|Year : 2014 | Volume
| Issue : 2 | Page : 143-147
Effect of perioperative oral pregabalin on the incidence of post-thoracotomy pain syndrome
Hazem M. Fawzi1, Sanaa A. El-Tohamy2
1 Anesthesia and Intensive Care Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
2 Anesthesia and Intensive Care Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
|Date of Submission||18-Sep-2013|
|Date of Acceptance||28-Oct-2013|
|Date of Web Publication||31-May-2014|
Hazem M. Fawzi
Anesthesia and Intensive Care Department, Faculty of Medicine, Ain Shams University, Cairo
Source of Support: None, Conflict of Interest: None
Chronic post-thoracotomy pain, which is defined as pain that recurs or persists for more than 2 months, is a common problem affecting the quality of life of patients. We have evaluated the efficacy of perioperative pregabalin for reducing postoperative pain and the incidence of chronic post-thoracotomy pain.
Patients and methods
Sixty patients aged 30-49 years undergoing thoracotomy were allocated randomly to receive either pregabalin (75 mg oral twice daily for 5 days before and 5 days after the operation) or placebo at corresponding times in a double-blinded manner. Both groups received the same anesthetic technique. Our primary target was to measure the incidence of chronic postsurgical pain using the Leeds Assessment of Neuropathic Symptoms and Signs Pain Scale at 3- and 6-month intervals. Morphine consumption was measured as well as the length of hospital stay and the occurrence of postoperative systemic complications.
Pregabalin decreased the incidence of chronic postoperative pain at 3 and 6 months from 60 and 40% to 10 and 6.7%, respectively. Also, pregabalin decreased the postoperative acute pain intensity as indicated by lower morphine consumption (P < 0.001). Pregabalin decreased postoperative hospital stay, with a time of discharge of 10 (9-10) days for the control group and 8 (7-8) days for the pregabalin group (P < 0.001). No statistical difference was found in the incidence of complications.
Perioperative pregabalin reduces the incidence of chronic post-thoracotomy pain, with less postoperative morphine consumption together with early hospital discharge.
Keywords: Chronic postsurgical pain, post-thoracotomy chronic pain, pregabalin
|How to cite this article:|
Fawzi HM, El-Tohamy SA. Effect of perioperative oral pregabalin on the incidence of post-thoracotomy pain syndrome. Ain-Shams J Anaesthesiol 2014;7:143-7
|How to cite this URL:|
Fawzi HM, El-Tohamy SA. Effect of perioperative oral pregabalin on the incidence of post-thoracotomy pain syndrome. Ain-Shams J Anaesthesiol [serial online] 2014 [cited 2021 Apr 11];7:143-7. Available from: http://www.asja.eg.net/text.asp?2014/7/2/143/133350
| Introduction|| |
Post-thoracotomy pain is the most common complication following thoracotomy ; 80% of patients experience pain after thoracotomy with different degrees of severity . Chronic postsurgical pain (CPSP) is defined as pathological pain that is persistent for more than 2 months . Post-thoracotomy chronic pain is also called post-thoracotomy neuralgia or post-thoracotomy pain syndrome, and is defined by the International Association for the Study of Pain (IASP) as pain that persists or recurs at the thoracotomy incision for at least 2 months after the operation . CPSP can affect the quality of life of patients suffering from it ,. Pregabalin has been proven to have antihyperalgesic action on humans , and it is also used in the treatment of chronic neuropathic pain . Pregabalin, when used in the perioperative period, may play a role in preventing acute pain from developing into chronic pain . Therefore, we carried out this study to test the effect of perioperative pregabalin on the incidence of chronic post-thoracotomy pain.
| Patients and methods|| |
After approval of the ethics committee and after obtaining consent, 60 patients aged 30-49 years, of either sex, ASA 1 and 2, and scheduled to undergo thoracotomy (lobectomy, bullectomy, segmentectomy, and wedge resection) by posterolateral incision were recruited into this prospective randomized placebo-controlled double-blinded study carried out at the Thoracic Surgery Unit, Ain Shams University Hospital. This age group was found in other studies to have the highest incidence of postoperative chronic pain ,. Exclusion criteria were as follows: patient refusal, patients with renal, hepatic impairment, or psychiatric illness, pregnant patients, and patients with previous ipsilateral thoracotomy or chronic pain from any cause, patients on chronic use of pain medications, alcohol and/or drug abuse, and patients allergic to any of the medications used. Patients were assigned randomly to one of two groups using computerized randomization and opaque envelopes to receive either the study drug (group P) or the placebo (group C). In group P (N = 30), each patient received pregabalin 75 mg capsule, orange-white color (Lyrica; Pfizer, New York, New York, USA), twice daily orally for 5 days preoperatively (with the last dose preoperatively before the operation by 2 h) and extended for 5 days postoperatively, whereas each patient in group C (control group) received an ascorbic acid/iron polysaccharides capsule, orange-white color (Ferrex 50 Plus; Breckenridge Pharmaceutical Inc., Boca Raton, Florida, USA), twice daily orally for 5 days preoperatively and extended for 5 days postoperatively. In the preoperative anesthesia visit, the visual analogue scale (VAS) for pain (0-10) was explained for the patients, with 0 = no pain and 10=worst imaginable pain. In the preoperative holding area, midazolam 0.03 mg/kg was administered intravenously 10 min before sending the patient to the operating theater. Before induction of general anesthesia, routine monitoring was applied in the form of ECG, dominant arm noninvasive blood pressure, and pulse oximetry (Cardio Cap II; Datex Omeda, Helsinki, Finland). A nondominant arm radial artery catheter was inserted for invasive blood pressure monitoring using local anesthesia. Induction of anesthesia was standardized for both groups in the form of fentanyl 3 mcg/kg intravenous, propofol 1-3 mg/kg intravenous, and Tracrium (atracurium besylate) 0.5 mg/kg intravenously to facilitate tracheal intubation. One-lung ventilation was achieved using a double-lumen endobronchial tube (HiTeCare; Shanghai HiTec Medical Co. Ltd, Shanghai, China) size 37 Fr for female patients and 39 Fr for male patients. Pressure-controlled ventilation was adjusted to maintain normocapnia. Patients were placed in the lateral decubitus position, with padding of the dependent axillae. Analgesia was maintained by fentanyl 1 mcg/kg/30 min, muscle relaxation was maintained using atracurium supplementary doses guided by a nerve stimulator, and anesthesia was maintained by sevoflurane 1.5-2 vol% in an air/oxygen mixture (50%/50%) with fresh gas flow at 2 l/min. After completion of the surgical procedure, patients were extubated in the operating room after reversal of the neuromuscular blockade using neostigmine and atropine. In the postoperative period, all patients in both groups regularly received paracetamol 1 g orally every 6 h starting 2 h after the operation and tramadol 50 mg orally every 8 h. VAS for pain was assessed every 6 h and morphine 0.1 mg/kg was administered intravenously for patients with VAS of 4 or more. The total amount of morphine consumed and the number of doses were recorded in the first 48 h postoperatively. Also, the side effects of pregabalin such as confusion, dizziness, headache, and dry mouth were also assessed and recorded every 6 h in the first 48 h postoperatively. Patients were discharged home according to the Chung et al.  discharge scoring system (PADSS); in addition, no infection at the wound site and the time to discharge home were recorded. Patients were asked to come to the anesthesia clinic 3 and 6 months after the operation, and the clinical diagnosis of neuropathic pain was made using the Leeds Assessment of Neuropathic Symptoms and Signs Pain Scale (S-LANSS) at 3 and 6 months postoperatively . S-LANSS is a validated neuropathic pain assessment tool that consists of seven items (with yes/or no for each pain measure) with a maximum score of 24. The seven variables consisted of two examination items: allodynia (assessed by gentle rubbing of the incision area) and hyperalgesia (gentle pressure application by the finger tips over the incision area), and the other five pain symptoms included pins and needles, changes in skin color, episodes of pain bursts, and sensitivity to touch and burning sensation; an S-LANSS of 12 or more was an indication of chronic neuropathic pain. The surgical and anesthesia teams, personnel involved in the study, and the patients were blinded to the drugs administered. Data were collected and statistically analyzed.
The required sample size was calculated using PASS (version 11; NCSS LLC, Kaysville, Utah, USA). The primary outcome measure was the incidence of chronic postoperative pain. A previous study by Guastella et al.  reported that the incidence of chronic post-thoracotomy pain was at least 70%. Thus, it was estimated that a sample of 30 patients in either group would have a power of 80% to detect a 50% reduction in the incidence of chronic post-thoracotomy pain using a two-sided z-test and setting the type I error at 0.05.
Data were analyzed on a personal computer using the IBM SPSS Statistics (version 21; IBM Corp., Armonk, New York, USA). The Shapiro-Wilk test was used to test the normality of numerical data distribution. Normally distributed data were presented as mean (SD) and the unpaired t-test was used for intergroup comparisons. Skewed data were presented as median (interquartile range) and the Mann-Whitney U-test was used to compare between-group differences. Nominal data were presented as number (%) and differences between the two groups were compared using the c2 -test or Fisher's exact test, when appropriate.
A P value of less than 0.05 was considered statistically significant.
| Results|| |
Sixty patients were eligible for inclusion in this study; they were randomized in equal numbers to two groups each of 30 patients. Demographic (age, sex, and weight) and surgical (duration of surgery and the length of the wound) data showed no statistical differences between the two groups [Table 1]. In terms of acute postoperative pain, the pregabalin group (group P) showed lower intensity of pain as shown by the lower number [4 (3-4) vs. 6 (5-6) and amount of morphine consumed (26.2 ± 4.6 vs. 41.8 ± 8.2 mg) for the pregabalin and control groups, respectively, P < 0.001] [Table 2]. In terms of the incidence of chronic postoperative pain as calculated by the S-LANSS at 3 and 6 months postoperatively, the control group showed a higher incidence of CPSP than the pregabalin group at both 3- and 6-month intervals, with number (%) of 18 (60%) and 3 (10%) at 3 months, respectively (P < 0.001), and 12 (40%) and 2 (6.7%) at 6 months, respectively (P < 0.002) [Figure 1]. In terms of the incidence of postoperative complications, there were no statistical differences between the two groups, although the pregabalin group had a higher incidence of complications, but this was statistically insignificant (P = 0.063); the incidences in the control group and pregabalin group were as follows: confusion 1 (3.3%) and 4 (13.3%), dizziness 3 (10.0%) and 5 (16.7%), headache 0 (0.0%) and 1(3.3%), and dry mouth 0 (0.0%) and 3 (10.0%), respectively [Table 2]. In terms of the postoperative hospital stay, the control group had longer duration of hospital stay than the pregabalin group, with a median of 10 (9-10) and 8 (7-8) days, respectively (P < 0.001) [Figure 2].
| Discussion|| |
Postsurgical pain is normally perceived as nociceptive pain. Surgical trauma has been known to induce central and peripheral sensitization and hyperalgesia, which, in untreated cases, could lead to chronic postoperative pain after surgery. Thoracotomy is one of the highest causes of postsurgical pain and disability among patients . The reason is that the procedure causes a very high amount of noxious stimuli, leading to central sensitization ,. We used pregabalin in our study because CPSP, like neuropathic pain, is mostly caused by the presence of a lesion or dysfunction in the nervous system ,, and pregabalin has efficacy of varying degrees in neuropathic pain conditions such as postherpetic neuralgia and chronic neuropathic pain ,. Pregabalin is a structural analogue of g-aminobutyric acid. It acts by presynaptic binding to the α2d subunit of voltage-dependent calcium channels that are widely distributed in the spinal cord and brain; thus, pregabalin modulates the release of several excitatory neurotransmitters, such as glutamate, substance P, and norepinephrine. It leads to inhibitory modulation of 'overexcited' neurons, returning them to a 'normal' state . Centrally, pregabalin could reduce the hyperexcitability of dorsal horn neurons that is induced by tissue damage. Also, in rat neuropathic pain models, the voltage-gated calcium channels in the dorsal root ganglia are upregulated  and pregabalin works by binding to these channels . Pregabalin prevents central sensitization from surgery and decreases postoperative pain ,,.
In our study, we used pregabalin 75 mg every 12 h for a period of 5 days preoperatively and postoperatively, we used this dose as higher doses, despite having greater antinociceptive efficacy, increase the incidence of somnolence and confusion ,. Our dose decreased the incidence of acute postoperative pain, indicated by the lesser amount and number of morphine needed postoperatively (P = 0.001 for both parameters). This was found previously for oral gabapentin when used preoperatively, leading to a decrease in opioid usage postoperatively . Also, this result is in agreement with the results of Mathiesen et al. , who found that administration of pregabalin before hip arthroplasty decreased postoperative morphine requirement, and in agreement with Hill et al. , who used pregabalin before molar tooth extraction, leading to a decrease in pain sensation after extraction. Also, Agarwal et al.  used pregabalin to decrease pain after laparoscopic cholecystectomy. Similarly, pregabalin, when administered preoperatively, can exert a good analgesic effect after spinal fusion surgery  and after laparoscopic hysterectomy . The definition of chronic pain is difficult; usually, 3-6 months are considered acceptable for the diagnosis of CPSP . In terms of postsurgical chronic pain after thoracotomy, we found that pregabalin decreased its incidence at the 3- and 6-month intervals (P = 0.001 and 0.002, respectively). This result is in keeping with the concept that the degree of acute postoperative pain after thoracotomy affects the incidence of CPSP . These results were consistent with those of Buvanendran et al. , who found that patients treated with preoperative pregabalin 300 mg before knee arthroplasty, followed by a 14-day course of 50-150 mg (twice daily) had lower neuropathic pain at the 3- and 6-month intervals than the placebo group, with 0% incidence at 3 and 6 months versus 8.7% at 3 months and 5.2% at 6 months in the placebo group. Also, Burke et al.  found that preoperative pregabalin 300 mg before and 150 mg at 12 and 24 h after operation decreased the pain score at 3 months after lumbar discectomy, indicated by lower VAS measured at that interval versus the placebo group. In support of this result, Pesonen et al.  used pregabalin before cardiac surgery for patients aged 75 years or more at a dose of 150 mg before operation and 75 mg twice daily for 5 days after; they found that pregabalin decreased opioid need postoperatively and also decreased the incidence of pain during movement 3 months after the operation. In terms of postoperative complications, although there were higher incidences of dry mouth, dizziness, and confusion in the pregabalin group, the difference was statistically insignificant. In contrast to our results, Buvanendran et al.  found that dry mouth, dizziness, and confusion occurred more in the pregabalin group than the placebo group on the day of operation and on the first postoperative day; this could be attributed to the higher number of patients in their study as they carried out their study on 240 patients; also, they used higher doses and for a longer duration. Both reasons could explain the disparity in the results between our study and the Buvanendran and colleagues' study. Also, in terms of the postoperative stay, the pregabalin group had faster discharge time than the placebo group; this effect could be attributed to the fact that we used the PADSS  score for discharge, one of its parameters depending on pain and how it is controlled. This result is somewhat similar to that of Buvanendran et al. , who found that patients who received pregabalin fulfilled the discharge criteria faster than the placebo group.
In conclusion, pregabalin 75 mg every 12 h for 5 days before and 5 days after thoracotomy leads to a decrease in acute postoperative pain, indicated by lesser narcotic consumption; it also leads to faster hospital discharge time, together with lesser incidence of CPSP at 3- and 6-month intervals than placebo, with minimal side effects.
| Acknowledgements|| |
Conflicts of interest
| References|| |
|1.||Karmakar MK, Ho AM. Postthoracotomy pain syndrome. Thorac Surg Clin 2004; 14:345-352. |
|2.|| Dajczman E, Gordon A, Kreisman H, Wolkove N. Long-term post-thoracotomy pain. Chest 1991; 99:270-274. |
|3.|| Macrae W, Davies H. Chronic post surgical pain. In: Crombie IK, Linton S, Croft P, Von Knorff M, LeResche L, editors. Epidemiology of pain. Washington, DC: IASP Press; 1999. 125-142. |
|4.|| Koehler RP, Keenan RJ. Management of postthoracotomy pain: acute and chronic. Thorac Surg Clin 2006; 16:287-297. |
|5.|| Blyth FM, March LM, Cousins MJ. Chronic pain-related disability and use of analgesia and health services in a Sydney community. Med J Aust 2003; 179:84-87. |
|6.|| Gálvez R, Marsal C, Vidal J, Ruiz M, Rejas J. Cross-sectional evaluation of patient functioning and health-related quality of life in patients with neuropathic pain under standard care conditions. Eur J Pain 2007; 11:244-255. |
|7.|| Chizh BA, Gohring M, Troster A, Quartey GK, Schmelz M, Koppert W. Effects of oral pregabalin and aprepitant on pain and central sensitization in the electrical hyperalgesia model in human volunteers. Br J Anaesth 2007; 98:246-254. |
|8.|| Ifuku M, Iseki M, Hidaka I, Morita Y, Komatus S, Inada E. Replacement of gabapentin with pregabalin in postherpetic neuralgia therapy. Pain Med 2011; 12:1112-1116. |
|9.|| Katz J, Clarke H, Seltzer Z. Preventive analgesia: quo vadimus? Anesth Analg 2011; 113:1242-1253. |
|10.||1Smith WC, Bourne D, Squair J, Phillips DO, Chambers WA. A retrospective cohort study of post mastectomy pain syndrome. Pain 1999; 83:91-95. |
|11.||1Poobalan AS, Bruce J, King PM, Chambers WA, Krukowski ZH, Smith WC. Chronic pain and quality of life following open inguinal hernia repair. Br J Surg 2001; 88:1122-1126. |
|12.||1Chung F, Chan V, Ong D. A post-anesthetic discharge scoring system for home-readiness after ambulatory surgery. J Clin Anesth 1995; 7:500-506. |
|13.||1Bennett M. The LANSS Pain Scale: the Leeds assessment of neuropathic symptoms and sign. Pain 2001; 92:147-157. |
|14.||1Guastella V, Mick G, Soriano C, Vallet L, Escande G, Dubray C, Eschalier A. A prospective study of neuropathic pain induced by thoracotomy: incidence, clinical description, and diagnosis. Pain 2011; 152:74-81. |
|15.||1Imani F, Rahinzadeh P. Gabapentinoids: gabapentin and pregabalin for postoperative pain. Anesth Pain Med 2012; 2:52-53. |
|16.||1Katz J, Jackson M, Kavanagh BP, Sandler AN. Acute pain after thoracic surgery predicts long-term post-thoracotomy pain. Clin J Pain 1996; 12:50-55. |
|17.||1Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. Lancet 2006; 367:1618-1625. |
|18.||1Katz J, Seltzer Z. Transition from acute to chronic postsurgical pain: risk factors and protective factors. Expert Rev Neurother 2009; 9:723-744. |
|19.||1Costigan M, Scholz J, Woolf CJ. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci 2009; 32:1-32. |
|20.||2Gilron I, Bailey JM, Tu D, Holden RR, Jackson AC, Houlden RL. Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial. Lancet 2009; 374:1252-1261. |
|21.||2Taylor CP. Mechanisms of analgesia by gabapentin and pregabalin-calcium channel alpha2-delta [Cavalpha2-delta] ligands. Pain 2009; 142:13-16. |
|22.||2Luo ZD, Calcutt NA, Higuera ES, Valder CR, Song YH, Svensson CI, Myers RR. Injury type-specific calcium channel alpha 2 delta-1 subunit up-regulation in rat neuropathic pain models correlates with antiallodynic effects of gabapentin. J Pharmacol Exp Ther 2002; 303:1199-1205. |
|23.||2Field MJ, Cox PJ, Stott E, Melrose H, Offord J, Su TZ, et al. Identification of the alpha2-delta-1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin. Proc Natl Acad Sci USA 2006; 103:17537-17542. |
|24.||2Mathiesen O, Jacobsen LS, Holm HE, Randall S, Adamiec-Malmstroem L, Graungaard BK, et al. Pregabalin and dexamethasone for postoperative pain control: a randomized controlled study in hip arthroplasty. Br J Anaesth 2008; 101:535-541. |
|25.||2Pandey CK, Priye S, Singh S, Singh U, Singh RB, Singh PK. Preemptive use of gabapentin significantly decreases postoperative pain and rescue analgesic requirements in laparoscopic cholecystectomy. Can J Anaesth 2004; 51:358-363. |
|26.||2McCartney CJ, Sinha A, Katz J. A qualitative systematic review of the role of N-methyl-d-aspartate receptor antagonists in preventive analgesia. Anesth Analg 2004; 98:1385-1400. |
|27.||2Pandey CK, Navkar DV, Giri PJ, Raza M, Behari S, Singh RB, et al. Evaluation of the optimal preemptive dose of gabapentin for postoperative pain relief after lumbar diskectomy: a randomized, double-blind, placebo-controlled study. J Neurosurg Anesthesiol 2005; 17:65-68. |
|28.||2White PF, Tufanogullari B, Taylor J, Klein K. The effect of pregabalin on preoperative anxiety and sedation levels: a dose-ranging study. Anesth Analg 2009; 108:1140-1145. |
|29.||2Hurley RW, Cohen SP, Williams KA, Rowlingson AJ, Wu CL. The analgesic effects of perioperative gabapentin on postoperative pain: a meta-analysis. Reg Anesth Pain Med 2006; 31:237-247. |
|30.||3Hill CM, Balkenohl M, Thomas DW, Walker R, Mathé H, Murray G. Pregabalin in patients with postoperative dental pain. Eur J Pain 2001; 5:119-124. |
|31.||3Agarwal A, Gautam S, Gupta D, Agarwal S, Singh PK, Singh U. Evaluation of a single preoperative dose of pregabalin for attenuation of postoperative pain after laparoscopic cholecystectomy. Br J Anaesth 2008; 101:700-704. |
|32.||3Reuben SS, Buvanendran A, Kroin JS, Raghunathan K. The analgesic efficacy of celecoxib, pregabalin, and their combination for spinal fusion surgery. Anesth Analg 2006; 103:1271-1277. |
|33.||3Jokela R, Ahonen J, Tallgren M, Haanpaa M, Korttila K. A randomized controlled trial of perioperative administration of pregabalin for pain after laparoscopic hysterectomy. Pain 2008; 134:106-112. |
|34.||3Merskey H, Bogduk N. Classification of chronic pain. Descriptions of chronic pain syndromes and definitions of pain terms, 2nd ed. Seattle: IASP Press; 1994. |
|35.||3Buvanendran A, Kroin JS, Della Valle CJ, Kari M, Moric M, Tuman KJ. Perioperative oral pregabalin reduces chronic pain after total knee arthroplasty: a prospective, randomized, controlled trial. Anesth Analg 2010; 110:199-207. |
|36.||3Burke SM, Shorten GD. Perioperative pregabalin improves pain and functional outcomes 3 months after lumbar discectomy. Anesth Analg 2010; 110:1180-1185. |
|37.||3Pesonen A, Suojaranta-Ylinen R, Hammaren E, Kontinen VK, Raivio P, Tarkkila P, Rosenberg PH. Pregabalin has an opioid-sparing effect in elderly patients after cardiac surgery: a randomized placebo-controlled trial. Br J Anaesth 2011; 106:873-881. |
[Figure 1], [Figure 2]
[Table 1], [Table 2]