Skip to main content
Log in

A Review of Adjunctive CNS Medications Used for the Treatment of Post-Surgical Pain

CNS Drugs Aims and scope Submit manuscript

Abstract

Inadequate post-operative pain management can have significant impacts on patients’ quality of life. Effective management of acute pain after surgery is important for early mobilization and discharge from hospital, patient satisfaction, and overall well-being. Utilizing multimodal analgesic strategies has become the mainstay of acute post-operative pain management. A comprehensive search was performed, assessing the published or otherwise publically available literature on different central nervous system (CNS) drugs [excluding opioids, non-steroidal anti-inflammatory drugs (NSAIDs), and acetaminophen] and their uses to treat acute post-surgical pain. Included among the drugs evaluated in this review are anticonvulsants, N-methyl-d-aspartic acid (NMDA) agonists, local anesthetics, α2-agonists, cannabinoids, serotonin–noradrenaline reuptake inhibitors (SNRIs), and serotonin–noradrenaline–dopamine reuptake inhibitors (SNDRIs). Timing, dosing, routes of administration, as well as mechanisms of action are discussed for these CNS drugs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

References

  1. Muller S, Zalunardo MP, Hubner M, Clavien PA, Demartines N. A fast-track program reduces complications and length of hospital stay after open colonic surgery. Gastroenterology. 2009;136:842–7.

    Article  PubMed  Google Scholar 

  2. De Oliveira GS Jr, Castro-Alves LJ, Khan JH, McCarthy RJ. Perioperative systemic magnesium to minimize postoperative pain: a meta-analysis of randomized controlled trials. Anesthesiology. 2013;119(1):178–90.

    Article  PubMed  Google Scholar 

  3. Brodner G. Acute pain management: analysis, implications and consequences after prospective experience with 6349 surgical patients. Eur J Anaesthesiol. 2000;17(9):566.

    Article  CAS  PubMed  Google Scholar 

  4. Katz J, Clarke H, Seltzer Z. Preventice analgesia: quo vadimus? Anesth Analg. 2011;113(5):1242–53.

    Article  PubMed  Google Scholar 

  5. Radvansky BM, Shah K, Parikh A, Sifonios AN, Le V, Eloy JD. Role of ketamine in acute postoperative pain management: a narrative review. Biomed Res Int. 2015. doi:10.1155/2015/749837

  6. Hakkarainen TWS, Steele SR, Bastaworous A, Delinger EP, Farrokhi E, Farjah F, Florence M, Helton S, Horton M, Pietro M, Varghese TK, Flum DR. Nonsteroidal anti-inflammatory drugs and the risk for anastomotic failure: a report from Washington State’s Surgical Care and Outcomes Assessment Program (SCOAP). JAMA Surg. 2015;150(3):223–8.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Pountos I, Georgouli T, Calori GM, Giannoudis PV. Do nonsteroidal anti-inflammatory drugs affect bone healing? A critical analysis. Sci World J. 2012. doi: 10.1100/2012/606404

  8. Clarke HA, Woodhouse LJ, Kennedy D, Stratford P, Katz J. Strategies aimed at preventing chronic post-surgical pain: comprehensive perioperative pain management after total joint replacement surgery. Physiother Can. 2011;63(3):289–304.

    Article  PubMed  PubMed Central  Google Scholar 

  9. White PF. The changing role of non-opioid analgesic techniques in the management of postoperative pain. Anesth Analg. 2005;101:S5–22.

    Article  PubMed  Google Scholar 

  10. Chang YCL, Liu CL, Liu TP, Yang PS, Chen MJ, Cheng SP. Effect of perioperative intravenous lidocaine infusion on acute and chronic pain after breast surgery: a meta-analysis of randomized controlled trials. Pain Pract. 2017;17(3):336–43.

  11. Elia N, Culebras X, Mazza C, Schiffer E, Tramer MR. Clonidine as an adjuvant to intrathecal local anesthetics for surgery: systematic review of randomized trials. Reg Anesth Pain Med. 2008;33(2):159–67.

    CAS  PubMed  Google Scholar 

  12. Schmidt PC, Ruchelli G, Mackey SC, Carroll IR. Perioperative gabapentinoids: choice of agent, dose, timing, and effects on chronic postsurgical pain. Anesthesiology. 2013;119(5):1215–21.

    Article  PubMed  Google Scholar 

  13. Zhai L, Song Z, Liu K. The effect of gabapentin on acute postoperative pain in patients undergoing total knee arthroplasty: a meta-analysis. Medicine (Baltimore). 2016;95(20):e3673.

    Article  CAS  Google Scholar 

  14. Dauri M, Faria S, Gatti A, Celidonio L, Carpenedo R, Sabato AF. Gabapentin and pregabalin for the acute post-operative pain management. A systematic-narrative review of the recent clinical evidences. Curr Drug Targets. 2009;10:716–33.

    Article  CAS  PubMed  Google Scholar 

  15. Turan A, White PF, Karamanlioglu B, Memis D, Tasdogan M, Pamukcu Z. Gabapentin: an alternative to the cyclooxygenase-2 inhibitors for perioperative pain management. Anesth Analg. 2006;109:981.

    Google Scholar 

  16. Lam DM, Choi SW, Wong SS, Irwin MG, Cheung CW. Efficacy of pregabalin in acute postoperative pain under different surgical categories: a meta-analysis. Medicine (Baltimore). 2015;94(46):e1944.

    Article  CAS  Google Scholar 

  17. Mishriky BM, Waldron NH, Habib AS. Impact of pregabalin on acute and persistent postoperative pain: a systematic review and meta-analysis. Br J Anaesth. 2015;114(1):10–31.

    Article  CAS  PubMed  Google Scholar 

  18. Eipe N, Penning J, Yazdi F, Mallick R, Turner L, Ahmadzai N, Ansari MT. Perioperative use of pregabalin for acute pain—a systematic review and meta-analysis. Pain. 2015;156(7):1284–300.

    Article  PubMed  Google Scholar 

  19. Klatt E, Zumbrunn T, Bandschapp O, Girard T, Ruppen W. Intra- and postoperative intravenous ketamine does not prevent chronic pain: a systematic review and meta-analysis. Scand J Pain. 2015;7:42–54.

    Article  Google Scholar 

  20. Laskowski K, Stirling A, McKay WP, Lim HJ. A systematic review of intravenous ketamine for postoperative analgesia. Can J Anaesth. 2011;58:911–23.

    Article  PubMed  Google Scholar 

  21. Wang L, Johnston B, Kaushal A, Cheng D, Zhu F, Martin J. Ketamine added to morphine of hydromorphone patient-controlled analgesia for acute postoperative pain in adults: a systematic review and meta-analysis of randomized trials. Can J Anesth. 2016;63:311–25.

    Article  PubMed  Google Scholar 

  22. Bell RF, Dahl JB, Moore RA, Kalso E. Peri-operative ketamine for acute post-operative pain: a quantitative and qualitative systematic review (Cochrane review). Acta Anaesthesiol Scand. 2005;49:1405–28.

    Article  CAS  PubMed  Google Scholar 

  23. Fukui S, Komoda Y, Nosaka S. Clinical application of amantadine, an NMDA antagonist, for neuropathic pain. J Anesth. 2001;15:179–81.

    Article  CAS  PubMed  Google Scholar 

  24. Yazdani J, Aghamohamadi D, Amani M, Mesgarzadeh AH, Asl DM, Pourlak T. Effect of preoperative oral amantadine on acute and chronic postoperative pain after mandibular fracture surgery. Anesthesiol Pain Med. 2016;6(3):e35900.

    Google Scholar 

  25. Gottschalk A, Schroeder F, Ufer M, Oncu A, Buerkle H, Standl T. Amantadine, a N-methyl-d-aspartate receptor antagonist, does not enhance postoperative analgesia in women undergoing abdominal hysterectomy. Anesth Analg. 2001;93:192–6.

    Article  CAS  PubMed  Google Scholar 

  26. Bujak-Gizycka B, Kącka K, Suski M, Olszanecki R, Madej J, Dobrogowski J, Korbut R. Beneficial effect of amantadine on postoperative pain reduction and consumption of morphine in patients subjected to elective spine surgery. Pain Med. 2012;13:459–65.

    Article  PubMed  Google Scholar 

  27. Snijdelaar DG, Koren G, Katz J. Effects of perioperative oral amantadine on postoperative pain and morphine consumption in patients after radical prostatectomy. Anesthesiology. 2004;100:134–41.

    Article  CAS  PubMed  Google Scholar 

  28. McCarthy RJ, Kroin JS, Tuman KJ, Penn RD, Ivankovich AD. Antinociceptive potentiation and attenuation of tolerance by intrathecal co-infusion of magnesium sulfate and morphine in rats. Anesth Analg. 1998;86:830–6.

    Article  CAS  PubMed  Google Scholar 

  29. Lauretti GR. Mechanisms of analgesia of intravenous lidocaine. Rev Bras Anestesiol. 2008;58(3):280–6.

    Article  CAS  PubMed  Google Scholar 

  30. Koppert W, Ostermeier N, Sittl R, Weidner C, Schmelz M. Low-dose lidocaine reduces secondary hyperalgesia by a central mode of action. Pain. 2000;85:217–24.

    Article  CAS  PubMed  Google Scholar 

  31. Hollmann MW, Durieux ME. Local anesthetics and the inflammatory response: a new therapeutic indication? Anesthesiology. 2000;93:858–75.

    Article  CAS  PubMed  Google Scholar 

  32. Vigneault L, Turgeon AF, Cote D, Lauzier F, Zarychanski R, Moore L, McIntyre LA, Nicole PC, Fergusson DA. Perioperative intravenous lidocaine infusion for postoperative pain control: a meta-analysis of randomized controlled trials. Can J Anaesth. 2011;58(1):22–37.

    Article  PubMed  Google Scholar 

  33. Pyati S, Gan TJ. Perioperative pain management. CNS Drugs. 2007;21(3):185–211.

    Article  CAS  PubMed  Google Scholar 

  34. Engelman E, Marsala C. Efficacy of adding clonidine to intrathecal morphine in acute postoperative pain: meta-analysis. Br J Anaesth. 2013;110(1):21–7.

    Article  CAS  PubMed  Google Scholar 

  35. Blaudszun G, Lysakowski C, Elia N, Tramer MR. Effect of perioperative systemic alpha2 agonists on postoperative morphine consumption and pain intensity: systematic review and meta-analysis of randomized controlled trials. Anesthesiology. 2012;116(6):1312–22.

    Article  CAS  PubMed  Google Scholar 

  36. Bhana NG, Goa KL, McClellan KJ. Dexmedetomidine. Drugs. 2000;59:263–8.

    Article  CAS  PubMed  Google Scholar 

  37. Arain SR, Ruehlow RM, Uhrich TD, Ebert TJ. The efficacy of dexmedetomidine versus morphine for postoperative analgesia after major inpatient surgery. Anesth Analg. 2004;98:153–8.

    Article  CAS  PubMed  Google Scholar 

  38. Schnabel A, Meyer-Friessem CH, Reichl SU, Zahn PK, Pogatzki-Zahn EM. Is intraoperative dexmedetomidine a new option for postoperative pain treatment? A meta-analysis of randomized controlled trials. Pain. 2013;154(7):1140–9.

    Article  CAS  PubMed  Google Scholar 

  39. Manzanares JJ, Julian MD, Carrascosa A. Role of the cannabinoid system in pain control and therapeutic implications for the management of acute and chronic pain episodes. Curr Neuropharmacol. 2006;4(3):239–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Beaulieu P. Effects of nabilone, a synthetic cannabinoid, on postoperative pain. Can J Anaesth. 2006;53(8):769–75.

    Article  PubMed  Google Scholar 

  41. Buggy DJ, Toogood L, Maric S, Sharpe P, Lambert DG, Rowbotham DJ. Lack of analgesic efficacy of oral delta-9-tetrahydrocannabinol in postoperative pain. Pain. 2003;106(1–2):169–72.

    Article  CAS  PubMed  Google Scholar 

  42. Kim KH, Abdi S. Rediscovery of nefopam for the treatment of neuropathic pain. Korean J Pain. 2014;27(2):103–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Girard P, Chauvin M, Verleye M. Nefopam analgesia and its role in multimodal analgesia: a review of preclinical and clinical studies. Clin Exp Pharmacol Physiol. 2016;43(1):3–12.

    Article  CAS  PubMed  Google Scholar 

  44. Na HS, Oh AY, Koo BW, Lim DJ, Ryu JH, Han JW. Preventive analgesic efficacy of nefopam in acute and chronic pain after breast cancer surgery: a prospective, double-blind, and randomized trial. Medicine (Baltimore). 2016;95(20):e3705.

    Article  CAS  Google Scholar 

  45. Kim K, Kim WJ, Choi DK, Lee YK, Choi IC, Sim JY. The analgesic efficacy and safety of nefopam in patient-controlled analgesia after cardiac surgery: a randomized, double-blind, prospective study. J Int Med Res. 2014;42(3):684–92.

    Article  PubMed  Google Scholar 

  46. Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, Gilron I, Haanpaa M, Hansson P, Jensen TS, Kamerman PR, Lund K, Moore A, Raja SN, Rice ASC, Rowbotham M, Sena E, Siddall P, Smith BH, Wallace M. Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations. Lancet Neurol. 2015;14(2):162–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Iyengar S, Webster AA, Hemrick-Luecke SK, Xu JY, Simmons RM. Efficacy of duloxetine, a potent and balanced serotonin–norepinephrine reuptake inhibitor in persistent pain models in rats. J Pharmacol Exp Ther. 2004;311(2):576–84.

    Article  CAS  PubMed  Google Scholar 

  48. Ho KY, Tay W, Yeo MC, Liu H, Yeo SJ, Chia SL, Lo NN. Duloxetine reduces morphine requirements after knee replacement surgery. Br J Anaesth. 2010;105(3):371–6.

    Article  CAS  PubMed  Google Scholar 

  49. Amr YM, Yousef AA. Evaluation of efficacy of the perioperative administration of venlafaxine or gabapentin on acute and chronic postmastectomy pain. Clin J Pain. 2010;26(5):381–5.

    Article  PubMed  Google Scholar 

  50. Dorr LD, Maheshwari AV, Long WT, Wan Z, Sirianni LE. Early pain relief and function after posterior minimally invasive and conventional total hip arthroplasty. A prospective, randomized, blinded study. J Bone Jt Surg Am. 2007;89(6):1153–60.

    Article  Google Scholar 

  51. Brennan TJ. Pathophysiology of postoperative pain. Pain. 2011;152(3 Suppl):S33–40.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Dray A. Inflammatory mediators of pain. Br J Anaesth. 1995;75(2):125–31.

    Article  CAS  PubMed  Google Scholar 

  53. Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288(5472):1765–9.

    Article  CAS  PubMed  Google Scholar 

  54. Imani F. Postoperative pain management. Anesthesiol Pain Med. 2011;1(1):6–7.

    Article  Google Scholar 

  55. White PF, Kehlet H. Improving postoperative pain management. What are the unresolved issues? Anesthesiology. 2010;112:220–5.

    Article  PubMed  Google Scholar 

  56. Eipe N, Penning J, Yazdi F, Mallick R, Turner L, Ahmadzai N, Ansari MT. Perioperative use of pregabalin for acute pain—a systematic review and meta-analysis. Pain. 2015;156(7):1284–300.

    Article  PubMed  Google Scholar 

  57. Suzuki M, Tsueda K, Lansing PS, Tolan MM, Fuhrman TM, Sheppard RA, Hurst HE, Lippmann SB. Midazolam attenuates ketamine-induced abnormal perception and thought process but not mood changes. Can J Anaesth. 2000;47(9):866–74.

    Article  CAS  PubMed  Google Scholar 

  58. Ho KY, Gan TJ, Habib AS. Gabapentin and postoperative pain—a systematic review of randomized controlled trials. Pain. 2006;126(1–3):91–101.

    Article  CAS  PubMed  Google Scholar 

  59. ASoATFoAP Management. Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology. 2012;116(2):248–73.

    Article  Google Scholar 

  60. Katz J, Weinrib A, Fashler SR, Katznelson R, Shah BR, Ladak SS, Jiang J, Li Q, McMillan K, Mina DS, Wentlandt K, McRae K, Tamir D, Lyn S, de Perrot M, Rao V, Grant D, Roche-Nagle G, Cleary SP, Hofer SO, Gilbert R. The Toronto General Hospital Transitional Pain Service: development and implementation of a multidisciplinary program to prevent chronic postsurgical pain. J Pain Res. 2015;8:695–702.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hance Clarke.

Ethics declarations

Conflict of interest

Ajit Rai, Howard Meng, Aliza Weinrib, Marina Englesakis, Dinesh Kumbhare, Liza Grosman-Rimon, Joel Katz, and Hance Clarke have no financial interests or conflicts of interest to declare.

Funding

No funding was received for conducting this review.

Additional information

Ajit Rai and Howard Meng are co-first authors.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 24 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rai, A., Meng, H., Weinrib, A. et al. A Review of Adjunctive CNS Medications Used for the Treatment of Post-Surgical Pain. CNS Drugs 31, 605–615 (2017). https://doi.org/10.1007/s40263-017-0440-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40263-017-0440-1

Navigation