Anaesthesia 2016, 71, 192–197


Original Article A randomised controlled trial of peri-operative pregabalin vs. placebo for video-assisted thoracoscopic surgery A. H. Konstantatos,1 W. Howard,2 D. Story,3 L. Y. H. Mok,4 D. Boyd5 and M. T. V. Chan6 1 Staff Specialist, 5 Pain Nurse Specialist, Department of Anaesthesia and Peri-operative Medicine, Alfred Hospital, Melbourne, Victoria, Australia 2 Staff Specialist, Department of Anaesthesia, Austin Hospital, Melbourne, Victoria, Australia 3 Professor and Chair of Anaesthesia, Anaesthesia, Peri-operative and Pain Medicine Unit, Melbourne Medical School, The University of Melbourne, Melbourne, Victoria, Australia 4 Associate Consultant, 6 Professor, Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China

Summary We allocated 52 participants to oral pregabalin 300 mg and 48 participants to placebo tablets before thoracoscopic surgery and for five postoperative days. The median (IQR [range]) cumulative pain scores at rest for nine postoperative months were 184 (94–274 [51–1454]) after pregabalin and 166 (66–266 [48–1628]) after placebo, p = 0.39. The corresponding scores on deep breathing were 468 (281–655 [87–2870]) and 347 (133–561 [52–3666]), respectively, p = 0.16. After three postoperative months, 29/100 participants had persistent surgical site pain, 19/52 after pregabalin and 10/48 after placebo, p = 0.12, of whom four and five, respectively, attended a pain management clinic, p = 0.24. The median (IQR [range]) morphine equivalent consumption six days after surgery was 273 (128–619 [39– 2243]) mg after pregabalin and 319 (190–663 [47–2258]) mg after placebo, p = 0.35.


Correspondence to: M. T. V. Chan Email: [email protected] Accepted: 22 September 2015

Introduction Post-thoracotomy pain syndrome is pain from a thoracotomy wound that recurs or persists for at least two postoperative months [1]. It affects at least one in two patients who have thoracotomies, 1 in 10 of whom have moderate or severe pain [2, 3]. Many prophylactic methods have failed to reduce the rate of persistent pain after thoracotomy, including intercostal local anaesthetic [4, 5], interpleural local anaesthetic [6], incisional local anaesthetic [5], cryoanalgesia alone [6] or in combination with other analgesic techniques [6– 8]. However, thoracic epidural analgesia started before 192

thoracotomy, with or without ketamine, is effective [9–11]. Video-assisted thoracoscopic surgery causes less tissue damage than thoracotomy and may reduce acute postoperative pain, although it does not appear to reduce persistent pain [12–14]. It is important to test analgesic techniques for thoracoscopic surgery as it is becoming popular and interventions might not have the same effects as they do after thoracotomy [15, 16]. Pregabalin blocks the a2 subunit of neural calcium channels and achieves rapid therapeutic levels after oral dosing [17]. Pregabalin reduces acute pain after

© 2015 The Association of Anaesthetists of Great Britain and Ireland

Konstantatos et al. | Pregabalin for thoracoscopic surgery

various operations [18, 19], but it is uncertain whether it has an effect on persistent pain [19, 20]. We therefore conducted a randomised controlled trial to determine the effect of pregabalin on pain up to nine months after thoracoscopic surgery, as well as opioid consumption and quality of life.

Methods The institutional review boards affiliated with the Alfred and Austin Hospitals in Australia, and the Prince of Wales Hospital in Hong Kong, approved this registered trial. We recruited patients aged 18-75 y scheduled for video-assisted thoracoscopic surgery. We excluded patients for whom a regional analgesic technique was planned and those with a contraindication or allergy to morphine, pregabalin or paracetamol. We also excluded patients with: pre-operative pain of at least three months’ duration; cognitive disorders; atrial fibrillation or myocardial infarction < 6 months before surgery; expiratory peak flow rates < 60% of predicted; serum creatinine > 125 lmol.l 1; aspartate or alanine aminotransferase > 40 lmol.l 1; and pregnant women. All participants provided written informed consent between October 2008 and April 2013. The Pharmacy Department at the Alfred Hospital, independent of the investigators, generated a computer sequence with equal numbers allocated to placebo or pregabalin, stratified by hospital site, in blocks of four participants. Assignment codes were concealed in opaque envelopes. The Pharmacy distributed envelopes and coded tablets to pharmacists at each of the three study sites. Placebo and pregabalin tablets were indistinguishable. Participants were sequentially assigned to two tablets of pregabalin 150 mg or placebo, 30 min before surgery. Participants then received one tablet of pregabalin 150 mg or placebo twice-daily for five postoperative days. Anaesthesia was induced and maintained with propofol or volatile agents. During surgery, intravenous morphine 0.10–0.15 1 was injected and the thoracoscopic port sites were infiltrated with ropivacaine, up to 3 1. Ketamine and nitrous oxide were not used. Participants used morphine patientcontrolled analgesia (PCA) with a 1 mg bolus and 5 min lockout for three postoperative days, together with oral paracetamol 1 g every 6 h and the study © 2015 The Association of Anaesthetists of Great Britain and Ireland

Anaesthesia 2016, 71, 192–197

medication, after which oral paracetamol and oxycodone were given to relieve pain. Participants were reviewed by independent pain physicians while in hospital. A referral to an independent pain physician was also offered to participants at the time of review, after discharge from hospital. Additional analgesics were given as recommended by the independent pain physician. The type and dose of analgesics were recorded. The primary outcome was the average pain score over the incision site during deep breathing from the time of surgery up to nine postoperative months after surgery. The sample size calculation was initially based on the calculation of mean pain score from an audit (see below). We subsequently calculated cumulative pain for participants as the area under the curve using the trapezoid rule. Secondary outcomes included opioid administration during the first six postoperative days, quality of recovery, peak expiratory flow at hospital discharge, and physical and mental health status measured by SF-12 at nine months after surgery [21]. We instructed participants pre-operatively to use a visual analogue scale (VAS) to indicate severity of pain, from none (0) to worst imaginable (10) [22]. We assessed pain at rest and during deep breathing in the recovery room and then twice-daily for six days, then by telephone interview in conjunction with the short form McGill pain questionnaire at six weeks and at three, six and nine months [23]. Participants rated their quality of recovery on the first postoperative day with a nine-item score or its validated Chinese version in Hong Kong [24, 25]. Sedation was recorded on the first postoperative day on a four-point scale: awake (1); asleep but easily roused (2); asleep and difficult to rouse (3); and unrousable (4). We recorded nausea or vomiting in hospital. We calculated that we would need to recruit 43 participants to each group to have 80% power to detect a 30% reduction in mean pain score during the first nine postoperative months, significance level 0.05, based on an audit of 20 patients. We subsequently recruited 100 participants to accommodate protocol violations and loss to follow-up. A post-hoc sample size calculation using cumulative area under the curve scores from the same audit, conducted after completion of our study, suggested that we would have needed to recruit 45 participants to each group to have 193

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80% power of detecting a 30% reduction from a control mean (SD) area under the pain curve of 459 (230), significance level 0.05. We assessed whether continuous outcomes were normally distributed with the Kolmogorov–Smirnov and Shapiro–Wilks tests. We analysed skewed data with the Mann–Whitney U-test and normally distributed data with Student’s t-test. We used Fisher’s exact test to analyse categorical variables. A p value < 0.05 was considered statistically significant.

Results We recruited 100 participants from 311 eligible patients (Fig. 1). We analysed on an intention-to-treat basis, including the results of five participants who had open thoracotomies, three of whom received pregabalin and two placebo. Three participants died while in hospital: two had received pregabalin and one placebo. We were unable to contact one participant from each group after discharge. Table 1 lists participants’ characteristics. Pregabalin did not affect median pain scores during nine months of follow-up (Fig. 2). After three postoperative months, 19/52 (37%) participants who had received pregabalin had surgical site pain, as did 10/48 (21%)

Konstantatos et al. | Pregabalin for thoracoscopic surgery

participants who had received placebo, p = 0.12; two participants in each group reported severe pain. Nine participants were attending outpatient clinics at three months for management of persistent postoperative pain, four (8%) from the pregabalin group and five (10%) from the placebo group, p = 0.24. At nine postoperative months, 5/52 (10%) participants who had received pregabalin had surgical site pain on deep breathing, as did 3/48 (6%) participants who had received placebo, p = 0.24. There were no differences in other outcomes (Table 2). Table 1 Characteristics of participants allocated to pregabalin or placebo for video-assisted thoracoscopic surgery. Values are number (proportion) or mean (SD).

Men Age; years Caucasian ASA status 1–2 ASA status 3 or more Weight; kg Duration of surgery; min Tumour-related surgery Current smoker

Pregabalin (n = 52)

Placebo (n = 48)

33 52 15 43 9 65.5 137 33 6

26 49 11 37 11 62.2 166 25 12

(63%) (18) (29%) (83%) (17%) (14.5) (60) (63%) (12%)

(54%) (19) (23%) (77%) (23%) (14.5) (104) (52%) (25%)

Figure 1 CONSORT flow chart of participant recruitment. 194

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Anaesthesia 2016, 71, 192–197

Figure 2 Median (IQR) pain scores (0–10) at rest and during deep breathing after thoracoscopic surgery in participants receiving pregabalin (black circles) or placebo (grey boxes). There were no significant differences in the area under pain curves between groups. Table 2 Postoperative secondary outcomes for participants allocated to pregabalin or placebo for video-assisted thoracoscopic surgery. Values are numbers, mean (SD) or median (IQR [range]), mean (SD) or number (proportion). Outcomes Quality of recovery Cumulative opioid consumption; mg* Postoperative nausea or vomiting Peak expiratory flow; l.min 1 Pre-operative postoperative day-six McGill pain score at nine postoperative months SF-12 physical domain score Pre-operative 9 months after surgery SF-12 mental domain score Pre-operative Mental domain

Pregabalin (n = 52)

Placebo (n = 48)

p value

13 (10–16 [6–17]) 402 (373) 14 (27%)

13 (10–15 [5–17]) 477 (421) 14 (29%)

0.77 0.35 0.82

355 (136) 294 (130) 1.1 (2.3)

345 (130) 276 (115) 1.4 (4.1)

0.41 0.27

50 (42–55 [24–64]) 50 (40–55 [25–59])

53 (48–56 [25–63]) 55 (49–55 [22–59])


53 (39–58 [26–64]) 57 (48–61 [30–67])

53 (45–56 [16–65]) 59 (51–60 [34–64])


*Morphine equivalents during the first six postoperative days.

Discussion Six days’ peri-operative pregabalin did not affect pain or any other outcome during nine months after thoracoscopic surgery. © 2015 The Association of Anaesthetists of Great Britain and Ireland

Two meta-analyses reported no effect of pregabalin on persistent postoperative pain [18, 19], although individual trials have reported effects for prophylactic pregabalin [26–28]. The first reported that 195

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24 h’ pregabalin reduced pain three months after lumbar discectomy [26]. The second reported that 14 days’ pregabalin reduced neuropathic pain at 3 and 6 months after knee arthroplasty [27]. The last reported that pregabalin reduced pain for two days and three months after cardiac surgery [28]. We excluded patients with chronic pain. The studies that reported an effect of pregabalin recruited participants who were in pain before surgery; pregabalin may prevent existing pain escalating but might not affect pain caused by surgery alone [29]. Although we planned our analgesic regimen in 2006, it remains similar to current treatments [30] and our follow-up was sufficient to characterise the presence of persistent pain [31]. Our study may have been improved by giving pregabalin for longer. We may have shown an effect of pregabalin if we had included patients with pre-operative pain. A third of our participants reported persistent pain with deep breathing at three postoperative months, most of whom also had significant pain earlier, supporting the idea that inadequately controlled acute pain predisposes to persistent pain [32, 33]. Persistent pain after thoracoscopic surgery might be limited by pre-operatively identifying vulnerable patients – who have multiple factors associated with persistent pain – and using interventions that are effective for preventing pain after thoracotomy. In addition, patients who experience severe acute pain after thoracoscopy might be treated with similar interventions. In conclusion, six days’ of peri-operative pregabalin did not reduce pain, quality of recovery and overall health status during nine months’ after videoassisted thoracoscopic surgery. Future research should consider giving pregabalin for longer and might concentrate on patients who have pre-operative risk factors for persistent pain and those who report acute severe postoperative pain.

Acknowledgements The authors also wish to acknowledge the assistance of Professor Paul Myles with the statistical analysis.

Competing interests This study was supported, in part, by an investigatorinitiated research grant provided by Pfizer pharmaceu196

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ticals. Pfizer pharmaceuticals (New York, NY, USA) donated the pregabalin and placebo study drug, but they had no role in the design, conduct and analysis of the trial.

References 1. Merskey H, Bogduk N. Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms/Prepared by the International Association for the Study of Pain, Task Force on Taxonomy, 2nd edn. Seattle, WA: IASP Press, 1994. 2. Pluijms WA, Steegers MA, Verhagen AF, Scheffer GJ, WilderSmith OH. Chronic post-thoracotomy pain: a retrospective study. Acta Anaesthesiologica Scandinavica 2006; 50: 804–8. 3. Wildgaard K, Ravn J, Kehlet H. Chronic post-thoracotomy pain: a critical review of pathogenic mechanisms and strategies for prevention. European Journal of Cardiothoracic Surgery 2009; 36: 170–80. 4. Doyle E, Bowler GM. Pre-emptive effect of multimodal analgesia in thoracic surgery. British Journal of Anaesthesia 1998; 80: 147–51. 5. Cerfolio RJ, Bryant AS, Bass CS, Bartolucci AA. A prospective, double-blinded, randomized trial evaluating the use of preemptive analgesia of the skin before thoracotomy. Annals of Thoracic Surgery 2003; 76: 1055–8. 6. Miguel R, Hubbell D. Pain management and spirometry following thoracotomy: a prospective, randomized study of four techniques. Journal of Cardiothoracic and Vascular Anesthesia 1993; 7: 529–34. 7. Ju H, Feng Y, Yang BX, Wang J. Comparison of epidural analgesia and intercostal nerve cryoanalgesia for post-thoracotomy pain control. European Journal of Pain 2008; 12: 378–84. 8. Gwak MS, Yang M, Hahm TS, Cho HS, Cho CH, Song JG. Effect of cryoanalgesia combined with intravenous continuous analgesia in thoracotomy patients. Journal of Korean Medical Science 2004; 19: 74–8. 9. Obata H, Saito S, Fujita N, Fuse Y, Ishizaki K, Goto F. Epidural block with mepivacaine before surgery reduces long-term post-thoracotomy pain. Canadian Journal of Anaesthesia 1999; 46: 1127–32. 10. Suzuki M, Haraguti S, Sugimoto K, Kikutani T, Shimada Y, Sakamoto A. Low-dose intravenous ketamine potentiates epidural analgesia after thoracotomy. Anesthesiology 2006; 105: 111–9. 11. Andreae MH, Andreae DA. Regional anaesthesia to prevent chronic pain after surgery: a Cochrane systematic review and meta-analysis. British Journal of Anaesthesia 2013; 111: 711– 20. 12. Landreneau RJ, Mack MJ, Hazelrigg SR, et al. Prevalence of chronic pain after pulmonary resection by thoracotomy or video-assisted thoracic surgery. Journal of Thoracic and Cardiovascular Surgery 1994; 107: 1079–85. 13. Steegers MAH, Snik DM, Verhagen AF, van der Drift MA, Wilder-Smith OHG. Only half of the chronic pain after thoracic surgery shows a neuropathic component. Journal of Pain 2008; 9: 955–61. 14. Wildgaard K, Ringsted TK, Hansen HJ, Petersen RH, Werner MU, Kehlet H. Quantitative sensory testing of persistent pain after video-assisted thoracic surgery lobectomy. British Journal of Anaesthesia 2012; 108: 126–33.

© 2015 The Association of Anaesthetists of Great Britain and Ireland

Konstantatos et al. | Pregabalin for thoracoscopic surgery 15. McKenna RJ Jr, Houck W, Fuller CB. Video-assisted thoracic surgery lobectomy: experience with 1,100 cases. Annals of Thoracic Surgery 2006; 81: 421–5. 16. Waller DA, Forty J, Morritt GN. Video-assisted thoracoscopic surgery versus thoracotomy for spontaneous pneumothorax. Annals of Thoracic Surgery 1994; 58: 372–6. 17. Gajraj NM. Pregabalin: its pharmacology and use in pain management. Anesthesia and Analgesia 2007; 105: 1805–15. 18. Clarke H, Bonin RP, Orser BA, Englesakis M, Wijeysundera DN, Katz J. The prevention of chronic postsurgical pain using gabapentin and pregabalin: a combined systematic review and meta-analysis. Anesthesia and Analgesia 2012; 115: 428–42. 19. Mishriky BM, Waldron NH, Habib AS. Impact of pregabalin on acute and persistent postoperative pain: a systematic review and meta-analysis. British Journal of Anaesthesia 2015; 114: 10–31. 20. Chaparro LE, Smith SA, Moore RA, Wiffen PJ, Gilron I. Pharmacotherapy for the prevention of chronic pain after surgery in adults. Cochrane Database of Systematic Reviews 2013; 7: CD008307. 21. Jenkinson C, Layte R, Jenkinson D, et al. A shorter form health survey: can the SF-12 replicate results from the SF-36 in longitudinal studies? Journal of Public Health Medicine 1997; 19: 179–86. 22. Breivik H, Borchgrevink PC, Allen SM, et al. Assessment of pain. British Journal of Anaesthesia 2008; 101: 17–24. 23. Dworkin RH, Turk DC, Revicki DA, et al. Development and initial validation of an expanded and revised version of the Short-form McGill Pain Questionnaire (SF-MPQ-2). Pain 2009; 144: 35–42. 24. Myles PS, Hunt JO, Nightingale CE, et al. Development and psychometric testing of a quality of recovery score after

© 2015 The Association of Anaesthetists of Great Britain and Ireland

Anaesthesia 2016, 71, 192–197










general anesthesia and surgery in adults. Anesthesia and Analgesia 1999; 88: 83–90. Chan MT, Lo CC, Lok CK, Chan TW, Choi KC, Gin T. Psychometric testing of the Chinese quality of recovery score. Anesthesia and Analgesia 2008; 107: 1189–95. Burke SM, Shorten GD. Perioperative pregabalin improves pain and functional outcomes 3 months after lumbar discectomy. Anesthesia and Analgesia 2010; 110: 1180–5. Buvanendran 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. Anesthesia and Analgesia 2010; 110: 199–207. Pesonen A, Suojaranta-Ylinen R, Hammaren E, et al. Pregabalin has an opioid-sparing effect in elderly patients after cardiac surgery: a randomized placebo-controlled trial. British Journal of Anaesthesia 2011; 106: 873–81. Voscopoulos C, Lema M. When does acute pain become chronic? British Journal of Anaesthesia 2010; 105(Suppl. 1): i69–85. Schmidt PC, Ruchelli G, Mackey SC, Carroll IR. Perioperative gabapentinoids: choice of agent, dose, timing, and effects on chronic postsurgical pain. Anesthesiology 2013; 119: 1215– 21. Werner MU, Kongsgaard UE.I. Defining persistent post-surgical pain: is an update required? British Journal of Anaesthesia 2014; 113: 1–4. Katz J, Jackson M, Kavanagh BP, Sandler AN. Acute pain after thoracic surgery predicts long-term post-thoracotomy pain. Clinical Journal of Pain 1996; 12: 50–5. Yarnitsky D, Crispel Y, Eisenberg E, et al. Prediction of chronic post-operative pain: Pre-operative DNIC testing identifies patients at risk. Pain 2008; 138: 22–8.


A randomised controlled trial of peri-operative pregabalin vs. placebo for video-assisted thoracoscopic surgery.

We allocated 52 participants to oral pregabalin 300 mg and 48 participants to placebo tablets before thoracoscopic surgery and for five postoperative ...
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