): Norman-Taylor FH, Palmer CR, Villar RN (1996) Quality-of-life improvement compared after hip and knee replacement. J Bone Joint Surg Br 78(1): Chelly JE, Ben-David B, Williams BA et al (2003) Anesthesia and postoperative analgesia: outcomes following orthopedic surgery. Orthopedics. 26(8 Suppl):s865 s871 (Review) 5. Cheville A, Chen A, Oster G et al (2001) A randomized trial of controlled-release oxycodone during inpatient rehabilitation following unilateral total knee arthroplasty. J Bone Joint Surg Am 83-A(4):

7 Arch Orthop Trauma Surg (2015) 135: Modig J, Borg T, Karlström G et al (1983) Thromboembolism after total hip replacement: role of epidural and general anesthesia. Anesth Analg 62(2): Rodgers A, Walker N, Schug S et al (2000) Reduction of postoperative mortality and morbidity with epidural or spinal anaesthesia: results from overview of randomised trials. BMJ 321(7275): Singelyn FJ, Deyaert M, Joris D et al (1998) Effects of intravenous patient-controlled analgesia with morphine, continuous epidural analgesia, and continuous three-in-one block on postoperative pain and knee rehabilitation after unilateral total knee arthroplasty. Anesth Analg 87(1): Harden RN, Bruehl S, Stanos S et al (2003) Prospective examination of pain-related and psychological predictors of CRPS-like phenomena following total knee arthroplasty: a preliminary study. Pain 106(3): Parvizi J (2012) Pain management following total joint arthroplasty: making strides. J Bone Joint Surg Am 94(16): American Society of Anesthesiologists Task Force on Acute (2012) Pain Management. Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology 116(2): Andersen KV, Bak M, Christensen BV et al (2010) A randomized, controlled trial comparing local infiltration analgesia with epidural infusion for total knee arthroplasty. Acta Orthop 81(5): Carli F, Clemente A, Asenjo JF et al (2010) Analgesia and functional outcome after total knee arthroplasty: periarticular infiltration vs continuous femoral nerve block. Br J Anaesth 105(2): Fischer HB, Simanski CJ, Sharp C, PROSPECT Working Group et al (2008) A procedure-specific systematic review and consensus recommendations for postoperative analgesia following total knee arthroplasty. Anaesthesia 63(10): Fu P, Wu Y, Wu H et al (2009) Efficacy of intra-articular cocktail analgesic injection in total knee arthroplasty a randomized controlled trial. Knee 16(4): Lombardi AV Jr, Berend KR, Mallory TH et al (2004) Soft tissue and intra-articular injection of bupivacaine, epinephrine, and morphine has a beneficial effect after total knee arthroplasty. Clin Orthop Relat Res 428: Maheshwari AV, Blum YC, Shekhar L et al (2009) Multimodal pain management after total hip and knee arthroplasty at the Ranawat Orthopaedic Center. Clin Orthop Relat Res 467(6): Parvataneni HK, Ranawat AS, Ranawat CS (2007) The use of local periarticular injections in the management of postoperative pain after total hip and knee replacement: a multimodal approach. Instr Course Lect 56: Koh IJ, Kang YG, Chang CB et al (2012) Does periarticular injection have additional pain relieving effects during contemporary multimodal pain control protocols for TKA?: a randomised, controlled study. Knee 19(4): Parker DA, Coolican MR, Mather LE et al (2009) Safety of combined use of local anesthetic infiltration and reinfusion drains in total knee arthroplasty. J Arthroplasty 24(6): Van Bastelaere M, Rolly G, Abdullah NM (1995) Postoperative analgesia and plasma levels after transdermal fentanyl for orthopedic surgery: double-blind comparison with placebo. J Clin Anesth 7(1): Minville V, Lubrano V, Bounes V et al (2008) Postoperative analgesia after total hip arthroplasty: patient-controlled analgesia versus transdermal fentanyl patch. J Clin Anesth 20(4): Abrisham SM, Ghahramani R, Heiranizadeh N et al (2014) Reduced morphine consumption and pain severity with transdermal fentanyl patches following total knee arthroplasty. Knee Surg Sports Traumatol Arthrosc 22(7): Sebel PS, Barrett CW, Kirk CJ et al (1987) Transdermal absorption of fentanyl and sufentanil in man. Eur J Clin Pharmacol 32(5): Gourlay GK, Kowalski SR, Plummer JL et al (1990) The efficacy of transdermal fentanyl in the treatment of postoperative pain: a double-blind comparison of fentanyl and placebo systems. Pain 40(1): Lehmann KA, Einnolf C, Eberlein HJ et al (1991) Transdermal fentanyl for the treatment of pain after major urological operations. A randomized double-blind comparison with placebo using intravenous patient-controlled analgesia. Eur J Clin Pharmacol 41(1): Kilbride M, Morse M, Senagore A (1994) Transdermal fentanyl improves management of postoperative hemorrhoidectomy pain. Dis Colon Rectum 37(11): Broome IJ, Wright BM, Bower S et al (1995) Postoperative analgesia with transdermal fentanyl following lower abdominal surgery. Anaesthesia 50(4): Miguel R, Kreitzer JM, Reinhart D et al (1995) Postoperative pain control with a new transdermal fentanyl delivery system. A multicenter trial. Anesthesiology 83(3): Ip HY, Abrishami A, Peng PW et al (2009) Predictors of postoperative pain and analgesic consumption: a qualitative systematic review. Anesthesiology 111(3): Sandler AN, Baxter AD, Katz J et al (1994) A double-blind, placebo-controlled trial of transdermal fentanyl after abdominal hysterectomy. Analgesic, respiratory, and pharmacokinetic effects. Anesthesiology 81(5): Apfel CC, Heidrich FM, Jukar-Rao S et al (2012) Evidence-based analysis of risk factors for postoperative nausea and vomiting. Br J Anaesth 109(5):

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