Original Investigation
Perioperative Pregabalin for Attenuation of Postoperative Pain After Eyelid Surgery Leslie A. Wei, M.D.,*† Brett W. Davies, M.D.,* Eric M. Hink, M.D.,* and Vikram D. Durairaj, M.D.*‡§ *Department of Ophthalmology, Oculoplastic and Orbital Surgery Service, University of Colorado, Denver, U.S.A.; †Department of Ophthalmology and Visual Sciences, Oculoplastic, Facial Cosmetic, and Orbital Surgery Division, University of Wisconsin–Madison, U.S.A.; ‡Department of Otolaryngology and Head and Neck Surgery, University of Colorado, Denver, U.S.A.; and §Texas Oculoplastic Consultants, Austin, Texas, U.S.A.
Purpose: To examine the effect of a 1-time dose of pregabalin (Lyrica) on the perception of pain and analgesic consumption after oculofacial plastic surgery. Methods: In this prospective, randomized, double-blind, placebo-controlled trial, patients presenting to the oculofacial plastic surgery service at University of Colorado Eye Center for functional eyelid surgery and who met the study criteria were consecutively enrolled between October 2011 and September 2012. Subjects were randomized to either placebo or 150 mg pregabalin administered 15 minutes to an hour prior to the procedure. The procedure was then performed under the usual standard of care. Postoperatively, study subjects recorded pain scores on visual analog scales (range 0–100) at 1 to 2 hours, 2 to 4 hours, 8 to 12 hours, 20 to 28 hours, and 36 to 48 hours and the amount of acetaminophen consumed. Data were analyzed with Statistical Analysis System software using mixed-effects linear models. Results: Fifty-two patients were enrolled. Three patients were excluded due to incomplete follow up (n = 2) and postoperative course requiring early unblinding (n = 1). Twenty-six subjects were men. Average age was 68 years (range, 25–89). Eyelid procedures performed included blepharoplasty (18), canthoplasty (11), ptosis repair (15), eyelid retraction repair (2), pentagonal wedge resection (1), and MOHS reconstruction (2). Twenty-six patients were randomized to receive pregabalin, while the remainder received placebo. There was no significant difference in demographics between the 2 groups. The pregabalin group reported pain scores that were 5.5 points lower on average compared with the placebo group (p = 0.0307). Patients in the pregabalin group also consumed half as much acetaminophen (1.3 g) on average as the placebo group (2.6 g) during the postoperative period. Conclusions: Pregabalin is effective in reducing postoperative pain after oculoplastic procedures when compared with placebo. It may be a useful adjunct for pain control in selected patients. (Ophthal Plast Reconstr Surg 2015;31:132–135)
P
ostoperative pain is inadequately treated in approximately half of all surgical procedures, with 10% of patients going
Accepted for publication April 26, 2014. Presentation at the American Society of Ophthalmic Plastic and Reconstructive Surgery Annual Meeting on November 15, 2013 in New Orleans, Louisiana, U.S.A. E.M.H. is a speaker for Synthes/AO Foundation. V.D.D. is a consultant for Stryker, speaker for KLS Martin and AO Foundation, and equity owner in OnPHarma. The remaining authors have no financial or conflicts of interest to disclose. Address correspondence and reprint requests to Vikram D. Durairaj, M.D., 3705 Medical Pkwy #120, Austin, TX 78705. E-mail: [email protected] DOI: 10.1097/IOP.0000000000000219
132
on to develop long-term postoperative pain.1,2 An evolving trend in the literature on postoperative pain management involves the administration of pre-emptive analgesics.3,4 Pregabalin is a 3-alkylated gamma-amino butyric acid analog that functions as a neuropathic pain modulator by binding to the α2δ subunit of voltage-gated calcium channels on neurons.5 This inhibits the release of excitatory neurotransmitters that mediate pain, such as substance P, calcitonin, and glutamate.5 It is currently US Food and Drug Administration–approved for the treatment of epilepsy, postherpetic neuralgia, diabetic neuropathy, and fibromyalgia.6 Pregabalin has been shown to be efficacious in reducing postoperative pain for patients undergoing dental surgery, spine surgery, hand surgery, podiatric surgery, laparoscopic hysterectomy and other gynecologic operations, knee replacement, refractive surgery, nephrectomy, rhinoplasty, photorefractive keratectomy, and laparoscopic cholecystectomy.7–20 To date, pregabalin has not been studied for oculoplastic eyelid procedures. Because postoperative pain can vary with the surgical site, the effectiveness of pregabalin demonstrated in previous studies should not be generalized to all surgeries. The purpose of this study was to determine the effectiveness of pregabalin after eyelid surgery.
METHODS This study was approved by the Colorado Multiple Institutional Review Board. Patients aged between 22 and 90 years presenting to the oculofacial plastic surgery service at University of Colorado Eye Center were consecutively screened and enrolled by trained study personnel. Inclusion criteria consisted of the age limits described above and a functional indication for blepharoplasty, lateral canthoplasty, eyelid retraction surgery, ptosis surgery, or eyelid reconstruction. Exclusion criteria included 1) renal disease (creatinine clearance 0.10).
DISCUSSION Controlling postoperative pain effectively requires an understanding of the various kinds of pain that can be induced
Hours after surgery, h
Pregabalin
Placebo
1–2 2–4 8–12 20–28 36–48
12.9 (0–73) 14.0 (0–48) 10.8 (0–63) 11.3 (0–80) 11.0 (0–57)
29.4 (0–94) 25.6 (0–76) 20.6 (0–97) 9.7 (0–69) 2.1 (0–10)
Pain scores were recorded on a 100-mm-long visual analog scale. Averages are listed with range in parentheses.
by surgery: somatic, visceral, and neuropathic. Pregabalin addresses the neuropathic pain component by diminishing hyperalgesia and central sensitization.21–23 It has ≥90% oral bioavailability, is minimally metabolized, and has a half-life of 6.3 hours.6 In addition to analgesic effects, pregabalin has anxiolytic and mild sedative properties that can improve patient comfort.5,13 It has been methodically compared with other analgesics/anti-inflammatories and placebo in a variety of surgical procedures, from photorefractive keratectomy to transperitoneal nephrectomy. In many studies, it has been found to be effective in decreasing pain scores, opioid and other analgesic consumption, and anxiety.7–13,15–21,23–27 Effective postoperative pain control is also dependent on the timing of analgesic administration. The goal of preemptive analgesia is to decrease inflammatory pain from surgical incision, decrease the pain memory response, and avoid the development of long-term postoperative pain.1,4 The use of neuropathic pain modulators such as pregabalin and gabapentin may lessen the possibility of developing long-term postoperative pain.17,28 They can be used alone or in combination with other medications, such as dexamethasone, patient-controlled analgesia, oral opioids, COX-2 inhibitors, acetaminophen, and tramadol.13,14,20,29 These multimodal postoperative pain control regimens are being used with increasing frequency and have been found to decrease length of hospital stay for surgical procedures.24 In this trial, a single 150-mg perioperative dose of pregabalin was found to reduce average pain scores compared with placebo in patients undergoing oculoplastic eyelid procedures. The pain-reducing effect of pregabalin was significant compared with placebo at the first 3 time points (1 to 2, 2 to 4, and 8 to 12 hours after surgery), but not thereafter. It was also found to reduce the amount of acetaminophen consumption during the first 48 hours after surgery. It is notable that a greater number of participants in the pregabalin group (9) experienced side effects compared with the placebo group (4); however, this difference was not found to be statistically significant. Pregabalin may be a useful alternative medication over narcotics for pain control in TABLE 3. Side effects in the pregabalin and placebo groups Side effects
TABLE 1. Patient characteristics
Male sex, n (%) Age, y, mean ± SD
TABLE 2. Pain scores
Overall (n = 49)
Lyrica (n = 26)
Placebo (n = 23)
p
26 (53.1%) 67.4 ± 11.8
14 (53.9%) 65.0 ± 13.4
12 (52.2%) 70.2 ± 9.2
0.9068* 0.1191†
The placebo and pregabalin groups were similar in age and gender distribution. *χ2 test. †t test.
Sleepiness Dizziness Nausea Headache Total
Pregabalin group (n = 26)
Placebo group (n = 23)
Total (n = 49)
4 (15.4%) 2 (7.7%) 1 (3.8%) 2 (7.7%) 9 (34.6%)
0 2 (8.7%) 2 (8.7%) 0 4 (17.4%)
4 (8.2%) 4 (8.2%) 3 (6.1%) 2 (4.1%) 13 (26.5%)
More patients in the pregabalin group experienced side effects compared with the placebo group.
© 2014 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.
133
Ophthal Plast Reconstr Surg, Vol. 31, No. 2, 2015
L. A. Wei et al.
patients who are not adequately controlled with Tylenol or other over-the-counter pain medications. While most studies, including ours, that investigated pregabalin for postoperative pain have found it to be effective, not all have found it a useful adjunct.26,30 Chaparro et al.26 randomized cosmetic surgery patients to pregabalin or placebo q12 hours for 5 days starting the night before surgery and found no difference in pain scores between the 2 groups.26 Yadeau et al.30 tested pregabalin as an adjunctive medication in patients undergoing ankle surgery and found no difference in moderate to severe pain scores or opioid use compared with placebo. Cheung et al.9 studied a group of patients undergoing dental surgery and found the analgesic efficacy of pregabalin to be more pronounced when administered postoperatively rather than preoperatively. In addition, like all medications, pregabalin can have adverse effects, and perioperative administration has been linked with postoperative respiratory depression.31 According to the US Food and Drug Administration, the most common adverse reactions to pregabalin are dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and abnormal thinking (primary difficulty with concentration/ attention).6 Pregabalin and other anticonvulsants also carry an increased risk of suicidal ideation.6,32 Several studies reported more adverse effects among those taking pregabalin.10,14,27,33 Limitations of this study include a relatively small number of subjects, although the study was appropriately powered to detect a difference in pain scores between the 2 groups. Due to the limited number of subjects, only 1 dose strength (150 mg) was administered to the treatment arm. A recent study by Wong et al.34 determined the median effective dose of pregabalin in humans to be 252 mg. Whether this means the treatment arm received a suboptimal dose remains unknown as there are no well-powered dose–response studies to date on pregabalin in humans. Conversely, some studies have shown pregabalin to be efficacious in single preoperative doses as low as 75 mg.9,18 Additionally, the eyelid procedures performed have inherently low morbidity, begging the question as to whether adjunctive pain control is worth extra cost if adequate pain control can be achieved with over-the-counter pain medications. More invasive surgical procedures, such as external dacryocystorhinostomy and orbital biopsy, were considered for inclusion in the study; however, the concomitant administration of variable amounts of intravenous and inhalational anesthetics was thought to be a large confounding factor. Patients who were taking antidepressants were not excluded from the study. While pregabalin is not an antidepressant, there is a risk of additive effects and increased central nervous system depression while on both medications. Oxygen saturation was not monitored while the patients were undergoing the procedure, and the authors acknowledge that this would have been a prudent addition to the methodology. Finally, the study drug and the placebo did not look identical. The manufacturer of the placebo was unable to print on the capsules to emulate the study drug. The authors considered overencapsulation of the study drug, but ultimately decided against this action due to concerns of decreased absorption. It is unknown whether the subjects drew any conclusions based on the appearance of the single pill they received. In fact, 4 patients in the placebo group reported what they perceived to be side effects. Because the subjects were neither informed to which group they were randomized, nor were they told that there was any difference between the medication being administered to each group, the authors maintain that the study was performed in a double-masked fashion. Future larger studies are warranted to explore the role of neuropathic pain modulators as adjuncts or as part of a multimodal postoperative pain control regimen after oculoplastic
134
procedures. The effectiveness of this class of drugs on pain after more invasive oculoplastic surgery, such as orbital and lacrimal procedures, is yet to be examined. The ideal timing of administration of this class of medication in relationship to surgical procedures is also yet to be studied. Opportunities for development of a standardized dosing protocol for neuropathic pain modulators also exist, as many of the studies that have been performed use different dosing regimens.
REFERENCES 1. Gottschalk A, Smith DS. New concepts in acute pain therapy: preemptive analgesia. Am Fam Physician 2001;63:1979–84. 2. Carroll I, Hah J, Mackey S, et al. Perioperative interventions to reduce chronic postsurgical pain. J Reconstr Microsurg 2013;29:213–22. 3. Lee SK, Lee JW, Choy WS. Is multimodal analgesia as effective as postoperative patient-controlled analgesia following upper extremity surgery? Orthop Traumatol Surg Res 2013;99:895–901. 4. Campiglia L, Consales G, De Gaudio AR. Pre-emptive analgesia for postoperative pain control: a review. Clin Drug Investig 2010;30 Suppl 2:15–26. 5. Bryans JS, Wustrow DJ. 3-substituted GABA analogs with central nervous system activity: a review. Med Res Rev 1999;19:149–77. 6. Lyrica (Pregabalin) Prescribing Information. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/ 021446s013s014lbl.pdf. Accessed February 7, 2011. 7. Balaban F, Yağar S, Özgök A, et al. A randomized, placebo-controlled study of pregabalin for postoperative pain intensity after laparoscopic cholecystectomy. J Clin Anesth 2012;24:175–8. 8. Bornemann-Cimenti H, Lederer AJ, Wejbora M, et al. Preoperative pregabalin administration significantly reduces postoperative opioid consumption and mechanical hyperalgesia after transperitoneal nephrectomy. Br J Anaesth 2012;108:845–9. 9. Cheung CW, Choi WS, Leung YY, et al. A double-blind randomized crossover study to evaluate the timing of pregabalin for third molar surgery under local anesthesia. J Oral Maxillofac Surg 2012;70:25–30. 10. Fassoulaki A, Melemeni A, Tsaroucha A, et al. Perioperative pregabalin for acute and chronic pain after abdominal hysterectomy or myomectomy: a randomised controlled trial. Eur J Anaesthesiol 2012;29:531–6. 11. Gianesello L, Pavoni V, Barboni E, et al. Perioperative pregabalin for postoperative pain control and quality of life after major spinal surgery. J Neurosurg Anesthesiol 2012;24:121–6. 12. Kim SY, Song JW, Park B, et al. Pregabalin reduces post-operative pain after mastectomy: a double-blind, randomized, placebo-controlled study. Acta Anaesthesiol Scand 2011;55:290–6. 13. Kumar KP, Kulkarni DK, Gurajala I, et al. Pregabalin versus tramadol for postoperative pain management in patients undergoing lumbar laminectomy: a randomized, double-blinded, placebo-controlled study. J Pain Res 2013;6:471–8. 14. Mathiesen O, Jørgensen DG, Hilsted KL, et al. Pregabalin and dexamethasone improves post-operative pain treatment after tonsillectomy. Acta Anaesthesiol Scand 2011;55:297–305. 15. Pakravan M, Roshani M, Yazdani S, et al. Pregabalin and gabapentin for post-photorefractive keratectomy pain: a randomized controlled trial. Eur J Ophthalmol 2012;22 Suppl 7:S106–13. 16. Peng PW, Li C, Farcas E, et al. Use of low-dose pregabalin in patients undergoing laparoscopic cholecystectomy. Br J Anaesth 2010;105:155–61. 17. Pesonen A, Suojaranta-Ylinen R, Hammarén E, et al. Pregabalin has an opioid-sparing effect in elderly patients after cardiac surgery: a randomized placebo-controlled trial. Br J Anaesth 2011;106:873–81. 18. Sagit M, Yalcin S, Polat H, et al. Efficacy of a single preoperative dose of pregabalin for postoperative pain after septoplasty. J Craniofac Surg 2013;24:373–5. 19. Spreng UJ, Dahl V, Raeder J. Effect of a single dose of pregabalin on post-operative pain and pre-operative anxiety in patients undergoing discectomy. Acta Anaesthesiol Scand 2011;55:571–6. 20. Choi YS, Shim JK, Song JW, et al. Combination of pregabalin and dexamethasone for postoperative pain and functional outcome in
© 2014 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.
Ophthal Plast Reconstr Surg, Vol. 31, No. 2, 2015
patients undergoing lumbar spinal surgery: a randomized placebocontrolled trial. Clin J Pain 2013;29:9–14. 21. Buvanendran A, Kroin JS, Kari M, et al. Can a single dose of 300 mg of pregabalin reach acute antihyperalgesic levels in the central nervous system? Reg Anesth Pain Med 2010;35:535–8. 22. Cao Y, Wang H, Chiang CY, et al. Pregabalin suppresses nociceptive behavior and central sensitization in a rat trigeminal neuropathic pain model. J Pain 2013;14:193–204. 23. Lee C, Lee HW, Kim JN. Effect of oral pregabalin on opioid-induced hyperalgesia in patients undergoing laparo-endoscopic single-site urologic surgery. Korean J Anesthesiol 2013;64:19–24. 24. Michelson JD, Addante R, Charlson MD. Multimodal analgesia therapy reduces length of hospitalization in patients undergoing fusions of the ankle and hindfoot. Foot Ankle Int 2013;34:1526–34. 25. Brunton LM, Laporte DM. Use of gabapentin and pregabalin for hand surgery patients. J Hand Surg Am 2012;37:1486–8. 26. Chaparro LE, Clarke H, Valdes PA, et al. Adding pregabalin to a multimodal analgesic regimen does not reduce pain scores following cosmetic surgery: a randomized trial. J Anesth 2012;26:829–35. 27. Zhang J, Ho KY, Wang Y. Efficacy of pregabalin in acute postoperative pain: a meta-analysis. Br J Anaesth 2011;106:454–62. 28. Clarke H, Bonin RP, Orser BA, et al. The prevention of chronic postsurgical pain using gabapentin and pregabalin: a
Pregabalin Postoperative Pain
combined systematic review and meta-analysis. Anesth Analg 2012;115:428–42. 29. Trabulsi EJ, Patel J, Viscusi ER, et al. Preemptive multimodal pain regimen reduces opioid analgesia for patients undergoing robotic-assisted laparoscopic radical prostatectomy. Urology 2010;76:1122–4. 30. Yadeau JT, Paroli L, Kahn RL, et al. Addition of pregabalin to multimodal analgesic therapy following ankle surgery: a randomized double-blind, placebo-controlled trial. Reg Anesth Pain Med 2012;37:302–7. 31. Eipe N, Penning J. Postoperative respiratory depression with pregabalin: a case series and a preoperative decision algorithm. Pain Res Manag 2011;16:353–6. 32. Silverman A, Samuels Q, Gikas H, et al. Pregabalin for the treatment of abdominal adhesion pain: a randomized, double-blind, placebo-controlled trial. Am J Ther 2012;19:419–28. 3 3. Engelman E, Cateloy F. Efficacy and safety of perioperative pregabalin for post-operative pain: a meta-analysis of randomized-controlled trials. Acta Anaesthesiol Scand 2011;55: 927–43. 34. Wong W, Wallace MS. Determination of the effective dose of pregabalin on human experimental pain using the sequential up-down method. J Pain 2014;15:25–31.
© 2014 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.
135
Perioperative Pregabalin for Attenuation of Postoperative Pain After Eyelid Surgery Leslie A. Wei, M.D.,*† Brett W. Davies, M.D.,* Eric M. Hink, M.D.,* and Vikram D. Durairaj, M.D.*‡§ *Department of Ophthalmology, Oculoplastic and Orbital Surgery Service, University of Colorado, Denver, U.S.A.; †Department of Ophthalmology and Visual Sciences, Oculoplastic, Facial Cosmetic, and Orbital Surgery Division, University of Wisconsin–Madison, U.S.A.; ‡Department of Otolaryngology and Head and Neck Surgery, University of Colorado, Denver, U.S.A.; and §Texas Oculoplastic Consultants, Austin, Texas, U.S.A.
Purpose: To examine the effect of a 1-time dose of pregabalin (Lyrica) on the perception of pain and analgesic consumption after oculofacial plastic surgery. Methods: In this prospective, randomized, double-blind, placebo-controlled trial, patients presenting to the oculofacial plastic surgery service at University of Colorado Eye Center for functional eyelid surgery and who met the study criteria were consecutively enrolled between October 2011 and September 2012. Subjects were randomized to either placebo or 150 mg pregabalin administered 15 minutes to an hour prior to the procedure. The procedure was then performed under the usual standard of care. Postoperatively, study subjects recorded pain scores on visual analog scales (range 0–100) at 1 to 2 hours, 2 to 4 hours, 8 to 12 hours, 20 to 28 hours, and 36 to 48 hours and the amount of acetaminophen consumed. Data were analyzed with Statistical Analysis System software using mixed-effects linear models. Results: Fifty-two patients were enrolled. Three patients were excluded due to incomplete follow up (n = 2) and postoperative course requiring early unblinding (n = 1). Twenty-six subjects were men. Average age was 68 years (range, 25–89). Eyelid procedures performed included blepharoplasty (18), canthoplasty (11), ptosis repair (15), eyelid retraction repair (2), pentagonal wedge resection (1), and MOHS reconstruction (2). Twenty-six patients were randomized to receive pregabalin, while the remainder received placebo. There was no significant difference in demographics between the 2 groups. The pregabalin group reported pain scores that were 5.5 points lower on average compared with the placebo group (p = 0.0307). Patients in the pregabalin group also consumed half as much acetaminophen (1.3 g) on average as the placebo group (2.6 g) during the postoperative period. Conclusions: Pregabalin is effective in reducing postoperative pain after oculoplastic procedures when compared with placebo. It may be a useful adjunct for pain control in selected patients. (Ophthal Plast Reconstr Surg 2015;31:132–135)
P
ostoperative pain is inadequately treated in approximately half of all surgical procedures, with 10% of patients going
Accepted for publication April 26, 2014. Presentation at the American Society of Ophthalmic Plastic and Reconstructive Surgery Annual Meeting on November 15, 2013 in New Orleans, Louisiana, U.S.A. E.M.H. is a speaker for Synthes/AO Foundation. V.D.D. is a consultant for Stryker, speaker for KLS Martin and AO Foundation, and equity owner in OnPHarma. The remaining authors have no financial or conflicts of interest to disclose. Address correspondence and reprint requests to Vikram D. Durairaj, M.D., 3705 Medical Pkwy #120, Austin, TX 78705. E-mail: [email protected] DOI: 10.1097/IOP.0000000000000219
132
on to develop long-term postoperative pain.1,2 An evolving trend in the literature on postoperative pain management involves the administration of pre-emptive analgesics.3,4 Pregabalin is a 3-alkylated gamma-amino butyric acid analog that functions as a neuropathic pain modulator by binding to the α2δ subunit of voltage-gated calcium channels on neurons.5 This inhibits the release of excitatory neurotransmitters that mediate pain, such as substance P, calcitonin, and glutamate.5 It is currently US Food and Drug Administration–approved for the treatment of epilepsy, postherpetic neuralgia, diabetic neuropathy, and fibromyalgia.6 Pregabalin has been shown to be efficacious in reducing postoperative pain for patients undergoing dental surgery, spine surgery, hand surgery, podiatric surgery, laparoscopic hysterectomy and other gynecologic operations, knee replacement, refractive surgery, nephrectomy, rhinoplasty, photorefractive keratectomy, and laparoscopic cholecystectomy.7–20 To date, pregabalin has not been studied for oculoplastic eyelid procedures. Because postoperative pain can vary with the surgical site, the effectiveness of pregabalin demonstrated in previous studies should not be generalized to all surgeries. The purpose of this study was to determine the effectiveness of pregabalin after eyelid surgery.
METHODS This study was approved by the Colorado Multiple Institutional Review Board. Patients aged between 22 and 90 years presenting to the oculofacial plastic surgery service at University of Colorado Eye Center were consecutively screened and enrolled by trained study personnel. Inclusion criteria consisted of the age limits described above and a functional indication for blepharoplasty, lateral canthoplasty, eyelid retraction surgery, ptosis surgery, or eyelid reconstruction. Exclusion criteria included 1) renal disease (creatinine clearance 0.10).
DISCUSSION Controlling postoperative pain effectively requires an understanding of the various kinds of pain that can be induced
Hours after surgery, h
Pregabalin
Placebo
1–2 2–4 8–12 20–28 36–48
12.9 (0–73) 14.0 (0–48) 10.8 (0–63) 11.3 (0–80) 11.0 (0–57)
29.4 (0–94) 25.6 (0–76) 20.6 (0–97) 9.7 (0–69) 2.1 (0–10)
Pain scores were recorded on a 100-mm-long visual analog scale. Averages are listed with range in parentheses.
by surgery: somatic, visceral, and neuropathic. Pregabalin addresses the neuropathic pain component by diminishing hyperalgesia and central sensitization.21–23 It has ≥90% oral bioavailability, is minimally metabolized, and has a half-life of 6.3 hours.6 In addition to analgesic effects, pregabalin has anxiolytic and mild sedative properties that can improve patient comfort.5,13 It has been methodically compared with other analgesics/anti-inflammatories and placebo in a variety of surgical procedures, from photorefractive keratectomy to transperitoneal nephrectomy. In many studies, it has been found to be effective in decreasing pain scores, opioid and other analgesic consumption, and anxiety.7–13,15–21,23–27 Effective postoperative pain control is also dependent on the timing of analgesic administration. The goal of preemptive analgesia is to decrease inflammatory pain from surgical incision, decrease the pain memory response, and avoid the development of long-term postoperative pain.1,4 The use of neuropathic pain modulators such as pregabalin and gabapentin may lessen the possibility of developing long-term postoperative pain.17,28 They can be used alone or in combination with other medications, such as dexamethasone, patient-controlled analgesia, oral opioids, COX-2 inhibitors, acetaminophen, and tramadol.13,14,20,29 These multimodal postoperative pain control regimens are being used with increasing frequency and have been found to decrease length of hospital stay for surgical procedures.24 In this trial, a single 150-mg perioperative dose of pregabalin was found to reduce average pain scores compared with placebo in patients undergoing oculoplastic eyelid procedures. The pain-reducing effect of pregabalin was significant compared with placebo at the first 3 time points (1 to 2, 2 to 4, and 8 to 12 hours after surgery), but not thereafter. It was also found to reduce the amount of acetaminophen consumption during the first 48 hours after surgery. It is notable that a greater number of participants in the pregabalin group (9) experienced side effects compared with the placebo group (4); however, this difference was not found to be statistically significant. Pregabalin may be a useful alternative medication over narcotics for pain control in TABLE 3. Side effects in the pregabalin and placebo groups Side effects
TABLE 1. Patient characteristics
Male sex, n (%) Age, y, mean ± SD
TABLE 2. Pain scores
Overall (n = 49)
Lyrica (n = 26)
Placebo (n = 23)
p
26 (53.1%) 67.4 ± 11.8
14 (53.9%) 65.0 ± 13.4
12 (52.2%) 70.2 ± 9.2
0.9068* 0.1191†
The placebo and pregabalin groups were similar in age and gender distribution. *χ2 test. †t test.
Sleepiness Dizziness Nausea Headache Total
Pregabalin group (n = 26)
Placebo group (n = 23)
Total (n = 49)
4 (15.4%) 2 (7.7%) 1 (3.8%) 2 (7.7%) 9 (34.6%)
0 2 (8.7%) 2 (8.7%) 0 4 (17.4%)
4 (8.2%) 4 (8.2%) 3 (6.1%) 2 (4.1%) 13 (26.5%)
More patients in the pregabalin group experienced side effects compared with the placebo group.
© 2014 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.
133
Ophthal Plast Reconstr Surg, Vol. 31, No. 2, 2015
L. A. Wei et al.
patients who are not adequately controlled with Tylenol or other over-the-counter pain medications. While most studies, including ours, that investigated pregabalin for postoperative pain have found it to be effective, not all have found it a useful adjunct.26,30 Chaparro et al.26 randomized cosmetic surgery patients to pregabalin or placebo q12 hours for 5 days starting the night before surgery and found no difference in pain scores between the 2 groups.26 Yadeau et al.30 tested pregabalin as an adjunctive medication in patients undergoing ankle surgery and found no difference in moderate to severe pain scores or opioid use compared with placebo. Cheung et al.9 studied a group of patients undergoing dental surgery and found the analgesic efficacy of pregabalin to be more pronounced when administered postoperatively rather than preoperatively. In addition, like all medications, pregabalin can have adverse effects, and perioperative administration has been linked with postoperative respiratory depression.31 According to the US Food and Drug Administration, the most common adverse reactions to pregabalin are dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and abnormal thinking (primary difficulty with concentration/ attention).6 Pregabalin and other anticonvulsants also carry an increased risk of suicidal ideation.6,32 Several studies reported more adverse effects among those taking pregabalin.10,14,27,33 Limitations of this study include a relatively small number of subjects, although the study was appropriately powered to detect a difference in pain scores between the 2 groups. Due to the limited number of subjects, only 1 dose strength (150 mg) was administered to the treatment arm. A recent study by Wong et al.34 determined the median effective dose of pregabalin in humans to be 252 mg. Whether this means the treatment arm received a suboptimal dose remains unknown as there are no well-powered dose–response studies to date on pregabalin in humans. Conversely, some studies have shown pregabalin to be efficacious in single preoperative doses as low as 75 mg.9,18 Additionally, the eyelid procedures performed have inherently low morbidity, begging the question as to whether adjunctive pain control is worth extra cost if adequate pain control can be achieved with over-the-counter pain medications. More invasive surgical procedures, such as external dacryocystorhinostomy and orbital biopsy, were considered for inclusion in the study; however, the concomitant administration of variable amounts of intravenous and inhalational anesthetics was thought to be a large confounding factor. Patients who were taking antidepressants were not excluded from the study. While pregabalin is not an antidepressant, there is a risk of additive effects and increased central nervous system depression while on both medications. Oxygen saturation was not monitored while the patients were undergoing the procedure, and the authors acknowledge that this would have been a prudent addition to the methodology. Finally, the study drug and the placebo did not look identical. The manufacturer of the placebo was unable to print on the capsules to emulate the study drug. The authors considered overencapsulation of the study drug, but ultimately decided against this action due to concerns of decreased absorption. It is unknown whether the subjects drew any conclusions based on the appearance of the single pill they received. In fact, 4 patients in the placebo group reported what they perceived to be side effects. Because the subjects were neither informed to which group they were randomized, nor were they told that there was any difference between the medication being administered to each group, the authors maintain that the study was performed in a double-masked fashion. Future larger studies are warranted to explore the role of neuropathic pain modulators as adjuncts or as part of a multimodal postoperative pain control regimen after oculoplastic
134
procedures. The effectiveness of this class of drugs on pain after more invasive oculoplastic surgery, such as orbital and lacrimal procedures, is yet to be examined. The ideal timing of administration of this class of medication in relationship to surgical procedures is also yet to be studied. Opportunities for development of a standardized dosing protocol for neuropathic pain modulators also exist, as many of the studies that have been performed use different dosing regimens.
REFERENCES 1. Gottschalk A, Smith DS. New concepts in acute pain therapy: preemptive analgesia. Am Fam Physician 2001;63:1979–84. 2. Carroll I, Hah J, Mackey S, et al. Perioperative interventions to reduce chronic postsurgical pain. J Reconstr Microsurg 2013;29:213–22. 3. Lee SK, Lee JW, Choy WS. Is multimodal analgesia as effective as postoperative patient-controlled analgesia following upper extremity surgery? Orthop Traumatol Surg Res 2013;99:895–901. 4. Campiglia L, Consales G, De Gaudio AR. Pre-emptive analgesia for postoperative pain control: a review. Clin Drug Investig 2010;30 Suppl 2:15–26. 5. Bryans JS, Wustrow DJ. 3-substituted GABA analogs with central nervous system activity: a review. Med Res Rev 1999;19:149–77. 6. Lyrica (Pregabalin) Prescribing Information. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/ 021446s013s014lbl.pdf. Accessed February 7, 2011. 7. Balaban F, Yağar S, Özgök A, et al. A randomized, placebo-controlled study of pregabalin for postoperative pain intensity after laparoscopic cholecystectomy. J Clin Anesth 2012;24:175–8. 8. Bornemann-Cimenti H, Lederer AJ, Wejbora M, et al. Preoperative pregabalin administration significantly reduces postoperative opioid consumption and mechanical hyperalgesia after transperitoneal nephrectomy. Br J Anaesth 2012;108:845–9. 9. Cheung CW, Choi WS, Leung YY, et al. A double-blind randomized crossover study to evaluate the timing of pregabalin for third molar surgery under local anesthesia. J Oral Maxillofac Surg 2012;70:25–30. 10. Fassoulaki A, Melemeni A, Tsaroucha A, et al. Perioperative pregabalin for acute and chronic pain after abdominal hysterectomy or myomectomy: a randomised controlled trial. Eur J Anaesthesiol 2012;29:531–6. 11. Gianesello L, Pavoni V, Barboni E, et al. Perioperative pregabalin for postoperative pain control and quality of life after major spinal surgery. J Neurosurg Anesthesiol 2012;24:121–6. 12. Kim SY, Song JW, Park B, et al. Pregabalin reduces post-operative pain after mastectomy: a double-blind, randomized, placebo-controlled study. Acta Anaesthesiol Scand 2011;55:290–6. 13. Kumar KP, Kulkarni DK, Gurajala I, et al. Pregabalin versus tramadol for postoperative pain management in patients undergoing lumbar laminectomy: a randomized, double-blinded, placebo-controlled study. J Pain Res 2013;6:471–8. 14. Mathiesen O, Jørgensen DG, Hilsted KL, et al. Pregabalin and dexamethasone improves post-operative pain treatment after tonsillectomy. Acta Anaesthesiol Scand 2011;55:297–305. 15. Pakravan M, Roshani M, Yazdani S, et al. Pregabalin and gabapentin for post-photorefractive keratectomy pain: a randomized controlled trial. Eur J Ophthalmol 2012;22 Suppl 7:S106–13. 16. Peng PW, Li C, Farcas E, et al. Use of low-dose pregabalin in patients undergoing laparoscopic cholecystectomy. Br J Anaesth 2010;105:155–61. 17. Pesonen A, Suojaranta-Ylinen R, Hammarén E, et al. Pregabalin has an opioid-sparing effect in elderly patients after cardiac surgery: a randomized placebo-controlled trial. Br J Anaesth 2011;106:873–81. 18. Sagit M, Yalcin S, Polat H, et al. Efficacy of a single preoperative dose of pregabalin for postoperative pain after septoplasty. J Craniofac Surg 2013;24:373–5. 19. Spreng UJ, Dahl V, Raeder J. Effect of a single dose of pregabalin on post-operative pain and pre-operative anxiety in patients undergoing discectomy. Acta Anaesthesiol Scand 2011;55:571–6. 20. Choi YS, Shim JK, Song JW, et al. Combination of pregabalin and dexamethasone for postoperative pain and functional outcome in
© 2014 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.
Ophthal Plast Reconstr Surg, Vol. 31, No. 2, 2015
patients undergoing lumbar spinal surgery: a randomized placebocontrolled trial. Clin J Pain 2013;29:9–14. 21. Buvanendran A, Kroin JS, Kari M, et al. Can a single dose of 300 mg of pregabalin reach acute antihyperalgesic levels in the central nervous system? Reg Anesth Pain Med 2010;35:535–8. 22. Cao Y, Wang H, Chiang CY, et al. Pregabalin suppresses nociceptive behavior and central sensitization in a rat trigeminal neuropathic pain model. J Pain 2013;14:193–204. 23. Lee C, Lee HW, Kim JN. Effect of oral pregabalin on opioid-induced hyperalgesia in patients undergoing laparo-endoscopic single-site urologic surgery. Korean J Anesthesiol 2013;64:19–24. 24. Michelson JD, Addante R, Charlson MD. Multimodal analgesia therapy reduces length of hospitalization in patients undergoing fusions of the ankle and hindfoot. Foot Ankle Int 2013;34:1526–34. 25. Brunton LM, Laporte DM. Use of gabapentin and pregabalin for hand surgery patients. J Hand Surg Am 2012;37:1486–8. 26. Chaparro LE, Clarke H, Valdes PA, et al. Adding pregabalin to a multimodal analgesic regimen does not reduce pain scores following cosmetic surgery: a randomized trial. J Anesth 2012;26:829–35. 27. Zhang J, Ho KY, Wang Y. Efficacy of pregabalin in acute postoperative pain: a meta-analysis. Br J Anaesth 2011;106:454–62. 28. Clarke H, Bonin RP, Orser BA, et al. The prevention of chronic postsurgical pain using gabapentin and pregabalin: a
Pregabalin Postoperative Pain
combined systematic review and meta-analysis. Anesth Analg 2012;115:428–42. 29. Trabulsi EJ, Patel J, Viscusi ER, et al. Preemptive multimodal pain regimen reduces opioid analgesia for patients undergoing robotic-assisted laparoscopic radical prostatectomy. Urology 2010;76:1122–4. 30. Yadeau JT, Paroli L, Kahn RL, et al. Addition of pregabalin to multimodal analgesic therapy following ankle surgery: a randomized double-blind, placebo-controlled trial. Reg Anesth Pain Med 2012;37:302–7. 31. Eipe N, Penning J. Postoperative respiratory depression with pregabalin: a case series and a preoperative decision algorithm. Pain Res Manag 2011;16:353–6. 32. Silverman A, Samuels Q, Gikas H, et al. Pregabalin for the treatment of abdominal adhesion pain: a randomized, double-blind, placebo-controlled trial. Am J Ther 2012;19:419–28. 3 3. Engelman E, Cateloy F. Efficacy and safety of perioperative pregabalin for post-operative pain: a meta-analysis of randomized-controlled trials. Acta Anaesthesiol Scand 2011;55: 927–43. 34. Wong W, Wallace MS. Determination of the effective dose of pregabalin on human experimental pain using the sequential up-down method. J Pain 2014;15:25–31.
© 2014 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.
135
