Pain Research and Management

Acute Postoperative Pain Control

Lead Guest Editor: Volkan Hancı Guest Editors: Bülent S. Yurtlu, Rudin Domi, Yasuyuki Shibata, and Can Eyigör Acute Postoperative Pain Control Pain Research and Management

Acute Postoperative Pain Control

Lead Guest Editor: Volkan Hanci Guest Editors: Bülent S. Yurtlu, Rudin Domi, Yasuyuki Shibata, and Can Eyigör Copyright © 2017 Hindawi. All rights reserved.

This is a special issue published in “Pain Research and Management.” All articles are open access articles distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Editorial Board

Jacob Ablin, Israel Parisa Gazerani, Denmark Joukje Oosterman, Netherlands Massimo Allegri, Italy José W. Geurts, Netherlands Andreas Sandner-Kiesling, Austria Anna Maria Aloisi, Italy Yelena Granovsky, Israel Masahiko Shibata, Japan Fabio Antonaci, Italy Manfred Harth, Canada Till Sprenger, Germany Emily J. Bartley, USA Gerrit Hirschfeld, Germany Stefano Tamburin, Italy Filippo Brighina, Italy Shinya Kasai, Japan Cristiano Termine, Italy Egidio Del Fabbro, USA Joel Katz, Canada Alison Twycross, UK Bruno Gagnon, Canada James H. Mcauley, Australia Fletcher A. White, USA Federica Galli, Italy Jordi Miró, Spain PhillipJ.Wiffen,UK MarekJ.Gawel,Canada Frauke Musial, Norway Contents

Acute Postoperative Pain Control Volkan Hancı, Bülent S. Yurtlu, Rudin Domi, Yasuyuki Shibata, and Can Eyigör Volume 2017, Article ID 7831014, 2 pages

The Effect of Peritubal Infiltration with Bupivacaine and Morphine on Postoperative Analgesia in Patients Undergoing Percutaneous Nephrolithotomy Isra Karaduman, Derya Karasu, Canan Yilmaz, Sedat Oner, Hilal Erdem Solak, and Gulsen Korfali Volume 2017, Article ID 2454267, 8 pages

The Antinociceptive Effect of Light-Emitting Diode Irradiation on Incised Wounds Is Correlated with Changes in Cyclooxygenase 2 Activity, Prostaglandin E2, and Proinflammatory Cytokines Yuan-Yi Chia, Chien-Cheng Liu, Guan-Ming Feng, Chia-Chih Alex Tseng, Kuo-Chuan Hung, Chih-Chieh Chen, and Ping-Heng Tan Volume 2017, Article ID 4792489, 9 pages

Gabapentin Does Not Appear to Improve Postoperative Pain and Sleep Patterns in Patients Who Concomitantly Receive Regional Anesthesia for Lower Extremity Orthopedic Surgery: A Randomized Control Trial Jean Daniel Eloy, Christy Anthony, Shawn Amin, Moorice Caparó, Mark C. Reilly, and Steven Shulman Volume 2017, Article ID 2310382, 5 pages

Peritoneal Nebulization of Ropivacaine during Laparoscopic Cholecystectomy: Dose Finding and Pharmacokinetic Study Massimo Allegri, Martina Ornaghi, Catherine E. Ferland, Dario Bugada, Yash Meghani, Serena Calcinati, Manuela De Gregori, Federica Lovisari, Krishnaprabha Radhakrishnan, Maria Cusato, Stefano Scalia Catenacci, Marta Somaini, Guido Fanelli, and Pablo Ingelmo Volume 2017, Article ID 4260702, 9 pages

Adherence to All Steps of a Pain Management Protocol in Intensive Care Patients after Cardiac Surgery Is Hard to Achieve L.vanGulik,S.J.G.M.Ahlers,P.Bruins,D.Tibboel,C.A.J.Knibbe,andM.vanDijk Volume 2017, Article ID 7187232, 7 pages

The Anatomic Relationship of the Tibial Nerve to the Common Peroneal Nerve in the Popliteal Fossa: Implications for Selective Tibial Nerve Block in Total Knee Arthroplasty Eric R. Silverman, Amaresh Vydyanathan, Karina Gritsenko, Naum Shaparin, Nair Singh, Sherry A. Downie, and Boleslav Kosharskyy Volume 2017, Article ID 7250181, 6 pages

Comparison of the Effects of Intrathecal Fentanyl and Intrathecal Morphine on Pain in Elective Total Knee Replacement Surgery Refika Kılıçkaya, Yavuz Orak, Mehtap Arda Balcı, Fatih Balcı, and İlker Ünal Volume 2016, Article ID 3256583, 5 pages

Combination Therapy with Continuous Three-in-One Femoral Nerve Block and Periarticular Multimodal Drug Infiltration after Total Hip Arthroplasty Tomonori Tetsunaga, Tomoko Tetsunaga, Kazuo Fujiwara, Hirosuke Endo, and Toshifumi Ozaki Volume 2016, Article ID 1425201, 6 pages Postthoracotomy Ipsilateral Shoulder Pain: A Literature Review on Characteristics and Treatment Fardin Yousefshahi, Oana Predescu, Melissa Colizza, and Juan Francisco Asenjo Volume 2016, Article ID 3652726, 9 pages

Effect of Intravenous High Dose Vitamin C on Postoperative Pain and Morphine Use after Laparoscopic Colectomy: A Randomized Controlled Trial YounghoonJeon,JunSeokPark,SuyoungMoon,andJinseokYeo Volume 2016, Article ID 9147279, 6 pages

A Comparison of Oxycodone and Alfentanil in Intravenous Patient-Controlled Analgesia with a Time-Scheduled Decremental Infusion after Laparoscopic Cholecystectomy Young Suk Kwon, Ji Su Jang, Na Rea Lee, Seong Su Kim, Young Ki Kim, Byeong Mun Hwang, Seong Sik Kang, Hee Jeong Son, and So Young Lim Volume 2016, Article ID 7868152, 8 pages Hindawi Pain Research and Management Volume 2017, Article ID 7831014, 2 pages https://doi.org/10.1155/2017/7831014

Editorial Acute Postoperative Pain Control

Volkan HancJ,1 Bülent S. Yurtlu,1 Rudin Domi,2 Yasuyuki Shibata,3 and Can Eyigör4

1 Department of Anesthesiology and Reanimation, Dokuz Eylul¨ University, Izmir,˙ Turkey 2Department of Anesthesiology and Reanimation, Mother Teresa University Hospital Center, Tirana, Albania 3Department of Anesthesiology and Reanimation, Nagoya University Hospital, Nagoya, Japan 4Department of Anesthesiology and Reanimation, Ege University, Izmir,˙ Turkey

Correspondence should be addressed to Volkan Hancı; [email protected]

Received 14 May 2017; Accepted 14 May 2017; Published 8 June 2017

Copyright © 2017 Volkan Hancı et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Recovery from anesthesia is a source of great stress for drugs or drug combinations used for them. There is an patients. Postanesthesia recovery must occur comfortably instance of looking for new or modified techniques or drug anduneventfullyinacontrolledenvironment.However, combinations in hope of reduced side effect but increased as it usually starts in the operating room, patients are efficiency [2–6]. In this specific issue, the readers will find brought to the recovery unit with airway blockage, shiver, eleven articles opening the gate bigger to our understanding agitation, delirium, pain, nausea, vomiting, hypothermia, of acute pain management after surgery. These articles cover and autonomic instability risks. Most surgical morbidities some of the missing parts on postoperative pain management and mortalities happen in the postoperative period. Among subject. patients who have had surgery, the early and late postoper- In this issue, readers will find eleven articles including ativeperiodsconstituteoneofthemostcriticalstages.All “The Effect of Peritubal Infiltration with Bupivacaine and of these facts emphasize the importance of postoperative Morphine on Postoperative Analgesia in Patients Undergo- recovery and postoperative care [1]. Millions of surgical ing Percutaneous Nephrolithotomy” by I. Karaduman and therapies are performed worldwide and patients suffer from colleagues, “The Antinociceptive Effect of Light-Emitting varying degrees of postoperative pain after these procedures Diode Irradiation on Incised Wounds Is Correlated with [2]. Postoperative pain is one of the most important prob- Changes in Cyclooxygenase 2 Activity, Prostaglandin E2, and lems in the postoperative period. Postoperative pain, with Proinflammatory Cytokines” by Y.-Y. Chia and colleagues, nociceptive, inflammatory, and neuropathic components, “GabapentinDoesNotAppeartoImprovePostoperative begins with surgical trauma and reduces as the tissue heals. Pain and Sleep Patterns in Patients Who Concomitantly Untreatedpaincausedbysurgicaltraumaproducesvery Receive Regional Anesthesia for Lower Extremity Orthope- important physiopathologic changes in children and adults. dicSurgery:ARandomizedControlTrial”byJ.D.Eloyand Eˇsective treatment of postoperative pain decreases surgical colleagues, “Peritoneal Nebulization of Ropivacaine during mortality and morbidity rates and has been shown to promote Laparoscopic Cholecystectomy: Dose Finding and Pharma- quicker healing [2]. One of the main components of early cokinetic Study” by M. Allegri and colleagues, “Adherence recovery after surgery programs is establishment of adequate to All Steps of a Pain Management Protocol in Intensive perioperative analgesia. Historically, systemic administration Care Patients after Cardiac Surgery Is Hard to Achieve” of opioid drug groups has been the cornerstone of acute by L. Gulik and colleagues, “The Anatomic Relationship postoperative pain control but trends have changed towards of the Tibial Nerve to the Common Peroneal Nerve in increased utilization of regional anesthetic and analgesic the Popliteal Fossa: Implications for Selective Tibial Nerve techniques during the last few decades. Of note, in the last BlockinTotalKneeArthroplasty”byE.R.Silvermanand decade, even the regional techniques affecting a big surface colleagues, “Comparison of the Effects of Intrathecal Fentanyl area of the body have been questioned together with the and Intrathecal Morphine on Pain in Elective Total Knee 2 Pain Research and Management

Replacement Surgery” by R. Kılıc¸kaya and colleagues, “Com- bination Therapy with Continuous Three-in-One Femoral Nerve Block and Periarticular Multimodal Drug Infiltration after Total Hip Arthroplasty” by T. Tetsunaga and colleagues, “Postthoracotomy Ipsilateral Shoulder Pain: A Literature Review on Characteristics and Treatment” by F. Yousefshahi and colleagues, “Effect of Intravenous High Dose Vitamin C on Postoperative Pain and Morphine Use after Laparoscopic Colectomy: A Randomized Controlled Trial” by Y. Jeon and colleagues, and “A Comparison of Oxycodone and Alfentanil in Intravenous Patient-Controlled Analgesia with a Time-Scheduled Decremental Infusion after Laparoscopic Cholecystectomy” by Y. S. Kwon and colleagues. Thisbodyofresearchasawholeemphasizestheimpor- tance of acute pain management after surgery and fills out the knowledge gaps in specific areas and presents new alternate therapies when applicable. Volkan Hancı Bulent¨ S. Yurtlu Rudin Domi Yasuyuki Shibata Can Eyigor¨

References

[1] V. Hanci and P. Ozcan,¨ “Recovery and Postanesthesia Care in Geriatric Anaesthesia,” Turkiye¨ Klinikleri Journal of Anesthesia and Reanimation-Special Topics, vol. 4, no. 1, p. 52-59, 2011. [2] V. Hancı, H. A. Kiraz, D. Om¨ ur,¨ B. S. Yurtlu, and D. A. Yurtlu et al., “Postoperative Pain in Children,” Journal of Anesthesia & Clinical Research,vol.03,no.06,2012. [3] B. Mugabure Bujedo, I. Tranque Bizueta, S. Gonzalez´ Santos, and R. Adrian´ Garde, “Multimodal approaches to postoperative pain management and convalescence,” Revista Espanola˜ de Anestesiolog´ıa y Reanimacion´ ,vol.54,no.1,pp.29–40,2007. [4] D. Om¨ ur,H.O¨ guzalp,˘ H. A. Kiraz et al., “The analgesic efficacy of ultrasound-guided transversus abdominis plane block on postoperative pain and morphine consumption in varicocelec- tomy,” Saudi Medical Journal,vol.37,no.6,pp.648–655,2016. [5] O.¨ Yagan,˘ N. Tas¸, A. Kuc¸¨ uk,¨ and V. Hancı, “A comparison of different densities of levobupivacaine solutions for unilateral spinal anaesthesia,” Brazilian Journal of Anesthesiology (English Edition),vol.66,no.2,pp.157–164,2016. [6] C. Altas¸, G. Kuc¸¨ ukosman,¨ B. S. Yurtlu et al., “Anesthesia methods used by anesthetic specialists for circumcision cases. National survey study for Turkey,” Saudi Medical Journal,vol. 38,no.1,pp.75–81,2017. Hindawi Pain Research and Management Volume 2017, Article ID 2454267, 8 pages https://doi.org/10.1155/2017/2454267

Clinical Study The Effect of Peritubal Infiltration with Bupivacaine and Morphine on Postoperative Analgesia in Patients Undergoing Percutaneous Nephrolithotomy

Isra Karaduman,1 Derya Karasu,1 Canan Yilmaz,1 Sedat Oner,2 Hilal Erdem Solak,1 and Gulsen Korfali1

1 Bursa Yuksek Ihtisas Training and Education Hospital, Clinic of Anesthesiology and Reanimation, Bursa, Turkey 2BursaYuksekIhtisasTrainingandEducationHospital,UrologyClinic,Bursa,Turkey

Correspondence should be addressed to Derya Karasu; [email protected]

Received 1 December 2016; Revised 4 February 2017; Accepted 7 February 2017; Published 18 April 2017

Academic Editor: Volkan Hancı

Copyright © 2017 Isra Karaduman et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Objective. We aimed to investigate the effect of peritubal local anesthetic and opioid infiltration on pain scores and analgesic consumption in patients who underwent percutaneous nephrolithotomy.MaterialandMethods.Patients aged between 18 and 65 years and ASA I-III were included in this double-blind, randomized study. The patients were divided into two groups. All patients underwent spinoepidural anesthesia. 20 mL of 0.25 percent bupivacaine + 5 mg morphine (0.5 mL), in Group P (𝑛=66), infiltrated the renal capsule, perinephric fat, muscles, subcutaneous tissue, and skin under fluoroscopy. In Group C (𝑛=64), none of the patients received a peritubal injection. In the first 24 h pain scores, time of the first analgesic demand, the mean number of analgesic demands, and postoperative complications were compared between groups. Results.ThemeanVASscoreatpostoperative8,12,and 24 h and dynamic VAS score at postoperative 4, 8, 12, and 24 h were significantly lower in Group P. VAS score at postoperative 4h was not significant. Time of the first analgesic demand was significantly longer in Group P. Conclusion. Ourstudyresultssuggestthat peritubal infiltration of bupivacaine with morphine after percutaneous nephrolithotomy is an effective method for postoperative pain control and reduces analgesic consumption.

1. Introduction through a patient-controlled analgesia (PCA) pump inserted through the epidural catheter. This approach, combining low Percutaneous nephrolithotomy (PNL) is the preferred choice doses of local anesthetics and opioids, provides a highly > of treatment for large ( 2 cm) and complex kidney stones. It selective and effective sensorial block. Recent studies have is a minimally invasive surgical procedure, during which the demonstrated that CSE anesthesia technique allows patients kidney stones can be removed by the insertion through a hole to be discharged early to their homes, as this technique created between the skin and the kidney [1]. results in minimal motor block by providing an opportunity Percutaneous nephrolithotomy is frequently performed for medication titration [2]. During PNL procedure, stones under general anesthesia. A recently performed meta-ana- are removed, while the patient is in the prone position, lysis established the superiority of regional anesthetic meth- andsubsequentlyanephrostomytubeisinsertedtoachieve ods to general anesthesia, thanks to their success in shorten- urinary drainage and adequate hemostasis [3]. ing duration of hospitalization, reducing morbidity, and anal- Most of the pain is experienced during dilatation of the gesic demand [1]. Combined spinoepidural (CSE) anesthesia renal capsule and the parenchymal tract and not during is a preferred method thanks to the rapid onset of anesthesia, intrarenal handling or stone disintegration at the time of PNL increased efficacy, minimal toxic effects of spinal block, and [3]. Thoracic paravertebral block, local anesthetic infiltration prolongation of anesthesia duration by epidural anesthe- around nephrostomy tract, and intravenous paracetamol can sia [2]. Moreover, postoperative analgesia can be regulated be used for postoperative pain relief [4–6]. 2 Pain Research and Management

In this study, we aimed to investigate the effect of Operation was initiated, when the sensorial block reached T6 peritubal infiltration on postoperative 24 h pain scores and level and Bromage score was found to be 1. analgesic consumption through an epidural PCA device in In addition, 5 to 10 mg ephedrine (Ephedrine HCl5,Osel, patients undergoing PNL under CSE anesthesia. Turkey) was administered to the patients whose systolic arterial blood pressure decreased more than 30%, compared to baseline, or mean arterial blood pressure (MAP) was below 2. Material and Methods 60 mmHg. The patients with a heartbeat rate (HBR) below 50 bpm were given 0.01 mg/kg i.v. atropine (Atropin Sulfat¨ 5, A written informed consent was obtained from each patient. Osel, Istanbul, Turkey). The study protocol was approved by the Local Ethics Com- In lithotomy position, a guidewire was inserted in the mittee and Australian New Zealand Clinical Trials Registry patients, using an 8 F ureterorenoscope, and 6 F ureteral (ACTRN12617000431325). The study was conducted in accor- catheter was placed. All patients were positioned in the prone dance with the principles of the Declaration of Helsinki. This position following the insertion of a 16 F Foley urethral was a single-center, prospective, randomized-controlled, and catheter. Then, 30 F Amplatz dilatation was performed over double-blind study carried out in patients who underwent the guidewire in all patients. Fluoroscopic examination was PNL due to kidney stones between May 2015 and May 2016. performed following the stone removal, and a 16 F reentry The patients aged between 18 and 65 years, whose the nephrostomy catheter was inserted. All operations were American Society of Anesthesiologists (ASA) score was I–III, carried out by a single surgical team. 2 body mass index was <30 kg/m , stone size measured >2cm, The patients were divided into two groups based on the and duration of surgery was <3 h, were included in the study. method of postoperative analgesia and randomization was Patients allergic to local anesthetics or morphine, patients done by closed envelope method. having a contraindication to neuroaxial block, patients given Group P (𝑛=66), peritubal infiltration group was given general anesthesia, those with a bleeding disorder, those 0.25% bupivacaine 20 mL + 5 mg morphine (0.5 ml) (Mor- having alcohol or substance abuse, patients who underwent phine HCl5, Galen, Istanbul, Turkey) into the renal capsule, surgical interventions from multiple sites, and patients who peripheral fat tissue, muscle tissue, subcutaneous tissues, and underwent bilateral PNL were excluded. skin after a nephrostomy tube was inserted using a 22 G spinal Patients with an intraoperative massive bleeding, those needle advanced towards 6 and 12 O’clock positions as guided switched to open surgery, patients in whom an epidural by a fluoroscopy along nephrostomy catheter. catheter was unable to be placed, patients who developed Group C (𝑛=64), control group was not given peritubal epidural catheter migration, patients switched to general infiltration for analgesia. anesthesia, patients having cardiopulmonary arrest, patients Epidural PCA was prepared including 40 mL 0.5% bupi- who were initiated on inotropic agents, and patients whose vacaine + 500 mg fentanyl + 110 mL 0.9% NaCl, to a total epidural catheter was removed after operation were also of 160 mL epidural solution as postoperative analgesic for excluded from the study. all patients (CADD-Legacy5 PCA, Smiths Medical, St Paul, As premedication, 0.01–0.02 mg/kg intravenous (i.v.) USA). Without a basal infusion, bolus dose was set as 5 mL, midazolam (Zolamid5, Defarma, Ankara, Turkey) was used. key duration as 20 min, and hourly limit as 15 mL. All patients were given 15 to 20 mL/kg i.v. physiological Patient’s age, educational status, previous experience with saline over 30 min to achieve preoperative hydration. While regional block, ASA score, preoperative Hemoglobin/hema- the patients were in the sitting position, epidural interval tocrit value, stone localization, intraoperative hypotension, was accessed through L1-2 or T12-L1 intervertebral space bradycardia, nausea, vomiting, and any blood transfusions midline by 18 G Touhy needle (Epifix Standard, Egemen5, were recorded. A criterion for preoperative blood transfusion Izmir, Turkey) using loss of resistance approach, and the was defined as the presence of a Hemoglobin level of catheter was advanced for 4 to 5 cm. Subsequently, 3 mL <10 mg/dl. Postoperative pain levels at rest were assessed lidocaine was administered in combination with 1 : 200.000 using the Visual Analogue Scale (VAS), and dynamic VAS epinephrine as an epidural test dose. The subarachnoid space (DVAS) was used to assess the level of pain during coughing was accessed through L3-4 or L4-5 intervertebral space midline anddeepbreathing.TheVASwasassessedonpostoperative by 25 G Quincke spinal needle (Egemen5,Izmir,Turkey) hours0,2,4,8,12,and24byananesthetistwhowasblinded and 0.125% bupivacaine 3 mL and 20 𝜇g intrathecal fentanyl to the treatment allocation in this study. The patients whose were administered, once free cerebrospinal fluid leakage was VAS score was not <3 despite bolus administration were observed. The differential sensory nerve block resulting from given concomitant analgesia by 50 mg i.v. tramadol HCl blocking the A-ß, A-𝛿, and C fibers at different degrees (Tramosel5, Haver, Istanbul, Turkey). Time of the first was maintained in all patients. The epidural catheter was analgesic use, analgesic requirement, amount of analgesics appropriately placed into the skin. After the patient was taken administered, and concomitant analgesic doses were also into supine position, 4 mL 0.5% bupivacaine (Bustesin5,Vem, recorded. Heart rate, mean arterial pressure, respiratory rate, Ankara, Turkey) + 25 𝜇gfentanyl(Talinat5,Vem,Istanbul, hypoxia (SpO2 < 90), nausea, vomiting, pruritus, allergic Turkey) + 3.5 mL saline were administered to a total of 8 mL reaction, urinary retention, and cognitive changes were throughanepiduralcatheter.Followingspinalanesthesia, recorded postoperatively. Postoperative complications were the level of sensorial block was assessed by pinprick test assessed according to the Modified Clavien Classification andmotorblockwasevaluatedusingtheBromagescores. (MCC). Pain Research and Management 3

Enrollment Assessed for eligibility (n = 214)

Excluded (n=39) (i) No Turkish speech (n=23) (ii) Declined to participate (n=16)

Randomized (n = 175)

Allocation

Group C (n= 90) Group P (n=85) Discontinued intervention (n=20) Discontinued intervention (n=17) (i) No insertion of epidural catheter (n=2) n=4 (i) No insertion of epidural catheter ( ) (ii) Inability to perform spinal anesthesia (ii) Intraoperative guidewire breakage (n=1) (n=1) (iii) More than one access (n=12) (iii) Intraoperative abdominal distension (n=1) (iv) More than one access (n=16)

Follow-up n=70 Group P (n=68) Group C ( ) Discontinued intervention (n=6) Discontinued intervention (n=2) (i) Epidural catheter displacement (n=4) (i) Epidural catheter displacement (n=2) (ii) Pleural effusion (n=1) (iii) Reoperation (n=1)

Analysis

Group P (n=66) Group C (n=64)

Figure 1: Trial flow diagram.

2.1. Statistical Analysis. Statistical analysis was performed 3. Results using SPSS version 18.0 for Windows program (Statistical Package for the Social Sciences, SPSS Inc., Chicago, IL, USA). Of a total of 214 patients who underwent surgery for PNL, 130 Descriptive data were expressed in mean and standard devi- were included into statistical analysis (Figure 1). The mean age ation for qualitative data and in frequency and percentage of the patients was 48.53 ± 11 years and 48.94 ± 12.3 years in for quantitative data. For between-group comparisons, the Groups P and C, respectively. Demographical characteristics chi-square and Fisher’s exact tests were used for categorical of the patients were not significantly different between two variables, while 𝑡-test was used to compare continuous groups (Table 1). Preoperative (Group P: 14.31, Group C: 14.31, variables between two groups. Values ranging from 0.10 to 𝑝 = 0.29) and postoperative (Group P: 12.77, Group C: 12.21, 0.29 were considered to indicate low/weak, from 0.30 to 𝑝 = 0.10) Hemoglobin levels were not significantly different 0.49 moderate, and from 0.50 to 1.00 strong correlation in between two groups. Single dose solution (bupivacaine + the correlation analysis. A 𝑝 value of <0.05 was considered fentanyl + saline) was applied at the beginning of surgery and statistically significant. Required sample size for each study there was no need for supplemental dose for intraoperative group was estimated as 64 at 0.05 significance level with pain relief through an epidural catheter. 80% power, based on a similar study [7–9] showing that the Duration of operation (Group P: 82.2 ± 31.20 min, standard deviation for the use of analgesics was 30 and the Group C: 87.6 ± 25.5 min, 𝑝 = 0.27) and time until difference between the means was 15. removal of nephrostomy catheter (Group P: 2.14 ± 0.52 days, 4 Pain Research and Management

Table 1: Patient characteristics [mean ± standard deviation, 𝑛, (%)].

Group P Group C 𝑝 (𝑛=66) (𝑛=64) Age (year) 48.53 ± 11 48.94 ± 12.3 0.84 Sex (i) Female 26, (39.4) 26, (40.6) 0.88 (ii) Male 40, (60.6) 48, (59.4) History of regional anesthesia (i) Yes 18, (27.3) 13, (20.3) 0.41 (ii) No 48, (72.7) 51, (79.7) ∗ ASA (i) I 22, (33.3) 15, (23.4) 0.50 (ii) II 43, (65.2) 48, (75) (iii) III 1, (1.5) 1, (1.6) Educational level (i) Not being illiterate 23 (34.8) 20 (31.3) (ii) Primary school 22 (33.3) 19 (29.7) 0.40 (iii) Middle school 5 (7.6) 7 (10.9) (iv) High school 10 (15.2) 16 (25) (v) University 6 (9.1) 2 (3.1) ∗ ASA:AmericanSocietyofAnesthesiology.

MAP ± 140 Table 2: Analgesic usage profile of the groups (mean standard 120 deviation). 100 80 Group P Group C 𝑝 60 𝑛=66 𝑛=64 40 ( ) ( ) 20 Time of first analgesia ∗ 262.2 ± 214.4 148.8 ± 110.3 <0.001 0 (minute) Number of demand ∗ 8.33 ± 8.8 16.9 ± 16.4 <0.001 doses Beginning 5th minute

10th minute 15th minute 30th minute 45th minute 60th minute 75th minute 90th minute Number of total ± ± <0.001 105th minute 120th minute ∗ 6.05 5 10.5 7. 7 After After sedation analgesic doses ∗ Group P 𝑝 <0.05. Group C

Figure 2: Distribution of mean blood pressure according to groups. Group C (𝑝 < 0.05) (Figure 3). Also, DVAS values were not significantly different between two groups at 0 and 2 h, while Group C: 2.42 ± 1.28 days, 𝑝 = 0.09)werenotsignificantly they were significantly lower in Group P at 4, 8, 12, and 24 h different between two groups. after surgery (𝑝 < 0.05)(Figure4).Noneofthepatientsinthis Comparison of vital findings (SpO2,HBR,andMAP) study needed tramadol supplementation as rescue analgesia. measured at arrival in the operating room, after sedation, Duration of hospital stay after surgery was 3.11 ± 1.68 days and at perioperative fifth, 10th, 15th, 30th, 45th, 60th, 75th, in Group P and 3.16 ± 1.60 days in Group C, indicating no 90th, 105th, and 120th min did not indicate any significant statistically significant difference𝑝 ( = 0.86). Assessment of difference between the groups (𝑝 > 0.05). The MAP findings the two groups in terms of patient satisfaction indicated that are shown in Figure 2. 99% of patients in Group P and 97% of the patients in Group The number of demanded and delivered analgesics from C were very satisfied. Only one patient in Group P reported a the PCA device for 24 h was significantly lower in Group P. discomfortduetoanepiduralcatheter. Moreover, time until the first postoperative analgesic demand Perioperative complications including hypotension, brady- was significantly longer in Group P than in Group C(𝑝< cardia, nausea-vomiting, and need for blood transfusion were 0.001)(Table2). not significantly different between two groups (𝑝 = 0.71). In addition, VAS values recorded 0, 2, and 4 h after Hypotension was recorded in nine (13.6%) and eight (12.5%) surgery were not significantly different between two groups patients in Groups P and C, respectively, and all patients were (𝑝 > 0.05). The VAS values recorded 8, 12, and 24 h after treatedwith10mgi.v.ephedrine(𝑝 = 0.65). During the surgery were significantly lower in Group P, compared to operation, four patients in Group P (6.1%) and three patients Pain Research and Management 5

Table 3: The distribution of complications according to groups [𝑛, (%)].

Group P Group C Modified Clavien Classification 𝑝 (𝑛=66) (𝑛=64) Grade 1 ∘ (i) Fever (>38 C) 1 (1.5) 2 (3.1) 0.54 (ii) Nausea 10 (15.2) 8 (12.5) 0.66 (iii) Vomiting 4 (6.1) 5 (7.8) 0.69 (iv) Headache 7 (10.6) 4 (6.3) 0.37 (v) Itching 2 (3) 3 (4.7) 0.62 Grade 2 (i) Blood transfusion 3 (4.5) 1 (1.6) 0.32 (ii) Infection 4 (6.1) 1 (1.6) 0.18 Grade 3a 0 (0) 0 (0) Grade 3b (i) Arteriovenous fistula 1 (1.5) 0 (0) 0.32 Grade 4 (i) Acute Coronary Syndrome 1 (1.5) 0 (0) 0.32

VAS 𝑝 = 0.65 2.5 ( ). During postoperative 24 h follow-up period, none of the patients developed respiratory depression, hypoten- 2 sion, bradycardia, delirium, or urinary retention. Compar- 1.5 ∗ ison of postoperative complications in terms of the MCC between the groups did not indicate any significant difference 1 ∗ (𝑝 > 0.05) (Table 3). However, one patient in Group P was ∗ 0.5 transferredtotheintensivecareunitonthepostoperative 0 third day due to Acute Coronary Syndrome. 0 Of all patients, 99% patients and 97% patients were very satisfiedinGroupPandGroupC,respectively. 4th hour 8th hour 2nd hour 24th hour 12th hour Group P Group C 4. Discussion Figure 3: Mean values of Visual Analogue Scale (VAS) according to In this study, we aimed to assess postoperative analgesic ∗𝑝 < 0.05 groups, . efficacy of peritubal infiltration in patients who underwent PNLwithCSEduetokidneystones.GroupPpatientsdemon- DVAS strated statistically lower VAS and DVAS scores. Moreover, 3 time to the first analgesic use was significantly longer, and 2.5 the total amounts of demanded and delivered analgesics were 2 ∗ ∗ significantly lower in Group P. Postoperative complications 1.5 ∗ basedontheMCCwerefoundtobecomparablebetweentwo 1 ∗ groups. 0.5 In a study performed by Parikh et al. [7], the authors 0 compared peritubal infiltration by 0.25% bupivacaine and 0 0.25% ropivacaine under the guidance of ultrasonography. The mean age of the patient groups was found to be 42.3 ± 4th hour 8th hour 2nd hour 24th hour 12th hour 11.49 and 42.5 ± 14.2 years, respectively, which are consistent Group P with our findings. However, as patients over the age of 65 Group C years were excluded from the present study, the mean age Figure 4: Mean values of Dynamic Visual Analogue Scale (DVAS) reported here may not reflect the actual mean age of PNL ∗ according to groups, 𝑝 < 0.05. patients in the population. Previous epidemiological studies indicated that stones of the urinary system are more commonly observed among in Group C (4.7%) developed bradycardia and were given menthanwomen[10].Inlinewiththeliteraturedata,sex atropine (𝑝 = 0.65). Two patients in Group P and one patient distribution in the present study showed male predominance in Group C were given intraoperative blood transfusion in both groups. 6 Pain Research and Management

In addition, durations of operation as reported in the muscle tissue, renal capsule, and renal parenchyma enriched literature vary between 61.2 ± 30.5 min and 108.75 ± 47.43 min with sensorial innervation along the nephrostomy tract may [11–13]. Our findings are consistent with the literature. Dura- actually contribute to the pain [19]. Previous studies investi- tion of hospital stay in cases receiving regional anesthesia gated several drug combinations in peritubal infiltration for varies between 1.57 ± 0.81 and 8.9 ± 3.2 days in the literature this purpose [5–7] and assessed pain levels using VAS. In [11, 12, 14, 15]. Similar to the previous studies, the mean peritubal infiltration, local anesthetics are injected alone or duration of hospital stay was 3.1 days in our study. in combination with opioids along the nephrostomy tract, In the present study, where all patients were given CSE and the pain is prevented at the level of peripheral receptors. anesthesia, double-segment, double-needle technique was While several local anesthetics (bupivacaine, levobupiva- used thanks to its advantages. Similarly, in a study performed caine, and ropivacaine) have been used, 0.25% bupivacaine by Singh et al. [11] on PNL cases, double-segment technique isthemostwidelypreferredoption [2,6,8]. Inthisstudy, was used for CSE and epidural catheter was inserted through we also used 0.25% bupivacaine for peritubal infiltration. L1-2 intervertebral space, while spinal block was achieved Reviewoftheliteraturedidnotrevealanystudyinvesti- through L2-3 intervertebral space. On the other hand, Kuz- gating peritubal infiltration under CSE anesthesia. Analysis gunbay et al. [15] preferred the same segment (L3-4)for ofthemeanVASvaluesat0,2,and4hafteroperation spinal and epidural block in their CSE group. Rawal et al. [2] did not demonstrate any significant difference between two recommended insertion at the same level, as they associated groups. In a study performed by Lojanapiwat et al. [19] in double-segment technique with back pain, dural puncture, 105 patients under general anesthesia, 0.35% bupivacaine was hematoma, infection risk, and technical difficulties. In our used for peritubal infiltration, while no injection was given study, including 130 patients, complications such as dural tothecontrolgroup,andpostoperativemorphinedemand puncture, hematoma, and infection were not recorded in any was evaluated. The mean VAS scores on the postoperative patient. Only one patient in Group P reported discomfort due first and fourth h were 4.64 and 3.41 in the study group to epidural catheter. and7.11and4.4inthecontrolgroup,respectively.TheVAS Singh et al. [11] used 0.5% hyperbaric bupivacaine 3 mL scores on the 1 and 4 h were significantly lower in the study +25𝜇g fentanyl for spinal anesthesia, administered a sin- group. Such a discrepancy from our findings can be explained gledoseof0.125%bupivacaine8mLthroughanepidural by the use of CSE anesthesia instead of general anesthesia catheter 6 h after operation, and preferred intramuscular tra- in our study and prolongation of the anesthetic activity for madol for postoperative analgesia. In contrast, we preferred almost up to 4 h after surgery. The aforementioned study [19] intrathecal hypobaric bupivacaine in the present study and did not demonstrate any significant difference in the VAS achieved differential spinal block by using lower concentra- scores measured at the 12th, 24th, and 48th h between two tions. Thus, the patients were more easily moved to prone groups.Onthecontrary,inourstudy,whereweusedthesame position during operation and they were mobilized early after dose and concentration of bupivacaine for peritubal injection, operation. Contrary to the aforementioned study, epidural VAS values measured at the eighth, 12th, and 24th h were solution prepared in this study was administered through the significantly lower in Group P, compared to Group C. The catheter before starting the operation and epidural catheter reason underlying this fundamental difference between the wasalsousedforpostoperativeanalgesia.Unlikeourstudy, two studies may be explained by prolongation of analgesia in the study of Singh et al. [11], the catheter was not by addition of morphine, as an opioid with a long half- actively used during postoperative period for analgesia in the life and high analgesic potency, to bupivacaine for peritubal epidural group and intramuscular injections were preferred infiltration in our study. for analgesia. InastudyperformedbyParikhetal.[8]tocompare On the other hand, we did not observe any significant dif- analgesic efficacy of 0.25% ropivacaine and 0.25% ropivacaine ference between the two groups in terms of the development + 5 mg morphine combination for peritubal infiltration, the of hypotension and bradycardia as complications associated mean VAS and DVAS were found to be significantly lower in with perioperative regional anesthesia. Hypotension is one of the combination group. In that study investigating addition the perioperative complications frequently following spinal of morphine to a local anesthetic, the mean VAS and DVAS block, and its incidence among PNL cases receiving regional over 24 h of follow-up were higher than the values recorded anesthesia varies between 11.3 and 18.9% [16, 17]. In the in the present study. In our study, the mean VAS and DVAS present study, hypotension related to sympathetic blockage scores in Group P were below 3 particularly on the eighth, after the insertion of combined spinoepidural catheter was 12th, and 24th h, while in the aforementioned study, the VAS noted in 13.6% and 12.5% of patients in Groups P and andDVASscoreswerehigherthan3inbothgroups.The C, respectively, and all cases were treated with 10 mg i.v. reason underlying this difference between the two studies is ephedrine. The rate of hypotension found in this study was, the use of epidural PCA device in our study, which allowed thus, consistent with the literature data. the patients to experience almost a pain-free recovery by self- Furthermore, Haleblian et al. [18] administered subcu- administering analgesics upon feeling any pain. taneous 0.25% bupivacaine infiltration around the nephros- In the present study, time to the first analgesic demand tomy tube to manage postoperative pain after PNL and was 262.2 ± 214.4 min in Group P, indicating a significantly hypothesized that the pain may be originating from struc- longer duration compared to the control group (148.8 ± tures beyond the skin incision (such as the renal capsule). 110.3 min). In a study performed by Lojanapiwat et al. [19], Further studies underlined that the skin, subcutaneous tissue, the time of first analgesic use after operation in the group Pain Research and Management 7 receiving peritubal infiltration (97 ± 87.7min) was signifi- during operation, and the risk of medication-related side cantly delayed compared to the control group (55 ± 60.5 min). effects was minimized. Early postoperative mobilization of InthestudyofParikhetal.[8],themeantimeoffirstanalgesic the patients was ensured by minimal motor blockage and use was 10.7 h in the group administered ropivacaine alone, early oral intake was initiated. Pain control was achieved by while it was significantly longer with 13.7 h in the ropivacaine epidural PCA during postoperative period and postoperative + morphine group. In line with the present study, the authors analgesic use was reduced in peritubal infiltration group by indicated that addition of morphine to a local anesthetic using multimodal analgesia. prolongs the duration of postoperative analgesia and reduces Limitations of this study include its single-center design the demand for analgesics [8]. In another study comparing and lack of a control group using saline for peritubal infil- the efficacy of 0.25% bupivacaine (Group B) and 0.25% tration. Due to the inclusion of patients undergoing a single ropivacaine (Group R) used for peritubal infiltration on surgical intervention and nephrostomy catheter, the absence postoperativepain,themeanVASandDVASwerefoundto of patients with multiple interventions performed during one be significantly different between two groups on the sixth session can be also deemed as other limitations. and eighth h, a finding that is consistent with our results [7]. The mean VAS was significantly lower in Group R (3.1 and 3.5)thaninGroupB(4.18and4.56).Similarly,themean 5. Conclusion DVAS in Group R was lower with 4.18 and 4.56, compared to In conclusion, the present study demonstrated that postop- Group B (4.86 and 5.24). In that study, DVAS values during erative 0.25% bupivacaine and 5 mg morphine infiltration follow-upperiodinbothgroupswerehigher,comparedto around nephrostomy catheter in patients undergoing PNL our study. This difference can be attributed to the use of under CSE anesthesia reduce VASand DVAS scores, analgesic epidural PCA device in the present study, which provided demand, and analgesic consumption during the postoper- sufficient sensorial blockage and effective analgesia. ative first 24 h, thereby, increasing the patient satisfaction. In the present study, the VAS and DVAS scores in both In addition, administration of bupivacaine + morphine into < groups were rather lower ( 3), compared to previous studies the nephrostomy tract prolongs the duration of postoperative investigating peritubal infiltration [8, 12, 20]. Pain conduction analgesia without inducing side effects and can be used safely. was prevented at transduction, transmission, and modulation Therefore, we believe that peritubal infiltration with regional stages in peritubal infiltration group, and very effective anesthesia is an easily administered method which can be postoperative analgesia was maintained. considered as a leading option to achieve effective postoper- Moreover, we evaluated postoperative complications ative analgesia and provide good patient’s satisfaction. basedontheMCCinthisstudy.Inaretrospectivestudy performed by Tefekli et al. [9] including 811 patients, Grade 1 fever was reported in 3% of the cases, while it was noted in Disclosure 1.5% and 3.1% of the patients in Groups P and C, respectively, in the present study, indicating no significant difference. Oral presentation of this manuscript has been done at the While none of the patients developed dural puncture during 50th Turkish Anesthesia and Reanimation Congress (Octo- the insertion of epidural catheter, seven patients in Group P ber 26–30, 2016). and four patients in Group C suffered from headaches. Since theheadachesreportedbythepatientswerenotunilateral, Conflicts of Interest not exacerbated by sitting or standing, and did not develop immediately after surgery, they were not considered to be The authors declare that they have no conflicts of interest. dural puncture-induced headaches. In addition, the MCC classifies bleeding requiring blood transfusion as Grade 2 bleeding [9]. Previous studies reported that the incidence References of blood transfusion varied between 1.8 and 15.5% in PNL [1] C. Pu, J. Wang, Y. Tang et al., “The efficacy and safety of procedures performed under regional anesthesia [11, 12, 16, percutaneous nephrolithotomy under general versus regional 20]. In the present study, both groups received CSE and blood anesthesia: a systematic review and meta-analysis,” Urolithiasis, transfusion rates are consistent with the literature data. An vol.43,no.5,pp.455–466,2015. arteriovenous fistula, one of the major complications, is a rare [2]N.Rawal,A.VanZimdert,B.Holmstrom,¨ and J. A. Crowhurst, occurrence classified as Grade 3b by the MCC and its inci- “Combined spinal-epidural technique,” Regional Anesthesia and dence varies between 0.2 and 1.5% [9]. An arteriovenous fis- Pain Medicine,vol.22,no.5,pp.406–423,1997. tula developed in one patient receiving peritubal infiltration [3] D. Dalela, A. Goel, P. Singh, and S. N. Shankhwar, “Renal in this study and the patient underwent embolization. Several capsular block: A novel method for performing percutaneous stages of the present study were designed to be consistent nephrolithotomy under local anesthesia,” Journal of Endourol- with the Enhanced Recovery After Surgery (ERAS) protocol ogy, vol. 18, no. 6, pp. 544–546, 2004. [21, 22]. In line with ERAS, short-acting sedative agents [4] K. Ak, S. Gursoy, C. Duger et al., “Thoracic paravertebral were used for preoperative sedation and a thoracal epidural block for postoperative pain management in percutaneous catheter was inserted for perioperative and postoperative nephrolithotomy patients: A randomized controlled clinical analgesia. Hemodynamic stability was maintained by the trial,” Medical Principles and Practice,vol.22,no.3,pp.229–233, use of low-dose and concentration of analgesic medications 2013. 8 Pain Research and Management

[5] O. E. Gokten, H. Kilicarslan, H. S. Dogan, G. Turker, and Y.Kor- pain following percutaneous nephrolithotomy - A prospective dan, “Efficacy of levobupivacaine infiltration to nephrosthomy randomized controlled study,” International Brazilian Journal of tract in combination with intravenous paracetamol on post- Urology,vol.41,no.5,pp.945–952,2015. operative analgesia in percutaneous nephrolithotomy patients,” [20] T. Tangpaitoon, C. Nisoog, and B. Lojanapiwat, “Efficacy and Journal of Endourology,vol.25,no.1,pp.35–39,2011. safety of percutaneous nephrolithotomy (PCNL): A prospective [6]J.Nirmala,A.Kumar,R.Devraj,S.Vidyasagar,G.Ramachand- and randomized study comparing regional epidural anesthesia raiah, and P. V. L. N. Murthy, “Role of buprenorphine in with general anesthesia,” International Brazilian Journal of prolonging the duration of post-operative analgesia in percu- Urology,vol.38,no.4,pp.504–511,2012. taneous nephrolithotomy: Comparison between bupivacaine [21] M. D. Tyson and S. S. Chang, “Enhanced recovery pathways versus bupivacaine and buprenorphine combination,” Indian versus standard care after cystectomy: a meta-analysis of the Journal of Urology, vol. 31, no. 2, pp. 132–135, 2015. effect on perioperative outcomes,” European Urology,vol.70,no. [7]G.P.Parikh,V.R.Shah,K.S.Vora,B.K.Parikh,M.P.Modi, 6, pp. 995–1003, 2016. and P. Kumari, “Ultrasound guided peritubal infiltration of [22] B. Persson, M. Carringer, O. Andren,´ S.-O. Andersson, J. Carls- 0.25% Bupivacaine versus 0.25% Ropivacaine for postoperative son, and O. Ljungqvist, “Initial experiences with the enhanced pain relief after percutaneous nephrolithotomy: A prospective recovery after surgery (ERAS5) protocol in open radical cystec- double blind randomized study,” Indian Journal of Anaesthesia, tomy,” Scandinavian Journal of Urology,vol.49,no.4,pp.302– vol. 58, no. 3, pp. 293–297, 2014. 307, 2015. [8]G.P.Parikh,V.R.Shah,K.S.Vora,M.P.Modi,T.Mehta, and S. Sonde, “Analgesic efficacy of peritubal infiltration of ropivacaine versus ropivacaine and morphine in percutaneous nephrolithotomy under ultrasonic guidance,” Saudi Journal of Anaesthesia,vol.7,no.2,pp.118–121,2013. [9] A. Tefekli, M. A. Karadag, K. Tepeler et al., “Classification of Percutaneous Nephrolithotomy Complications Using the Modified Clavien Grading System: Looking for a Standard,” European Urology,vol.53,no.1,pp.184–190,2008. [10] H. H. Kim, M. K. Jo, C. Kwak et al., “Prevalence and epidemi- ologic characteristics of urolithiasis in Seoul, Korea,” Urology, vol. 59, no. 4, pp. 517–521, 2002. [11] V. Singh, R. J. Sinha, S. N. Sankhwar, and A. Malik, “A prospec- tive randomized study comparing percutaneous nephrolitho- tomy under combined spinal-epidural anesthesia with percu- taneous nephrolithotomy under general anesthesia,” Urologia Internationalis, vol. 87, no. 3, pp. 293–298, 2011. [12] T. Cicek, U. Gonulalan, R. Dogan et al., “Spinal anesthesia is an efficient and safe anesthetic method for percutaneous nephrolithotomy,” Urology,vol.83,no.1,pp.50–55,2014. [13]D.Olvera-Posada,T.Tailly,H.Alenezietal.,“Riskfactorsfor postoperative complications of percutaneous nephrolithotomy at a tertiary referral center,” Journal of Urology,vol.194,no.6, pp. 1646–1651, 2015. [14] S. S. Kim, J. W. Lee, J. H. Yu, L. H. Sung, J. Y. Chung, and C. H. Noh, “Percutaneous nephrolithotomy: comparison of the efficacies and feasibilities of regional and general anesthesia,” Korean Journal of Urology,vol.54,no.12,pp.846–850,2013. [15] B. Kuzgunbay, T. Turunc, S. Akin, P. Ergenoglu, A. Aribo- gan, and H. Ozkardes, “Percutaneous nephrolithotomy under general versus combined spinal-epidural anesthesia,” Journal of Endourology, vol. 23, no. 11, pp. 1835–1838, 2009. [16] S. Mehrabi and K. K. Shirazi, “Results and complications of spinal anesthesia in percutaneous nephrolithotomy,” Urology Journal,vol.7,no.1,pp.22–25,2010. [17] S. Mehrabi, A. M. Zadeh, M. A. Toori, and F. Mehrabi, “General versus spinal anesthesia in percutaneous nephrolithotomy,” Urology Journal,vol.10,no.1,pp.756–761,2013. [18] G. E. Haleblian, R. L. Sur, D. M. Albala, and G. M. Preminger, “Subcutaneous Bupivacaine Infiltration and Postoperative Pain Perception After Percutaneous Nephrolithotomy,” Journal of Urology,vol.178,no.3,pp.925–928,2007. [19] B. Lojanapiwat, T. Chureemas, and P. Kittirattarakarn, “The efficacy of peritubal analgesic infiltration in postoperative Hindawi Pain Research and Management Volume 2017, Article ID 4792489, 9 pages https://doi.org/10.1155/2017/4792489

Research Article The Antinociceptive Effect of Light-Emitting Diode Irradiation on Incised Wounds Is Correlated with Changes in Cyclooxygenase 2 Activity, Prostaglandin E2, and Proinflammatory Cytokines

Yuan-Yi Chia,1 Chien-Cheng Liu,2,3 Guan-Ming Feng,4 Chia-Chih Alex Tseng,5 Kuo-Chuan Hung,2 Chih-Chieh Chen,2 and Ping-Heng Tan2,6

1 Department of Anesthesiology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan 2Department of Anesthesiology, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan 3Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan 4Department of Plastic & Reconstructive Surgery, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan 5Department of Anesthesiology, National Cheng Kung University Medical College and Hospital, Tainan, Taiwan 6School of Medicine, I-Shou University, Kaohsiung, Taiwan

Correspondence should be addressed to Chih-Chieh Chen; [email protected] and Ping-Heng Tan; [email protected]

Received 2 December 2016; Accepted 2 March 2017; Published 2 April 2017

Academic Editor: Bulent¨ S. Yurtlu

Copyright © 2017 Yuan-Yi Chia et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background. Light-emitting diode (LED) phototherapy has been reported to relieve pain and enhance tissue repair through several mechanisms. However, the analgesic effect of LED on incised wounds has never been examined. Objectives. We examined the analgesic effect of LED therapy on incision pain and the changes in cyclooxygenase 2 (COX-2), prostaglandin E2 (PGE2), andthe proinflammatory cytokines interleukin 6 (IL-6), IL-1𝛽, and tumor necrosis factor 𝛼 (TNF-𝛼). Methods. Rats received LED therapy on incised skin 6 days before incision (L-I group) or 6 days after incision (I-L group) or from 3 days before incision to 3days after incision (L-I-L group). Behavioral tests and analysis of skin tissue were performed after LED therapy. Results.LEDtherapy attenuated the decrease in thermal withdrawal latency in all the irradiated groups and the decrease in the mechanical withdrawal threshold in the L-I group only. The expression levels of COX-2, PGE2, and IL-6 were significantly decreased in the three LED- treated groups, whereas IL-1𝛽 and TNF-𝛼 were significantly decreased only in the L-I group compared with their levels in the Igroups(𝑝 < 0.05). Conclusions. LED therapy provides an analgesic effect and modifies the expression of COX-2, PGE2, and proinflammatory cytokines in incised skin.

1. Introduction [5, 6], and decreased inflammation [7]. Through several path- ways, LED phototherapy can also diminish pain sensation Low-intensity light therapy, commonly referred to as pho- and enhance tissue repair [4, 8]. tobiomodulation, uses light in the far-red to near-infrared Surgical trauma produces injuries in skin, fascia, muscle, region (NIR) of the spectrum (630–1000 nm) and modulates andthenervefibersinnervatingthesetissuesandinduces numerous cellular functions. The light-emitting diode (LED), subsequent postoperative acute pain. Although many basic a light source, is as efficient as laser light and can be applied and clinical research studies have improved our understand- more economically [1]. Many advantageous effects of LED ing of the pathologic mechanisms, controlling postsurgical light treatment have been reported, such as increases in ATP pain well remains a challenge for physicians. The behavioral synthesis [2], angiogenesis [3], collagen synthesis, fibroblast characteristics of a postoperative pain model in rats produced proliferation [2–4], inhibition of pain and oxidative stress by hind paw incision resemble postoperative hypersensitivity 2 Pain Research and Management in humans [9]. The nature of hypersensitivity in this pain heeltothebaseofthetoes.Theflexortendonfromtheheel model is different from that in other sustained pain models, to the toes was elevated with small forceps. The incision was such as the neuropathic pain model [10]. then sutured with 5-0 nylon. Since LED therapy can reduce the inflammation response, Pain behavior was tested by measuring the mechani- enhance tissue repair, and relieve pain, this therapy is cal withdrawal threshold for mechanical allodynia and the considered a suitable method for preventing and treating thermal withdrawal latency for thermal hyperalgesia. To test symptomsoftissuedamageaftertraumaorsurgery.Thus, themechanicalwithdrawalthreshold,aseriesofvonFrey the antinociceptive effect of 940 nm wavelength LED therapy filaments(0.4,0.6,1,2,4,6,8,and15g;Stoelting,WoodDale, on acute pain resulting from tissue injury in a rat incision IL, USA) were tested perpendicular to the plantar surface for model was examined and the mechanism of antinociception 5-6 s for each filament. The 50% paw withdrawal threshold wasexploredinthisstudy. was determined using Dixon’s up-and-down method [13]. Each threshold value measurement was used to calculate the thresholdtowithdrawalwitha50%probabilitytotestingwith 2. Methods calibrated von Frey filaments. These thresholds were deter- 2.1. Animals. Male Sprague–Dawley rats (180–220 g) were mined 1-2 mm distal to the incision into the foot pad. Thermal used in this study and were purchased from the National sensitivity was evaluated using Plantar Test Apparatus (Ugo Science Council (Taiwan) according to the guidelines for pain Basile, Comerio, Italy), and the data were presented as the research [11] and the ARRIVE guidelines [12]. All animal paw withdrawal latency. The hind paw with or without the protocols were approved by the Institutional Review Board of incised wound was heated by a calibrated radiant heat source, I-Shou University, Kaohsiung, Taiwan. Two rats were housed and the time to paw withdrawal was recorded. The radiant ∘ per cage. The cages were maintained at 23±1 Cwitha12-hour heat intensity was adjusted so that the basal paw withdrawal light/dark cycle (lights on at 09:00), and the rats were left in latency before incision was 10–12 s, with a cut-off of 20 s to the experimental room for 24 hours for acclimatization before prevent tissue damage. Each hind paw was tested three times. the test. These three measurements were averaged for each animal.

2.2. Experimental Groups. The rats were randomly assigned 2.4. LED Therapy. The rats in the LED-treated groups received LED irradiation on the left hind paw at a 940 nm tothefollowinggroups.RatsreceivedLEDtherapy6days 2 before incision (preincision group; L-I group) or 6 days wavelength for a period of 30 min to administer 4 J/cm of after incision (postincision group; I-L group) or from 3 energy density at a power output of 160 mW. The therapeutic days before incision to 3 days after incision (preincision procedure began before or after the incision according to the plus postincision group; L-I-L). Three groups of control rats assigned groups and was repeated every 24 hours. The rats received only a skin incision (incision only groups; I-3 h, I- were held in the ventral decubitus position to receive LED irradiation. The LED source was kept 1 cm above the injury 3 d, and I-6 d groups) and underwent behavioral tests and ∘ tissue dissection at 3 hours, 3 days, or 6 days after skin incision at a 90 angle. A power checker (13PEM001/J, Melles Griot, for comparison to the L-I, L-I-L, and I-L groups, respectively. Didam, Netherlands) was used to check the optical output Three groups of LED-treated rats received a sham incision power of the light source before the beginning of the experi- and the same LED therapy procedure on the contralateral mental procedure. The equipment was specially developed for paw for 6 days and were also considered as control (C) this experiment at the Department of Electronic Engineering groups. The baseline mechanical withdrawal threshold and of I-Shou University, Taiwan. After LED therapy, the animals baseline thermal withdrawal latency were tested in na¨ıve were kept in their cages and observed until recovery from rats before undergoing a skin incision or LED irradiation, anesthesia. that is, before the incision was made in the I-6 d and I-L groups and before LED irradiation in the other groups. The 2.5. Quantitative Real-Time Polymerase Chain Reaction (qRT- mechanical withdrawal threshold and thermal withdrawal PCR). One microgram of total RNA was used for cDNA latencywerethentested3hoursafterincisionintheL-IandI- synthesis and qRT-PCR gene expression analysis. First, 3 h groups, 3 days after incision in the L-I-L and I-3 d groups, reverse transcription (RT) was performed using a High and 6 days after incision in the I-L and I-6 d groups. Skin Capacity cDNA Reverse Transcription Kit according to the tissues dissected from all groups were collected for mRNA manufacturer’s protocol (Applied Biosystems, Foster City, 𝑛=6 ∘ and protein analyses ( ) after behavioral testing. The staff CA). The reaction mixtures were incubated at 25 C for 10 min, ∘ ∘ members who performed the behavioral tests and collected 37 Cfor120min,andthen85Cfor5sec.ThefinalcDNA ∘ and analyzed the skin tissues were blinded to the animal products were stored at −20 C until use. Next, the cDNA groups. products were amplified by qRT-PCR on a 7500 Real-Time PCR System (Applied Biosystems, California, USA) using 2.3. Incision Wound and Behavioral Test. An incision wound the SYBR5 GreenPCRMasterMix(AppliedBiosystems, was made under 2% isoflurane in oxygen as anesthesia. The California, USA). The following thermal cycling program was ∘ ∘ procedure was based on a previous report [9]; the plantar used: 50 Cfor2minand95C for 10 min, followed by 40 ∘ ∘ surface of one hind paw was prepared with 10% povidone- cycles at 95 Cfor15secandat60C for 1 min. Experiments iodine solution, draped, and incised with a scalpel from the were performed in triplicate for each data point. The primers Pain Research and Management 3

Table 1: Real-time polymerase chain reaction primers.

Gene Direction Primers 󸀠 󸀠 Fwd. 5 -TGT ATG CTA CCA TCT GGC TTC GG-3 COX-2 󸀠 󸀠 Rev. 5 -GTT TGG AAC AGT CGC TCG TCA TC-3 󸀠 󸀠 Fwd. 5 -CAT ATG TTC TCA GGG AGA TCT TGG A-3 IL-6 󸀠 󸀠 Rev. 5 -CAG TGC ATC ATC GCT GTT CAT AC-3 󸀠 󸀠 𝛽 Fwd. 5 -CAC AGC AGC ATC TCG ACA AGA G-3 IL-1 󸀠 󸀠 Rev. 5 -GAC ATA GGT AGC TGC CAC AGC TT-3 󸀠 󸀠 𝛼 Fwd. 5 -AGG CTG CCC CGA CTA TGT-3 TNF- 󸀠 󸀠 Rev. 5 -AGG AGG CTG ACT TTC TCC-3 󸀠 󸀠 𝛽 Fwd. 5 -CGT ACC ACT GGC ATT GTG ATG-3 -Actin 󸀠 󸀠 Rev. 5 -CAC GCT CGG TCA GGA TCT TC-3 The COX-2, IL-6, IL-1𝛽, TNF-𝛼,and𝛽-actin primer sequences were derived from the National Center for Biotechnology Information (Bethesda, Virginia) nucleotide sequence (accession numbers NM_017232.3, NM_012589.2, NM_031512.2, NM_012675.3, and NM_031144.3, resp.).

used for qRT-PCR are listed in Table 1. 𝛽-Actin was used 30 min, and the antibodies were then revealed using an as a reference gene. The mRNA amounts of the genes of enhanced chemiluminescence (ECL) detection kit (Merck interest and 𝛽-actin were calculated from the threshold cycle Millipore, Darmstadt, Germany). For densitometric analyses, (Ct) number. The relative expression level of each sample theblotswerescannedandquantifiedwithImage-ProPlus was normalized to the 𝛽-actin expression as an endogenous analysis software (Media Cybernetics, Silver Spring, MD, RNA control. The ΔCt values of the samples were determined USA), and the results were expressed as the ratio of PGE2 as the difference between the Ct of the sample mRNA and immunoreactivity to 𝛽-actin immunoreactivity. the reference gene. ΔΔCt was determined as the difference between the ΔCt of the control groups (C groups) and the 2.7. Statistical Analysis. The Kolmogorov–Smirnov test was ΔCt of the other LED-treated groups. Data were expressed as −ΔΔCt performed to verify the dependent variables’ normality of 2 to provide an estimate of the amount of sample mRNA distribution. The comparison of the mechanical withdrawal present in the LED-treated groups relative to the control threshold and thermal withdrawal latency after treatment group. and baseline value in each group was analyzed using the paired 𝑡-test. The qRT-PCR data for COX-2, IL-6, IL-1𝛽,and 2.6. Western Blot Analysis. Total protein from skin tissue TNF-𝛼 and the western blot data for PGE2 were analyzed was prepared by the addition 1 : 20 of T-PER Tissue Protein by the Kruskal-Wallis test to determine differences among Extraction Reagent (PIERCE, Rockford, IL, USA) (25 mM groups followed by the Mann–Whitney 𝑈 test for intergroup bicine, 150 mM sodium chloride [pH 7.6]) containing pro- differences. The data were expressed as the means and tease inhibitors [100 mM 4-(2-aminoethyl) benzenesulfonyl standard deviation. Differences were considered statistically fluoride hydrochloride, 80 mM aprotinin, crystalline, 5 mM significant at 𝑝 < 0.05. The statistical analysis was performed bestatin, 1.5 mM E-64, protease inhibitor, 2 M leupeptin, with SPSS software (14.0; SPSS Inc., Chicago, IL, USA). and 1 mM pepstatin A]. The tissue was homogenized with a homogenizer. After being placed on ice for 30 min, the ∘ 3. Results homogenate was centrifuged at 10,000𝑔 for 15 min at 48 C. Proteins (30 𝜇g per lane) were separated in a 10% sodium The test of the analgesic effect of LED therapy on incision pain dodecyl sulfate- (SDS-) polyacrylamide gel and transferred produced the following results. After the skin was incised, onto a polyvinylidene difluoride membrane (Merck Milli- the thermal withdrawal latency was significantly decreased pore, Darmstadt, Germany). The membrane was blocked comparedwiththebaselinevalueinthreeIgroups(𝑝 < 0.05), with blocking solution (5% skim milk in TBST [2.42 g/L Tris- but not in the three LED-treated groups (Figures 1(a), 1(b), HCl, 80 g/L NaCl, and 0.1% Tween 20, pH 7.6]) for 0.5 hours and 1(c)). Significantly decreased mechanical withdrawal and was rinsed briefly in TBST. The membrane was incubated thresholds compared with the baseline value were noted after ∘ overnight at 4 Cwithrabbitanti-PGE2polyclonalantibody skin incision in the L-I-L and I-L groups but not in the L-I (1 : 5,000) (Bioss Inc., Woburn, MA, USA). A mouse anti- group (𝑝 < 0.05) (Figures 2(a), 2(b), and 2(c)). actin monoclonal antibody (1 : 10,000) (Millipore, Bedford, The production of IL-6, COX-2, PGE2, 𝛽IL-1 ,andTNF- MA, USA) was used as a control. 𝛼 fromskintissueinresponsetoincisionandtheinhibitory After being rinsed with washing buffer for 30 min, the effects of LED irradiation are shown in Figures 3 and4. membrane was incubated for 1.5 hours with a horseradish Compared with the C groups, significant upregulation of peroxidase-conjugated secondary antibody: goat anti-rabbit COX-2, PGE2, IL-6, IL-1𝛽,andTNF-𝛼 was noted. The IgG-HRP (1 : 10,000) (Santa Cruz Biotechnology, Texas, expression levels of COX-2, PGE2, and IL-6 were significantly USA). The membrane was washed in washing buffer for decreased in the LED-treated groups compared with those 4 Pain Research and Management

18 18 16 16 14 14 12 12 10 10 8 ∗ 8 6 6 ∗ 4 4 Withdrawal latency (s) latency Withdrawal 2 (s) latency Withdrawal 2 0 0 Baseline LED Baseline LED Group Group

C C I-3h I-3d L-I L-I-L (a) (b) 18 16 14 12 10 8 ∗ 6 4 Withdrawal latency (s) latency Withdrawal 2 0 Baseline LED Group

C I-6 d I-L (c)

Figure 1: Mean withdrawal latency in the six groups (𝑛=6each group) 6 days after LED irradiation performed before or after skin incision. C indicates LED irradiation for 6 days before or after sham skin incision on the paw contralateral to the LED-irradiated incised paw; I-3 h, I-3 d, and I-6 d indicate incision only groups that underwent behavioral testing 3 hours, 3 days, and 6 days after skin incision; L-I indicates LED irradiation for 6 days before skin incision; I-L indicates LED irradiation for 6 days after skin incision; L-I-L indicates LED irradiation ∗ from 3 days before skin incision to 3 days after skin incision. 𝑝 < 0.05 compared with the baseline value in each group. The values represent the means ± SD.

in groups I-3 h, I-3 d, and I-6 d (𝑝 < 0.05) (Figures 3(a), L-I, L-I-L, and I-L groups, respectively. Thus, the inhibition 3(b), 3(c), 3(d), and 4(a)). IL-1𝛽 and TNF-𝛼 were significantly of IL-1𝛽 and TNF-𝛼 by LED irradiation was short term and decreasedintheL-Igroupcomparedwiththeirlevelsin occurred only in the preemptive LED irradiation group (L-I group I-3 h (𝑝 < 0.05) (Figures 4(b) and 4(c)). However, group). compared with the I-6 d and I-3 d groups, in the I-L and L-I- A previous study reported an increase in the level of L groups, no significant differences in the expression of IL-1𝛽 IL-6, but not of IL-1𝛽 or TNF-𝛼,incirculatingblood or TNF-𝛼 were noted (Figures 4(b) and 4(c)). 3 hours after carrageenan-induced inflammation. A prior injection of IL-6 antiserum abolished the induction of COX- 2 activity and PGE2 release in vascular endothelial cells and 4. Discussion attenuated thermal hyperalgesia [14, 15]. A-nociceptive inputs mediate mechanical secondary hyperalgesia [16]. Thermal In the present study, LED irradiation significantly alleviated latency reflects the activation of primarily C-fiber function thermal hyperalgesia in all three LED-treated groups and [17]. Prostaglandins in the midbrain periaqueductal gray mechanical allodynia in only the L-I group. LED irradiation (PAG) matter exert tonic facilitatory control that targets C- also significantly decreased the expression of IL-6, COX-2, rather than A-fiber-mediated spinal nociception [18]. Ther- and PGE2 in all the treatment groups and decreased IL-1𝛽 and mal hyperalgesia after infusion of PGE2 into the ventrolateral TNF-𝛼 in the L-I group only. The measurement of cytokines PAG has been observed [19]. Thus, the decrease in IL-6 was performed 3 hours, 3 days, or 6 days after incision in the observed in this study also contributed to the decreased Pain Research and Management 5

14 14 12 12 10 10 8 8 6 6 4 4 ∗ ∗ ∗ 2 2 Withdrawal threshold (g) threshold Withdrawal Withdrawal threshold (g) threshold Withdrawal 0 0 Baseline LED Baseline LED Group Group

C C I-3h I-3d L-I L-I-L (a) (b) 14 12 10 8 6 ∗ 4 ∗ 2 Withdrawal threshold (g) threshold Withdrawal 0 Baseline LED Group

C I-6 d I-L (c)

Figure 2: Mean withdrawal threshold in the six groups (𝑛=6each group) 6 days after LED irradiation performed before or after skin incision. C indicates LED irradiation for 6 days before or after sham skin incision on the paw contralateral to the LED-irradiated incised paw; I-3 h, I-3 d, and I-6 d indicate incision only groups that underwent behavioral testing 3 hours, 3 days, and 6 days after skin incision; L-I indicates LED irradiation for 6 days before skin incision; I-L indicates LED irradiation for 6 days after skin incision; L-I-L indicates LED irradiation ∗ from 3 days before skin incision to 3 days after skin incision. 𝑝 < 0.05 compared with the baseline value in each group. The values represent the means ± SD.

expression of COX-2 and PGE2. The decrease in IL-6 and of inflammatory cells to the inflammation site [7]. However, PGE2 also contributed to the attenuation of thermal hyper- whether LED irradiation could inhibit Schwann cells remains algesiabutnotofmechanicalallodynia. unclear. Another possible explanation is that the production The peripheral actions of cytokines in inflammatory pain of cytokines, such as TNF-𝛼 and IL-1𝛽, is regulated at local include the activation of immune cells, such as mast cells, inflammatory sites [22, 23], where their conversion toIL-6 macrophages, and Schwann cells, to produce proinflamma- was inhibited; thus, they remained increased in the tissue. tory cytokines (e.g., IL-1𝛽,TNF-𝛼, and IL-6) [20]. These IL-1𝛽 and TNF-𝛼 have also been reported to be associated cytokines exert algesic effects directly by acting on nocicep- with the development of allodynia and hyperalgesia [24, 25]; tors or indirectly through the release of other mediators, thiscouldalsobeareasonwhymechanicalallodyniawasnot most notably prostanoids that are synthesized through COX- attenuated by LED irradiation in the L-I-L and I-L groups. 1 and COX-2 [21]. We showed that IL-6 concentrations were In addition to being blocked by IL-6, COX activity could significantly decreased after LED irradiation, whereas TNF-𝛼 be inhibited by LED irradiation. A study by Xavier et al. [26] and IL-1𝛽 were not suppressed by LED irradiation in the I-L showed that LED could inhibit the early chemotactic effects and L-I-L groups. A possible reason why TNF-𝛼 and IL-1𝛽 of inflammatory mediators by inhibiting COX. Similar results were not suppressed by LED irradiation in the I-L and L-I-L were observed by Campana et al. [27], who reported that groups is that some amount of TNF-𝛼 and IL-1𝛽 was secreted LED therapy acted in the early stages of inflammation since by Schwann cells that were not inhibited by LED irradiation. a decrease in COX-2 mRNA was observed. Previous studies LED irradiation was reported to be able to reduce the influx have shown that low-intensity LED could significantly reduce 6 Pain Research and Management

C I-3h L-I

PGE-2

Actin

5 100 4.5 90 4 80 3.5 70 3 60 2.5 50 2 ∗ ∗ ∗ 40 ∗ 1.5 ∗ ∗ ∗ 30 1 20 ∗ 0.5 PGE-2/b-actin (%) 10

Expression of COX-2 (ratio) COX-2 of Expression 0 0 L-I L-I-L I-L C I-3h L-I Group Group C I LED (a) (b) C I-3d L-I-L C I-6 d I-L

PGE-2 PGE-2

Actin Actin

90 80 80 70 70 60 60 50 50 40 40 30 ∗ 30 20 ∗ 20 ∗ PGE-2/b-actin (%) PGE-2/b-actin (%) ∗ 10 10 0 0 C I-3d L-I-L C I-6 d I-L Group Group (c) (d)

Figure 3: Changes in mRNA levels of cyclooxygenase-2 (COX-2) and representative western blots of prostaglandin E2 (PGE2) expression after LED irradiation. COX-2 mRNA is shown in (a), and representative western blots of PGE2 expression after LED irradiation areshown in (b, c, and d). Compared with the C groups, significant upregulation of COX-2 and PGE2 was noted in the I groups. Significantly decreased expression of COX-2 and PGE2 was noted in the LED irradiation groups compared with the incision only group. C indicates LED irradiation for 6 days on sham skin incision in the paw contralateral to the LED-irradiated paw; I-3 h, I-3 d, and I-6 d indicate incision only groups that underwent behavioral testing 3 hours, 3 days, and 6 days after skin incision; L-I indicates LED irradiation for 6 days before skin incision; I-L indicates LED irradiation for 6 days after skin incision; L-I-L indicates LED irradiation from 3 days before skin incision to 3 days afterskin ∗ incision. 𝑝 < 0.05 compared with the I groups. The values represent the means ± SD.

the mRNA expression of COX [28, 29], precursors such as 940 nm to incised wounds. The behavioral characteristics of phospholipase A2 (PLA2), and reactive oxygen species (ROS) a postoperative pain model in rats produced by hind paw [28]. In studies by Xavier and Lim [26, 28], irradiation at incision resemble postoperative hypersensitivity in humans wavelengths of 880 nm and 635 nm was applied to Achilles [9]. Our study was the first to apply 940 nm LED to reduce tendinitis and human gingival fibroblasts. A wavelength of incision-induced nociception and the expression of COX-2, 940 nm was applied to damaged or sore muscles in studies PGE2, and proinflammatory cytokines in incised wounds. by Vinck et al. [30] and Camargo et al. [31]. To the best of our Howdoes940-nmlighttherapyinhibittheactivation knowledge, no researcher has evaluated the analgesic effect of of COX enzymes and decrease the production of PGE2? LED irradiation on incised wounds. In this study, we applied In a previous study [28], light irradiation decreased the Pain Research and Management 7

10 ∗ ∗ 8 # 9 ∗ 7 ∗ # 8 (ratio) 6

7 1
훽 6 5 5 4 4 3 3 2 2 1 1 Expression of IL- of Expression

Expression of IL-6 (ratio) IL-6 of Expression 0 0 L-I L-I-L I-L L-I L-I-L I-L Group Group C C I I LED LED (a) (b) 5 # # 4.5 ∗ (ratio) 4
훼 3.5 3 2.5 2 1.5 1 0.5

Expression of TNF- of Expression 0 L-I L-I-L I-L Group C I LED (c)

Figure 4: Changes in mRNA levels of interleukin-6 (IL-6), IL-1𝛽, and tumor necrosis factor 𝛼 (TNF-𝛼) after LED irradiation. Compared with the C groups, significant upregulation of IL-1𝛽, IL-6, and TNF-𝛼 was noted in all the I groups (a, b, and c). Significantly decreased expression of IL-6 was noted in all the LED-irradiated groups compared with the incision only group (a). After LED irradiation, significantly decreased expression of IL-1𝛽 and TNF-𝛼 was noted only in the L-I group (b, c). C indicates LED irradiation for 6 days on sham skin incision in the paw contralateral to the LED-irradiated paw; I indicates incision only; L-I indicates LED irradiation for 6 days before skin incision; I-L indicates LED irradiation for 6 days after skin incision; L-I-L indicates LED irradiation from 3 days before skin incision to 3 days after skin incision. ∗ # 𝑝 < 0.05 compared with the C and LED-irradiated groups; 𝑝 < 0.05 compared with the C groups. The values represent the means ± SD.

ROS level, indicating that irradiation functions as a ROS on IL-1𝛽 or TNF-𝛼 more than three days after the incision. scavenger.ThemajoreffectsofROSduringinflammation Similar results were reported by previous studies showing are the oxidative modification of PLA2 activation within that the antinociceptive effects produced by nonsteroidal the cell membrane and the stimulation of COX-2 mRNA anti-inflammatory drugs (NSAIDs; COX inhibitors) were the expression [32, 33]. Therefore, light irradiation can directly same whether the NSAID was administered before or after disrupt ROS and subsequently inhibits the expression of the noxious stimulus [37, 38]. cPLA2,sPLA2,andCOX,resultingintheinhibitionofPGE2 In conclusion, the results of the present study demon- release. strated that 940-nm LED phototherapy could effectively Preemptive analgesia is an antinociceptive treatment reduce incision-induced thermal hyperalgesia in all the LED- administered before a noxious stimulus to prevent the estab- treated groups, regardless of whether irradiation occurred lishment of neural nociception processing. Basic physiologic before or after the skin incision, whereas mechanical allo- research has created great interest in the potential benefits dynia was reduced only 1 day after incision. The antither- of preemptive analgesia [34]. However, some clinical studies mal hyperalgesic and mechanical allodynic effects of this [35, 36] comparing the beneficial effects of preoperative treatment are probably related to the decreased expression analgesictreatmentstothesametreatmentadministeredafter of COX-2, PGE2, IL-6, IL-1𝛽,andTNF-𝛼.PreemptiveLED incision did not show a significant preemptive effect. Our phototherapy transiently suppressed the expression of IL- results showed that preemptive LED irradiation was effective 1𝛽 and TNF-𝛼 several hours after incision. However, LED at inhibiting the production of COX-2, PGE2, and IL-6. There phototherapy could not suppress the expression of IL-1𝛽 or was only a transient effect on the production of IL-1𝛽 and TNF-𝛼 beyond 3 days after incision. This LED therapy holds TNF-𝛼 3 hours after the incision, but there was no effect therapeutic potential for postsurgical pain. 8 Pain Research and Management

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Clinical Study Gabapentin Does Not Appear to Improve Postoperative Pain and Sleep Patterns in Patients Who Concomitantly Receive Regional Anesthesia for Lower Extremity Orthopedic Surgery: A Randomized Control Trial

Jean Daniel Eloy,1 Christy Anthony,1 Shawn Amin,1 Moorice Caparó,1 Mark C. Reilly,2 and Steven Shulman1

1 Department of Anesthesiology and Perioperative Medicine, Department of Acute Pain, Rutgers New Jersey Medical School, 185 South Orange Avenue, MSB E-538, Newark, NJ 07101-1709, USA 2Department of Orthopedic Surgery, Rutgers New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07101-1709, USA

Correspondence should be addressed to Christy Anthony; [email protected]

Received 9 December 2016; Accepted 4 January 2017; Published 27 February 2017

Academic Editor: Rudin Domi

Copyright © 2017 Jean Daniel Eloy et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

In recent years, gabapentin has gained popularity as an adjuvant therapy for the treatment of postoperative pain. Numerous studies have shown a decrease in pain score, even with immediate postoperative activity, which is significant for early post-op ambulation and regaining functionality sooner. However, studies have been in conclusive in patients undergoing lower extremity orthopedic surgery. For this reason, we hoped to study the effect of gabapentin on postoperative pain in patients undergoing total knee arthroplasty, total hip arthroplasty, or a hip fracture repair. This was done in the setting of ensuring adequate postoperative analgesia with regional blocks and opioid PCA, as is protocol at our institution. Given the sedative effects of gabapentin and the potential for improving postoperative sleep patterns, we also studied the drug’s effect on this aspect of our patient’s postoperative course. We utilized the Pittsburg Sleep Quality Index and Visual Analog Scale for pain to obtain a more objective standardized score amongst our study population. Our results indicate that gabapentin does not offer any additional relief in pain or improve sleep habits in patients who have received either a femoral or lumbar plexus block for lower extremity orthopedic surgery. This trial is registered with NCT01546857.

1. Introduction reduced opioid consumption and pain scores during the first 24 hours after surgery [7]. The same meta-analysis showed Gabapentin is a structural analog of the neurotransmitter that gabapentin reduced preoperative anxiety, postoperative GABA that has been used to treat epilepsy and neuropathic nausea,vomiting,andpruritus.Recentstudieshavealso pain [1]. Gabapentin, despite being structurally similar to supportedtheuseofgabapentinasanadjuvantagentin GABA, does not have a direct or indirect action on the GABA postoperative pain management [8] in different patient pop- receptors. Instead, it acts on the 𝛼2𝛿 subunitofvoltagegated ulation and after a variety of different surgical procedure. For calcium channels within the CNS and modulates the release example, studies have suggested decreased pain with activity of neurotransmitters [2]. In recent years, gabapentin has been in postmastectomy patients [9], and Gilron et al. showed a used as an adjunct for the treatment of acute postsurgical pain combination of gabapentin and rofecoxib was superior in [3] with meta-analyses showing that it significantly reduces relieving pain after hysterectomy than each agent alone [10]. postoperativeopioiduseaswellaspainscores[4–6].A Later, Gilron et al. evaluated the effect of adding meloxicam recent meta-analysis showed that perioperative gabapentin to gabapentin in patients undergoing outpatient laparoscopic 2 Pain Research and Management surgery, but data suggested that this provided little additional 2. Materials and Methods benefit. Other studies by Clarke et al. demonstrated the decrease in the use of opioids in patients who received 2.1. Patient Sample and Recruitment Procedures. This study preoperative and postoperative gabapentin after total knee was submitted to approval by the IRB and, once obtained, arthroplasty [3]. They also noted that optimum timing and all patients were provided with informed written consent in dosage of the gabapentin needed to be further elucidated. order to participate in the study. The patients were between 18 However,inthesameyear,Clarkeetal.alsoreportedthat and70yearsoldundergoingeitheratotalkneearthroplasty, gabapentin provided no benefit after total hip arthroplasty total hip arthroplasty, or a hip fracture repair. The patients when a robust multimodal analgesic regimen was combined selected had an ASA score between I and III. Patients were with spinal anesthesia [11]. not eligible to participate in the study if they met any of the One of the side effects of gabapentin includes sleepiness, following criteria: pregnancy or breast feeding, allergy to any which may be beneficial to surgical patients in the immediate of the drugs to be used in the study or to aspirin and other postoperative period. In a meta-analysis, Peng showed a 35% NSAIDs (such as ibuprofen), a history of a sleep disorder decrease in total opioid consumption in the first 24 hours (such as obstructive sleep apnea or daytime somnolence), postoperatively with the use of gabapentin [5]. Despite the a history of taking chronic narcotic pain medications or myriad of literature on gabapentin and postoperative pain, gabapentin, a history of rheumatoid arthritis, a psychiatric little is known about the use of perioperative gabapentin disorder, diabetes with nephropathy, a history of alcohol and its effect on sleep quality. While a recent investigation orillicitdrugabuse,intrinsichepaticorrenaldisease,the did not find a direct correlation between sleep disturbances inability or unwillingness to use patient-controlled analgesia, and postoperative pain, a questionnaire study found that inability to meet extubation criteria in the operating room, a the most common reason for nighttime awakenings was history of asthma, a history of stroke or heart attack or throm- pain and that analgesia was the most helpful intervention botic event within the past 3 months, lactose intolerance, or [12]. In healthy subjects, gabapentin has been shown to a history of cardiac surgery. increase slow wave sleep (SWS), maintain a stable REM, Once confirmed to be eligible, the patients were recruited and reduce arousals, awakenings, and stage shifts—all of for the study. Demographic information was obtained in a which are features of sleep fragmentation [13]. Sleep, however, detailed preoperative interview the morning of the surgery. deviates from the normal sleeping pattern in the postop- Furthermore, a preoperative sleep history was obtained by erative patient. Total sleep time, proportion of REM sleep, andproportionofslowwavesleep(SWS)areallreduced. using a modified version of the Pittsburgh Sleep Quality Postoperatively, pain tends to be highly fragmented with Index (PSQI), described below. Out of the 50 intended multiple spontaneous awakenings and movement arousals. subjects,wewereabletoenrollonly29patients,whichwere Most of these changes occur during postoperative days 1 and randomized into two groups: the placebo group and the 2; however, patients also incur a REM sleep rebound in days gabapentin group. 3 and 4 that can extend up to a week [14]. Studies have demonstrated that these postoperative sleep disturbances, 2.2. Drug Preparation, Dispensing, and Randomization. Both notably the prolonged REM sleep rebound, may contribute the gabapentin and placebo tablets were formulated and to the development of altered mental function [15], postoper- encapsulated by the University Hospital research pharmacist. ative episodic hypoxemia [16], and hemodynamic instability The placebo capsules were composed of a mixture of lactose [17]. A recent study even found that postoperative sleep andgranulose.Therandomizationprotocolwascompleted disruptions independently predicted functional limitations solely by the research pharmacist, who was not involved in three months following surgery in patients who underwent the care of the patients. total knee replacement [18]. The pathogenesis of these sleep changes appears to be strongly correlated with the magnitude 2.3. Pre-, Intra-, and Postoperative Anesthesia Care. Prior ofthesurgeryasopposedtothetypeofanesthesiaused. to surgery, all patients were given midazolam 1–3 mg intra- Many specific mediators of surgical stress response have venously to achieve anxiolysis. The patients also received a been indicated, including catecholamines, cortisol, and IL- lumbar plexus block or a femoral nerve block, depending 1. However, as REM sleep is controlled by many regions of on the surgery performed, as this is the current standard of the brain, disturbances may be due to a global excitatory CNS carefororthopedicpatientsatUniversityHospitalinNewark. effect. All patients received celecoxib 200 mg orally twice daily for The primary purpose of this randomized, double- three postoperative days. In the operating room, standard blinded, placebo-controlled study was to determine whether, general anesthesia technique or neuraxial anesthesia was in the context of a lumbar plexus or femoral nerve block utilized. Upon extubation, the patients were transferred to (depending on the surgery), a single dose of gabapentin the postanesthesia care unit (PACU), where baseline pain improves self-reported measures of a patient’s sleep quality and sedation scores were obtained using the Visual Acuity in the form of a modified version of the Pittsburg Sleep Scale (VAS), the Modified Wilson Sedation Scale (WSS), and Quality Index (PSQI), a subjective sleep scale. The secondary Ramsay Sedation Scale (RSS), respectively. All pain scores endpoint examined whether the addition of gabapentin were assessed with subjects in the resting position. A con- improves postoperative pain, assessed on both postoperative tinuous infusion of bupivacaine 0.125 mg/L was started at a days one and two. rate of 10 mL/hr and continued to postoperative day 2. An IV Pain Research and Management 3

PCA hydromorphone pump was initiated and set to deliver Table 1: Demographics of patients in the control (placebo) versus a 0.2 mg bolus per demand with a 5-minute lockout period study group (gabapentin). without a basal infusion. If hydromorphone was unavailable Gabapentin (𝑛=17) Placebo (𝑛=12) PC, Morphine Sulfate was utilized and set to deliver a 1 mg bolus per demand with a 5-minute lockout. At the time of Mean patient age (yr) 54.6 53.33 data analysis, for the subjects who received PCA Morphine, Sex (Male/Female) 7/10 6/6 their dosages were converted to the equivalent dosage of ASA hydromorphone. All patients were instructed to maintain Class I 1 0 theirVASpainscoreatlessthan4outof10.IftheVAS Class II 5 5 pain score was 5 or greater at rest on two consecutive pain Class III 11 7 assessments, the dose of intravenous PCA hydromorphone was increased to deliver a 0.3 mg bolus per demand and the PCA Morphine was increased to deliver a 1.5 mg bolus per of the primary orthopedic joint replacement surgeon caused demand. oursamplesizetobereducedsignificantly. In addition to this, a single 400 mg dose of gabapentin was given at 9 pm of the procedure day and another dose 2.6. Data Analysis. The data compiled blindly and anony- wasgivenat9pmonpostoperativeday(POD)1.Allteams mously by the study team was transferred into a confidential involved in the care of the patient were aware not to order any study database. Data was analyzed as intent-to-treat. The additional sleep adjuvants. The following mornings, on POD1 investigators, with the assistance of the statistician, conducted and POD2, a questionnaire addressing the quality of sleep, an analysis using a two-sample Kolmogorov-Smirnov test, a hours of sleep, number of awakenings throughout the night, two-tailed test. The primary endpoint is quality of sleep as and contributing reasons for these awakenings (pain, noise, evidenced by the modified PSQI questionnaire. urination, temperature discomfort, positional discomfort, for nursingcare,orotherreasons)wasgiven.Patientswerealso 3. Results assessed for pain, sedation, and the incidence of any side effects, including nausea, vomiting, dizziness, and pruritus. 3.1. Recruitment and Retention of Patients. Patients were In addition, all patients began an as-tolerated weight-bearing recruited between years 2010 and 2011. The patients screened rehabilitation program for range of motion, strengthening, were undergoing either a total knee arthroplasty (TKA), balance, and ambulation beginning the first day after surgery. total hip arthroplasty, or a hip fracture repair. A total of 36 Success in completion of the physical therapy goals of being additional patients were screened. The three most common outofbedinachairbypost-opday1andambulatingbypost- reasons why patients were not enrolled included the follow- op day 2 was determined for each group. No functionality ing: (1) patient did not speak the English language, (2) patient testing was done in this study since a previous study was had obstructive sleep apnea, and (3) patients were having a unable to show an association between gabapentin and revision surgery. A total of 29 patients were used for the study. improvement in function after TKA [19]. 3.2. Baseline Characteristics and Clinical Variables. The 2.4. Questionnaire. The Pittsburg Sleep Quality Index (PSQI) placebo and gabapentin subject groups were comparable in [20, 21] is a self-rating questionnaire used to measure the terms of age, sex, and ASA status (Table 1). quality and other parameters of sleep in adults. The PSQI is comprised of seven categories which are graded and equally 3.3. Primary Outcome. Outcomes in the pre-op PSQI ques- weighedonascalefrom“0”to“3”withthevalueof“3”being tionnaire and the post-op sleep questionnaire for POD1 and the most negative endpoint. The categories are subjective POD2 for the placebo and gabapentin groups can be found in sleep quality, sleep latency, sleep duration, sleep efficiency, Tables 2(a) and 2(b), respectively. As expected, there was no sleep disturbances, use of sleep medication, and daytime significant difference between the PSQI scores of the placebo dysfunction over the last month. The seven components are and gabapentin groups the morning prior to the surgery. added up to a global score which ranges between “0” and “21” Difference in sleep quality between the two groups on POD1 with higher scores indicating worse sleep quality. Studies have was also found to be statistically insignificant. Although sleep implemented the PSQI to assess the relationship between quality did seem to improve in POD2 for the gabapentin sleep quality and postoperative pain at 1 and 6 months group, the 𝑃 value was found to be 0.64. Thus, no significant following TKA [18, 22]. differences were found on these questionnaires. We also used the Visual Analog Scale for pain (VAS) as a secondary outcome. The VAS was used due to its simplicity 3.4. Secondary Outcomes. As previously mentioned, we used and due to its acceptability as a generic pain measure. We the VAS as our secondary outcome due to its simplicity and askedforthehighestmeasureofpainwithinthefirst12hours, duetoitsacceptabilityasagenericpainmeasure.Weaskedfor onPOD1andonPOD2. the highest measure of pain within the first 12 hours, on POD1 and on POD2. There was no significant difference inpain 2.5. Sample Size Estimate. Atotalof60patientswere scores between the gabapentin and placebo groups within the intended to be enrolled in the study. However, the departure first 12 hours after surgery. This result was expected, due tothe 4 Pain Research and Management

Table 2: The 𝑃 value comparing quality of sleep between the control (a) and Gabapentin (b) groups preoperatively, POD1, and POD 2.

(a)

Placebo statistic PSQI Quality of sleep Quality of sleep POD1 (Scale 0–3) POD2 (Scale 0–3) (𝑛)1212 12 Mean 7.333 1.333 1.000 Variance (𝑛−1) 18.970 0.424 0.727 Standard deviation (𝑛−1) 4.355 0.651 0.853 (b)

Gabapentin statistic PSQI Quality of sleep Quality of sleep POD1 (Scale 0–3) POD2 (Scale 0–3) (𝑛)1717 17 Mean 6.765 1.235 0.647 Variance (𝑛−1)12.691 1.191 0.743 Standard deviation (𝑛−1)3.562 1.091 0.862

effects of the peripheral blocks performed perioperatively. We performing these operations. In conclusion, a single pre- also found no significant difference in pain scores between operative dose of gabapentin 400 mg followed by a second thegabapentinandplacebogroupsonbothPOD1andPOD2. doseofgabapentin400mgonPOD1showednosignificant improvement on self-reported sleep quality or pain scores on POD1 and POD2. Future studies should consider using 4. Discussion the same standardized version of the PSQI preoperatively This study was designed with the aim of examining whether and on POD1 and POD2 in order to allow for more uniform gabapentin in the context of peripheral nerve blocks and comparison between different studies. opioid PCA would show an improvement in sleep quality. Though no specific dosage of gabapentin has been shown Competing Interests to be optimal, we selected to use a 400 mg preoperative dose. The present study did not find a significant difference The authors declare that they have no competing interests. between gabapentin and placebo groups in terms of the self-reported sleep quality questionnaire on either POD1 or References POD2. Furthermore, pain scores on POD 1 and POD 2 did [1]M.A.RoseandK.L.Larrimore,“Knowledgeandaware- not differ between groups. Although the aforementioned ness concerning chemical and biological terrorism: continuing studies and meta-analyses have shown a positive correlation education implications,” Journal of Continuing Education in between gabapentin use and reduction of postsurgical pain, Nursing,vol.33,no.6,pp.253–258,2002. it is clear that more evidence is needed to determine whether [2] C. P.Taylor, N. S. Gee, T.-Z. Su et al., “Asummary of mechanistic gabapentin has a positive effect on sleep quality. The results hypotheses of gabapentin pharmacology,” Epilepsy Research, obtained from this study are unable to support the hypothesis vol. 29, no. 3, pp. 233–249, 1998. of improved sleep quality in patients who receive gabapentin [3] H. Clarke, S. Pereira, D. Kennedy et al., “Gabapentin decreases perioperatively, as opposed to patients who do not receive this morphine consumption and improves functional recovery fol- adjunctive treatment. lowing total knee arthroplasty,” Pain Research and Management, With regard to pain scores, immediate postoperative pain vol.14,no.3,pp.217–222,2009. was minimal equally amongst both groups, which is expected [4] K.-Y.Ho,T.J.Gan,andA.S.Habib,“Gabapentinandpostopera- with effective sciatic and femoral nerve blocks. However, tive pain—a systematic review of randomized controlled trials,” Pain,vol.126,no.1–3,pp.91–101,2006. even as local anesthetic effect dissipated with time, there still [5] P. W. H. Peng, D. N. Wijeysundera, and C. C. F. Li, “Use of appeared to be no difference in pain scores on POD1 and gabapentin for perioperative pain control—a meta-analysis,” POD2 between patients who received gabapentin and those Pain Research and Management,vol.12,no.2,pp.85–92,2007. allocatedtotheplacebogroup.Theresultsofthisstudyshould [6] R. K. Seib and J. E. Paul, “Preoperative gabapentin for postoper- not be generalized to alternative perioperative pain regimens ative analgesia: a meta-analysis,” Canadian Journal of Anesthe- (i.e., regimens without a peripheral block or opioid PCA) sia,vol.53,no.5,pp.461–469,2006. as these results were specific to our regimen. Furthermore, [7] B. Doleman, T. P. Heinink, D. J. Read, R. J. Faleiro, J. N. Lund, the power of this study, which was expected to be greater and J. P. Williams, “A systematic review and meta-regression when the study was first designed, was greatly compromised analysis of prophylactic gabapentin for postoperative pain,” due to the unexpected departure of the orthopedic surgeon Anaesthesia, vol. 70, no. 10, pp. 1186–1204, 2015. Pain Research and Management 5

[8] V. K. F. Kong and M. G. Irwin, “Gabapentin: a multimodal perioperative drug?” British Journal of Anaesthesia,vol.99,no. 6, pp. 775–786, 2007. [9]Y.M.AmrandA.A.A.-M.Yousef,“Evaluationofefficacyof the perioperative administration of venlafaxine or gabapentin on acute and chronic postmastectomy pain,” Clinical Journal of Pain,vol.26,no.5,pp.381–385,2010. [10]I.Gilron,E.Orr,D.Tu,J.P.O’Neill,J.E.Zamora,andA.C.Bell, “Aplacebo-controlled randomized clinical trial of perioperative administration of gabapentin, rofecoxib and their combination for spontaneous and movement-evoked pain after abdominal hysterectomy,” Pain,vol.113,no.1-2,pp.191–200,2005. [11] H. Clarke, S. Pereira, D. Kennedy et al., “Adding Gabapentin to a multimodal regimen does not reduce acute pain, opioid consumption or chronic pain after total hip arthroplasty,” Acta Anaesthesiologica Scandinavica,vol.53,no.8,pp.1073–1083, 2009. [12] S. J. Closs, “Patients’ night-time pain, analgesic provision and sleep after surgery,” International Journal of Nursing Studies,vol. 29,no.4,pp.381–392,1992. [13] N. Foldvary-Schaefer, I. De Leon Sanchez, M. Karafa, E. Mascha,D.Dinner,andH.H.Morris,“Gabapentinincreases slow-wave sleep in normal adults,” Epilepsia,vol.43,no.12,pp. 1493–1497, 2002. [14] S. Rosenberg-Adamsen, H. Kehlet, C. Dodds, and J. Rosenberg, “Postoperative sleep disturbances: mechanisms and clinical implications,” British Journal of Anaesthesia,vol.76,no.4,pp. 552–559, 1996. [15] M. C. Helton, S. H. Gordon, and S. L. Nunnery, “The corre- lation between sleep deprivation and the intensive care unit syndrome,” Heart and Lung,vol.9,no.3,pp.464–468,1980. [16] J. Rosenberg, G. Wildschiodtz, M. H. Pedersen, F. Von Jessen, and H. Kehlet, “Late postoperative nocturnal episodic hypox- aemia and associated sleep pattern,” British Journal of Anaesthe- sia,vol.72,no.2,pp.145–150,1994. [17] G. Mancia, “Autonomic modulation of the cardiovascular sys- tem during sleep,” New England Journal of Medicine,vol.328, no. 5, pp. 347–349, 1993. [18]J.K.Cremeans-Smith,K.Millington,E.Sledjeski,K.Greene, and D. L. Delahanty, “Sleep disruptions mediate the relation- ship between early postoperative pain and later functioning following total knee replacement surgery,” Journal of Behavioral Medicine,vol.29,no.2,pp.215–222,2006. [19]H.A.Clarke,J.Katz,C.J.L.McCartneyetal.,“Perioperative gabapentin reduces 24 h opioid consumption and improves in- hospital rehabilitation but not post-discharge outcomes after total knee arthroplasty with peripheral nerve block,” British Journal of Anaesthesia, vol. 113, no. 5, pp. 855–864, 2014. [20] D. J. Buysse, C. F.Reynolds III, T. H. Monk, S. R. Berman, and D. J. Kupfer, “The Pittsburgh sleep quality index: a new instrument for psychiatric practice and research,” Psychiatry Research,vol. 28,no.2,pp.193–213,1989. [21] D. J. Buysse, C. F. Reynolds III, T. H. Monk, C. C. Hoch, A. L. Yeager, and D. J. Kupfer, “Quantification of subjective sleep quality in healthy elderly men and women using the Pittsburgh Sleep Quality Index (PSQI),” Sleep,vol.14,no.4,pp.331–338, 1991. [22]A.F.Chen,F.R.Orozco,L.S.Austin,Z.D.Post,C.A. Deirmengian, and A. C. Ong, “Prospective evaluation of sleep disturbances after total knee arthroplasty,” Journal of Arthro- plasty,vol.31,no.1,pp.330–332,2016. Hindawi Pain Research and Management Volume 2017, Article ID 4260702, 9 pages https://doi.org/10.1155/2017/4260702

Clinical Study Peritoneal Nebulization of Ropivacaine during Laparoscopic Cholecystectomy: Dose Finding and Pharmacokinetic Study

Massimo Allegri,1,2,3 Martina Ornaghi,4 Catherine E. Ferland,3,5,6 Dario Bugada,1,2,3,7 Yash Meghani,5 Serena Calcinati,4 Manuela De Gregori,3,7,8 Federica Lovisari,4 Krishnaprabha Radhakrishnan,5 Maria Cusato,9 Stefano Scalia Catenacci,4 Marta Somaini,10 Guido Fanelli,1,2 and Pablo Ingelmo3,5,6

1 Department of Anaesthesia, ICU and Pain Therapy, University Hospital of Parma, Parma, Italy 2 Department of Surgical Sciences, University of Parma, Parma, Italy 3 SIMPAR Group (Study in Multidisciplinary Pain Research), Parma, Italy 4 Department of Anaesthesia and Intensive Care, San Gerardo Hospital of Monza, Milan Bicocca University, Milan, Italy 5 Department of Anaesthesia, Montreal Children’s Hospital, McGill University, Montreal,´ QC, Canada 6 Alan Edwards Centre for Research on Pain, Montreal, QC, Canada 7 YAP Group (Young Against Pain), Firenze, Italy 8 Pain Therapy Service, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy 9 Laboratory of Clinical Pharmacokinetics, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy 10DepartmentofAnaesthesiaandIntensiveCareI,ASSTGrandeOspedaleMetropolitanoNiguarda,UniversityofMilano-Bicocca, Milan, Italy

Correspondence should be addressed to Catherine E. Ferland; [email protected]

Received 30 November 2016; Accepted 30 January 2017; Published 20 February 2017

Academic Editor: Volkan Hancı

Copyright © 2017 Massimo Allegri et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background. Intraperitoneal nebulization of ropivacaine reduces postoperative pain and morphine consumption after laparoscopic surgery. The aim of this multicenter double-blind randomized controlled trial was to assess the efficacy of different dosesand dose-related absorption of ropivacaine when nebulized in the peritoneal cavity during laparoscopic cholecystectomy. Methods. Patients were randomized to receive 50, 100, or 150 mg of ropivacaine 1% by peritoneal nebulization through a nebulizer. Morphine consumption, pain intensity in the abdomen, wound and shoulder, time to unassisted ambulation, discharge time, and adverse effects were collected during the first 48 hours after surgery. The pharmacokinetics of ropivacaine was evaluated usinghigh performance liquid chromatography. Results. Nebulization of 50 mg of ropivacaine had the same effect of 100 or 150 mg in terms of postoperative morphine consumption, shoulder pain, postoperative nausea and vomiting, activity resumption, and hospital discharge timing (>0.05). Plasma concentrations did not reach toxic levels in any patient, and no significant differences were observed between groups (𝑃 > 0.05). Conclusions. There is no enhancement in analgesic efficacy with higher doses of nebulized ropivacaine during laparoscopic cholecystectomy. When administered with a microvibration-based aerosol humidification system, the pharmacokinetics of ropivacaine is constant and maintains an adequate safety profile for each dosage tested.

1. Introduction laparoscopic surgery is usually attributed to surgical manipu- lations, including intraperitoneal insufflation of carbon diox- Postoperative pain remains a major problem after laparo- ide, resulting in peritoneal stretching, diaphragmatic irrita- scopy, having direct consequences on the patient’s quality of tion, changes in intra-abdominal pH, and retention of the life as well as increasing health care costs [1, 2]. Pain after insufflated gas within the abdominal cavity after surgery [3]. 2 Pain Research and Management

These manipulations also result in the irritation of peritoneal acute preoperative pain other than biliary colic, chronic pain nerves causing visceral and shoulder pain. Previous studies treatments, or antiepileptic treatment, history of alcohol or have reported that as many as 80% of patients required opioid drug addiction, severe hepatic or renal impairment, allergy to analgesia after laparoscopic surgery [1, 4, 5], which also may the study drugs, or cognitive impairment or communication increase postoperative morbidity and hospital stay [2]. problems or were pregnant or lactating. Intraperitoneal nebulization of local anesthetics through Asthegoalofthistrialwastoevaluatetheeffectof microvibration-based aerosol humidification devices com- intraperitoneal ropivacaine nebulization, conversion to an bines the analgesic benefits of gas conditioning (humid- open technique was considered a protocol dropout. Dropout ification) and local anesthetic instillation, allowing for a patients were excluded from the efficacy analysis but received uniform dispersion of the solution throughout the peri- the same analgesia protocols and evaluations until their toneum [6]. This method has shown great efficacy inthe hospital discharge for the safety analysis. control of postoperative pain [7–12] and in the reduction of postoperative morphine consumption when compared with 2.2. Randomization Procedures. Patients were randomized both placebo and peritoneal instillation in different clinical with a computer-generated randomization sequence into scenarios [12–14]. However, in all those studies there were three groups: peritoneal nebulization of 5 mL (50 mg group), patients experiencing residual pain and requiring significant 10 mL (100 mg group), or 15 mL (150 mg group) of ropivacaine amount of opioids. Moreover, there was no formal analysis of 1%. The coordinators of the research centres received a the least effective dose of local anesthetic. Pharmacokinetic studies on animal models have shown package containing sequentially numbered, opaque, sealed, that intraperitoneal cold nebulization of ropivacaine is a and stapled envelopes during the research team meetings. The safe technique, and the drug’s kinetics is similar to the anesthesia nurse received the sealed envelope containing allo- instillationmethod[7,15].Humanstudieshaveconfirmed cation number and instructions for the solution preparation favorable pharmacokinetics and pharmacodynamics of neb- from a research assistant before patients entered the operating ulized ropivacaine. Peak concentration is attained between 10 room. Corresponding envelopes were opened only after the and 30 minutes following the end of aerosolized ropivacaine enrolled participants completed the identification checklist. delivery and the plasma concentration of local anesthetics The research assistants involved in data collection and the remained within safe levels even after nebulization of 3 mg/kg anesthesiologist and the surgeon of the case (not involved of ropivacaine [16]. However, the delivery of high doses with the study) were unaware of the study group assignment. of ropivacaine (i.e., 3 mg/kg) may be unnecessary or even The blinding was disclosed only after the statistical analysis. impractical due to the long nebulization time with the actual In case of an emergency related or possible related to study commercially available systems. Moreover, it is possible that drugs, the nurse or the research assistant of the coordinator lowereffectivedosescouldhavelessanddifferentkineticsdue centre was authorized to disclose the content of the syringe to the postnebulization loses during normal (less controlled) totheanesthesiologistandclinicians.Theresearchassistants surgical procedures [17]. involved in data collection as well as nurses and doctors who The aim of this multicenter, double-blind, randomized, had direct patient contact were unaware of the study group controlled phase III clinical trial was to assess if an increase assignment. on the doses of nebulized ropivacaine is associated with an increase on its analgesic efficacy expressed through the reduc- tion of morphine consumption after laparoscopic cholecys- 2.3. Anesthesia Procedures. A standard anesthetic technique tectomy. As a second aim, we evaluated the possibility of was used for all patients. Patients were premedicated with diazepam 5–7 mg, 30 minutes before surgery. General anes- a dose-dependent systemic absorption of ropivacaine, when −1 thesia was induced with propofol 2-3 mg kg IV and tracheal nebulized in the peritoneal cavity during everyday clinical −1 conditions. intubation was facilitated with cisatracurium 0.15 mg kg IV. Anesthesia was maintained with sevoflurane 1.5–2.5% end- 2. Methods tidal concentration titrated to maintain state entropy values between 45 and 60 (Entropy sensor6,M-ENTROPYTM module, GE Healthcare, Helsinki, Finland), fentanyl boluses After Ethics Committee approval by the two hospitals −1 involved in the study (San Gerardo Hospital, Monza and 1-2 mcg kg titrated to maintain noninvasive mean arterial blood pressure and heart rate ±20% of basal values, and IRCCS Policlinico S. Matteo, Pavia, Italy), this trial was reg- −1 isteredonclinicaltrials.gov(NCT0114302506/09/2010).The cisatracurium 0.03 mg kg titrated to maintain a train of study was designed according to the CONSORT guidelines four count (TOF) of 1-2, as well as according to clinical (https://www.consort-statement.org). needs. Ventilation was controlled to maintain end-tidal CO2 between 35 and 40 mmHg. After tracheal intubation, an orogastric tube and an oesophageal temperature probe were 2.1. Patients. All patients in this study provided written ∘ informed consent. Eligible patients were adults between 18 placed.Theoperatingroomtemperaturewassetto20C, and and75yearsofage,hadanAmericanSocietyofAnes- patients were kept warm using a forced warm-air device and warmed intravenous solutions. At the end of surgery, residual thesiologist physical status score of I–III, and were sched- −1 uled for elective laparoscopic cholecystectomy. Patients were muscle paralysis was reversed with neostigmine 0.05 mg kg −1 excluded if they had a clinical diagnosis of acute pancreatitis, and atropine 0.02 mg kg , and tracheal extubation was Pain Research and Management 3 performed once clinical signs were observed and a TOF ratio 90, 240, and 360 minutes after the end of nebulization. Each of 0.9 was achieved. sample (10 mL) was collected into a tube containing EDTA Surgerywasperformedwiththe4-accesstechnique; and immediately centrifuged at 3000 rpm for 10 minutes. the pneumoperitoneum was obtained through nonheated, Each plasma sample was then transferred into 2 polypropy- ∘ nonhumidified CO2. Nebulization was performed from the lene tubes and sealed and stored at −20 Cuntilanalysis. beginning of the pneumoperitoneum through the main All analyses were conducted at the Laboratory of Clinical trocar using Aeroneb Pro5 nebulizer, while the other ports Pharmacokinetics of the IRCCS Fondazione Policlinico San werebeinginserteduntiltheendoftheavailabledose.The Matteo, Pavia. nebulization unit was placed in series between the insufflator The following parameters were evaluated: total and free and the insufflation tubing. ropivacaine plasma concentrations, with estimation of peak All patients received dexamethasone 4 mg IV after the concentrations (𝐶max), time to peak concentrations (𝑇max), induction of anesthesia and ondansetron 4 mg IV at the end absorption rate constant (𝑘𝑎), absorption half-life (𝑡1/2 abs), of surgery for postoperative nausea and vomiting prophy- elimination half-life (𝑡1/2) and elimination rate constant (𝑘𝑒), laxis. A bolus of paracetamol 15 mg/kg (up to a maximum and area under the concentration-time curve of the drug of 1 g) was administered during surgery together with wound from the time of dosing to 6 h later (AUC0–6 h). Total and infiltration with 3 mL of ropivacaine 0.5% after completion of free ropivacaine concentrations were assessed using high surgery. performance liquid chromatography validated for precision, accuracy, linearity, specificity, and recovery. 2.4. Analgesia Protocol. Upon arrival to the postanesthesia care unit (PACU) morphine 3 mg boluses were administered 2.6. Statistical Analysis. This study consisted of a continuous in order to obtain a numerical rating score (NRS) less response variable (morphine consumption). In a previous than 3 points on a 0–10 scale, of which 0 represented study [18], the response within patients receiving preopera- “no pain” and 10 represented “worst possible pain.” In the tive nebulization was normally distributed with a mean mor- surgical ward analgesia was provided with IV paracetamol phine consumption 48 hours after surgery of 12 mg ± 15 mg. (1 g every 6 hours) and patient controlled analgesia (PCA) BasedonStudent’stwo-sample𝑡-test, if a true difference in with morphine (1 mg bolus, 5-minute lock-out, and 4 hours the experimental and control means morphine consumption ofmaximumdoseof20mg)duringthefirst48hours. is 6 mg, therefore a minimum of 50 experimental subjects This allowed us to measure morphine consumption more per group would be needed to reject the null hypothesis that accurately. Ondansetron 4 mg was administered every 12 morphine consumption 48 hours after surgery of patients hours for PONV prevention. Patients were encouraged to receiving nebulization of ropivacaine 50, 100, and 150 mg ambulate as soon as possible. On the basis of our routine is equal, with a power of 0.9 and Type I error = 0.05 (2- practice, all patients remained in the hospital for 48–72 hours. sided)(PSPowerandSampleSizeCalculations©Version3.0, The primary endpoint of this study was the total con- January 2009). Fifty-five patients were enrolled in each group sumption of morphine (PACU and ward) during the first 48 to allow for protocol violations. hours after surgery. We also assessed the proportion of the Continuous variables (age, surgery duration, intra- patients requiring morphine during the first 24 hours and 48 abdominal pressure during pneumoperitoneum, CO2 vol- hours after surgery. ume, nebulization duration, residual volume, effective neb- Collected data included patient age, gender, weight, and ulization volume, percentage of nonadministered volume, height, intraoperative opioid use, duration of surgery, post- body temperature variation, PACU permanence duration, nebulization volume of ropivacaine (residual volume in the morphine consumption, intensity of postoperative general nebulization unit plus the volume in the silicon connection pain and pain localized to abdomen wound and shoulder, tubes), signs of local anesthetic toxicity (e.g., intraoperative time of unassisted ambulation, and time of hospital dis- arrhythmias, unexplained hypotension, burst suppression charge) were presented as means and standard deviations and on entropy monitor, and unexplained delayed awakening), were analyzed with ANOVA. patient temperature in the PACU, and duration of PACU Discrete variables (sex, drain presence, morphine use, stay. Patients were evaluated in PACU and at 4, 6, 24, and time of unassisted ambulation, m-PADDS score ≥ 9, presence 48 hours after nebulization. At each control, we registered of adverse events, or other complications) were reported as pain intensity static pain (at rest) and dynamic pain (on deep percentages and were analyzed with either the chi-square or breathing, coughing, or movement), using the NRS, discrim- Fisher exact test. Statistical analyses were performed with Epi inating between general, abdominal, wound, and shoulder Info 2007 (Epi Info, CDC, Atlanta, USA). pain. Morphine consumption, time to unassisted ambulation, Pharmacokineticdatawereanalyzedasgroupmeanswith discharge criteria according to modified postanesthetic dis- standard deviation. We calculated the mean of nebulization charge scoring system (PADSS), and possible adverse effects time, the average and percentage drug loss, 𝐶max for each such as shivering, nausea, or vomiting were also collected. group,thenumberofpatientsachievingthisvalue,and the maximum concentration stratified by group. ANOVAs 2.5. Pharmacokinetic Assessment. The analysis of ropivacaine were used to examine the differences in pharmacokinetic pharmacokinetics was structured as a single dose study. Ropi- parameters of anesthetics. A 𝑃 value < 0.05 was considered vacaine plasma concentrations were determined on venous statistically significant for all tests. AUC0–6 was calculated blood samples collected before the procedure and 20, 40, 60, using the trapezoidal rule from 0 to 6 hours. Pharmacokinetic 4 Pain Research and Management

Table 1: Clinical and surgical characteristics. Data are presented as wounds, and shoulder) (Figure 1). The mean pain intensity at mean ± standard deviation or as percentage (%). thewoundsandintheabdomenwassimilarandhigherthan the referred pain in the shoulder. 50 mg 100 mg 150 mg Population There were no significant differences in the hospital stay, (𝑛=54) (𝑛=52) (𝑛=53) in the readiness for discharge (m-PADDS score ≥ 9), or in 53 ± 13 48 ± 14 52 ± 12 Age (years) the incidence of nausea or vomiting among the three groups Sex (F/M) 29/25 34/17 34/19 (Table 4). There was a strong relationship between the dose Surgery time (min) 81 ± 28 85 ± 24 74 ± 27 of ropivacaine and the incidence of shivering after surgery. Mean abdominal pressure 13 ± 1 13 ± 1 13 ± 1 One patient from the 50 mg group (2%), four patients from (mmHg) the 100 mg group (8%), and 11 patients from the 150 mg group 𝑃 = 0.004 CO2 total volume (L) 124 ± 72 140 ± 89 126 ± 82 (21%) shivered in PACU ( ). Drain presence 66% 60% 60% PACU permanence (min) 44 ± 15 43 ± 17 42 ± 17 3.3. Pharmacokinetics Assessment. We were unable to detect Body temperature variation ropivacaine in the plasma of seven patients (1 patient in ∘ −0.2 ± 0.4 −0.2 ± 0.4 −0.1 ± 0.4 ( ) the 50 mg group, 4 patients in the 100 mg group, and 2 patients in the 150 mg group). Mean plasma concentrations of ropivacaine among the three groups were not significantly calculations were performed using the Kinetica 4.0 software different, while they are never reaching toxic values (Table 5). (INNAPHASE Corporation, Philadelphia, PA, USA). Peak plasma concentrations were detected between 20 and 40 minutes after the end of nebulization, followed by a plateau 3. Results at 60–90 minutes, in all groups. In 5 patients, peak time was detected at 240 or even 360 minutes after the end of One hundred and seventy-six patients were enrolled dur- nebulization. No clinical signs of toxicity or adverse events ing the preoperative evaluation. Eleven patients did not were observed. receive the intervention during surgery due to logistical difficulties (mainly lack of nebulization units). Six patients 4. Discussion were excluded from the efficacy analysis, one in the 50 mg group,threeinthe100mggroup,andtwointhe150mg In this multicenter, double-blind, randomized, controlled, group. Five of them were converted to open technique; one phase III clinical trial, we compared the analgesic effects disclosed a previous history of drug abuse after receiving the and the pharmacokinetics of intraperitoneal nebulization of intervention. One hundred and fifty-nine patients completed 50 mg, 100 mg, and 150 mg of ropivacaine using the Aeroneb the study and the efficacy analysis. The pharmacokinetic Pro system in patients undergoing laparoscopic cholecys- study included 36 patients (12 patients from each group) of tectomy. Increasing the dose of ropivacaine from 50 mg to the 165 patients recruited from the main study. 150mgdidnotreducetheuseofmorphineaftersurgery.The There were no clinical or statistical differences between absorption of ropivacaine and the pharmacokinetics profile groups in age, sex, duration of surgery, intra-abdominal pres- was independent of the dose, and plasma concentrations sure during pneumoperitoneum, CO2 volume, temperature remained within safe limits in all cases. The increase of the variation, need of abdominal drainage, and PACU length of dose of ropivacaine was not associated with a reduction of stay (Table 1). pain intensity, incidence of PONV,or readiness for discharge, The nebulization time as well as the residual volume after but was associated with the incidence of shivering after nebulization was significantly different between groups. The surgery. actual dose of ropivacaine nebulized in the peritoneal cavity was 43 ± 7 mg (86%) for the 50 mg group, 93 ± 7 mg (93%) 4.1. Morphine Consumption. Peritoneal nebulization of ropi- for the 100 mg group, and 115 ± 32 mg (76%) for the 150 mg vacaine was associated with reduced morphine consumption group, respectively (Table 2). when compared with both placebo and peritoneal instillation in different clinical scenarios [12–14]. Our data suggest lack of 3.1. Primary Endpoint of the Study: Morphine Consumption. dose-dependent reduction on morphine requirements after We did not find significant differences in the total morphine surgery. The total consumption of morphine in this study was consumption between groups (Table 3). The majority of consistent with the findings in previous studies of ropivacaine patients needed morphine in the PACU (79%) and during nebulization for pain prevention after laparoscopic cholecys- the first day after surgery (81%), whereas only half of the tectomy. Bucciero et al. reported that patients receiving 60 mg patients (44%) used morphine during the second day after of nebulized ropivacaine consumed 16 ± 12 mg of morphine surgery. Interestingly, 17% of patients did not require further in the first two days after surgery [19]. In the series of Ingelmo administration of morphine after PACU discharge. et al., the mean morphine consumption after receiving 30 mg of ropivacaine was 12 ± 15 mg [12, 18]. As in our study, 3.2. Secondary Outcome Measures. We did not find sig- less than half of the patients required morphine during the nificant differences between groups in pain intensity after second day, and a significant proportion of patients did not surgery at any evaluation time or place (i.e., abdominal wall, require morphine after discharge from PACU. Collectively, Pain Research and Management 5

Table 2: Nebulization variables. Data are presented as mean ± standard deviation.

50 mg 100 mg 150 mg 𝑃 value (𝑛=54)(𝑛=52)(𝑛=53) Nebulization time (min) 16 ± 8 30 ± 18 36 ± 19 <0.001 Residual nebulization volume (mL) 0.2 ± 0.3 0.9 ± 1.2 2 ± 2 <0.001 Effective nebulization volume (mL) 4.8 ± 0.3 9.1 ± 1 13 ± 2 <0.001 Nonadministered ropivacaine (%) 4 9 14 <0.001

Table 3: Morphine consumption and proportion of patients receiving morphine during the first two days after surgery. Data are presented as mean ± standard deviation and percentages.

50 mg 100 mg 150 mg Morphine 𝑃 value (𝑛=54)(𝑛=52)(𝑛=53) Consumption (mg) PACU 4±3 4±4 4±3 0.845 First day 8±9 7±7 7±11 0.845 Second day 3±4 2±5 2±4 0.586 Total 15 ± 12 13 ± 12 13 ± 14 0.756 Proportion of patients receiving morphine (%) PACU 80% 75% 83% 0.596 4 h 66% 61% 71% 0.607 6 h 69% 73% 67% 0.825 24 h 83% 84% 81% 0.911 48 h 50% 43% 38% 0.511

Table 4: Ambulation and discharge criteria. Data are presented as mean ± standard deviation and percentage.

50 mg 100 mg 150 mg 𝑃 value Patients ambulating at 6 hours (%) 46% 54% 49% 0.712 Time to unassisted walking (hours) 13 ± 9 10 ± 9 11 ± 9 0.338 mPADSS score > 8 at 6 hours 40% 42% 43% 0.947 mPADSS score > 8 at 24 hours 76% 82% 81% 0.682 Ready for discharge (hours) 22 ± 14 19 ± 14 22 ± 7 0.886 Hospital stay (days) 2.4 ± 0.8 2.3 ± 0.7 2.3 ± 0.1 0.910

Table 5: Pharmacokinetic data. Data are presented as mean ± standard deviation.

50 mg 100 mg 150 mg (𝑛=12)(𝑛=12)(𝑛=13)

𝐶max (mcg/mL) 1.8 1.76 2.01

Mean 𝐶max (mcg/mL) 0.52 ± 0.45 0.59 ± 0.51 0.79 ± 0.66 AUC (mcg/mL∗min) 131 ± 152 86 ± 34 115 ± 91 1/2 𝑇 (min) 281 (72–405) 224 (221–246) 167 (123–354) Undetected ropivacaine in plasma 1 4 2 these results suggest the uselessness of increasing the dose of surgery when compared with nebulization of saline after ropivacaine to reduce the mean morphine consumption after laparoscopic surgery [12–14]. laparoscopic cholecystectomy. Postoperative pain after laparoscopic cholecystectomy has both a somatic and a visceral origin. Somatic pain is 4.2. Pain after Surgery. We did not find differences between usually well localized to the surgical wounds. Visceral pain groups in the pain intensity after surgery. Nebulization of is poorly discriminated and involves the entire abdomen or is ropivacaine was associated with both statistical and clinical referred to as the shoulder due to irritation of the diaphrag- significant reduction of pain intensity after laparoscopic matic peritoneum. As in previous studies, the nebulization of 6 Pain Research and Management

4 4 ) 3 ) 3 10 10 – – 0 0

2 2 6 hours 24 hours Pain intensity ( intensity Pain 1 ( intensity Pain 1

0 0 Global Abdominal Wound Shoulder Global Abdominal Wound Shoulder Pain location Pain location 50 mg 50 mg 100 mg 100 mg 150 mg 150 mg (a) (b) 3 )

10 2 – 0 48 hours 1 Pain intensity ( intensity Pain

0 Global Abdominal Wound Shoulder Pain location 50 mg 100 mg 150 mg (c)

Figure 1: Dynamic pain intensity between the three treated groups 6 hours (a), 24 hours (b), and 48 hours (c) after surgery. Between the three groups, no differences were found in either the intensity of postoperative pain localized at abdominal wall, wound, and shoulder (𝑃 > 0.05). Data are presented as mean ± standard deviation.

ropivacaine was able to prevent shoulder pain considerably anesthetic. By the contrary, the Aeroneb device allows for [16, 18, 19]. simultaneous humidification [22]. Patients in our study received a significant amount of CO2 during surgery. Pain after laparoscopic surgery could 4.3. Nebulization Methods and Doses. The higher the dose of be influenced by the temperature, humidity, and volume ropivacaine, the higher the residual local anesthetic in the of insufflated [3]. Several devices based on heated or on nebulization unit and within insufflating tubes, resulting in semipermeable membrane evaporation have been used for hinder parts of the drug from reaching its site of action and humidification and warming of insufflated airway gases. to greater wastage of ropivacaine [13, 17, 22]. Nebulization of However these devices are unable to efficiently deliver local higher doses of ropivacaine required more time due to the fix anesthetic including ropivacaine both in in vitro and in nebulization rate of the nebulization system. Nebulization of clinical trials [20, 21]. These results could be explained with 50 mg of ropivacaine required less than 15 minutes and had the physical principle that evaporation enables only evapo- no impact on surgical time as suggested by our and previous ration of the solvent (e.g., water) and not of the solute (e.g., results [12, 18, 19]. local anesthetic). Thus, although these devices are efficient We used ropivacaine 1% for the study, since it is the most in humidification, they are inappropriate for delivering local concentrated formulation available in the clinical practice Pain Research and Management 7 in Italy. The higher the local anesthetic concentration, the local action is greater than the systemic one that, if present, is lower the nebulization time and consequently the lesser the minimal. “fog” in the abdominal cavity. We decided to use 50 mg as By carefully analyzing the pharmacokinetics and clinical the minimum dose for this study because it is an in-between data, our results suggest that the lack of clinical difference quantity of the doses used in our previous studies [12–14]. in analgesic efficacy, as well as the unexpected absorption This initial dosage, proved to be effective, allowed for double profile of ropivacaine, is just part of the current method of the doses up to what we considered useful in clinical practice. nebulization (fix amount per minute) site of effect (most likely Our data suggest that increasing the doses of ropivacaine sensitivefibersintheperitoneumsurface)andabsorption. over 50 mg is useless, since it only increases the time of The similar rate of absorption between groups is a further nebulization and the preperitoneal loses of local anesthetics proof on how increasing the dose only leads to increased without a proportional increase of the beneficial effects. losses and unchanged delivery of local anesthetic.

4.4. Pharmacokinetics Evaluation. We did not identify sig- 4.5. Adverse Effects. We did not find major clinically evi- nificant differences on 𝐶max, 𝑇max,andtheAUC,among dent side effects during or after surgery. Patients receiving the three administered dosages. The plasma concentrations higher doses of ropivacaine (i.e., 150 mg group) presented a remained consistent under the mean toxic plasma concen- significant incidence of shivering in the PACU. Shivering isa tration described in healthy volunteers (4.3 mg/L, range 3.4– common finding during spinal and epidural anesthesia due 5.3 mg/L) [23]. Our data are similar to those of previous to vascular dilatation caused by the sympathetic blockade, animal and human studies [16, 17]. inducing heat distribution from central to peripheral body The peak time was reached between 20 and 40 minutes areas. We suggest that nebulization realizes a similar mech- after the end of administration, except for 5 patients in whom anism, based on a dose-dependent vascular dilatation [13]. we measured a second peak at 240 or 360 minutes. This late peak of concentration could be explained on different local 4.6. Limitations. A possible limitation of this study is the anesthetic absorption during real life surgical conditions. lack of a control group. The decision not to have a control The absorption of ropivacaine could vary depending on the group was based on previous studies that were held in similar increased peritoneal drug permeability after surgical dissec- clinical conditions, which had demonstrated that ropivacaine tion, reduced intraperitoneal pressure after 2CO desufflation nebulization reduced pain and morphine consumption when with reduction of peritoneal vessels compression, instillation compared with placebo [12, 18]. drug amount condensed into connectors, a delayed absorp- Patients undergoing laparoscopic cholecystectomy tion of ropivacaine collected in the abdominal cavity, and so remained in the hospital for two days due to institutional forth. policy at the time of the recruiting phase. Therefore, we could When the absorption process is not a limiting factor, the not assess the potential benefits of the different doses on half-life is a hybrid parameter controlled by plasma clearance the actual discharge time. However, according to a modified anddistributionvolume.Iftheprocessislimited,theelimina- postanesthetic discharge scoring system, 40% of patients tion half-life reflects mainly the rate and extent of absorption were ready for hospital discharge 6 hours after surgery and and not the elimination process (flip-flop kinetics) [24]. As 80% after 24 hours. themeandrughalf-lifewaslessthan5hours,wecanposit Theoretically, a comprehensive pharmacokinetic study that the drug had a rapid washout, eliminating the risk of should have included intravenous administration of ropi- accumulation, interaction with other drugs, or long-lasting vacaine. This point involves important ethical issues that cytochromes inhibition. hinder the application of the model in the clinical scenario. It is somehow unexpected not to find differences in Additionally, this is not a pure pharmacokinetic study, but ropivacaine uptake with a 3-fold increase in the amount of a clinical study with concomitant assessment of ropivacaine nebulized local anesthetic. This may be due to preperitoneal exposure. The aim was not a detailed description of ropiva- and postperitoneal losses. In the preperitoneal loss, the local caine kinetics, but to test whether nebulization of ropivacaine anesthetic never arrived to the peritoneal cavity because it at higher doses lead patients to be exposed to toxic concen- was not nebulized or remained entrapped in the connecting trations and/or clinical toxicity. We therefore did not attempt tubes. Since the abdominal cavity is not a close system to formulate a PK modeling with IV administration, but to during surgery, the local anesthetic may be vented out of the analyze systemic exposure and quantify the effect of local abdomen during the surgical procedure. For example, when anesthetic reuptake on pain and toxicity. the surgeon removes the trocars, there is a significant amount of the aerosolized local anesthetic flowing out of the abdomen 4.7. Strengths and Future Directions. We were able to demon- that will not be absorbed. strate the lack of a dose-dependent effect and the futility We were not able to detect ropivacaine in the plasma of of higher doses of ropivacaine, along with safety profile seven patients, as plasma concentrations of ropivacaine were of nebulized ropivacaine after laparoscopic cholecystectomy. below the limit of quantification (LOQ = 0.1 mcg/mL). Due to We were also able to describe the effects of ropivacaine nebu- the absence of a statistically significant difference regarding lization in the different components of pain after laparoscopic the main endpoint of the study among patients in whom cholecystectomy. plasma concentrations were measured and those in which Future technical developments should be oriented to they were below the limit of quantification, we posit that the produce devices that enable faster nebulization closer to the 8 Pain Research and Management umbilical port, ideally without significant fog during the after laparoscopic cholecystectomy,” Annals of the Royal College procedure. of Surgeons of England,vol.75,no.6,pp.437–439,1993. [8]A.P.Boddy,S.Mehta,andM.Rhodes,“Theeffectofintraperi- 5. Conclusions toneal local anesthesia in laparoscopic cholecystectomy: a systematic review and meta-analysis,” Anesthesia and Analgesia, Higher doses of nebulized ropivacaine were not associated vol. 103, no. 3, pp. 682–688, 2006. with a reduction of morphine consumption or in pain inten- [9]L.Buck,M.N.Varras,T.Miskry,J.Ruston,andA.Magos, sity after laparoscopic cholecystectomy. Moreover, the higher “Intraperitoneal bupivacaine for the reduction of postoperative thedoseofropivacaine,thehigherthetimeofnebulization, pain following operative laparoscopy: a pilot study and review the wither the losses of preperitoneal local anesthetics, and of the literature,” Journal of Obstetrics and Gynaecology,vol.24, the greater the incidence of shivering after surgery. Intraperi- no. 4, pp. 448–451, 2004. toneal nebulization of ropivacaine was associated with a [10]A.Ng,A.Swami,G.Smith,A.C.Davidson,andJ.Emembolu, better control of shoulder pain, than abdominal or wound “The analgesic effects of intraperitoneal and incisional bupi- pain. The plasma concentration of ropivacaine remained vacaine with epinephrine after total abdominal hysterectomy,” Anesthesia and Analgesia,vol.95,no.1,pp.158–162,2002. within safe margins during and after nebulization with the Aeroneb Pro system. [11] A. Gupta, A. Perniola, K. Axelsson, S. E. Thorn,¨ K. Crafoord, and N. Rawal, “Postoperative pain after abdominal hysterec- tomy: A double-blind comparison between placebo and local Competing Interests anesthetic infused intraperitoneally,” Anesthesia and Analgesia, vol.99,no.4,pp.1173–1179,2004. The authors declare that they have no competing interests. [12]M.Somaini,P.Brambillasca,P.M.Ingelmoetal.,“Effectsof peritoneal ropivacaine nebulization for pain control after lap- Acknowledgments aroscopic gynecologic surgery,” Journal of Minimally Invasive Gynecology,vol.21,no.5,pp.863–869,2014. This study was supported by internal departmental founds of [13] S. S. Catenacci, F. Lovisari, S. Peng et al., “Postoperative analge- the Department of Anaesthesia and Intensive Care, Ospedale sia after laparoscopic ovarian cyst resection: double-blind mul- San Gerardo di Monza, Milan Bicocca University, Italy; Pain ticenter randomized control trial comparing intraperitoneal Therapy Service, IRCCS Fondazione Policlinico San Matteo, nebulization and peritoneal instillation of ropivacaine,” Journal Pavia, Italy; Laboratory of Clinical Pharmacokinetics, IRCCS of Minimally Invasive Gynecology,vol.22,no.5,pp.759–766, Fondazione Policlinico San Matteo, Pavia, Italy. 2015. [14] A. M. McDermott, K. H. Chang, K. 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[21] P. W. Zimmer, M. J. McCann, and M. M. O’Brien, “Bupivacaine use in the Insuflow5 device during laparoscopic cholecys- tectomy: results of a prospective randomized double-blind controlled trial,” Surgical Endoscopy and Other Interventional Techniques,vol.24,no.7,pp.1524–1527,2010. [22] N. Greib, H. Schlotterbeck, W.A. Dow, G. P. Joshi, B. Geny, and P. A. Diemunsch, “An evaluation of gas humidifying devices as a means of intraperitoneal local anesthetic administration for laparoscopic surgery,” Anesthesia and Analgesia,vol.107,no.2, pp.549–551,2008. [23] K. Knudsen, M. Beckman Suurkula,¨ S. Blomberg, J. Sjovall,¨ and N. Edvardsson, “Central nervous and cardiovascular effects of i.v. infusions of ropivacaine, bupivacaine and placebo in volunteers,” British Journal of Anaesthesia,vol.78,no.5,pp.507– 514, 1997. [24] L. Perotti, M. Cusato, P. Ingelmo et al., “A comparison of differences between the systemic pharmacokinetics of levobupi- vacaine and ropivacaine during continuous epidural infusion: a prospective, randomized, multicenter, double-blind controlled trial,” Anesthesia and Analgesia,vol.121,no.2,pp.348–356,2015. Hindawi Pain Research and Management Volume 2017, Article ID 7187232, 7 pages https://doi.org/10.1155/2017/7187232

Clinical Study Adherence to All Steps of a Pain Management Protocol in Intensive Care Patients after Cardiac Surgery Is Hard to Achieve

L. van Gulik,1 S. J. G. M. Ahlers,2,3 P. Bruins,1 D. Tibboel,3 C. A. J. Knibbe,2,3 and M. van Dijk3

1 Department of Anaesthesiology, Intensive Care and Pain Management, St. Antonius Hospital, Koekoekslaan 1, 3440 EM Nieuwegein, Netherlands 2Department of Clinical Pharmacy, St. Antonius Hospital, Koekoekslaan 1, 3440 EM Nieuwegein, Netherlands 3Intensive Care, Erasmus Medical Centre, Sophia Children’s Hospital, Dr. Molewaterplein 60, 3015 GJ Rotterdam, Netherlands

Correspondence should be addressed to L. van Gulik; [email protected]

Received 3 November 2016; Accepted 23 January 2017; Published 16 February 2017

Academic Editor: Volkan Hancı

Copyright © 2017 L. van Gulik et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Purpose. To investigate adherence to our pain protocol considering analgesics administration, number and timing of pain assessments, and adjustment of analgesics upon unacceptably high (NRS ≥ 4) and low (NRS ≤ 1) pain scores. Material and Methods. The pain protocol for patients in the intensive care unit (ICU) after cardiac surgery consisted of automated prescriptions for paracetamol and morphine, automated reminders for pain assessments, a flowchart to guide interventions upon high and low pain scores, and reassessments after unacceptable pain. Results. Paracetamol and morphine were prescribed in all 124 patients. Morphine infusion was stopped earlier than protocolized in 40 patients (32%). During the median stay of 47 hours [IQR 26 to 74 hours], 702/706 (99%) scheduled pain assessments and 218 extra pain scores were recorded. Unacceptably high pain scores accounted for 96/920 (10%) and low pain scores for 546/920 (59%) of all assessments. Upon unacceptable pain additional morphine was administered in 65% (62/96) and reassessment took place in 15% (14/96). Morphine was not tapered in 273 of 303 (90%) eligible cases of low pain scores. Conclusions. Adherence to automated prescribed analgesics and pain assessments was good. Adherence to nonscheduled, flowchart-guided interventions was poor. Improving adherence may refine pain management and reduce side effects.

1. Introduction the occurrence of unacceptable pain (NRS ≥ 4) from 41% to 23% [4]. However, still 46% of patients experienced at International clinical guidelines recommend systematic eval- least one event of unacceptable pain during ICU stay. In uation of pain in patients in intensive care units (ICUs) order to improve further pain management, we then studied [1]. Pain education and pain management protocols helped two different dosages of morphine for the prevention and reduce pain scores in patients in mixed ICUs [2] and in treatment of procedural pain in patients after cardiac surgery postcardiac surgery patients [3, 4]. However, adherence to inarandomizedcontrolledtrial[9].Inaddition,weevaluated guidelines in general is often poor [5, 6] and the same holds in that study adherence to the pain protocol used to assess and true for pain management in the ICU specifically [7, 8]. In treat pain, in order to investigate if pain management in rest a prospective, observational study in 44 ICUs in France pain could be ameliorated. assessment was performed in 42% of patients, while 90% of The aim of the current study was to determine the adher- patients received opioids [7]. In a study when caregivers knew ence to the unit’s postoperative pain management protocol in that their pain assessments were monitored, still less than adult patients in the ICU after cardiac surgery in terms of the 50% of ICU patients were adequately assessed [8]. administration of analgesics, the number and timing of pain We previously implemented a pain management program assessments, and adjustment of analgesics upon unacceptably for postcardiac surgery patients in the ICU, thereby reducing high (NRS ≥ 4) and low (NRS ≤ 1) pain scores. 2 Pain Research and Management

2. Material and Methods Table 1: Patient characteristics. 𝑁 = 124 2.1. Patients and Study. In this analysis, data were retrieved from a study on postoperative pain management (Clinical- Male, 𝑛 (%) 92 (74%) Trials.gov identifier NCT00558090) that took place in a 30- Age, years, median [IQR] 69 [64 to 78] 2 bed mixed ICU from February 2008 until November 2008. BMI, kg/m , median [IQR] 27 [24 to 29] Inthatstudybothpainlevelsinrestandpainlevelsuponan Type of surgery, 𝑛 (%) unavoidable medical procedure were measured. Procedural CABG and valve surgery 55 (44%) pain levels in the patients upon two randomized dosages of Aortic surgery 25 (20%) morphine are described elsewhere [9]. The study protocol CABG 19 (15%) was approved by the local Ethics Committee of the St. Valve surgery 25 (20%) Antonius Hospital, a large teaching hospital in Nieuwegein, Netherlands (approval number R0715A, 7 November 2007). LOSICU,hours,median[IQR] 47[26to74] Written informed consent was obtained from 128 patients Duration of mechanical ventilation, hours [IQR] 10 [7 to 15] before elective cardiac surgery. Three patients were excluded IQR=interquartilerange,BMI=bodymassindex,CABG=coronaryartery becausetheywerenotadmittedtothisICUpostoperatively bypass graft, LOS = length of stay, and ICU = intensive care unit. andonepatientdiedwithinhoursaftertheadmissiontothe ICU. Thus the study group numbered 124 patients. Omissions to administer prescribed medication, to assess scheduled pain scores, to reassess and intervene pharmaco- 2.2. Pain Protocol for Treatment of Postoperative Pain. In logically upon NRS ≥ 4, to taper or stop continuous infusion our ICU, a pain protocol consisting of paracetamol 4 grams of morphine earlier than the protocol dictated, and to not daily and a continuous intravenous infusion of morphine taper continuous infusion of morphine upon NRS ≤ 1after for all patients after cardiac surgery had been in place for at least 2-3 hours without sedation were registered. In case of one year before start of the study (Figure 1). The dosing of deviations from the protocol, electronic medical files of the paracetamol and morphine infusion could be reduced by patients were searched for reasons for these deviations. the anesthesiologist if this was deemed appropriate. Twice a year and before start of the study, physicians and nurses had 2.4. Data Analysis. Descriptive analyses were performed been (re)trained in assessing pain and in providing adequate using IBM SPSS Statistics (version 19.0 for Windows; SPSS, analgesia [4]. Pain was measured with the 11-point numeric Chicago, IL, USA). Patient characteristic and clinical vari- rating scale (NRS) in which “0” represents no pain and “10” ables are expressed as frequencies with percentages (%) or represents the worst pain imaginable [10, 11] and which has median with interquartile range (IQR) where appropriate. been proven to be valid in ICU patients [12]. Scores 0 and 1 Chi square tests were used to test categorical data. indicate low, scores 2 and 3 indicate acceptable, and scores of 4 or more indicate unacceptable pain [13]. Pain scores 3. Results were preferably reported by patients themselves. The NRS had been explained to all patients the day before surgery. 3.1. Patients and Data. Demographic characteristics, type of Intubated patients could either nod when the correct pain surgery, and duration of mechanical ventilation are shown in score was said out loud by the nurses (nurses counted up from Table 1. Median age was 69 years and males predominated 0 to 10) or point out on the visually enlarged VAS (Visual (92/124, 74%). Median length of stay in the ICU after cardiac Analogue Scale) so that these patients could also score their surgery was 47 hours [IQR 26 to 74 hours]. pain intensity. When a patient was not able to report pain, for example, due to sedation, the attending nurse applied the 3.2. Duration and Dosage of Analgesic Treatment (Figure 1, NRS. Nurses based the NRS pain scores on behavioral signs Numbers1(a,b,c,d)).All patients received paracetamol. of pain such as used in the Behavioral Pain Scale [12]. Nurses Paracetamol was prescribed and administered 4 grams daily, received automated reminders to ask patients to provide a according to protocol, in 109/124 (88%) patients. 15/124 (12%) pain score at least three times a day: at 8:00, at 16:00, and at patients received paracetamol at a lower dosage (range 2.5 0:00 [4]. Additional pain scores were to be provided within to 4 grams). All patients received a continuous infusion of half an hour after the recording of unacceptable pain scores morphine directly after ICU admittance (Figure 1, 1a). This ≥ (NRS 4) (Figure 1). Extra pain scores could be recorded at morphine infusion was stopped earlier than protocolized as any time on nurses’ own initiative. described under 1b, 1c, and 1d in Figure 1 in 40 (32%) patients.

2.3. Data Collection. Patient characteristics, type of surgery 3.3. Pain Scores. In 124 patients, 920 NRS scores were anddataonlengthofstayintheICU,anddurationof recorded with a median of 7 [IQR 5 to 10] measurements mechanical ventilation were prospectively registered. Pain per patient. Patients were able to provide self-reported pain scores and administered medication during the first 72 hours scores in 570/920 (62%) of the scores. Scheduled pain scores in the ICU were retrieved from the patient data monitoring were performed 702 times of the maximum scheduled 706 system (PDMS). The 72-hour time frame was chosen as most scores, which equals an adherence of 99%. Extra pain scores, patients are discharged from the ICU within this period. for example, on suspicion of pain and reassessment after Pain Research and Management 3

Contact physician if: ≥4 >7 Start pain protocol (i) NRS and pCO2 kPa directly on admission (ii) Morphine continuous infusion ≥3mg/h (iii) 2×NRS ≥4

Contraindication Yes for paracetamol, Alternative medication for pain → contact physician morphine?

No 1 4 1a (i) Start paracetamol g times daily (ii) Start morphine infusion 2 mg/h

(1) Decrease/stop propofol Stable Yes a (2) Decrease morphine if patient? (i) propofol continuous infusion is stopped >2-3 hours and 1b (ii) the patient has no pain, or (iii) in case of insufficient breathing No

2 Evaluate NRS and RASS every 8 hours

Yes 0.5 3 NRS 0 or 1? Decrease morphine continuous infusion with mg/h every - 1c 4 hours

No

Yes NRS 2 or 3? Do not change morphine dosage 1d

No Morphine intravenously 2.5–5 mg 4×daily if Continuous Yes No necessary, or 3 NRS ≥4? infusion of morphine subcutaneously 7.5–10 mg 4×daily if morphine? necessary

Yes

Mechanically ventilated patient: Bolus of5 mg morphine intravenously and increase in continuous infusion of morphine with 0.5 mg/h Nonmechanically ventilated patient: 3 Bolus of2.5 mg morphine intravenously and increase in continuous infusion of morphine with 0.5 mg/h

Reevaluate NRS after 30 minutes

Discharge from ICU: (i) Morphine continuous infusion stop, administer 7.5–10 mg of morphine subcutaneously (ii) Continue paracetamol 1 g, 4×daily (iii) Check prescriptions of paracetamol and morphine in ICU discharge letter

a Figure 1: Pain management protocol after cardiac surgery. Stable patient: haemodynamically stable, acceptable leakage through thoracic drains, adequate time after muscle relaxation, and adequate core temperature; NRS: numeric rating scale, RASS: Richmond Agitation and Sedation Scale, ICU: intensive care unit, and 1(a, b, c, d), 2, and 3: items concerning adherence to the pain protocol referred to in the Results. 4 Pain Research and Management

920 NRS scores

96 scores NRS≥4

No change in Extra bolus of Increase of Extra bolus of Other change in medication morphine continuous morphine and medication infusion of increase in morphine continuous infusion

n=28(30%) n=51(53%) n=4(4%) n=7(7%) n=6(6%)

No n=10(10%) n=2(2%) n=1(1%) n=1(1%) reassessments reassessments reassessments reassessment reassessment

Figure 2: Actions upon pain scores with NRS ≥ 4. NRS: numeric rating scale.

cessation of sedation, accounted for 24% of all recorded pain 3.5. Reasons for Deviation from the Pain Protocol. Reasons for scores (218/920). the lower paracetamol dosage than recommended, prescribed Ten per cent (96/920) of NRS scores were ≥4, signifying to 14/124 patients (11%), were not documented except for one unacceptable pain (Figure 2) and 59% (546/920) of NRS patient who missed one dose of paracetamol because he was scores were ≤1, signifying low/no pain. Patients whose mor- in the operating room for a resternotomy at the scheduled phine was stopped earlier than protocolized had significantly time of administration. more often unacceptable pain scores afterwards than patients In the nurses’ notes motivations for terminating or with morphine treatment according to protocol, that is, 71% tapering continuous morphine earlier than by protocol or for versus 33%, respectively (𝑝 = 0.002). not administering extra morphine upon an unacceptable pain score could be found in 43 times (Table 2). In 7 of 273 (3%) 3.4. Actions upon Unacceptably High (NRS ≥ 4) and Low cases where morphine should have been tapered upon a NRS (NRS ≤ 1) Pain Scores. In 28 of the 96 cases of NRS scores of0or1,thenursehaddocumentedwhythiswasnotdone ≥ 4 (29%), medication was not changed whereas protocol (Table 2). dictated this (Figure 2). In 51 cases (53%), an extra bolus of morphine was administered, in 4 cases the continuous 4. Discussion infusion of morphine was increased, and in 6 cases another change in medication was made (extra paracetamol 𝑛=1, In this study we evaluated the level of adherence to the pain decrease of continuous morphine infusion 𝑛=3,orabolusof protocol for patients in ICU patients after cardiac surgery. morphine combined with a decrease of continuous morphine Adherence to scheduled pain assessments was excellent, as 𝑛=2). Seven patients each received once the protocolized 99% was performed. Adherence to initiation of prescribed combination of an extra bolus of morphine with an increase analgesics with automated reminders via the PDMS at admin- of continuous morphine (Figure 2). Overall, in 14/96 cases istration times was also good. However, adherence to the (15%) NRS reassessment after NRS ≥ 4wasperformedas nonscheduled items of the protocol that rely on the initiative dictated by protocol; all of these NRS were ≥4. of the caregiver was less adequate. Unacceptable pain was In 273 of the 303 cases (90%) where morphine should followed by reassessment of pain in 15% and administration have been tapered, because of NRS scores ≤ 1anddiscon- of additional morphine in 65% of the events. Furthermore, tinuation of propofol (see 1b-1c in Figure 1), morphine was in only 10% of low pain scores, morphine was tapered. Time continued. In 243 of the 243 cases (100%) of NRS ≤ 1where to discharge to the ward was not delayed due to respiratory morphine should not have been tapered, that is, within 2- depression, nor were there any serious adverse events such 3 hours after discontinuation of propofol, morphine was as need for reintubation in the studied patients. We may continued according to protocol. As such, in a total of 50% therefore conclude that the use of this pain protocol was safe (30 + 243)/546 of the cases of NRS scores ≤ 1theprotocolwas in our ICU. Although overall pain management was good followed (Figure 3). with 90% of pain scores reflecting acceptable pain intensity, Pain Research and Management 5

920 NRS scores

546 scores NRS≤1

Morphine should be Morphine should not be tapered according to tapered due to sedation protocol (see Figure 1, 1c) (see Figure 1, 1b)

n=303 n = 243

Morphine tapered Morphine not Morphine not tapered tapered

n=30(6%) n = 273 (50%) n = 243 (44%)

Figure 3: Actions upon pain scores with NRS ≤ 1. NRS: numeric rating scale.

Table 2: Reasons for deviating from the protocol. to guidelines in general [5, 6] and more specifically to pain management [7, 14]. Diby et al. [3] found that only 70% of Reasons for terminating or tapering morphine earlier than 𝑛 scheduled pain assessments in the ICU after cardiac surgery protocolized (𝑁=43) ∗ were carried out. Pain was assessed in only 40% of patients Respiratory depression 14 in an observational study in 44 ICUs in France, although Sleepiness 11 90% of patients received opioids [7]. A study on nurses’ Too slow awakening after cessation of sedation 9 knowledge and management of pain after cardiac surgery Nausea 2 patients reported moderate to severe pain, even though only 47% of the prescribed dose of analgesics was given [15]. Discrepancy between patients’ high pain score and behavior 2 according to the nurse These studies did not use automated reminders to assess pain and to administer analgesics in contrast with our pain Hypotension 1 protocol, resulting in excellent adherence to scheduled pain 1 Delirium suspected to be caused by morphine assessments and administration of prescribed analgesics in Refusal of a patient to receive more morphine 1 our ICU. Decrease of pain immediately after removal of chest tubes 1 However, only 15% of unacceptable high pain scores Planned extubation directly after pain scoring 1 were followed by reassessments of pain. Nonadherence to Reasons for not tapering morphine infusion upon NRS 0 or 1 𝑛 obliged reassessments was previously reported by others as (𝑁=7) well [3, 14, 16]. Reassessments after recorded pain events Painful in the previous shift 2 were performed in 36% in a pediatric ICU [14], in 45% in ICU patients after cardiac surgery [3] and in 60% of Pain assessments were only within a few hours after surgery 2 recorded pain events in critically patients [16]. Bucknall Hypertension 2 et al. suggested 3 explanations for nurses not performing Low pain scores in rest, but still painful while moving 1 reassessments in postoperative patients: their busyness or ∗ Respiratory depression was defined as respiratory rate of less than 10/min workload, the lack of knowledge concerning the importance or pCO2 of 7 kPa or more. None of the patients with respiratory depression of adequate pain management and pharmacologic properties wasreintubatedorrequirednaloxone. of analgesics, and, thirdly, patients not reporting their pain [17]. In our study, both nurses and patients were informed on the importance of adequate pain management due to the there may be room for improvement as adherence to different fact that they were participating in a clinical trial. We did not items of the pain protocol varied from excellent to poor. investigate the nurses’ workload. Another explanation could Hospital departments in general, and intensive care be that nurses did not feel the need to reassess because they units in particular, are still struggling with nonadherence treated the pain through a pharmacological intervention. 6 Pain Research and Management

Adherence to pharmacological interventions in our study may have been augmented due to extra reminders of the upon high or low pain scores, both nonscheduled parts of protocol both by the PDMS and by the researchers as thepainprotocol,waspooraswell.Partofthesedeviations partoftheclinicaltrial.Thecurrentpainprotocoldidnot from the protocol were justifiable as reported explanations includepainmanagementforproceduralpainotherthanan were mostly related to side effects of morphine. However, extra morphine dose before the removal of thoracic drains explanations for all deviations from the protocol should and/or turning on the morning after surgery [9]. On the be recorded in order to uncover pitfalls in the protocol. other hand, although these procedures are known to be As patients in whom continuous morphine was stopped potentially painful, in many ICUs, analgesia for procedural earlier than protocolized experienced unacceptable pain pain is still not part of standard care [7]. Fortunately, pain significantly more often than patients in whom protocol protocols for procedural pain are recommended and effective was not violated (71% versus 33% resp., 𝑝 = 0.002), the to reduce pain and adverse events [21]. The current study protocol should be adjusted to suggest alternative analgesics did not research an unspoken resistance to the concept of and antiemetic medication for patients suffering from side the protocol as explanation for nonadherence to the pain effects. protocol. Franck and Bruce suggested that lack of evidence In order to prevent side effects of morphine such as based improvement in outcome may be an underlying rea- respiratory depression, nausea, and vomiting, the protocol son for resistance to guideline adherence in pediatric pain dictated that continuous infusion of morphine had to be management [22]. In ICU patients however improvement tapered in patients with no or low pain scores (NRS ≤ 1). in clinical outcome, for example, duration of mechanical This was executed in 10% of required cases. This lack of ventilation[2,23,24],nosocomialinfections[2],andICU titrating medication to effect was seen even more extremely length of stay [23, 24], has been demonstrated after the in the aforementioned study in 44 ICUs in France [7] where implementation of pain management protocols and should fentanyl and morphine dosages were not changed during therefore not be a reason for resistance to a pain protocol. the week. A reason for not tapering continuous morphine at low pain scores could be that nurses took other issues into account than a pain score at a scheduled moment, such as 5. Conclusions pain while coughing or moving or an upcoming potentially We conclude that adherence to scheduled pain management painful procedure. Furthermore, nurses could be reluctant was good and overall pain management adequate. Unfortu- to taper morphine because they were concerned this would nately, adjustment of continuous infusion of morphine upon alter the comfortable state of the patient. Similar findings are pain scores (high and low) and reassessment of pain after reported for sedatives. In a study by Dodek et al. nurses were unacceptably high pain scores was poor. Better adherence more likely to increase sedatives than decrease them [18]. The to these items, such as reassessments and adjustment of reason had to do with fear of agitation when sedation was morphine upon low and high pain scores, may further lowered too much and depended on physician availability and improve pain management and reduce side effects. other organizational features. In order to improve adherence to pain management guidelines, Ista et al. recommended interactive education sessions, involving local champions and Competing Interests giving feedback on individual or unit level to increase the intrinsic motivation of professionals. Finally, in the current The authors declare that they have no competing interests. study, the patient data monitoring system did not remind nurses that morphine may be tapered when low pain scores Acknowledgments were recorded. A computerized version of a guideline was reported to The authors thank Ko Hagoort for editing the manuscript. significantly improve timeliness of measurements compared with a paper-based version in glucose level regulation for References critically ill patients [19]. Another study showed that an electronic visual feedback tool to monitor adherence to [1] J. Barr, G. L. Fraser, K. 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Clinical Study The Anatomic Relationship of the Tibial Nerve to the Common Peroneal Nerve in the Popliteal Fossa: Implications for Selective Tibial Nerve Block in Total Knee Arthroplasty

Eric R. Silverman,1 Amaresh Vydyanathan,2 Karina Gritsenko,2 Naum Shaparin,2 Nair Singh,2 Sherry A. Downie,3 and Boleslav Kosharskyy2

1 Department of Anesthesiology, Albany Medical Center, Albany, NY, USA 2Department of Anesthesiology, Montefiore Medical Center, Bronx, NY, USA 3Albert Einstein Medical College, Bronx, NY, USA

Correspondence should be addressed to Boleslav Kosharskyy; [email protected]

Received 25 August 2016; Accepted 12 December 2016; Published 2 February 2017

Academic Editor: Can Eyigor¨

Copyright © 2017 Eric R. Silverman et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background. A recently described selective tibial nerve block at the poplitealcreasepresentsaviablealternativetosciaticnerveblock for patients undergoing total knee arthroplasty. In this two-part investigation, we describe the effects of a tibial nerve block at the popliteal crease. Methods. In embalmed cadavers, after the ultrasound-guided dye injection the dissection revealed proximal spread of dye within the paraneural sheath. Consequentially, in the clinical study twenty patients scheduled for total knee arthroplasty received the ultrasound-guided selective tibial nerve block at the popliteal crease, which also resulted in proximal spread of local anesthetic. A sensorimotor exam was performed to monitor the effect on the peroneal nerve. Results. In the cadaver study, dye was observed to spread proximal in the paraneural sheath to reach the sciatic nerve. In the clinical observational study, local anesthetic wasobservedtospreadameanof4.7+1.9 (SD) cm proximal to popliteal crease. A negative correlation was found between the excess spread of local anesthetic and bifurcation distance. Conclusions. There is significant proximal spread of local anesthetic following tibialnerveblockatthepoplitealcreasewithpossibilityoftheundesirablemotorblocksoftheperonealnerve.

1. Introduction (CPN), which may mask surgically induced CPN injury [8]. The reported incidence of CPN injury after TKA ranges Arthroplasty of the knee is associated with moderate to from 0.3% to 2.2% [9–15]. Potential risk factors for CPN severe postoperative pain [1]. Peripheral nerve blocks for total injury include severe valgus deformity, preexisting neuropa- knee arthroplasty (TKA) are effective for postoperative pain thy, rheumatoid arthritis, prolonged tourniquet time, and management and may hasten the recovery process [2]. There constrictive dressings. However, no single risk factor has been are a number of regional techniques that have been used consistentlyshowntobeassociatedwithCPN[16]. for TKA. A combination of the femoral nerve (FN) block Anatomical variation in the location where the SN andsciaticnerve(SN)blockisanacceptedtechniquefor bifurcates may predispose patients to complete blockade the postoperative pain management after TKA. Although the following selective TN block. In this combined anatomic evidence for adding the SN block to FN block is controversial, investigation and prospective observational study, we aim to it is commonly performed for TKA in many institutions [3– observe and describe the effects of this block. We hypothesize 7]. that proximal spread of local anesthetic towards the CPN Addition of the SN block may provide superior analgesia occurs following selective TN block and accounts for partial but can produce foot-drop or weakness of the tibialis anterior CPNblock.Secondly,wepostulatethatthemoredistalthe muscle due to blockade of the common peroneal nerve bifurcation occurs, the more likely there will be spread from 2 Pain Research and Management the popliteal injection site to the common sciatic nerve, proximally, the convergence of the CPN and TN was iden- resulting in unintended CPN blockade. tified and the distance from the convergence to popliteal crease was measured and recorded. A selective TN block was 2. Methods performed at the popliteal crease using a technique similar to that described by Andersen et al. (2012) but at the level 2.1. Anatomical Study. Approval was obtained from the of the popliteal crease [17]. This was the same approach as local institutional review board at Albert Einstein College used in the anatomic study. Tenmilliliters of 0.5% ropivacaine of Medicine. Four adult embalmed cadavers were used in was injected. Immediately following injection, the bifurcation this study. Each cadaver was placed in the prone position. of the SN was reidentified and traced proximally to identify Using a 13 to 6 MHz linear transducer (HFL38, SonositeTM, the extension of local anesthetic around the target nerves. Bothell, WA), the tibial nerve (TN) was identified at the Since local anesthetic was intended to encircle the TN and not popliteal crease. Using a short-axis in-plane approach, a the SN, local anesthetic extension proximal to the bifurcation 50 mm, 21-gauge, stimulating needle (Arrow International, was referred to as excess spread. The distance between the Teleflex Medical, Research Triangle Park, NC, USA) was bifurcation and proximal extension of local anesthetic was advanced in a lateral to anteromedial direction toward the recorded. Values were positive if spread extended proximal TN and 10 mL of blue dye (1% methylene blue diluted 1 : 10 to the bifurcation and negative if spread extended but with sterile water) was injected to encircle the target nerve. did not reach the bifurcation. For quality control, images Subparaneural spread of local anesthetic was achieved using were obtained and reviewed by a second expert in regional a technique similar to that described by Andersen et al. anesthesia. (2012)butatthelevelofthepoplitealcrease[17].Immediately Twenty minutes following TN block, tibial and peroneal after injection, vertical skin incisions were performed over sensorimotor functions were recorded. Tibial motor function the popliteal fossa. The biceps femoris, semitendinosus, (plantar flexion of the foot) and peroneal motor function and semimembranosus muscles were carefully dissected to (dorsiflexion of the foot) were tested with a 3-point scale (0 = reveal the sciatic nerve and its branches. The sciatic nerve normal, 1 = weak, and 2 = absent). Cold sensation was tested bifurcation was identified and the distance from the popliteal using an alcohol swab. Tibial sensation (plantar surface of the crease was recorded. If needed, the skin incision and muscle foot) and peroneal sensation (dorsal surface of the foot) were dissection were extended to identify the most proximal tested. Sensation was tested using a 3-point scale (0 = normal, spread of dye within the paraneural sheath. 1 = absent cold perception, but touch sensation intact, and 2 = absence of touch sensation), as described in the study by 2.2. Case Series. Next, an observational prospective study on Sinha et al. [8]. patients undergoing TKA was conducted. This investigation was also approved by the local institutional review board 2.3. Statistical Analysis. An a priori sample size calculation is (Albert Einstein College of Medicine). The requirement for absent from the present observational study because the aim written informed consent was waived by the institutional was to collect data for a larger investigation. A convenience review board and verbal consent was acceptable for data sampling method was used to recruit patients into the collection. All patients scheduled for primary total knee study. The measurements obtained were plotted and analyzed arthroplasty were candidates for this observational study. using Prism 6.04 (GraphPad Software, Inc., San Diego, CA, Exclusion criteria included age younger than 18 years, inabil- USA). Spearman’s rank correlation coefficient was applied ity to communicate with the investigators or hospital staff, for continuous data with 𝑃 < 0.05 considered statistically preexisting valgus deformity, flexion contracture or history of significant. Results of the sensorimotor exams were reported allergic reaction to amide local anesthetics, or patient refusal. and described and statistical analysis was not performed. Preoperatively, intravenous access was secured, standard noninvasive monitors were applied, and supplemental oxy- gen was administered via nasal cannula. Patients were placed 3. Results in the supine position and intravenous fentanyl and mida- 3.1. Anatomical Study. Six injections and dissections, in 4 zolam were titrated for patient comfort. Immediately prior embalmed cadavers, were performed. Two limbs from two to performing the block, thigh length and circumference separate cadavers were not suitable for the procedure due to were measured. Thigh length was recorded as the distance from inguinal crease to patella tendon insertion. A high- incidental finding of femoral fracture in one cadaver and a frequency linear array ultrasound transducer (SonoSite M- large venous thrombosis in the second. There were 3 males Turbo, Bothell, WA) was utilized for the identification of rel- and 1 female with a mean age of 80 years (range 58–93 years). evant landmarks and a continuous adductor canal block was In all cases, the SN and its branches were easily visualized with performed using a mid-thigh approach described by Jæger ultrasound and paraneural injection was achieved. Following et al. [18], whereas the needle positioning was accomplished dissection, blue dye was observed to be contained within under ultrasound guidance using a subsartorial approach the paraneural sheath of the tibial nerve with only minimal with the visible local anesthetic spread around the femoral extravasation to adjacent structures, Figure 1(a). There was artery. no blue dye observed around the CPN at the level of After the adductor canal catheter was placed, the lower injection; however, dye was observed extending proximal to extremity was flexed at the knee joint. By tracing the TN the SN bifurcation, Figure 1(b). The mean distance from SN Pain Research and Management 3

MSN

TN CPN

Needle insertion site at popliteal crease Cranial

(a) (b)

Figure 1: Blue dye injected around the tibial nerve at the popliteal crease. (a) Spread of blue dye is observed with significant extension proximal to the bifurcation point of the sciatic nerve. Complete sparing of the common peroneal nerve is observed at the level of the popliteal crease, (b) MSN = medial sural nerve; TN = tibial nerve; CPN = common peroneal nerve; SN = sciatic nerve.

SN LA CPN TN

LA PA

(a) (b)

Figure 2: Ultrasound image of the common peroneal nerve and tibial nerveatthepoplitealcreaseafterselectivetibialnerveblock.Local anesthetic was observed around the tibial nerve but not the common peroneal nerve. (a) Local anesthetic could be traced proximally toward the bifurcation which was observed to encircle the sciatic nerve proximal to the bifurcation, (b) CPN = common peroneal nerve; TN = tibial nerve; LA = local anesthetic; SN = sciatic nerve; PA = popliteal artery. bifurcation to the popliteal crease was 6.6 cm (range 4.5– Table 1: Demographics. 9cm).Dyewasobservedtospread14.5cm(range8–21cm) proximal to the popliteal crease. Excess spread beyond the Mean ± bifurcation occurred in all specimens and was observed to Age (years) 67.3 (11.1) ± extend a mean of 7.9 cm (range 1.6–14 cm) proximal to the Height (cm) 162.2 (8.6) Weight (kg) 77.2 ± (12.8) bifurcation. 2 BMI (kg/m )29.5± (4) Leg length (cm) 33.5 ± (4) 3.2. Case Series. Twenty patients were included in the analy- ± sis. Demographic and biometrical data of the study subjects Leg circumference (cm) 52.8 (7.7) areshowninTable1.Ineverysubject,theSNanditsbranches, Distance BifurcationofSNfrompoplitealcrease(cm) 4.8± (1.6) CPNandTN,werevisualizedandcouldbetracedbackto ∗ Spread of LA from popliteal crease (cm) 4.7 ± (1.9) the proximal bifurcation using the ultrasound probe. The − ± bifurcation was found to be 4.8 ± 1.6 (SD) cm proximal to Spread of LA proximal to bifurcation (cm) 0.0 (2.5) ± ∗ the popliteal crease. After selective TN block was performed, Values expressed as mean and standard deviation. For spread of LA, + values represent spread reaching proximal to the bifurcation and − values thelocalanestheticcouldbetracedproximallytowardthe represent spread reaching distal to the bifurcation. SN = sciatic nerve; LA = bifurcation without difficulty in all patients. At the level of the local anesthetic. popliteal crease, local anesthetic encircled the TN, but not the CPN, Figure 2. Mean spread was 4.7 ± 1.9 (SD) cm proximal to popliteal crease and extended proximal to the bifurcation coefficient, a negative correlation was found between the in 9 cases. Using a two-tailed Spearman’s correlation rank excess spread of local anesthetic and bifurcation length, 𝑟= 4 Pain Research and Management

Local anesthetic spread and bifurcation- 10 A recent randomized-controlled trial by Sinha et to-popliteal crease distance al. (2012) demonstrated the feasibility of performing an ultrasound-guided selective tibial nerve (TN) block to avoid 8 complete peroneal motor block. In the study involving 80 patients undergoing TKA, patients were randomized to 6 receive a traditional SN block or selective tibial nerve block at the popliteal crease [8]. The authors reported similar pain 4 scores and 24-hour opioid consumption across study arms. None of the patients who received the selective TN block developed complete motor block; however, nearly a quarter 2 of the patients developed partial peroneal motor block. The LA spread from bifurcation (cm) bifurcation from LA spread authors postulated that proximal spread of local anesthetic 0 from the site of blockade could have been responsible for 2 468 the sensory block involving the CPN, but this was not Bifurcation (cm) investigated. Performing a selective TN block may decrease Figure 3: Scatter plot showing the relationship between bifurcation the likelihood of masking a surgically induced foot-drop length and excess spread of local anesthetic. Excess spread was compared with SN block; however, partial blockade of the measured as the distance between the bifurcation point and maximal CPN may be undesirable when a thorough postoperative spread of local anesthetic proximal to the bifurcation. A negative neurologic exam is needed. correlation was found between the excess spread of local anesthetic We confirm some of the findings reported by Sinha et and bifurcation length, 𝑟 = −0.5605, 𝑝 = 0.01. al. (2012) in which a similar technique and local anesthetic dose were used. We observed similar rates of block success, 75% compared with 95% by Sinha et al. Three patients had reduced motor strength in the distribution of the CPN and −0.5605, 𝑝 = 0.01, Figure 3. No significant correlation none had complete motor block. Reduced motor strength of was observed between bifurcation length and thigh length the CPN was consistent with the previously published report (−0.4383, 𝑝 = 0.0532). (15% compared with 22.5%, resp.). No patients developed completeCPNmotorblockineitherstudy. 3.3. Sensorineural Examination. Sensory block in the distri- Our findings on bifurcation distance are supported by the bution of the TN was observed in 95% of the patients. Of literature [19]. In an anatomic investigation using MRI, the these, 14 patients had partial sensory block (sensory score of TNandCPNwerefoundtodivideat5.8cmwitharange 1)while5hadcompletesensoryblock(sensoryscoreof2). from 3.6 cm to 12.4 cm above the popliteal crease [19]. In In the distribution of the CPN, sensory block was observed ourstudy,mediandistancewas4.8cmwitharangefrom in 75% patients. Of these 12 had a partial sensory block and 3 2.5 cm to 9 cm. A shorter bifurcation length correlated with had a complete sensory block. statistically significant spread above the bifurcation, 𝑟= Motor block in the distribution of the TN was observed in −0.5605 (𝑝 < 0.01). While the present study was not powered 70% of patients. Of these, 12 had a partial motor block (motor to detect a correlation between bifurcation length and degree score of 1) and 2 had a complete motor block (motor score of ofCPNblock,weobservedthatlocalanestheticalmostalways 2). Motor block of the CPN was observed in 15% (3 patients); extended above the bifurcation when it was less than 5 cm however, complete motor block was not observed. from the popliteal crease. Since the report published by Sinha et al. on the selec- tive tibial nerve block we have adopted the technique to 4. Discussion our practice and have observed excellent satisfaction from Proximal spread of local anesthetic occurs following selective both patients and our surgeons. Despite this, we continue to observe a subset of patients that develop partial CPN TN block at the popliteal crease. This was observed both in block following selective TN block. This is likely due to embalmed cadavers and in human subjects. In the clinical the proximal spread of local anesthetic that was observed case series, a statistically significant negative correlation was in this investigation and may be occurring in patients with observed between bifurcation length and spread above the 𝑝 = 0.01 more distal SN bifurcations. Further studies should be aimed bifurcation ( ), such that a shorter bifurcation at stratifying patients based on bifurcation length and the length correlated with a greater degree of local anesthetic analgesic benefit of lower volumes of injectate. extension proximal to the bifurcation. Interestingly, in the Weacknowledgeseverallimitationsofthisstudy.Asmen- anatomic study, blue dye was observed to extend within the tioned earlier, the tissues of embalmed cadavers differ from in paraneural sheath to a much greater degree than that seen vivo. These differences make ultrasound identification of the under ultrasound in the case series (mean 14.5 cm compared nerves more challenging; however, feasibility in embalmed with 4.7 cm, resp.). This was likely due to differences in the cadavers has been previously established [20]. In the clinical injectate dynamics between embalmed cadavers and living case series, patients with preexisting valgus deformity were tissue. It is difficult to draw any correlations between these excluded because these patients are at higher risk of post- findings which is a limitation of this investigation. operative peroneal nerve injury. Future investigations could Pain Research and Management 5 attempt to evaluate SN bifurcation height in this subset of References patients to identify candidates who could be safely managed with selective tibial nerve block. However, further studies [1] S. S. Liu, A. Buvanendran, J. P. Rathmell et al., “Predictors for moderate to severe acute postoperative pain after total hip and with larger sample size may be necessary before considering knee replacement,” International Orthopaedics,vol.36,no.11, this block in higher risk patients. pp. 2261–2267, 2012. An additional limitation was that patients were selected [2]X.Capdevila,Y.Barthelet,P.Biboulet,Y.Ryckwaert,J.Ruben- for this study based on availability of the research team. ovitch, and F. D’Athis, “Effects of perioperative analgesic tech- In reviewing Table 1, our study group contained 17 females nique on the surgical outcome and duration of rehabilitation and 3 males. It is possible that this skewed sample of men after major knee surgery,” Anesthesiology,vol.91,no.1,pp.8–15, andwomencouldhaveinfluencedourresults.Wereviewed 1999. twelve months of data from our institution on patients who [3] P. Cook, J. Stevens, and C. Gaudron, “Comparing the effects underwent TKA. There were 561 patients of which 136 were of femoral nerve block versus femoral and sciatic nerve block males and 425 were females (76%). Therefore, we felt that the on pain and opiate consumption after total knee arthroplasty,” cohort in our case series was consistent with our demographic Journal of Arthroplasty, vol. 18, no. 5, pp. 583–586, 2003. of patients undergoing TKA. A more even ratio of females to [4] K. J. Hunt, M. H. Bourne, and E. M. Mariani, “Single-injection males may have yielded different results; however, this would femoral and sciatic nerve blocks for pain control after total knee not have reflected our patient population. arthroplasty,” The Journal of Arthroplasty,vol.24,no.4,pp.533– Finally, the anesthesiologist performing the block and 538, 2009. collecting the measurements and performing the neurolog- [5]J.T.Wegener,B.vanOoij,C.N.vanDijk,M.W.Hollmann,B. ical exam was not blinded and this could have led to a bias. Preckel, and M. F. Stevens, “Value of single-injection or con- This may have been avoided if a second anesthesiologist was tinuous sciatic nerve block in addition to a continuous femoral immediately available to measure the local anesthetic and nerve block in patients undergoing total knee arthroplasty: a perform the neurological exam. For quality control, we had prospective, randomized, controlled trial,” Regional Anesthesia a second anesthesiologist validate the ultrasound images but and Pain Medicine, vol. 36, no. 5, pp. 481–488, 2011. this was not available in real-time. [6] G. Cappelleri, D. Ghisi, A. Fanelli, A. Albertin, F.Somalvico, and In conclusion, we have demonstrated that selective tibial G. Aldegheri, “Does continuous sciatic nerve block improve nerve block at the popliteal crease results in significant postoperative analgesia and early rehabilitation after total proximal spread of local anesthetic toward the SN bifurcation. knee arthroplasty?: a prospective, randomized, double-blinded study,” Regional Anesthesia and Pain Medicine,vol.36,no.5,pp. Furthermore, a shorter bifurcation length is statistically 489–492, 2011. significantly correlated with extension of local anesthetic proximal to the SN bifurcation. This may lead to at least [7] F.W.AbdallahandR.Brull,“Issciaticnerveblockadvantageous partial blockade of the CPN, which may be undesirable in when combined with femoral nerve block for postopera- tive analgesia following total knee arthroplasty?: a systematic patients who are at increased risk for peroneal nerve injury review,” Regional Anesthesia and Pain Medicine,vol.36,no.5, after TKA. pp. 493–498, 2011. [8]S.K.Sinha,J.H.Abrams,S.Arumugametal.,“Femoral Ethical Approval nerve block with selective tibial nerve block provides effective analgesia without foot drop after total knee arthroplasty: a The study was approved by Albert Einstein Medical College, prospective, randomized, observer-blinded study,” Anesthesia Bronx, NY, USA. and Analgesia, vol. 115, no. 1, pp. 202–206, 2012. [9]K.Knutson,I.Leden,G.Sturfelt,I.Rosen,andL.Lidgren, “Nerve palsy after knee arthroplasty in patients with rheuma- Disclosure toid arthritis,” Scandinavian Journal of Rheumatology,vol.12, no.3,pp.201–205,1983. The work was conducted at Montefiore Medical Center and [10] J. P.L. Asp and J. A. Rand, “Peroneal nerve palsy after total knee Albert Einstein Medical College, Bronx, NY, USA. arthroplasty,” Clinical Orthopaedics and Related Research,no. 261, pp. 233–237, 1990. Competing Interests [11] O. B. Idusuyi and B. F. Morrey, “Peroneal nerve palsy after total knee arthroplasty: assessment of predisposing and prognostic The authors do not report any relevant conflict of interests. factors,” The Journal of Bone & Joint Surgery—American Volume, vol.78,no.2,pp.177–184,1996. [12]H.A.Rose,R.W.Hood,J.C.Otis,C.S.Ranawat,andJ.N. Acknowledgments Insall, “Peroneal-nerve palsy following total knee arthroplasty. AreviewofTheHospitalforSpecialSurgeryexperience,” The authors wish to thank the individuals who donate their Journal of Bone and Joint Surgery - Series A,vol.64,no.3,pp. bodies and tissues for the advancement of education and 347–351, 1982. research. This work is supported by the Department of [13] M. B. Coventry, J. E. Upshaw, and L. H. Riley, “Geometric total Anesthesiology at Montefiore Medical Center. Departmental knee arthroplasty. II. Patient data and complications,” Clinical funding only was used to support this investigation. Orthopaedics and Related Research, no. 94, pp. 177–184, 1973. 6 Pain Research and Management

[14] D. A. Webster and D. G. Murray, “Complications of variable axis total knee arthroplasty,” Clinical Orthopaedics and Related Research, vol. 193, pp. 160–167, 1985. [15]T.T.Horlocker,M.E.Cabanela,andD.J.Wedel,“Doespost- operative epidural analgesia increase the risk of peroneal nerve palsy after total knee arthroplasty?” Anesthesia and Analgesia, vol. 79, no. 3, pp. 495–500, 1994. [16] O. A. Nercessian, O. F. C. Ugwonali, and S. Park, “Peroneal nerve palsy after total knee arthroplasty,” The Journal of Arthro- plasty,vol.20,no.8,pp.1068–1073,2005. [17] H. L. Andersen, S. L. Andersen, and J. Tranum-Jensen, “Injec- tion inside the paraneural sheath of the sciatic nerve: direct comparison among ultrasound imaging, macroscopic anatomy, and histologic analysis,” Regional Anesthesia and Pain Medicine, vol.37,no.4,pp.410–414,2012. [18] P. Jæger, U. Grevstad, M. H. Henningsen, B. Gottschau, O. Mathiesen, and J. B. Dahl, “Effect of adductor-canal-blockade on established, severe post-operative pain after total knee arthroplasty: a randomised study,” Acta Anaesthesiologica Scan- dinavica,vol.56,no.8,pp.1013–1019,2012. [19] W. Freund, A. Brinkmann, F. Wagner et al., “MR neurogra- phy with multiplanar reconstruction of 3D MRI datasets: an anatomical study and clinical applications,” Neuroradiology,vol. 49, no. 4, pp. 335–341, 2007. [20] T. Akkaya, E. Ozturk, A. Comert et al., “Ultrasound-guided obturator nerve block: a sonoanatomic study of a new method- ologic approach,” Anesthesia and Analgesia,vol.108,no.3,pp. 1037–1041, 2009. Hindawi Publishing Corporation Pain Research and Management Volume 2016, Article ID 3256583, 5 pages http://dx.doi.org/10.1155/2016/3256583

Clinical Study Comparison of the Effects of Intrathecal Fentanyl and Intrathecal Morphine on Pain in Elective Total Knee Replacement Surgery

Refika KJlJçkaya,1 Yavuz Orak,2 Mehtap Arda BalcJ,1 Fatih BalcJ,3 and Elker Ünal4

1 Anesthesiology and Reanimation Clinic, Bor State Hospital, Nigde,˘ Turkey 2Anesthesiology and Reanimation Clinic, Mardin State Hospital, Mardin, Turkey 3Anesthesiology and Reanimation Clinic, Nigde˘ State Hospital, Nigde,˘ Turkey 4Medical Biostatistics Department, C¸ukurovaUniversity,Adana,Turkey

Correspondence should be addressed to Yavuz Orak; [email protected]

Received 16 October 2016; Accepted 28 November 2016

Academic Editor: Rudin Domi

Copyright © 2016 Refika Kılıc¸kaya et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Objective. Total knee replacement is one of the most painful orthopedic surgical procedures. In this study, our goal was to compare the intraoperative and postoperative hemodynamic effects, the side effects, the effect on the duration of pain start, the 24-hour VAS, and the amount of additional analgesia used, of the fentanyl and morphine we added to the local anesthetic in the spinal anesthesia we administered in cases of elective knee replacement. Materials and Methods. After obtaining the approval of the Erciyes University Medical Faculty Clinical Drug Trials Ethics Committee, as well as the verbal and written consent of the patients, we included 50 patients in our prospective, randomized study. Results. In our study, the morphine group (Group M) had lower pain scores in the 2nd, 6th, 12th, and 24th hours compared to the fentanyl group (Group F). When additional analgesic requirements were compared, it was found that in the 2nd, 6th, and 24th hours fewer Group M patients needed more analgesics than did Group F patients. Conclusion. The fentanyl group also had lower first analgesic requirement times than did the morphine group. In terms ofnausea and vomiting, there was no statistically significant difference between the two groups.

1. Introduction The patients in our study were all between the ages of 60 and 90. Postoperative pain is the acute inflammatory pain that begins The purpose of this study was to compare fentanyl and with the trauma of surgery and ends with the healing morphine in terms of their intraoperative and postoperative of the tissue. This pain has deleterious effects on organ effects, their side effects, and their effects on the onset of systems and may lead to pathophysiological changes in the pulmonary/cardiovascular system [1]. The treatment of post- pain,24-hourVAS,andtheamountofadditionalanalgesic operative pain is crucial for homeostasis. Additionally, it has a required when they were added to the local anesthetics significant impact not only on lowering the cost of treatment in the spinal anesthesia we administered to elective knee but also on shortening the length both of the patient’s replacement patients. recovery time and, consequently, of her hospital stay [2, 3]. Total knee replacement is one of the most painful orthopedic 2. Materials and Methods surgical procedures. Patients who undergo total knee replace- ment are usually older and have limited cardiac and pul- After obtaining the approval of the Erciyes University Medical monary reserves. The increased sensitivity of elderly patients FacultyClinicalDrugTrialsEthicsCommittee,aswellas to drugs makes it necessary to choose postoperative anal- the verbal and written consent of the patients, we included gesia agents and methods that have minimal side effects [4]. 50 patients in our prospective, randomized study. All were 2 Pain Research and Management to undergo elective arthroplasty operations between July 1 Table 1: Patients’ demographic data (mean ± SD). and November 1, 2013; they ranged in age from 60 to 90 𝑝 and were classified as ASA 1–3. Patients who had bleeding Group M Group F Value of disorders; heart, liver, or renal failure; systemic infections or Age (years) 70.96 ± 6.94 68.56 ± 5.50 𝑝 = 0.275 infections of their injection sites; psychological disorders; or Height (cm) 163.24 ± 7.65 164.32 ± 7. 2 1 𝑝 = 0.076 drug allergies were not considered for this study. Likewise Weight (kg) 73.24 ± 17.70 76.28 ± 5.50 𝑝 = 0.106 patients who did not wish to be included in the study were Sex (M/F) 15/10 19/6 𝑝 = 0.225 not considered. All patients were visited the day before their surgery. They Table 2: Intraoperative systolic (S) and diastolic (D) blood pressure were given detailed information concerning the procedures values (mmHg) (mean ± SD). about to be implemented, such as the Visual Analog Scale (VAS), sedation, nausea and vomiting, respiratory depres- Group M Group F Value of p sion, and spinal anesthesia. The patients were taken to the Beginning S 163.4 ± 15.5 167.2 ± 12.8 𝑝 = 0.327 preoperative room 30 minutes prior to the operation. A Beginning D 86.4 ± 14.3 91.4 ± 10.6 𝑝 = 0.260 physiological infusion of 0.9% was begun intravenously via 5th min. S 146.6 ± 18.7 154.8 ± 12.1 𝑝 = 0.089 an 18-gauge intracath. The patients were given 0.02 mg/kg 5th min. D 81.1 ± 12.0 84.1 ± 10.2 𝑝 = 0.251 dormicum as a premedication. Later, in the operating room, ± ± 𝑝 = 0.013 each patient’s noninvasive blood pressure (NIBP), electrocar- 15th min. S 130.2 15.9 140.6 12.2 15th min. D 74.2 ± 12.9 74.4 ± 8.2 𝑝 = 0.846 diogram (ECG), end tidal carbon dioxide (ETCO2), and pulse oximetry were monitored, after which the baseline values 30th min. S 125.9 ± 11.9 133.4 ± 10.8 𝑝 = 0.031 were recorded for systolic blood pressure (SBP), diastolic 30th min. D 70.0 ± 9.9 74.2 ± 7. 7 𝑝 = 0.127 blood pressure (DBP), and heart rate (HR). All patients 60th min. S 124.3 ± 12.3 128.7 ± 10.9 𝑝 = 0.183 received 2 l/min. O2 by nasal cannula. 60th min. D 70.4 ± 8.1 73.4 ± 7. 9 𝑝 = 0.193 Patients who met the criteria for the study were randomly divided into two groups. The patients were seated in positions to facilitate location of intervertebral spaces and the skin was sterilized at the site Patients who complained of pain (VAS > 3) and needed where spinal anesthesia was to be administered. Following analgesics were treated intramuscularly every six to eight identification of either the L3-L4 or the L4-L5 interspace, a hours with Diclofenac Na. 25-gauge spinal needle was inserted midline. While Group F Postoperative pain was assessed using the Visual Analog (𝑛=25)received0.5%heavybupivacaine(2.5ml)+25mcg Scale (VAS). The Visual Analog Scale is one of the methods fentanyl (0.5 ml), Group M (𝑛=25)wasgiven0.5%heavy commonlyusedintheevaluationofpainintensity.TheVAS bupivacaine (2.5 ml) + 0.1 mg of morphine (0.5 ml) (total is a verbal scale numbered from 0 to 10, with 0 being “no 3 ml for each group). As soon as the sensory block reached pain” and 10 being “the worst pain possible or imaginable.” the appropriate level for surgery, the operation was begun. Accordingly, the patient is requested to verbally express his During surgery, systolic blood pressure (SBP), diastolic blood degree of pain using this scale. pressure (DBP), and heart rate (HR) were recorded at the 1st, 5th, 15th, 30th, and 60th minutes. At the end of each case, 2.1. Presentation of Statistical Analysis and Data. The SPSS sensorial block was evaluated as a dermatome level using the 18.0 software package, the nonparametric Mann–Whitney 𝑈 pinprick test. Following surgery, the patients were followed Test, the chi-squared test, and the independent sample 𝑡-test up for 30 minutes in the postoperative care room before were used in the statistical analysis of the data; and 𝑝 > 0.05 being sent back to their ward, after which their systolic blood was considered statistically significant. pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), nausea, vomiting, VAS values, and additional analgesic 3. Results requirements (if any) were observed and recorded for the 1st, 2nd, 6th, 12th, and 24th postoperative hours. Any patient who A total of 50 patients were included in the study. All of them vomited or complained of nausea was given a single 10 mg completed the study. Their demographic data (age, height, IV dose of metoclopramide. Any patient who complained of weight, and gender) are shown in Table 1. There was no itching was given a single 50 mg IV dose of diphenhydramine statistically significant difference𝑝 ( < 0.05) between the two HCl. A 30% reduction in systolic blood pressure was regarded groups. as hypotension and was increased using a liquid infusion of Although there was a decrease in the SBP in both groups 10 mg IV ephedrine. A heart rate of <50/min. was considered from the 1st to the 60th intraoperative minutes, there was no to be bradycardia and was treated with 0.5 mg IV atropine. statistically significant difference between the groups in terms The period of time from the moment the intrathecal injection of intraoperative systolic and diastolic blood pressure. Table 2 was made postoperatively until the first analgesic became shows that the change over time for the groups was similar necessary was recorded as the postoperative first-analgesic (𝑝 > 0.05). requirement time and was likewise recorded. Although there was a decrease in the intraoperative pulse Desaturation was defined as the falling of the SpO2 below pressure in both groups from the 1st to the 60th opera- 96% and was treated by administering 2 l/min. of O2 by mask. tive minutes, there was no statistically significant difference Pain Research and Management 3

Table 3: Intraoperative pulse pressure values (mmHg) (mean ± SD). Table 10 shows that in our study there was no statistically 𝑝 significant difference between Groups M and F in terms of Group M Group F Value of nausea and vomiting (𝑝 > 0.05). Beginning 83.5 ± 14.3 86.9 ± 9.8 𝑝 = 0.299 ± ± 𝑝 = 0.248 5th min. 78.9 11.0 83.0 10.8 4. Discussion 15th min. 76.4 ± 10.3 78.0 ± 7. 5 𝑝 = 0.593 30th min. 74.8 ± 9.5 75.5 ± 8.2 𝑝 = 0.846 Multimodal analgesia protocol may increase analgesic activ- 60th min. 78.3 ± 10.9 74.1 ± 8.2 𝑝 = 0.150 ity. Severe pain can be treated with intravenous opioids and NSAIDs used as patient-controlled analgesia (PCA), epidural local anesthetics and/or opioids, techniques called peripheral Table 4: Postoperative systolic blood pressure (SBP) and diastolic nerve blocks, or different combinations of drugs [5, 6]. Of all blood pressure (DBP) values (mmHg) (mean ± SD). knee replacement surgery patients, 60% describe the after- Group M Group F Value of 𝑝 surgery pain they feel as severe, while 30% call it moderate 1st hr. SBP 123.6 ± 14.5 121.4 ± 20.7 𝑝 = 0.783 [7]. In order to reduce analgesia and avoid side effects in 1st hr. DBP 72.6 ± 7. 7 7 1 . 8 ± 12.9 𝑝 = 0.952 thesepatients,useofregionalanesthesiainconjunction with multimodal techniques is more effective pain control 2nd hr. SBP 126.6 ± 12.9 120.0 ± 19.7 𝑝 = 0.124 ± ± 𝑝 = 0.867 [8]. It has been reported that implementation of intrathecal 2nd hr. DBP 73.0 6.8 73.2 10.5 morphine is effective in postoperative pain control. The ± 𝑝 = 0.847 6th hr. SBP 125.7 10.4 125.0 + 14.8 analgesic effects and intrathecal side effects of morphine in 6th hr. DBP 74.1 ± 8.1 73.2 ± 9.8 𝑝 = 0.761 the 0.0–0.3 mg dose range were studied. The result of that 12th hr. SBP 127.0 ± 0.0 124.8 ± 12.9 𝑝 = 0.734 studywasthattheauthorsfoundthat0.2mgand0.3mgdoses 12th hr. DBP 75.6 ± 7.0 74.1 ± 9.4 𝑝 = 0.694 ofintrathecalmorphineofferedmoreeffectivepainreliefthan 24th hr. SBP 126.6 ± 6.5 132.4 ± 7. 9 𝑝 = 0.005 did 0.0 mg and 0.1 mg doses of the same in hip and knee 24th hr. DBP 73.6 ± 9.6 77.4 ± 7. 1 𝑝 = 0.125 arthroplasty. Itching, nausea, and vomiting were determined to be dependent on 0.1 mg and 0.3 mg intrathecal use and ± dose-dependent as discussed by Rathmell et al. [9]. On the Table 5: Postoperative heart rate values (beats/min) (mean SD). otherhanditisunacceptabletouseevensmalldosesof Group M Group F Value of 𝑝 morphine because of these side effects as discussed byGurkan¨ 1st hr. 77.8 ± 5.9 78.4 ± 5.7 𝑝 = 0.840 et al. [10]. The usage of 0.5 mg intrathecal morphine was as safe as and more effective than 0.2 mg injections as discussed 2nd hr. 77.0 ± 5.8 77.2 ± 6.8 𝑝 = 0.590 ± ± 𝑝 = 0.993 by Gupta [11]. Also the analgesic effect of the additional 6th hr. 76.7 6.0 77.7 6.8 opioids provides a long postoperative period without pain. As ± ± 𝑝 = 0.757 12th hr. 77.5 12.5 75.9 6.4 shown in several previous studies, the patients with morphine 24th hr. 76.8 ± 8.5 76.8 ± 6.8 𝑝 = 0.792 had a long duration of analgesia [12]. This adjuvant anal- gesic technique is expected to decrease postoperative pain intensity and opioid requirements and to speed up recovery. between the groups. Table 3 shows that the variations of the Intrathecal morphine, which is less hydrophobic than other groups over time were similar (𝑝 > 0.05). opioids, has a longer residence time in the cerebrospinal Table 4 shows that although there was a decrease in the fluid and provides excellent postoperative analgesia [13]. systolic and diastolic blood pressure in both groups from the Adjuvants are often added to local anesthetics to increase the 1st to the 24th postoperative hour, there was no statistically quality of anesthesia in patients undergoing spinal anesthesia, significant difference between the groups𝑝 ( > 0.05). prolong the duration of the anesthesia, and reduce the side Table 5 illustrates that no statistically significant differ- effects of (lower dose) anesthetics. The most commonly ence was observed between the groups in terms of postop- used adjuvant drugs are opioids. Opioids, when used in erative heart rate values (𝑝 > 0.05). combination with local anesthetics, are known to produce In terms of End-of-Case Sensory Block Level measure- more effective and longer-term anesthesia [14, 15]. Time to ments, a statistically significant difference between the two first-analgesic requirement was also significantly longer in groups was not detected, as is shown in Table 6. Group C (hyperbaric bupivacaine, fentanyl, and MgSO4). Table 7 shows that there was no statistically significant Total morphine consumption was significantly less in Group difference in first-analgesic requirement time measurements C. The severity of pain was significantly less in C group as between the two groups. discussed by Attari et al. [16]. In addition, the duration of AscanbeseeninTable8,whenpostoperativeVASpain sensory analgesia is significantly prolonged with addition of scores are compared, Group M’s scores for the 2nd, 6th, 12th, morphine ensuring neonatal well-being [17]. and 24th hours are, statistically speaking, significantly lower In another study, the qualities of postoperative analgesia than those of Group F (𝑝 < 0.05). between intrathecal fentanyl 25 mcg and intrathecal mor- When the additional analgesic requirements of the two phine 0.1 mg in patients undergoing cesarean section were groups were compared, it was found that in the 2nd, 6th, compared. The postoperative analgesia of intrathecal fentanyl and24thhours,statisticallyspeaking,GroupM’sneedswere wasinferiortothatofintrathecalmorphinediscussedby significantly lower than those of Group F. Table 9 reflects this. Salmah and Choy [18]. Similarly, the current study found 4 Pain Research and Management

Table 6: End-of-Case Sensory Block Level (T).

Group M (T8-T9) Group F (T8-T9) Value of 𝑝 End-of-Case Sensory Block Level 8.7 ± 0.9 8.8 ± 0.9 𝑝 = 0.783

Table 7: First analgesic requirement time.

Group M Group F Value of 𝑝 First analgesic requirement time 5.9 ± 1.3 2.6 ± 0.6 𝑝 < 0.001

Table 8: Postoperative Visual Analog Scale (VAS) pain score values vomiting, and shivering by the addition of fentanyl to bupi- (Mean ± SD). vacaine. It has been discussed by Saracoglu et al. [19] in the study that intrathecal 15 mg isobaric bupivacaine with 200 𝜇g Group M Group F Value of 𝑝 morphine provides longer duration of analgesia and similar 1st hr. 0.4 ± 0.2 0.8 ± 0.4 𝑝 = 0.977 ∗ ∗ haemodynamic effects and ephedrine requirement and side 2nd hr. 0.2 ± 0.7 1.6 ± 2.1 𝑝 = 0.006 ∗ ∗ effects when compared to heavy bupivacaine-morphine or 6th hr. 4.2 ± 1.6 6.7 ± 1.6 𝑝 = 0.001 bupivacaine-fentanyl combinations during cesarean section. ∗ ∗ 12th hr. 3.2 ± 1.7 5.6 ± 1.5 𝑝 = 0.001 The additional analgesic requirement period was signif- ∗ ∗ 24th hr. 1.3 ± 1.3 4.1 ± 0.5 𝑝 = 0.001 icantly longer in Group Morphine than in Group Fentanyl 0=nopain;10=worstpossiblepain. (𝑝 < 0.001). Intraoperative and postoperative complications ∗ 𝑝 <0.05. were significantly higher in Group Fentanyl than in Group Morphine (𝑝 < 0.05). Intended, delivered, and total analgesic amount values were significantly higher in Group Fentanyl 𝑛 Table 9: Additional analgesic needs of the groups ( (%)). than in Group Morphine (𝑝 < 0.001)[20]. Group M Group F Value of 𝑝 In our study it was found that the morphine group had lower pain scores than did the fentanyl group in the 2nd, 6th, 1st hr. 0 (0%) 0 (0%) ∗ ∗ 12th, and 24th hours. And in the 2nd, 6th, and 24th hours the 2nd hr. 0 (0%) 7 (28%) 𝑝 = 0.004 morphine group was also found to have fewer patients who (56 )∗ (96 )∗ 𝑝 = 0.001 6th hr. 14 % 24 % required additional analgesics than did the fentanyl group. 12th hr. 19 (76%) 22 (88%) 𝑝 = 0.269 ∗ ∗ 24th hr. 6 (24%) 23 (92%) 𝑝 < 0.001 ∗ 5. Conclusion 𝑝 <0.05. Group M, as compared to Group F. In conclusion, the fentanyl group had lower first-analgesic requirement times than compared to the morphine group. Table 10: Nausea/vomiting. And there was no statistically significant difference between Group M Group F Value of 𝑝 the two groups in terms of nausea and vomiting. 1st hr. 1 (4%) 3 (12%) 𝑝 = 0.297 2nd hr. 2 (8%) 3 (12%) 𝑝 = 0.637 Competing Interests 𝑝 = 0.000 6th hr. 1 (4%) 1 (4%) The authors declare that there is no conflict of interests 12th hr. 1 (4%) 1 (4%) 𝑝 = 0.312 regarding the publication of this paper. 24th hr. 0 (0%) 0 (0%) References

[1]J.Stephens,B.Laskin,C.Pashos,B.Pena,˜ and J. Wong, “The that the postoperative VAS pain scores of Group M (the burden of acute postoperative pain and the potential role of the morphine group) were statistically significantly lower in the COX-2-specific inhibitors,” Rheumatology, vol. 42, S3, pp. iii40– 2nd, 6th, 12th, and 24th hours in comparison with those iii52, 2003. 𝑝 < 0.05 of Group F (the fentanyl group) ( ). Meanwhile, [2] A. Gurbet, A. Bekar, H. Bilgin, G. Korfali, S. Yilmazlar, and M. when the two groups were compared in terms of additional Tercan, “Pre-emptive infiltration of levobupivacaine is superior analgesics required, it was found that fewer patients in Group to at-closure administration in lumbar laminectomy patients,” M, to a statistically significant degree, needed additional European Spine Journal,vol.17,no.9,pp.1237–1241,2008. analgesics in the 2nd, 6th, and 24th hours compared to those [3] R. W. D. Mitchell and G. Smith, “The control of acute postop- of Group F. There was also a statistically significant difference erative pain,” British Journal of Anaesthesia,vol.63,no.2,pp. in first-analgesic requirement times between the two groups: 147–158, 1989. Group F had lower times than Group M. We also found no [4] H.-J. Priebe, “The aged cardiovascular risk patient,” British significant difference, statistically, between the two groups in Journal of Anaesthesia,vol.85,no.5,pp.763–778,2000. terms of nausea and vomiting. It was discussed by Agrawal [5]P.-A.Vendittoli,P.Makinen,P.Droletetal.,“Amultimodal et al. [17] that there is reduction in the incidence of nausea, analgesia protocol for total knee arthroplasty: A Randomized, Pain Research and Management 5

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Clinical Study Combination Therapy with Continuous Three-in-One Femoral Nerve Block and Periarticular Multimodal Drug Infiltration after Total Hip Arthroplasty

Tomonori Tetsunaga,1,2 Tomoko Tetsunaga,1 Kazuo Fujiwara,3 Hirosuke Endo,1 and Toshifumi Ozaki1

1 Department of Orthopaedics, Okayama University, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan 2Department of Orthopaedics, Okayama Medical Center, 1711-1 Tamasu, Kitaku, Okayama 701-1192, Japan 3Department of Intelligent Orthopedic Systems, Okayama University, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan

Correspondence should be addressed to Tomonori Tetsunaga; tomonori [email protected]

Received 6 August 2016; Accepted 23 November 2016

Academic Editor: Volkan Hancı

Copyright © 2016 Tomonori Tetsunaga et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background. Various postoperative pain relief modalities, including continuous femoral nerve block (CFNB), local infiltration analgesia (LIA), and combination therapy, have been reported for total knee arthroplasty. However, no studies have compared CFNB with LIA for total hip arthroplasty (THA). The aim of this study was to compare the efficacy of CFNB versus LIA afterTHA. Methods. We retrospectively reviewed the postoperative outcomes of 93 THA patients (20 men, 73 women; mean age 69.2 years). Patients were divided into three groups according to postoperative analgesic technique: CFNB, LIA, or combined CFNB+LIA. We measured the following postoperative outcome parameters: visual analog scale (VAS) for pain at rest, supplemental analgesia, side effects, mobilization, length of hospital stay, and Harris Hip Score (HHS). Results. The CFNB+LIA group had significantly lower VAS pain scores than the CFNB and LIA groups on postoperative day 1. There were no significant differences among the three groups in use of supplemental analgesia, side effects, mobilization, length of hospital stay, or HHS at 3 months after THA. Conclusions. Although there were no clinically significant differences in outcomes among the three groups, combination therapy with CFNB and LIA provided better pain relief after THA than CFNB or LIA alone, with few side effects.

1. Introduction blockade is difficult and is associated with complications, including sensory nerve injury and retroperitoneal hemor- Acute postoperative pain is a distinct risk factor for prolonged rhage. Therefore, only experienced anesthesiologists should pain [1]. Postoperative pain relief after joint surgery can be perform this procedure. achieved with various modalities, such as patient-controlled Local infiltration analgesia (LIA) offers better pain con- analgesia (PCA) with morphine, epidural analgesia, and lum- trol, reduced narcotic consumption, and earlier mobilization, bar plexus and/or sciatic blocks [2–6]. The advantages of PCA without increased risks [9]. Moreover, LIA reduces hospital include fewer technical problems than other modalities and stays compared with epidural anesthesia after total hip uniform, sustained analgesia with autonomy [7, 8]. Although arthroplasty (THA) [10]. Continuous femoral nerve block both PCA and continuous epidural analgesia provide suf- (CFNB) is a popular analgesic modality after total knee ficient pain relief, they are associated with multiple side arthroplasty (TKA), with fewer side effects than morphine effects, including arterial hypotension, respiratory depres- or fentanyl [2, 6]. One study reported that CFNB was more sion, nausea/vomiting, and urinary retention [6]. Because the effective than continuous epidural anesthesia or PCA after lumbar plexus is located in a deep tissue layer, lumbar plexus THA[11].However,fewstudieshavereportedgoodoutcomes 2 Pain Research and Management with CFNB after THA [3, 6, 12]. The problem with using of 4 ml/h beginning immediately postoperatively. In the LIA CFNB alone is that achieving adequate analgesia in the sciatic group, 225 mg of 0.75% ropivacaine (7.5 mg/ml, Anapeine; nerve region is difficult. Periarticular anesthetic infiltration AstraZeneca), 10 mg of morphine hydrochloride (10 mg/ml, offers a practical and potentially safer alternative to sciatic Shionogi, Osaka, Japan), and 0.5 mg of epinephrine (1 : 1000) nerve block for patients undergoing TKA [13]. CFNB and were mixed with 18.5 ml of sterile normal saline solution LIA can complement one another. Koh et al. [14] compared tomakeacombinedvolumeof50ml,whichwasinjected combination therapy with CFNB and LIA with the use of into the periarticular soft tissue. In the CFNB+LIA group, CFNB alone and reported reduced pain with combination both a continuous 3-in-1 block and LIA were administered as therapy in the initial 48 hours after TKA, along with reduced described above. Breakthrough pain relief was achieved with need for opioids in the initial 24 hours. However, the effects a diclofenac sodium suppository (25 mg). Use of a diclofenac of combining CFNB and LIA on postoperative outcomes in sodium suppository was allowed for all patients at any time patients undergoing THA have not been fully evaluated. The after surgery; postoperative diclofenac sodium suppository aim of the present study was to compare three-in-one CFNB, use was assessed. Metoclopramide hydrochloride was used to LIA, and the combination of CFNB and LIA on postoperative treat postoperative nausea and vomiting (PONV). outcomes in patients after THA. On the first postoperative day, all patients started anti- coagulation therapy with fondaparinux (2.5 mg/day), which 2. Methods was continued for 14 days. On the first postoperative day, all patients began a regimen of movement and strengthening All patients included in this study gave their written, exercises; they were encouraged to achieve full weight- informed consent. Ethical approval was obtained from the bearing exercises on postoperative day 2. Institutional Review Board of our institution. We retro- spectively reviewed and analyzed the clinical outcomes of 2.1. Clinical Assessment. The primary outcome was patient patients who received one of three postoperative analgesia pain intensity at rest on postoperative day 1. Early (postoper- protocols after THA. Inclusion criteria included patients ative days 1 to 7) walking capacity was assessed with straight- who underwent THA at our hospital from January 2014 leg raising and T-cane ambulation. Middle-term walking toMarch2015andwhowereabletoprovideinformed capacity was measured 2 weeks after surgery with the 10- consent and cooperate with the study. We excluded patients meter walking test and timed up and go test. Late-term with local infection, cemented THA, revision THA, bleeding physical activity was assessed 3 months after surgery with tendency due to anticoagulant therapy, renal insufficiency, or theHarrisHipScore(HHS)[17].Foodconsumption,useof allergy to local anesthetics or other medications. This study diclofenac sodium suppositories, side effects, and length of included 93 patients (20 men and 73 women). The mean hospital stay were recorded for each group. ageatsurgerywas69years(range37–92).Thepreoperative diagnoses were osteoarthritis in 81 hips, avascular necrosis 2.2. Pain Assessment. The patient’s pain intensity at rest of the femoral head in eight hips, rheumatoid arthritis in was self-assessed using a visual analog scale (VAS) 24 h two hips, and femoral neck fracture in two hips. Three postoperatively. The VAS for pain self-assessment is a widely experienced surgeons performed all operations in this study. used, valid, and reliable tool to measure pain intensity [18]. All THA surgeries were performed via the direct lateral Patients rated pain intensity on a 100 mm VAS from no pain (Hardinge) approach and used cementless implants (PINNA- (0 mm) to unbearable pain (100 mm). CLE, TRILOCK; DePuy Synthes, Tokyo, Japan). Anesthesiologists instituted one of the following analgesic 2.3. Ten-Meter Walking Test. The 10-meter walking test has modalities: CFNB (CFNB group, 𝑛=30), LIA (LIA group, been used in gait studies of patients with neurologic move- 𝑛=32), or combined CFNB and LIA (CFNB+LIA group, 𝑛= ment disorders in general [19] and to evaluate the spatial, 31) (Table 1). In the CFNB group, a continuous 3-in-1 block, temporal, and kinematic aspects of gait. This test measures which blocks the femoral nerve, obturator nerve, and lateral the time it takes patients to walk 10 meters and assesses short- femoral cutaneous nerve, was administered after the induc- duration walking speed. Three trials were performed and the tion of general anesthesia, according to the method described mean value was reported. byWinnieetal.[15].Thefemoralarterywaslocatedbelowthe inguinal ligament; an 18-G needle (1.3 × 50-mm, Contiplex5; 2.4. Timed Up and Go Test. Global muscle performance was B-Braun, Tokyo, Japan) connected to a nerve stimulator assessed with the timed up and go test. First described by (Stimuplex5 HNS12; B-Braun, Tokyo, Japan) was inserted just Podsiadlo and Richardson [20], this is a reliable and valid lateral to the artery under ultrasound guidance (MICRO- test that predicts the patient’s ability to go outside alone MAXX5; SonoSite, Tokyo, Japan). The femoral nerve was safely.Subjectswereinstructedtositinachairataheight ∘ accurately identified by eliciting contractions of the quadri- that maintained the hips and knees at 90 flexion, with their ceps with minimal stimulator settings (frequency, 2 Hz; back very lightly touching the backrest. Stable posture was current, 0.5 mA) [16]. Using the Seldinger technique, a 20-G confirmed by the examiner. We observed and timed how long catheter (0.85 × 1000 mm, Contiplex; B-Braun, Tokyo, Japan) it took subjects to rise from the chair, walk 3 meters at a was advanced 10 to 15 cm into the psoas compartment. After a comfortable speed, turn, walk back, and sit down again. The negative aspiration test for blood, 0.2% ropivacaine (2 mg/ml, complete sequence was measured three times, and the mean Anapeine5; AstraZeneca, Tokyo, Japan) was injected at a rate value was reported. Pain Research and Management 3

Table 1: Patient characteristics. Total CFNB LIA CFNB+LIA 𝑝 value (𝑛=93)(𝑛=30)(𝑛=32)(𝑛=31) Age (years) 69.2 ± 11.2 64 ± 10.4 66.6 ± 12.7 68 ± 11 0.25 Sex(male:female) 20:73 9:21 5:27 6:25 0.28 2 BMI (kg/m )24± 3.9 24 ± 4.3 23 ± 3.4 25 ± 3.8 0.19 Diagnosis OA 81 28 27 26 ANFH 8 2 3 3 0.89 RA 2 0 1 1 Fracture 2 0 1 1 VAS (mm) 53.6 ± 22.2 50.5 ± 20.7 54.4 ± 21.3 56.1 ± 24.8 0.51 10 m test (s) 11.6 ± 4.2 11.5 ± 2.6 11.9 ± 3.9 11.5 ± 5.5 0.94 TUG (s) 12 ± 3.9 11.8 ± 2.7 12.8 ± 5.2 11.5 ± 3.6 0.48 HHS (points) 45.8 ± 16.3 45.5 ± 16.1 45.4 ± 14.1 42.6 ± 19.1 0.35 Operation time (min) 77 ± 25.3 81.1 ± 30.6 80.7 ± 19.7 79.5 ± 25 0.25 Blood loss (ml) 227 ± 183 252 ± 168 212 ± 219 217 ± 157 0.74 CFNB = continuous femoral nerve block; LIA = local anesthetic infiltration; BMI = body mass index; OA = osteoarthritis; ANFH = avascular necrosis of the femoralhead;RA=rheumatoidarthritis;VAS=visualanaloguescale;TUG=timedupandgotest;HHS=HarrisHipScore.

∗ 2.5. Statistical Analysis. Differences in data among groups 60 were tested with one-way or two-way repeated-measures ∗ ∗ 50 analysis of variance (ANOVA) with Tukey’s post hoc test. The PearsonChi-squaredtestwasusedtocomparedifferencesin 40 sex ratio and diagnosis. A pilot study was performed with ten 30 patientsineachgroup.Inthepilotstudy,themeanVASwas 30.5 mm in the CFNB group, 20.5 mm in the LIA group, and 20 VAS score (mm) score VAS 13 mm in the CFNB+LIA group, with a standard deviation 10 of 10. Based on the effect size in this pilot study, a power 𝑝 < 0.05 0 calculation for a trial ( ;power:0.8)suggestedthat CFNB LIA CFNB+LIA 29 patients would be needed in each group. Values are shown as mean ± standard deviation; values of 𝑝 < 0.05 were con- Figure 1: Visual analog scale (VAS) for pain at rest 24 hours post- sidered significant. Statistical analysis was conducted with operatively. Significant differences are seen among groups 24 hours SPSS version 22 (IBM Corporation, Armonk, NY, USA) for after surgery. Data are presented as mean ± SD. CFNB, continuous ∗ 𝑝< Windows (Microsoft Corporation, Redmond, WA, USA). femoral nerve block; LIA, local infiltration analgesia. indicates 0.05. 3. Results day (𝑝 = 0.56). The incidence of nausea/vomiting was not 3.1. Analgesic Activity. No significant differences in patient affected by the treatment modality (𝑝 = 0.88). None of background were identified among groups. These data are the patients experienced systemic toxicity from ropivacaine. summarized in Table 1. The VASscore at rest was 30.4±19.4 in There were no cases of delayed wound healing, wound infec- the CFNB group, 20.9±14.9 in the LIA group, and 13.3±11.5 tion, or prosthesis infection. None of the patients required in the CFNB+LIA group (Figure 1). Statistically significant repeat surgery during the study period. differences were observed among the three groups in post- operative pain intensity at rest on the first postoperative day. 3.2. Mobilization. To evaluate early walking capacity, we The VAS score at rest in the CFNB+LIA group was signifi- assessed quadriceps strength and T-cane ambulation. Patients cantly lower than those of the CFNB and LIA groups (𝑝< achieved straight-leg raise 5.6 ± 2.9 days after surgery and 0.0001 and 𝑝 = 0.04, resp.). The use of diclofenac sod- assisted ambulation with a walking cane 6.8±2.6 days postop- ium suppositories within 24 hours after surgery was similar eratively. No significant differences were found among groups among the three groups (𝑝 = 0.18, Table 2). Although three regarding either the straight-leg raise or T-cane ambulation patients (8.6%) in the CFNB group, two (6.3%) in the LIA (𝑝 = 0.69 and 0.51, resp.). Walking capacity was measured 2 group,andthree(9.7%)intheCFNB+LIAgrouphadnausea/ weeks after surgery with the 10-meter walking test and timed vomiting, patients consumed 71.8% of food offered on the up and go test. No significant differences were seen among first postoperative day. There were no significant differences groups in either test on postoperative day 14. The mean in food consumption among groups on the first postoperative hospital stay after surgery, including postoperative physical 4 Pain Research and Management

Table 2: Overall comparison of outcomes.

Total CFNB LIA CFNB+LIA 𝑝 value (𝑛=93)(𝑛=30)(𝑛=32)(𝑛=31) NSAIDs (𝑛 used/patient) 1.39 (0–4) 1.69 (0–4) 1.57 (0–4) 0.94 (0–3) 0.18 PONV 8 (8.6%) 3 (10%) 2 (6.3%) 3 (9.7%) 0.88 Meal (% consumed) 71.8 ± 23.4 74.2 ± 22.4 70.2 ± 25.2 71 ± 22.6 0.56 SLR achieved (day) 5.6 ± 2.9 6.1 ± 3.2 5.5 ± 2.7 5.2 ± 3.1 0.69 T cane walking (day) 6.8 ± 2.6 7.3 ± 3.0 6.6 ± 2.5 6.5 ± 2.4 0.51 10 m walking test (s) 14.2 ± 4.4 14.7 ± 4.6 14.4 ± 4.0 13.4 ± 4.7 0.67 TUG (s) 16.1 ± 5.2 16 ± 4.7 16.9 ± 5.6 15.2 ± 5.1 0.62 Hospital stay (days) 19.2 ± 2.5 19.7 ± 2.6 19 ± 2.4 19 ± 2.6 0.48 HHS (points) 83.2 ± 5.5 80.4 ± 14.9 80.4 ± 14.2 81.9 ± 14.6 0.90 CFNB = continuous femoral nerve block; LIA = local anaesthetic infiltration; VAS = visual analogue scale; NSAIDs = nonsteroid anti-inflammatory drugs; PONV = postoperative nausea and vomiting; SLR = straight leg raising; TUG = timed up and go; HHS = Harris Hip Score. therapy, was 19.2 ± 2.5 days. No significant differences in first 24 hours after THA. Lunn et al. [29] reported the use length of hospital stay were observed among the three groups of intraoperative high-volume LIA with 0.2% ropivacaine (𝑝 = 0.48). The HHS was similar in the three groups 3 months combined with a multimodal oral analgesic regimen con- after surgery (𝑝 = 0.90). HHS improved significantly in all sisting of acetaminophen, celecoxib, and gabapentin after three groups postoperatively (all 𝑝 < 0.0001). THA, and use of LIA alone is not recommended. Given this information, we consider that additional postclosure analge- 4. Discussion sia including CFNB provides great value. In this study, we administered combined therapy with CFNB and LIA for the Thisstudycomparedtheacutepostoperativepainlevels first time in patients after THA. After TKA, combined therapy in patients receiving CFNB, LIA, or combined CFNB and with femoral nerve block and LIA has shown no evidence LIAafterTHA.OurresultsindicatethatcombinedCFNB of added benefits for recovery of function [13]. Although and LIA provided significantly better pain relief on the first no significant differences were seen in clinical function 3 postoperative day than either modality alone. PONV and months after surgery in the present study, acute pain was other perioperative complications were comparable among significantly lower with combination therapy. Reducing acute the three study groups. No significant differences were seen in postoperative pain, which is a risk factor for chronic pain after patient mobilization among the three postoperative analgesia THA, could lower the incidence of prolonged pain [1]. groups at 2 weeks or 3 months after surgery. Because we found only slight differences among interven- CFNB has been widely used in TKA patients [6, 21]. Com- tions, clinicians should focus on other factors such as cost and pared with PCA and continual epidural anesthesia, CFNB intervention-related complications when choosing analgesic provides good pain relief and is associated with fewer side treatments after THA [25]. A potential disadvantage of CFNB effects such as PONV, hematomas, arterial hypotension, and is an increased risk of falling due to quadriceps weakness. drowsiness [3, 12]. However, few reports have analyzed CFNB Ilfeld et al. [30] reported that 42% to 43% of patients experi- in THA patients [3, 12]. Inadequate analgesia in the sciatic enced quadriceps femoris weakness at a dose of 0.2% ropi- nerve region is the main reason CFNB is not widely used in vacaine at 8 ml/h; they recommended 0.2% ropivacaine at THA.AlthoughCFNBcanbecombinedwithasciaticnerve 3.0 ml/h in patients with quadriceps femoris weakness at block, periarticular anesthetic infiltration offers a practi- 6.0 ml/h [31]. The concentration and flow rate of CFNB cal and potentially safer alternative as an adjunct to CFNB should be adjusted based on its effect [32]. In this study, no in TKA patients [22]. patients in the CFNB or CFNB+LIA groups complained of In TKA, peri- and intra-articular infiltration of analgesics postoperative quadriceps weakness. We consider 0.2% ropi- can improve early analgesia and mobilization more effectively vacaine at a rate of 4 ml/h to be appropriate to minimize the than CFNB [23]. However, CFNB is associated with lower risk of falling after THA. To avoid dense sensory and motor opioid consumption and better recovery at 6 weeks than blockade, a combination of an opioid and a local anesthetic is periarticular infiltration [24]. Jimenez-Almonte´ et al. [25] also recommended [7]. Opioid medication is a key strategy reported no differences between LIA versus peripheral nerve in the management of postsurgical pain but its associated blocks in analgesia or opioid consumption 24 hours after PONV can delay mobilization and rehabilitation [11, 33]. Our THA. Different protocols for femoral nerve blocks and LIA infiltration analgesia injection contained 10 mg of morphine in these trials hinder interpretation and conclusions. There is hydrochloride. The incidence of PONV was comparable with strong evidence that pain at rest is lower in patients receiving or without morphine in this study. Marques et al. [28] LIAthanincontrols24hoursafterTHA[26–28].However, reported that patients receiving local anesthetic infiltration Marques et al. [28] reported that the effects of LIA alone consumed 20% less morphine than patients receiving epidu- without additional postclosure analgesia were limited to the ral analgesia and 12% less than patients receiving intrathecal Pain Research and Management 5 analgesia. The lack of difference in PONV incidence among References groups in our study might be explained by the low dose of morphine used. Neuropathy after peripheral nerve blockade [1] W. A. Macrae, “Chronic post-surgical pain: 10 years on,” British is another complication of the analgesic procedure, estimated Journal of Anaesthesia,vol.101,no.1,pp.77–86,2008. tooccurinalmost3%ofcases,althoughpermanentinjury [2] J. E. Chelly, J. Greger, R. Gebhard et al., “Continuous femoral blocks improve recovery and outcome of patients undergoing is rare [34]. In the current study, there were no neurological total knee arthroplasty,” The Journal of Arthroplasty,vol.16,no. complications after CFNB. The use of ultrasound with elec- 4, pp. 436–445, 2001. trostimulation in this study enabled us to identify the femoral [3]F.J.Singelyn,T.Ferrant,M.F.Malisse,andD.Joris,“Effectsof nerve and place the local block more precisely. intravenous patient-controlled analgesia with morphine, con- This study has some limitations. First, this is a retrospec- tinuous epidural analgesia, and continuous femoral nerve tive study rather than a randomized-control trial. A prospec- sheath block on rehabilitation after unilateral total-hip arthro- tive, randomized, controlled study should be conducted to plasty,” Regional Anesthesia and Pain Medicine,vol.30,no.5,pp. eliminate selection bias and obtain more consolidated results. 452–457, 2005. However, the present study had little selection bias because all [4] C. C. Buckenmaier III, J. S. Xenos, and S. M. 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Hindawi Publishing Corporation Pain Research and Management Volume 2016, Article ID 3652726, 9 pages http://dx.doi.org/10.1155/2016/3652726

Review Article Postthoracotomy Ipsilateral Shoulder Pain: A Literature Review on Characteristics and Treatment

Fardin Yousefshahi,1,2 Oana Predescu,3 Melissa Colizza,3 and Juan Francisco Asenjo4

1 Department of Anesthesia, Tehran University of Medical Sciences, Tehran, Iran 2Montreal General Hospital, McGill University Health Centre, Montreal, QC, Canada 3Department of Anesthesia, Montreal General Hospital, McGill University Health Centre, Montreal, QC, Canada 4Department of Anesthesia, McGill University Health Centre, Montreal, QC, Canada

Correspondence should be addressed to Juan Francisco Asenjo; [email protected]

Received 11 August 2016; Accepted 25 September 2016

Academic Editor: Rudin Domi

Copyright © 2016 Fardin Yousefshahi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Context. Postthoracotomy Ipsilateral Shoulder Pain (IPS) is a common and sometimes intractable pain syndrome. IPS is different from chest wall pain in type, origin, and treatments. Various treatments are suggested or applied for it but none of them is regarded as popular accepted effective one. Objectives. To review data and collect all present experiences about postthoracotomy IPS and its management and suggest future research directions. Methods. Search in PubMed database and additional search for specific topics and review them to retrieve relevant articles as data source in a narrative review article. Results. Even in the presence of effective epidural analgesia, ISP is a common cause of severe postthoracotomy pain. The phrenic nerve has an important role inthe physiopathology of postthoracotomy ISP.Different treatments have been applied or suggested. Controlling the afferent nociceptive signals conveyed by the phrenic nerve at various levels—from peripheral branches on the diaphragm to its entrance in the cervical spine—could be of therapeutic value. Despite potential concerns about safety, intrapleural or phrenic nerve blocks are tolerated well, at least in a selected group of patient. Conclusion. Furtherresearchescouldbedirectedonselectivesensoryblockandmotorfunction preservation of the phrenic nerve. However, the safety and efficacy of temporary loss of phrenic nerve function and intrapleural local anesthetics should be assessed.

1. Introduction 2. Material and Method Open thoracotomy surgeries constitute very painful pro- We performed a search in PubMed database for “thoraco- cedures [1, 2]. While thoracic epidural analgesia may help tomy”, “pain”, and “shoulder” and applied filters to obtain control the incisional component of the pain, an excruciat- human studies only. All relevant studies related to posttho- ing postthoracotomy Ipsilateral Shoulder Pain (ISP) could racotomy shoulder pain, released until November 2015, were undermine pain management in the postthoracotomy patient reviewed in detail. Further searches were performed based on [3]. Shoulder pain is also common in abdominal surgery our primary findings in related topics. The retrieved articles with some similarities, but its management seems somewhat were organized in order to prepare a narrative review article different. Very little specific data exists about ISP in the focusedonpostthoracotomyISPtreatment. literature [4]. Furthermore, the majority of studies about ISP are not well designed clinical trials. The present literature 3. Frequency and Importance review is an attempt to organize the present clinical knowl- edge and comprehension about postthoracotomy ISP and its In the presence of good thoracic epidural analgesia, ISP management, to orient future research directions. may contribute to all the pain experienced by thoracotomy 2 Pain Research and Management patients. As, by blocking the phrenic nerve and in presence of The relationship between a longer duration of surgery in a competent epidural analgesia, most patients do not report the lateral decubitus position and ISP has been suggested as as much pain [5]. an explanation for the role of strain of the shoulder joint ISP could affect 31% to 85% of patients after thoracic capsule and ligaments in the etiology of ISP [6, 20]. Patients surgery [5–13]. Even, one study reported a prevalence of up with a higher Body Mass Index (BMI) report an increased to 97% [9]. ISP could impair effective breathing and the prevalence of postthoracotomy IPS, representing a possibly effectiveness of physical therapy in the early postoperative higher strain on the shoulder and thus supporting this period [14]. hypothesis in another study [22]. Meanwhile, the distraction of the ipsilateral shoulder joint was suggested as a possible 4. Pain Characteristics cause for the limited effect of an intrapleural block, the supraclavicular nerve block was ineffective in palliating ISP Postthoracotomy ISP is limited to the operative side [11]. [13], which suggests it is not a common cause of ISP. Postthoracic surgery ISP is reported as moderate to severe Myofascial involvement has also been reported to con- in the majority of patients [3, 6, 8, 15–18]. In approximately tribute at least partially to postthoracotomy shoulder pain half of the patients, ISP was located at the posterior side of [21]. the shoulder [6], but it may be felt around the deltoid region AnotherhypothesisisthatISPistheresultofreferred [16, 18], the superior-posterior area of the shoulder [3], or pain from the irritated pericardium, mediastinum, or pleural the lateral third of the clavicle [17]. All those areas share surface of the diaphragm, transmitted via the phrenic nerve innervation from C4 and C5 with the diaphragm. [5, 11, 23]. Many studies support this hypothesis, since ISP onset could be as early as the first postoperative hour the intraoperative infiltration of the phrenic nerve at the [9, 11]. With treatment, the pain severity will decrease over level of the diaphragm could diminish the incidence of ISP the first 4 to 6 hours [5, 11, 13]. significantly[5,9,10].Furthermore,thereisareductionin Less intense pain could extend to the second postopera- the incidence of ISP, following the block of phrenic nerve as tive day [7, 15]. a side effect of stellate ganglion block [16] and interscalene ISPisoftendescribedasdull,achingpain[3,16,18].While brachial plexus block [7, 17, 18, 24]. There is also a report on the majority of reports define the pain as independent from effective treatment of postthoracotomy ISP by direct blocking movement[3,11,16,18],otherreportsdescribeISPtobe thephrenicnerveattheneck[17]. aggravated by movement [17]. However, effective treatment The phrenic nerve is a mixed nerve that contains afferent of pain will decrease ISP severity, both during rest and cough supply from the subdiaphragmatic peritoneum, liver, spleen, [9]. diaphragm, lower part of the pleura, and pericardium [23, 25]. It is originating from 3rd, 4th, and 5th cervical nerve roots. Stimulation of these afferent nerves could translate 5. Etiology into referred pain, which is perceived clinically as neck and shoulder pain. The diaphragmatic afferents comprise small As ISP may be aggravated by movement, it is suggestive for a unmyelinated C-fibers, which have a high excitation thresh- somatic rather than neuropathic origin of pain [6]. However, old [26]. This mechanism is supported by the occurrence both inflammatory [3] and neuropathic [19] behavior had of IPS in the presence of phrenic nerve stimulation devices been suggested for ISP. [5, 27]. There are many unproved or partially proved hypotheses Pleural irritation by chest drains is considered to be the regarding the etiology of ISP including transection of major most probable cause of ISP in postthoracotomy patients. A bronchi, ligament distraction or strain as the result of surgical study by Pennefather et al. suggested that, in some patients, retraction, shoulder joint strain from intraoperative mal- ISP could be the result of direct irritation of the apical or basal positioning, myofascial involvement, irritation of the pleura pleura by chest tubes or by blood [11]. However, intrapleural by chest drains, and referred pain from irritation of the administration of bupivacaine via basal chest tubes could not pericardium, mediastinum, or diaphragmatic surface [3, 5, 11, relieve the shoulder pain [11]. 17, 20, 21]. Transection of the major bronchi was suggested in a study as the cause of ISP after thoracic surgeries in 1993 [3]. 6. Risk Factors However, it was not confirmed in other studies [6]. Severe incisional pain of thoracotomy could be the result Predisposing and risk factors for developing ISP are not of surgical trauma to some major elements in the chest wall, well known. However, in a prospective observational study including the latissimus dorsi muscles and ribs. It had been by Bunchungmongkol et al., the potential risk factors for suggested that the shoulder pain after thoracotomy could be developing ISP were surgery performed by a thoraco- caused by strain of ligaments and muscles of scapula [17], tomy approach compared with Video-Assisted Thoracoscopic arcuation of patient in lateral decubitus position [13], or Surgeries (VATS) (risk ratio: 2.12, 95% confidence interval: ligament injury following rib retraction [20]. Furthermore, 1.16–3.86, 𝑝 = 0.014)andsurgeryduration>2 hours (risk the localization of ISP to the posterior side of shoulder, in a ratio: 1.61, 95% confidence interval: 1.07–2.44, 𝑝 = 0.023) majority of patients, could suggest the muscle strain around [6]. In a retrospective study by Misiołek et al., higher Body the scapula as the cause of ISP [6]. Mass Index (BMI), thoracotomy versus VATS approaches, Pain Research and Management 3 andepiduralcatheterlevellowerthanT5werefoundtobe 10 mL of ropivacaine 0.2% was shown to be effective and associated with a higher prevalence of IPS [22]. In this study without additional compromise of oxygenation [9]. 4.35% of patients with an epidural catheter placed at T5 or Stellate ganglion block [7, 16] and interscalene brachial higher developed ISP while 40.47% of patients with epidural plexus block [7, 17, 18, 24] are effective in reducing post- catheter placed lower than T5 developed it [22]. However, thoracotomy ISP, possibly because the phrenic nerve is often coincidence of open thoracotomy, long duration of surgery, blocked concomitant on the same side. Interscalene blockade andhighBMIcouldnotbeignored. in treatment of ISP has yielded better results than diclofenac; The direct relationship between long duration of surgery however the phrenic nerve motor function is also blocked and ISP occurrence [20] and also superiority of VATS on most times [7]. There is also a report of effective treatment of thoracotomy [28] were reported by other authors, too. postthoracotomy ISP by direct blockade of the phrenic nerve, after its inadvertent identification during attempt to locate 7. Treatments brachial plexus [17]. The lower prevalence of postthoraco- tomy ISP when an epidural catheter is inserted higher than ISP is often difficult to manage, as it is relatively resistant to T5 is considered as supportive of the role of phrenic nerve in parenteral opioids and increases in epidural infusion rates [5, treatment of ISP [22]. 15]. ISP after VATS is reported in few studies [4, 6, 28]. Some reports address the effectiveness of Nonsteroidal Considering the smaller surgical incisions and the shorter Anti-Inflammatory Drugs (NSAIDs), such as ketorolac and duration of the procedures, VATS is helpful in reducing early indomethacin for postthoracotomy ISP treatment [3, 6–8]. postoperative incisional pain [6, 28]. Though others report only a partial efficacy of NSAIDs The intrapleural block, that is, local anesthetic injection [5]. However, the efficacy of NSAIDs still requires further between visceral and parietal pleura, is effective in relieving investigation as well as consideration to contraindications to the shoulder pain after cholecystectomy [42]. While there the use in several populations. are reports which address safety and advantages of intrapleu- Preemptive, regular prescription of acetaminophen dur- ral block in postthoracotomy patients [43–50], most other ing the first 48 hours from thoracotomy may decrease ISP studies showed little or no benefit for ISP [11, 51–55]. As [15]. While gabapentin is effective in prevention of shoulder an interesting finding, intrapleural block could not decrease pain after abdominal surgeries [29], it was not effective epidural analgesia requirement and have little effect on in treatment of postthoracotomy IPS, even as preemptive intercostal incisional pain after thoracotomy, too [11, 57]. The analgesia [19, 31]. Other popular molecules used for neuro- difference between the results with cholecystectomy versus pathic pain (i.e., pregabalin) are regarded to be effective for thoracotomy could be explained by the presence of blood treatment of ISP by other authors [27, 30]. and air in the pleural space after thoracotomy, which limits Systemic ketamine is reported to be effective to decrease effective local anesthetic spread [11]. Local anesthetic loss via the acute postthoracotomy pain [32–36]. Epidural ketamine the chest tubes, insufficient volume of local anesthetic, and is also reported to be effective in prevention of acute posttho- dilution of local anesthetic by blood or pleural effusion fluid racotomy pain and development of chronic postthoracotomy andpresenceofanaccessoryphrenicnervehavebeencon- pain syndrome [37]. However, other studies could not find sidered as possible causes of unsuccessfulness of intrapleural such a beneficial effect on chronic pain for systemic [32, 35, block [11, 45, 54]. Moreover, a phrenic nerve block at the 36] or epidural ketamine [36]. However, none of these studies diaphragm level may or may not be necessarily effective at address ISP as an outcome in their studies. controlling ISP in all patients [5]. Additionally, it has been Thoracic epidural analgesia likely provides optimal anal- shown that sensory and sympathetic block after intrapleural gesia for thoracotomy incision, along with a reduction in analgesia is incomplete, even in abdominal surgeries [58]. morbidity and mortality after open thoracic surgeries [38– As mediastinal pleura and pericardium receive some 41]. However, a perfectly adequate thoracic epidural analgesia sensory innervation from the phrenic nerve [23], it is possible for the incisional site is not effective in preventing posttho- that a more proximal block is necessary to block these racotomy ISP [6, 8, 16]. ISP is often resistant to increases branches [11]. in the epidural infusion rate [5, 15]. However, in a recent Interestingly, intrapleural morphine was shown to be study, epidural catheters located in spaces higher than T5 more effective in pain control when compared to intravenous were effective in preventing postthoracotomy ISP [22]. morphine in postthoracotomy patients. Moreover, plasma Intraoperative local anesthetic infiltration of the phrenic levels of morphine were lower and respiratory rate was higher nerve at the level of the diaphragm could significantly reduce in intrapleural route [59]. There is no report about ISP in this the incidence of ISP [5, 7, 9, 10]. However, the benefit of study. this technique is limited by its short duration of effect and Intrapleuralblockwasusedsafelyandsuccessfullyfor impossibilitytoberepeated[5].Usinglongactinglocal pain management after VATS and thoracotomy, either as anesthetics to block the phrenic nerve may provide longer intermittent bolus doses or as continuous infusion [60–63]. analgesia, but there are concerns about longer hemidiaphrag- Ithasbeenusedinlong-termpainmanagementofcancer matic weakness and its consequences in patients that require patients, chronic thoracotomy pain with intermittent injec- full function of the diaphragm after surgery [11]. But in tion [64–67], chronic abdominal or pancreatic pain [68–70], another study, intraoperative phrenic nerve infiltration with chest wall trauma, rib fractures [71], and even postoperative 4 Pain Research and Management

Table 1: Advantages and disadvantages of different techniques of management of ISP.

Efficacy in Ipsilateral Technique Advantages Disadvantages Comments Shoulder Pain (ISP) Unwanted side effects Nonsteroidal Simplicity of use Yes [3, 6–8] and contraindications Considered as Anti-Inflammatory Cross-effectivity for Partial effect [5] Limited level of coanalgesia Drugs (NSAIDs) other pain syndromes efficacy Simplicity of use Cross-effectivity for other pain syndromes Limited level of Considered as Acetaminophen Yes [15] May be effective as efficacy coanalgesia preemptive analgesia Well tolerated More effective in ISP Simplicity of use Yes [27, 29, 3 0] in abdominal Cross-effectivity for Considered as Gabapentin No [19, 31] surgeries other pain syndromes coanalgesia May cause dizziness or sedation There is no report(s) Simplicity of use about ISP Cross-effectivity for May cause dizziness, Several reports about other pain syndromes sedation, or other More researches are Systemic ketamine efficacy thoracotomy May be effective in neurologic or cardiac required pain management prevention of chronic side effects [32–37] or against it post thoracotomy [32, 35, 36] pain development Optimal analgesia for Limited or no efficacy Recommended for all incisional pain on ISP thoracotomy patients [38–41] Excellent pain relief Hemodynamic effects More research about At levels higher than Thoracic epidural for incisional pain Invasive method the efficacy of T5 effective on ISP Needing further epidurals higher than [22] assessments T5 in management of Not effective for ISP ISP [5,6,8,15,16] Recommended as a preventive effective Short duration of method in otherwise effect Intraoperative local Significant effect on healthy patients Impossibility to repeat anesthetic infiltration prevention of ISP Need more Concerns about ofthephrenicnerveat Yes [5, 7, 9, 10] Simple and effective assessments of safety hemidiaphragmatic the level of the There are reports at least in special weakness diaphragm about its safety subgroups of patient Needing surgical Needs development of access technique and medication selection To be considered as a possibility to Invasive treatment of ISP in Unwanted effects and Stellate ganglion block Yes[7,16] Possibletorepeat special patient side effects of stellate Needing development ganglion block of technique and medication selection To be considered as a possibility to treatment of ISP in Invasive special patient Interscalene brachial Unwanted effects and including multiple Yes[7,17,18,24] Possibletorepeat plexus block side effects of brachial trauma of shoulder or plexus block arm Needing development of technique and medication selection Pain Research and Management 5

Table 1: Continued. Efficacy in Ipsilateral Technique Advantages Disadvantages Comments Shoulder Pain (ISP) Needing more Invasive assessments of safety Concerning about Direct blockade of the and efficacy Yes (inadvertent) [17] Possible to repeat hemidiaphragmatic phrenic nerve Needing development weakness of technique and medication selection Could be considered as the first option in Some systemic side early postoperative effects of intrapleural Safe and easy phase, when clots, medications Could be repeated as secretions, and No effect on incisional Yes [42–5 0] needed adhesion bonds are Intrapleural block pain or epidural No [11, 51–55] Could be perform via minimal and ISP have analgesia requirement chest tubes the highest severity Sometimes Needing more studies incomplete block for development of technique and medication selection Needing more assessments of safety and efficacy Invasive To be considered as a Unwanted effects and Suprascapular nerve possibility to Yes [10, 12, 17, 56] side effects of block Possible to repeat treatment of ISP in No [13] Less effectiveness in special patient compare with phrenic including multiple nerve block trauma of shoulder or arm

coronary artery bypass graft (CABG) [72–74]. However,none in postoperative CABG patients with concomitant chronic of these applications regards ISP after thoracotomy or VATS. obstructive pulmonary disease (COPD) [74], as previously While diaphragmatic (phrenic nerve) block could be reported in postthoracotomy patients [44, 50, 82]. induced by intrapleural block [57, 75], required doses in Repositioning of the chest tubes should be considered the postthoracotomy setting are potentially large and within when direct irritation of the apical pleura is suspected as a the toxic range. Furthermore, a large irritated pleural space cause for ISP based on chest X-ray assay [11]. after thoracotomy could enhance local anesthetic absorption In a 2002 study, suprascapular nerve block was not [76, 77] and cause systemic toxicity. For example, while the successful in controlling postthoracotomy ISP [13], but other toxicity risk increases with bupivacaine plasma levels above studies did report a beneficial effect in patients with posttho- −1 2–4 𝜇g⋅mL , peak plasma concentrations of bupivacaine in racotomy ISP [56], at least in the subgroup of patient with −1 postthoracotomy patients who received 1.5 mg⋅kg for an localized musculoskeletal tenderness in shoulder [12, 17]. intrapleural block (40 mL of bupivacaine 0.25% in a 70 kg HoweveritseffectinpostthoracotomyISPseemstobeofless −1 magnitude compared to the phrenic nerve block [10]. patient) have been shown to be 1.50 𝜇g⋅mL [44]. However, Both intercostal nerve block [83] and paravertebral block adding epinephrine may potentially lower the plasma con- [84–89] are considered to decrease the postthoracotomy pain. centration of local anesthetics and enhance duration of effect However, they were not effective in prevention of ISP [83] or [43, 78]. In one report, preemptive preoperative intrapleural their efficacy on ISP is not reported. block results in a blunted hemodynamic response to surgery ISP could lead to shoulder dysfunction after thoracotomy and decrease of anesthetic requirements, with significantly and postoperative physiotherapy could improve shoulder lower arterial blood pressure and heart rate, likely secondary function [90], provided that the pain is first under control. to the sympathetic blockade versus concomitant isoflurane Acupuncture in conjunction with other treatments is use [79]. Other side effects of intrapleural block include reported to be helpful for postabdominal laparoscopy shoul- respiratory arrest, which was reported in a narcotized patient der pain [91], but there is no data about such complementary [80] and Horner’s syndrome [81]. Nevertheless, intrapleural treatments for postthoracotomy ISP. analgesia resulted in the improvement of respiratory per- Table 1 is summarizing advantages and disadvantages of formance as well as a decrease in pulmonary complications different techniques of management of ISP. 6 Pain Research and Management

8. Future Directions [7]M.Barak,D.Iaroshevski,E.Poppa,A.Ben-Nun,andY. Katz, “Low-volume interscalene brachial plexus block for post- The paucity of well-organized studies on postthoracotomy thoracotomy shoulder pain,” Journal of Cardiothoracic and ISP, along with the high prevalence, severity of pain, and Vascular Anesthesia,vol.21,no.4,pp.554–557,2007. its suboptimal response to common treatments mandates [8]M.Barak,A.Ziser,andY.Katz,“Thoracicepidurallocal further well designed trial studies that compare potentially anesthetics are ineffective in alleviating post-thoracotomy ipsi- effective and safe treatments. Different sources for pain after lateral shoulder pain,” Journal of Cardiothoracic and Vascular thoracotomy require the application of different modalities Anesthesia, vol. 18, no. 4, pp. 458–460, 2004. of pain management, simultaneously. 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Clinical Study Effect of Intravenous High Dose Vitamin C on Postoperative Pain and Morphine Use after Laparoscopic Colectomy: A Randomized Controlled Trial

Younghoon Jeon,1 Jun Seok Park,2 Suyoung Moon,3 and Jinseok Yeo4

1 Department of Anesthesiology and Pain Medicine, School of Dentistry, Kyungpook National University, Daegu, Republic of Korea 2Colorectal Cancer Center, Kyungpook National University Medical Center, School of Medicine, Kyungpook National University, Daegu, Republic of Korea 3Department of Anesthesiology and Pain Medicine, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, Republic of Korea 4Department of Anesthesiology and Pain Medicine, Kyungpook National University Medical Center, School of Medicine, Kyungpook National University, Daegu, Republic of Korea

Correspondence should be addressed to Jinseok Yeo; [email protected]

Received 29 August 2016; Accepted 10 October 2016

Academic Editor: Bulent¨ S. Yurtlu

Copyright © 2016 Younghoon Jeon et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background and Objective. Vitamin C has antioxidant, neuroprotective, and neuromodulating effects. Recently, it showed antinociceptive effect as a result of the antioxidant properties. Therefore, we designed this study to assess the effect of intravenous vitamin C on opiate consumption and pain in patients undergoing laparoscopic colectomy. Methods.Atotalof100patientswere enrolled and allocated to receive 50 mg/kg vitamin C or placebo by intravenous infusion immediately after induction of anesthesia. Morphine consumption and scores of pain were assessed at 2, 6, and 24 h after completion of surgery. Results. There were 97 patients included in the analysis. Patients who received vitamin C had higher plasma concentrations of vitamin C at the end of surgery, significantly lower morphine consumption at the 2 h after end of surgery, and significantly lower pain scores at rest during first 24 h postoperatively. There was no significant difference between groups in side effects, fatigue score, or pain score during cough. Conclusion. This study shows high dose vitamin C infusion decreased postoperative pain during the first 24 h and reduced morphine consumption in the early postoperative period. Additional research needed to examine whether higher doses of vitamin C and longer infusion times can amplify these effects.

1. Introduction postoperative pain management, can increase the risk of postoperative nausea and vomiting (PONV) and can delay The importance of providing adequate pain control during postsurgical recovery of gastrointestinal mobility. Recently, recoveryfromsurgerycannotbeoveremphasized[1].Laparo- nonopioid analgesic alternatives have been introduced with scopic surgical approaches might reduce postoperative pain the aim of improving pain management and limiting opioid- associated with colorectal surgery [2], but postoperative related side effects [4]. Vitamin C (ascorbic acid) is a water- pain management remains a complex challenge. Inadequate soluble vitamin that has antioxidant, neuroprotective, and postoperative analgesia can lead to adverse events such as neuromodulating effects [5, 6]. Recent studies have shown pneumonia, myocardial infarction, insomnia, and depres- that vitamin C supplementation might be a useful adjunct sion, thereby increasing morbidity and mortality and dimin- to pain management without significant side effects [7–9]. ishing quality of life and patient satisfaction [3]. Opioids, Therefore, we designed a randomized placebo-controlled trial which are still the most widely used class of analgesics in to examine the effect of high dose vitamin C (50 mg/kg) on 2 Pain Research and Management postoperative opiate consumption and pain scores in colon initiated for all patients upon arrival in the postanesthesia cancer patients during the first 24 h after laparoscopic colec- careunit(PACU).ThePCAconsistedofbolusdosesof1mg tomy. Postoperative fatigue and side effects were analyzed as morphine with a lockout time of 5 min and no basal infusion. secondary outcomes. Patients were instructed to push the PCA button any time they experienced pain. Rescue analgesia (50 mg tramadol 2. Patients and Methods injection) was given when the pain intensity exceeded VAS 4for≥30 min. 2.1. Patients. This study received approval from the ethics A research assistant who was blinded to the study group committeeofKyungpookNationalUniversityMedicalCen- assignments checked patients for pain, fatigue, PONV, mor- ter (ref: KNUMC 13-1048) and was registered with CRiS phine consumption, and rescue analgesic requirement every (Clinical Research Information Service, http://cris.nih.go.kr/, 10 min during their stay in the PACU and again at 2, 6, and ref: KCT0000984, 2013.10.18). This randomized, double-blind 24 h after discharge from the PACU to the ward. study was conducted between November 2013 and October 2014.Weenrolledcoloncancerpatientsaged20to75years 2.3. Sample Size Calculation. We estimated a sample size on who were scheduled for elective laparoscopic colectomy thebasisofapilotstudythatpredicteda24hmorphine under general anesthesia. We excluded patients who had a requirement of 39.3 ± 20.5 mg for patients undergoing history of allergy to systemic opioids, substance use disorder, laparoscopic colectomy. We believed that a 30% reduction coagulopathy, chronic opioid use, sleep apnea, and analgesic in morphine consumption after administration of vitamin use within 24 h. A member of the research team contacted the C would be clinically relevant, and we determined that a patients, explained the study protocol, and obtained informed minimum sample size of 48 patients per group would be consent for participation in the study. The day before surgery, necessary for 80% power to detect a 30% difference between all patients were taught how to use the patient-controlled the treatment group and the control group. A total of 50 analgesia (PCA) system (AIM plus; Hospira, Lake Forest, IL, patients per group were required to account for dropouts. USA) and how to rate pain intensity on the numeric rating scale (NRS), with 0 indicating no pain and 10 representing 2.4. Statistical Analysis. Statistical analysis was performed the worst pain imaginable (Table 1). using SPSS software version 21.0 (IBM Corporation, Armonk, NY). Continuous data were reported as mean ± standard 2.2. Protocol. Patients were randomly allocated to two groups deviation and analyzed using Student’s 𝑡-test for comparisons using a computer-generated randomization table. Group allo- between groups. Categorical data were reported as numbers cation was concealed in sealed opaque envelopes. Baseline and percentages and were analyzed using Chi square test. The fatigue was assessed by NRS before induction of anesthesia. differences in fatigue scores were compared using analysis General anesthesia was administered according to a standard of covariance (ANCOVA), which included baseline fatigue protocol and monitored according to American Society score as a covariate to account for individual variations in the of Anesthesiologists guidelines. Blood samples (5 mL) for level of fatigue. All reported 𝑃 values are two-sided and the measurement of plasma vitamin C levels were taken from level of significance was set at 𝑃 < 0.05. all patients before induction of anesthesia and prior to discharge from the operating room. Propofol (1 to 2 mg/kg) 3. Results was administered for induction of anesthesia and rocuro- nium (0.4 mg/kg) was administered to facilitate intubation. We assessed 118 patients for eligibility. After excluding 18 Immediately after induction of anesthesia, a nurse who played patients, 12 who did not meet inclusion criteria (2 with allergy no other role in the study selected an envelope for each to morphine, 4 with a history of chronic opioid use, and 6 patient and prepared an injection according to the group who were taking nonsteroidal anti-inflammatory drugs for allocation. Patients in the vitamin C group received vitamin osteoarthritis and spinal stenosis) and 6 who did not want to C 50 mg/kg (ascorbic acid 10 g/20 mL, Daewon, Korea) mixed enter the study, 100 patients who were scheduled to undergo with normal saline for a total injection volume of 50 mL, and elective laparoscopic colectomy were included. Three of these those in the placebo group received normal saline 50 mL. The were excluded from the final analysis due to complications syringes were covered with black plastic and the solution was (anastomotic leak and additional ileostomy). All operations infused over 30 min using an infusion pump. Anesthesia was were performed by a single surgeon (Figure 1). maintained using 4 to 8% desflurane in a mixture of 50% Data from a total of 97 patients were analyzed. There oxygen in air and remifentanil infusion. Additional doses of were no significant differences between groups in baseline rocuronium were administered to maintain adequate muscle patient characteristics, duration of surgery and anesthesia, relaxation, and all patients received intravenous lactated intraoperative blood loss, and intraoperative fluid require- Ringer’s solution at rate 5 to 10 mL/kg/h during surgery. ment. Postoperative pain scores at rest at 2, 6, and 24 h were All patients received ramosetron 0.3 mg intravenously to significantly lower in the vitamin C group, but postoperative prevent postoperative nausea and vomiting (PONV). All pain scores while coughing were not significantly different, surgeries were performed using a 4-port technique with a and there was no difference between groups in postopera- minilaparotomy incision below the umbilicus at the camera tive fatigue scores. Morphine use during the first 2 h was port [10]. After the completion of surgery, the neuromuscular significantly lower in the vitamin C group, but there was no blockade was reversed with sugammadex 2 mg/kg. PCA was significant difference between the two groups at 6 and 24h. Pain Research and Management 3

Table 1: Patient characteristics and perioperative data.

Placebo Vitamin C Group 𝑃 value (𝑛=48)(𝑛=49) Age (y) 64.5 ± 10.6 65.4 ± 9.6 0.65 Sex (male/female) 29/21 28/22 0.84 Height (cm) 160.7 ± 8.8 160.2 ± 8.2 0.74 Weight (kg) 61.0 ± 9.4 61.8 ± 10.0 0.67 ASA PS (I/II) 16/34 15/35 0.83 Duration of surgery (min) 160.7 ± 46.0 160.2 ± 39.3 0.90 Duration of anesthesia (min) 186.5 ± 41.6 196.9 ± 39.0 0.20 Fluid (mL) 1324.0 ± 344.9 1363.3 ± 356.9 0.58 Estimated blood loss (mL) 212.8 ± 154.8 288.0 ± 223.9 0.62 Data are shown as mean ± standard deviation. ASA, American Society of Anesthesiologists Physical Status.

Assessed for eligibility (n = 118)

Excluded (n=18) (i) Not meeting inclusion criteria (n = 12) (ii) Refused (n=6)

Randomization (n = 100)

Placebo group (n=50) Vitamin C group (n=50) received saline 50 mL for 30 min received vitamin C 50 mg/kg immediately after immediately after induction of anesthesia induction of anesthesia

Check NRS of pain and fatigue and morphine consumption at 2, 6, and 24 h after end of anesthesia

Analyzed (n=48) Analyzed (n=49) Excluded from analysis (n=2) Excluded from analysis (n=1)

Figure 1: Flow chart describing recruitment, allocation, follow-up, and analysis. NRS, numeric rating scale.

The baseline vitamin C concentration was slightly higher in and postoperative morphine consumption during the first theplacebogroup,butthedifferencewasnotsignificant, 2 h after laparoscopic colectomy. There was no difference in while the vitamin C concentration at the completion of sur- cumulative morphine consumption between treatment and gery was significantly higher in the vitamin C group. Rescue control groups at 6 h and 24 h. High dose vitamin C infusion analgesics were required more frequently in the placebo also decreased the frequency of demand for rescue analgesics. group, and the difference was significant compared to the The NRS pain scores during coughing and the NRS fatigue treatment group (𝑃 = 0.00). The incidence of PONV and the scores were comparable between the two groups at all time length of hospital stay were similar between the two groups, intervals (Figure 3). and all patients were discharged home without significant Vitamin C is an essential micronutrient that serves as a complications within one to two days of resuming normal cofactor in a number of enzymatic and chemical pathways diets (Figure 2). [11]. The exact mechanism of the analgesic effect of vitamin C is not well understood, and several of the functions of vitamin 4. Discussion C may contribute. As an antioxidant, vitamin C inhibits the formation of reactive oxygen and nitrogen species. Reactive Intravenous supplementation with 50 mg/kg vitamin C oxygen species (ROS) are a known factor in neuropathic pain, decreased postoperative pain at rest during the first 24 h and ROS scavengers can ameliorate mechanical discomfort 4 Pain Research and Management

Pain while coughing Pain at rest 10 10

8 8

∗ 6 6 ∗ ∗

4 4

2 2

0 0 2 624 2 624 (Hour) (Hour)

Placebo Placebo Vitamin C Vitamin C (a) (b)

Figure 2: Pain scores at rest (a) and during coughing (b) by numeric rating scale at 2, 6, and 24 h after surgery (mean ± standard deviation). ∗ 𝑃 < 0.05.

Postoperative morphine consumption 60 10 Fatigue

50 8 40 6 30

(mg) 4 20 ∗ 10 2 0 0 2 624 Baseline 2 6 24 (Hour) (Hour)

Placebo Placebo Vitamin C Vitamin C (a) (b)

Figure 3: Postoperative morphine consumption (a) at 2, 6, and 24 h after surgery and numeric rating scores of fatigue (b) before surgery and ∗ at 2, 6, and 24 h after surgery. Data are shown as means ± standard deviation. 𝑃 < 0.05.

[12]. A combination of antioxidants reduced levels of ROS known to be the main components of the inhibitory pain and normalized tail flick latency in a mechanically induced pathway [19]. animal pain model [13]. Aplasmaascorbateconcentrationof<20 𝜇mol/L is Vitamin C also has a neuromodulating function [14], spe- accepted as a reliable indicator of an inadequate vitamin C cifically of dopamine- and glutamate-mediated neurotrans- reserve [11]. Vitamin C deficiency is commonly found in mission [15]. Inhibition of the NMDA receptor by vitamin C cancer patients [20], and patients who are scheduled for colon decreasespaininchemicallyinducedpainmodels[16].Vita- surgery generally need to be fasting for at least 24 h prior min C is a key cofactor of dopamine b-monooxygenase and it tosurgerytoensureadequatebowelpreparation;itisnot is essential for norepinephrine biosynthesis. The conversion surprising that the baseline plasma vitamin C concentration of dopamine to norepinephrine by dopamine b-monooxy- was <20 𝜇mol/L in both of our study groups. Laparoscopic genase is maximally efficient only in environments replete colectomy generates oxidative stress and ROS-related injury with extracellular ascorbic acid [17]. Finally, vitamin C is has been attributed to abdominal inflation/deflation and use required for the release of noradrenaline and acetylcholine of carbon dioxide for the creation of pneumoperitoneum [21]. from synaptic vesicles [18]. These neurotransmitters are Response to surgical trauma, manipulation of the bowel, and Pain Research and Management 5

Table 2: Plasma vitamin C concentrations (𝜇mol/L) and frequency scores at rest during the first 24 h after surgery. Further of postoperative rescue analgesics. research is warranted to examine whether higher doses and longer infusion times would amplify this effect. Placebo Vitamin C Group 𝑃 value (𝑛=48) (𝑛=49) Competing Interests Vitamin C concentration Before surgery 15.0 ± 4.8 13.8 ± 4.6 0.55 All the authors do not have any conflict of interests. End of surgery 12.1 ± 4.4 16.0 ± 3.7 0.03 Frequency of rescue Authors’ Contributions 1.4 ± 1.0 0.8 ± 0.8 0.00 analgesia Data are shown as mean ± standard deviation. Younghoon Jeon and Jinseok Yeo participated in the con- ception and design of the study. Suyoung Moon collected, analyzed, and interpreted the data. Jun Seok Park, Younghoon exposureoftheboweltoroomairarealsoassociatedwith Jeon, and Jinseok Yeo wrote and critically revised the man- ROS generation [22]. 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[13] R. Rokyta, V. Holecek, I. Pekarkov´ a´ et al., “Free radicals after painful stimulation are influenced by antioxidants and anal- gesics,” Neuroendocrinology Letters,vol.24,no.5,pp.304–309, 2003. [14] G. V. Rebec and R. C. Pierce, “A vitamin as neuromodulator: ascorbate release into the extracellular fluid of the brain regu- lates dopaminergic and glutamatergic transmission,” Progress in Neurobiology,vol.43,no.6,pp.537–565,1994. [15]R.A.Grunewald,¨ “Ascorbic acid in the brain,” Brain Research Reviews,vol.18,no.1,pp.123–133,1993. [16]K.A.Rosa,V.M.Gadotti,A.O.Rosa,A.L.S.Rodrigues,J.B. Calixto,andA.R.S.Santos,“Evidencefortheinvolvementof glutamatergic system in the antinociceptive effect of ascorbic acid,” Neuroscience Letters, vol. 381, no. 1-2, pp. 185–188, 2005. [17]F.E.Harrison,S.S.Yu,K.L.VanDenBossche,L.Li,J. M. May, and M. P. McDonald, “Elevated oxidative stress and sensorimotor deficits but normal cognition in mice that cannot synthesize ascorbic acid,” Journal of Neurochemistry,vol.106, no. 3, pp. 1198–1208, 2008. [18] M. E. Rice, “Ascorbate regulation and its neuroprotective role in the brain,” Trends in Neurosciences,vol.23,no.5,pp.209–216, 2000. [19] W. D. Willis and K. N. Westlund, “Neuroanatomy of the pain system and of the pathways that modulate pain,” Journal of Clinical Neurophysiology,vol.14,no.1,pp.2–31,1997. [20] C. R. Mayland, M. I. Bennett, and K. Allan, “Vitamin C defi- ciency in cancer patients,” Palliative Medicine,vol.19,no.1,pp. 17–20, 2005. [21] M. Sare, I. Yilmaz, D. Hamamci, M. Birincioglu, M. Ozmen,¨ and O.¨ Yesilada, “The effect of carbon dioxide pneumoperitoneum on free radicals,” Surgical Endoscopy,vol.14,no.7,pp.649–652, 2000. [22] G. Pappas-Gogos, C. Tellis, K. Lasithiotakis et al., “Oxidative stress markers in laparoscopic versus open colectomy for can- cer: a double-blind randomized study,” Surgical Endoscopy and Other Interventional Techniques, vol. 27, no. 7, pp. 2357–2365, 2013. [23] R. Fukushima and E. Yamazaki, “Vitamin C requirement in surgical patients,” Current Opinion in Clinical Nutrition & Metabolic Care, vol. 13, no. 6, pp. 669–676, 2010. [24] T. K. Nielsen, M. Højgaard, J. T. Andersen, H. E. Poulsen, J. Lykkesfeldt, and K. J. Mikines, “Elimination of ascorbic acid after high-dose infusion in prostate cancer patients: a pharma- cokinetic evaluation,” Basic and Clinical Pharmacology and Toxicology,vol.116,no.4,pp.343–348,2003. [25] S.-Y. Suh, W. Bae, H.-Y. Ahn, S.-E. Choi, G.-C. Jung, and C. Yeom, “Intravenous vitamin C administration reduces fatigue in office workers: a double-blind randomized controlled trial,” Nutrition Journal,vol.11,no.1,article7,2012. Hindawi Publishing Corporation Pain Research and Management Volume 2016, Article ID 7868152, 8 pages http://dx.doi.org/10.1155/2016/7868152

Clinical Study A Comparison of Oxycodone and Alfentanil in Intravenous Patient-Controlled Analgesia with a Time-Scheduled Decremental Infusion after Laparoscopic Cholecystectomy

Young Suk Kwon,1 Ji Su Jang,1 Na Rea Lee,1 Seong Su Kim,2 Young Ki Kim,2 Byeong Mun Hwang,3 Seong Sik Kang,3 Hee Jeong Son,3 and So Young Lim1

1 Department of Anesthesiology and Pain Medicine, College of Medicine, Hallym University, Chuncheon Sacred Heart Hospital, Chuncheon, Republic of Korea 2Department of Anesthesiology and Pain Medicine, College of Medicine, University of Ulsan, Gangneung Asan Hospital, Gangneung, Republic of Korea 3Department of Anesthesiology and Pain Medicine, College of Medicine, Kangwon National University, Kangwon National University Hospital, Chuncheon, Republic of Korea

Correspondence should be addressed to So Young Lim; [email protected]

Received 13 July 2016; Accepted 23 August 2016

Academic Editor: Volkan Hancı

Copyright © 2016 Young Suk Kwon et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background. Oxycodone, a semisynthetic opioid, has been widely used for acute and chronic pain. Objectives.Theaimofthis study was to compare the analgesic and adverse effects of oxycodone and alfentanil on postoperative pain after laparoscopic cholecystectomy. Methods. This was a prospective, randomized, double-blind study. A total of 82 patients undergoing laparoscopic cholecystectomy were randomly assigned to receive either oxycodone or alfentanil using intravenous patient-controlled analgesia (PCA). PCA was administered as a time-scheduled decremental continuous infusion based on lean body mass for 48 hours postoperatively. Patients were assessed for pain with a visual analogue scale (VAS), the cumulative PCA dose, adverse effects, sedationlevelat1,4,8,16,24,and48hourspostoperatively,andsatisfactionduringthepostoperative48hours.Results.There were no significant differences (𝑝 < 0.05) between the two groups in VAS score, cumulative PCA dose, adverse effects, sedation level at 1, 4, 8, 16, 24, and 48 hours postoperatively, and satisfaction during the postoperative 48 hours. Conclusions.Ourdatashowed that the analgesic and adverse effects of oxycodone and alfentanil were similar. Therefore, oxycodone may be a good alternative to alfentanil for pain management using intravenous PCA after laparoscopic cholecystectomy when used at a conversion ratio of 10 :1. This trial is registered with KCT0001962.

1. Introduction pain control and typically involves the administration of an analgesic agent, most commonly an opioid, using a Laparoscopic cholecystectomy (LC) is often accompanied by programmed infusion pump [3]. severe postoperative pain, although it has the advantages Oxycodone, a semisynthetic opioid synthesized from the- of fast recovery and short hospital stay [1]. Postoperative baine, is used to manage moderate to moderately severe acute pain management is a critical component of patient care or chronic pain. It is a potent 𝜇-agonist, with a potency com- and is associated with patient satisfaction. The major goal of parable to that of morphine [4]. Many studies have demon- postoperative pain management is to minimize the dose of strated good efficacy of oxycodone against postoperative medications to decrease the side effects, while still providing pain [5, 6], and some studies have suggested that oxycodone adequate analgesia [2]. Patient-controlled analgesia (PCA) attenuates visceral pain better than other opioids [5, 7, 8]. is among the most popular methods used for postoperative Recently, several studies have compared oxycodone and 2 Pain Research and Management fentanyl in PCA after laparoscopic cholecystectomy [9–11]. Patients were randomized to either Group A (alfen- Although oxycodone has demonstrated better or similar tanil) or Group O (oxycodone) by a simple randomiza- analgesic effects compared with fentanyl, those studies have tion method using Excel (Microsoft Corp., Seoul, Korea). shown that a fixed-rate background infusion of oxycodone is Group A received IV PCA with 10 mg of alfentanil (Alfe- associated with a high incidence of adverse effects. nil5 2.5 mg/5 mL, Daewon Pharm, Seoul, Korea), 0.6 mg of Alfentanil has a rapid onset of action and appropriate ramosetron (Nasea5 0.3 mg/2 mL, Astellas Pharma, Tokyo, pharmacokinetic properties in continuous infusion [12], and Japan), and 76 mL of normal saline. Group O received IV it has a lower incidence of nausea and vomiting than fentanyl PCA with 100 mg of oxycodone (OxyNorm5 10 mg/1 mL, or sufentanil [13]. For this reason, alfentanil may be a good Mundipharma, Limburg an der Lahn, Germany), 0.6 mg of analgesic in background infusions of PCA. Many clinical ramosetron, and 86 mL of normal saline. The rate of PCA, studies of PCA have shown that alfentanil with its ease of loading dose, and demand dose were calculated based on the rapid titration does not cause pulmonary depression/cardiac lean body mass (LBM), which was calculated using Hume’s stress while providing satisfactory analgesia [14]. formula [19]. Intravenous (IV) PCA has not always provided reliable ( ) = {0.32810 × ( )} and adequate analgesia. The analgesic concentration in the Men: LBM kg weight kg body might be insufficient for the severity of the early postop- + {0.33929 × height (cm)} erative pain during fixed-rate infusion of the recommended regimen [15]. Fixed higher rates might increase the risk of − 29.5336 side effects, such as ventilatory depression. Therefore, we (1) used a time-scheduled decremental continuous infusion to Women: LBM (kg) = {0.29569 × weight (kg)} reduce the adverse effects while maintaining analgesic effects by changing the PCA dose over time [16]. + {0.41813 × height (cm)} Various studies have compared the effects of oxycodone, − 43.2933. morphine, and fentanyl on postoperative pain. However, no studies have compared the effects of oxycodone and alfentanil Loading doses, demand doses, and background infusion rates on postoperative pain, and there is no published study of the were as follows: efficacy and side effects of oxycodone and alfentanil. In this randomized, prospective, double-blind study, Loading dose (mL) = LBM (kg) × 0.05 mL we compared the analgesic and side effects of oxycodone (2) ( ) = ( ) × 0.02 . and alfentanil on postoperative pain in patients who were Demand (bolus) dose mL LBM kg mL given IV PCA in a time-scheduled decremental mode after laparoscopic cholecystectomy. Background infusion rate (BIR) is described as follows: First 8-hours BIR after operation (mL/h) 2. Methods = LBM (kg) × 0.02 mL/h 2.1. Study Design. This prospective, randomized, double- blind study was conducted between August 2014 and Septem- 8∼24-hours BIR after operation (mL/h) (3) ber 2015. The study protocol was approved by our Institu- = ( ) × 0.01 / tional Review Board (IRB) and all patients provided informed LBM kg mL h consent before surgery. 24 ∼ 48-hours BIR after operation (mL/h)

2.2. Subject. We enrolled 90 patients who underwent laparo- = LBM (kg) × 0.005 mL/h. scopic cholecystectomy and belonged to the American Soci- ety of Anesthesiologists (ASA) physical status class I or Doses have been rounded to the second decimal place. The time-scheduled decremental infusion mode was performed II. Both men and women aged 18–70 years were included. 5 Exclusion criteria were patients who had used preoperative using a PCA device (Accumate 1100 ,WooYoungMedical, acetaminophen or nonsteroidal anti-inflammatory drugs or Jincheon, Korea) automatically. The patients provided informed consent on the day opioids, patients who could not describe their pain using the beforetheoperationandwereinstructedontheuseof visual analogue scale (VAS), patients who had abnormal liver PCA. Anesthesia was performed in the same manner in and kidney function, and pregnant patients. both groups and all patients received 0.2 mg of intramuscular (IM) glycopyrrolate 30 minutes preoperatively. After entering 2.3. Methods. We referred to references on the conversion the operating room, patients were monitored using standard of oxycodone to morphine that suggest a potency ratio of monitoring devices. Anesthesia was induced with 2 mg/kg 1 : 1 because there were no recommendations concerning the of propofol and 0.6 mg/kg of rocuronium and maintained direct conversion factor of IV oxycodone and IV alfentanil with desflurane and2 N O. Then, 0.3 mg of ramosetron was dosages [17, 18]. Alfentanil is approximately ten times more injected intravenously and a loading dose of PCA was potent than morphine [12]. Therefore, we decided on an administered 15 minutes before the end of the operation. alfentanil-to-oxycodone ratio of 1 : 10. Immediately after the loading doses, the background infusion Pain Research and Management 3

Enrollment

Assessed for eligibility (n=90)

Refusal of participating in the study (n=4)

Randomized (n=86)

Allocation

Alfentanil group (n=43) Oxycodone group (n=43)

Conversion to open Conversion to open n=2 surgery ( ) surgery (n=1) Incorrect operation of PCA device (n=1)

Analyzed (n=41) Analyzed (n=41)

Figure 1: CONSORT flowchart. was started. Neuromuscular blockade was reversed with nausea, vomiting, and other adverse effects was performed 0.4 mg of glycopyrrolate and 10 mg of pyridostigmine. After using the chi-square test and Fisher’s exact test. The cumu- surgery, patients were extubated, provided their vital signs lativePCAdoseandthesedationscalewereassessedusing were within normal limits, and were transferred to the the Mann-Whitney 𝑈 test, while the VAS was assessed postanesthesia care unit. by repeated-measures analysis of variance (ANOVA). The satisfaction score of the two groups was assessed via the chi- 2.4. Assessment. Pain level, cumulative doses, sedation scale, square test. A probability of <0.05 was considered to indicate and adverse effects were measured at 1, 4, 8, 16, 24, and statistical significance. All data were analyzed using SPSS ver. 48 hours postoperatively. The severity of the patients’ pain 22 (SPSS, Chicago, IL, USA). was evaluated using the visual analogue scale (VAS), with Based on previous similar studies, the sample size was scores ranging from 0 (no pain) to 10 (worst pain possible). 41 patients per group. The cumulative PCA dose difference The VAS was evaluated when coughing and resting. Sedation between the two groups was 5 mL and the standard deviation was scored using the Inova Sedation Scale (ISS): 1, alert; 2, 𝛼 = 0.05 occasionally drowsy, easy to rouse; 3, dozing intermittently; was 8.0 with power of 80% and . Therefore, we 4, asleep, easy to wake; 5, difficult to wake; 6, unresponsive enrolled 90 subjects into our study considering 10% as the [20]. exclusion rate. Any nausea, vomiting, dizziness, headache, respiratory depression, pruritus, or difficulty voiding was recorded as 3. Results an adverse effect. The patient’s satisfaction with PCA during the 48 hours postoperatively was assessed according to the 90 patients were assessed for eligibility. Four patients declined followingscale:1,verysatisfactory;2,satisfactory;3,neutral; to participate in the study, and 86 patients were randomized 4, unsatisfactory; 5, very unsatisfactory. to treatment with alfentanil (𝑛=43)oroxycodone(𝑛= 43). Two patients in Group A and one patient in Group 2.5. Statistical Analysis. Data are expressed as the mean ± O were excluded because they ultimately underwent open standard deviation (SD). The demographic data of the two laparotomy. One patient in Group O was excluded due to groups were analyzed with Student’s 𝑡-test and chi-square incorrect operation of the PCA device. In total, 41 patients test. Comparison analysis of the incidence of postoperative were left for analysis in each group (Figure 1). There were no 4 Pain Research and Management

Table 1: Demographic characteristics of patients.

Characteristics Alfentanil group (𝑁=41)Oxycodonegroup(𝑁=41) 𝑝 value Age (years) 46.2 ± 12.8 46.4 ± 13.8 0.588 ∗ Sex (male/female, 𝑁 (%)) 16 (39)/25 (61) 14 (34.1)/27 (65.9) 0.647 Height (cm) 163.0 ± 7. 8 1 62 . 4 ± 9.0 0.411 Weight (kg) 67.8 ± 11.9 67.9 ± 12.7 0.677 LBM (kg) 48.5 ± 7.2 48.1 ± 8.1 0.372 OP time (minutes) 44.6 ± 19.2 42.8 ± 16.7 0.174 LBM: lean body mass; OP: operation. ∗ All data are expressed as mean ± standard deviation or number (percentage). The data were analyzed using Student’s 𝑡-test and chi-square test. There were no significant differences between two groups𝑝 ( value < 0.05).

Table 2: Incidence rate of postoperative nausea and vomiting.

Alfentanil group (𝑁=41)Oxycodonegroup(𝑁=41) Time after operation 𝑝 value (N/V) Nausea Vomiting Nausea Vomiting ∗ <8 h 14 (34.1%) 2 (4.9%) 8 (19.5%) 0 (0%) 0.135/0.494 ∗ <1 h 8 (19.5%) 1 (2.4%) 7 (17.1%) 0 (0%) 0.775/1.000 1∼4 h 5 (12.2%) 1 (2.4%) 2 (4.9%) 0 (0%) 0.432/1.000 4∼8 h 5 (12.2%) 0 (0%) 3 (7.3%) 0 (0%) 0.712/— 8∼24 h 2 (4.9%) 1 (2.4%) 5 (12.2%) 0 (0%) 0.432/1.000 8∼16 h 2 (4.9%) 1 (2.4%) 3 (7.3%) 0 (0%) 1.000/1.000 16∼24 h 0 (0%) 0 (0%) 3 (7.3%) 0 (0%) 0.241/— 24∼48 h 0 (0%) 0 (0%) 1 (2.4%) 0 (0%) 0.494/— N: nausea; V: vomiting. ∗ Values are expressed as number of patients (percentage). The data were analyzed using Fisher’s exact test and chi-square test. There were no significant differences between two groups𝑝 ( value < 0.05).

10 10 9 9 8 8 p = 0.444 p = 0.664 7 7 6 6 5 5 VAS VAS 4 4 3 3 2 2 1 1 0 0 148162448 148162448 Time (h) Time (h)

Alfentanil Alfentanil Oxycodone Oxycodone

Figure 2: Visual analogue scale of pain during coughing between Figure 3: Visual analogue scale of pain at resting between 1 and 1 and 48 h after the operation. Means and standard deviation are 48 h after the operation. Means and standard deviation are shown. shown. 𝑝 values were calculated by repeated-measures analysis of 𝑝 values were calculated by repeated-measures analysis of variance. variance. There were no significant differences between two groups There were no significant differences between two𝑝 groups( value (𝑝 value < 0.05). VAS: visual analogue scale. < 0.05). VAS: visual analogue scale. significant differences between the two groups with regard to age, sex, height, weight, LBM, or operation time (Table 1). The incidence of postoperative nausea and vomiting in There was no significant difference in the VAS when Group O was not significantly different from Group Aat resting or coughing between the two groups at 1, 4, 8, 16, 24, 1, 4, 8, 16, 24, and 48 h postoperatively (Table 2). Regard- and 48 h postoperatively (Figures 2 and 3). ing adverse effects such as headache, dizziness, respiratory Pain Research and Management 5

Table 3: Incidence rate of postoperative adverse effects.

Incidence of adverse effects Alfentanil group𝑁=41 ( )Oxycodonegroup(𝑁=41) 𝑝 value ∗ Dizziness 6 (14.6%) 13 (31.7%) 0.067 Headache 1 (2.4%) 2 (4.9%) 1.000 Respiratory depression 1 (2.4%) 1 (2.4%) 1.000 Pruritus 0 (0%) 1 (2.4%) 1.000 Urinary retention 1 (2.4%) 1 (2.4%) 1.000 ∗ Values are expressed as number of patients (percentage). The data were analyzed using Fisher’s exact test and chi-square test. There were no significant differences between two groups𝑝 ( value < 0.05).

Table 4: Satisfaction of patients at the postoperative 48 hours. 100 90 Alfentanil group Oxycodone group Satisfaction 80 (𝑁=41) (𝑁=41) p = 0.371 70 Very satisfied 14 (34.1%) 17 (41.5%) p = 0.274 60 Satisfied 17 (41.5%) 15 (36.6%) p = 0.262 50 Neutral 8 (19.5%) 6 (14.6%) 40 p = 0.297 Dissatisfied 2 (4.9%) 3 (7.3%) 30 p = 0.361 Very dissatisfied 0 (0%) 0 (0%) 20

Cumulative PCA dose (mL) Cumulative p = 0.767 Values are expressed as number of patients (percentage). The data were 10 analyzed using chi-square test (𝑝 value = 0.710). 0 1 4 8 16 24 48 4 Time (h)

Alfentanil Oxycodone 3 p = 0.491 Figure 5: Cumulative patient-controlled analgesia dose measured p = 0.513 between 1 and 48 h after the operation. Means and standard 2 deviation are shown. 𝑝 values were calculated by Mann-Whitney 𝑈 ISS p = 0.482 𝑝 p = 0.239 p = 0.980 test. There were no significant differences between two groups ( p = 1.000 value < 0.05). PCA: patient-controlled analgesia. 1 4. Discussion 0 148162448 Oxycodone was first synthesized from thebaine in 1916, and Time (h) it is now one of the most widely used opioids for pain management[21–23].Oxycodoneisaspotentasmorphine Alfentanil but has superior analgesic effects over both morphine and Oxycodone placebos regarding mechanical and thermal noxious stimuli Figure 4: Inova Sedation Scale of patients between 1 and 48 h after of the esophagus [5–7]. Therefore, oxycodone may be more the operation. Means and standard deviation are shown. 𝑝 values effective than other opioids at equianalgesic dosages after were calculated by Mann-Whitney 𝑈 test. There were no significant surgeryinwhichthevisceralpaincomponentisalarge differences between two groups𝑝 ( value < 0.05). ISS: Inova Sedation contributor to a patient’s overall postoperative pain [7, 24]. Scale. Oxycodone had similar and sometimes better effects in post- operative analgesia compared to fentanyl [11]. Koch et al. [6] compared the effects of intravenous oxycodone and fentanyl depression, voiding difficulty, and pruritus, there were no dif- onpostoperativevisceralpainafteroutpatientlaparoscopic ferences between Group A and Group O at 1, 4, 8, 16, 24, and cholecystectomy and found that oxycodone provided better 48 h postoperatively (Table 3). Sedation grade was expressed analgesia but also had more side effects. using the ISS, and there were no differences between the two Alfentanil hydrochloride, a derivative of fentanyl, is a groups at 1, 4, 8, 16, 24, and 48 h postoperatively (Figure 4). potent analgesic characterized by a quick onset time, short In addition, there was no difference in satisfaction during the duration of action, low toxicity, and short elimination time 48 h postoperatively between the two groups (Table 4). [25, 26]. The advantage of alfentanil over other opioids The cumulative PCA dose of the 2 groups was not istheshortrecoverytimeanditsuseforPCAhasbeen significantly different at 1, 4, 8, 16, 24, and 48 h postoperatively described for postoperative analgesia [27]. With respect to (Figure 5). rapid recovery, alfentanil is superior to fentanyl [28], but 6 Pain Research and Management the speed of recovery is associated with a reduction in the Nausea and vomiting are common postoperative adverse postoperative duration of analgesia. Therefore, a concurrent effects in PCA. Opioids stimulate the chemoreceptor trigger infusion of alfentanil may be necessary for optimum analgesia zone in the medulla to cause nausea and vomiting, which because postoperative pain is generally more constant and of decrease overall patient satisfaction. Also, nausea and vomit- longer duration. ing may worsen the severity of incisional pain. Many patients Considering the lack of guidelines for the direct con- have reported that postoperative vomiting is more unpleasant version dose ratio of intravenous oxycodone to intravenous than postoperative pain [34]. Several studies that used a alfentanil, this study reviewed previous research in order to routine fixed background infusion of oxycodone found a identify the used ratios. Parenteral oxycodone appears to be notably higher incidence of nausea, which did not decrease equipotent to morphine [17]. The potency of alfentanil is significantly over time [10, 11], while alfentanil caused less approximately 10 times that of morphine [12]. On that basis, postoperative nausea and vomiting (PONV) than equipotent we calculated a workable alfentanil-to-oxycodone ratio of doses of fentanyl or sufentanil in outpatients [13]. In our 1:10.Inthisstudy,GroupOshowednosignificantdifference study, however, oxycodone did not differ significantly from in the cumulative PCA dose, while maintaining similar VAS alfentanil and had a low incidence of nausea. In the first values comparable to that of Group A. Therefore, oxycodone postoperative hour, the incidence of nausea in Groups A had comparable effects for pain relief compared to alfentanil and O was relatively higher than in other periods. This when used at a conversion ratio of 10 : 1 in our study. would include the effects of a loading dose given before Postoperative pain can cause many adverse effects such the end of the operation, the inhalation agent used during as atelectasis, prolonged hospital stay, and decreased patient the operation, and laparoscopic surgery. Another factor may satisfaction. A background infusion of PCA can improve bethetime-scheduleddecrementalinfusionbecauseofthe the level of analgesia and reduce breakthrough pain in the administration of a high opioid concentration given several postoperative period [29]. However, a routine fixed-rate hours postoperatively. Regarding the incidence of vomiting, background infusion increases the analgesic dosage and the three patients in Group A experienced vomiting whereas no incidence of adverse respiratory events in the postoperative patients in Group O did, but this difference was not statis- period. With a routine fixed background infusion of oxy- tically significant. Several studies have demonstrated good codone, postoperative nausea and vomiting (PONV) was efficacy of the antiemetic ramosetron against PONV after common and relatively long-lasting [10, 11]. Therefore, it is laparoscopic surgery [35–37]; we opted to use ramosetron necessary to establish the infusion method while varying the postoperatively in our study patients. Without this drug, the infusion rates of the analgesics. We devised a study to reduce incidence of PONV would have been higher in this study. the adverse effects, while maintaining analgesic effects, by Patients experienced dizziness more frequently in Group changing the PCA dose over time. Kim et al. [16] reported that O(13patients)thanGroupA(6patients),butthedifference a time-scheduled decremental continuous infusion provided was not statistically significant. One patient in each group sufficient analgesic effect without increasing side effects. experienced urinary retention. Although the incidence was In this study, we compared oxycodone and alfentanil in very low and statistically insignificant, both patients also terms of the adequacy of postoperative pain control using a complained of lower abdominal discomfort and severe inci- time-scheduled decremental mode IV PCA in patients who sional pain concurrent with urinary retention. underwent laparoscopic cholecystectomy. The intensity of The VAS score decreased gradually over time and changes postoperative pain depends on the type of surgery performed of VAS are not different over time when resting and when [30]. Our preliminary study found that the pain grade with- coughing in both groups. However, one patient in each out PCA was the highest until 6 to 8 hours after laparoscopic group had flatulence and was not discharged until 24 hours cholecystectomy and decreased significantly after 24 hours postoperatively. Both patients complained of abdominal dis- postoperatively. Considering these changes, in this study, comfort and maintained a high VAS score until discharge. weusedthetime-scheduledcontinuousinfusionmethodto Opioids tend to inhibit intestinal propulsion and increase reducetheflowrateofthebackgroundinfusionat8and24 guttransittime,whichcanleadtopostoperativeileus[38]. hours postoperatively. Therefore, careful monitoring and management of flatulence We also used opioids based on the LBM to reduce are essential to lessen postoperative pain. adverse effects in this study. Many opioid pharmacokinetic There are many studies comparing the effects of different parameters such as clearance are considered to be more opioids on acute postoperative pain. To the best of our closely related to lean body mass [31]. Obesity has been knowledge, no previous study has compared intravenous demonstrated to prolong the elimination half-life of alfentanil oxycodone and intravenous alfentanil. We hypothesized that [32]. Oxycodone has a duration of action similar to morphine alfentanilwouldbesuperiortooxycodoneintermsofthe but lower clearance [33], and the duration of action can adverse effects of postoperative PCA. However, alfentanil be prolonged in obese patients. As a result, in an obese and oxycodone did not differ significantly in terms of pain patient, total body weight-based dosing may increase the control and adverse effects in our study. These results may incidence of adverse effects compared with lean body mass- indicate that oxycodone had comparable effects compared to based dosing. Therefore, opioid dosages based on LBM rather alfentanil at a conversion ratio of 10 : 1 with a time-scheduled than total body weight may be more accurate. Therefore, we decremental infusion mode of PCA based on the LBM. administered doses based on LBM using Hume’s method in Therefore, using a conversion factor of 10 : 1, oxycodone is a this study. useful alternative to alfentanil for IV PCA after laparoscopic Pain Research and Management 7

cholecystectomy. Further studies in various clinical settings patient-controlled analgesia after laparoscopic gynecological will be needed to determine the adequate potency ratio. surgery,” Korean Journal of Anesthesiology,vol.68,no.2,pp.153– 158, 2015. [12] B. A. Coda, “Opioids,” in Clinical Anesthesia,P.G.Barash,B. 5. Conclusions F. Cullen, and R. K. Stoelting, Eds., pp. 353–383, Lippincott Intravenous oxycodone produces similar analgesic and Williams & Wilkins, Philadelphia, Pa, USA, 5th edition, 2006. adverse effects to intravenous alfentanil in the treatment of [13] S. Langevin, M. R. Lessard, C. A. Trepanier,´ and J.-P. Baribault, postoperative pain after laparoscopic cholecystectomy when “Alfentanil causes less postoperative nausea and vomiting than equipotent doses of fentanyl or sufentanil in outpatients,” used at a conversion ratio of 10:1. 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