Patient interactions for the treatment of acute pain in the perioperative phase of care are often necessarily brief. Goals of care tend to address only immediate perioperative outcomes and the impact of acute pain interventions on the development of chronic pain and opioid dependency remains poorly studied. Perioperative pain management strategies outside of the immediate postoperative arena (ie, 1 week following surgery) have been limited by fewer patient interactions resulting from minimally invasive surgical procedures, enhanced recovery protocols and shortened hospitalizations. However, despite changes in surgical technique and hospitalization strategies, patients are continuing to experience pain, and this pain is now occurring outside of a hospital setting where it might be more expeditiously addressed. This semi-acute recovery period represents a crucially important time in the recovery process for patients. Consequently, the challenge of bending the acute pain trajectory and improving long term outcomes via prevention of chronic severe postsurgical pain and reductions in long term opioid use requires the focused commitment of acute pain physicians.

Severe CPSP occurs in 5-10% of patients undergoing major surgery (eg, amputation, mastectomy, thoracotomy and total join replacement), while mild to moderate CPSP occurs in 10-50% of patients undergoing these larger surgical procedures.^1-4 Given that global surgical volume is expected to exceed 300 million cases this year, CPSP profoundly impacts both individuals and society. Time, effort, and expense are associated with rehabilitation needs and mitigation of reductions in health-related quality of life caused by CPSP. These efforts and resource requirements have the potential to further stress already strained healthcare systems.

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Regional anesthesia can reduce the risk of acute postoperative pain transitioning into a chronic and disabling affliction.

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Our understanding of how surgical pain transitions from acute to subacute to chronic and persistent pain is incomplete; however, decades of research have identified component mechanisms for pain sensitization via molecular and cellular changes in the peripheral and central nervous system.⁵ Important pathophysiologic factors include the intensity of the initial nociceptive stimulation, gene expression in the nervous system resulting in peripheral nerve and spinal central sensitization, and exposure to potent/high-dose opioids culminating in opioid-induced hyperalgesia. In addition, changes in peripheral nerve stimulation may result in changes at the spinal cord, thalamus, and somatosensory cortex and culminate in cortical reorganization, chronic hypoesthesia, hyperesthesia and pain.^6,7 Research into these maladaptive changes suggests that intervention at the time of initial surgical stimulation and during the acute pain phase can reduce the progression to chronic pain.⁵

Interventions in the perioperative period are divided into identifying individuals at risk and implementing the most effective techniques for each specific surgical procedure and patient condition. Identification of at-risk individuals is the first step in making a clinical impact. Risk factors for CPSP include pre-existing pain, pre-operative opioid exposure, pain catastrophizing, an elevated intensity of acute postoperative pain, elevated perioperative potent opioid exposure, and psychological disorders such as mood disorders, post-traumatic stress disorder, and substance abuse.^8-10 Although mainstays of multimodal analgesia, such as acetaminophen, NSAIDs, and corticosteroids are beneficial in acute pain management and in reducing perioperative opioid consumption, they have not demonstrated an ability to directly prevent CPSP. Ketamine is an additional treatment with a significant role in managing acute pain, particularly for patients with pre-existing chronic pain and opioid tolerance, however, the evidence for a role in preventing the transition from acute pain to CPSP is lacking. A similar lack of evidence exists for gabapentinoids, alpha-2-agonists, and other non-opioid analgesics despite many investigations and meta-analyses.¹¹

In contrast, regional anesthesia can reduce the risk of acute postoperative pain transitioning into a chronic and disabling affliction.^5,12-14 Continuous peripheral nerve blockade with local anesthesia directly inhibits nociception, and when used for extended duration, can prevent CPSP. The continuous administration of perineural local anesthesia may also act in an anti-inflammatory capacity to decrease CPSP.^13,14 In contrast, single injection nerve blocks and local wound infiltration may not exert a great enough physiologic impact to alter the development of CPSP. Studies are lacking to determine whether adjuvants or extended duration formulations, such as liposomal bupivacaine, may make single injection peripheral nerve blockade more useful in this context. Thus, pharmacologic modalities and interventions of limited duration have not proved helpful in preventing CPSP, but those of extended duration are more promising.

Since evidence to support long lasting impacts from short term treatments is lacking, acute pain physicians may consider novel and longer duration interventions in the acute pain setting for the prevention of CPSP, such as cryoneurolysis and percutaneous nerve stimulation (PNS). Cryoneurolysis has existed for the treatment of chronic pain for decades. Increased interest in the perioperative administration of this technique for the treatment of acute pain has been stimulated by newly described devices and techniques. Studies addressing acute pain treatment efficacy are limited and fewer address the prevention of transitioning from acute to chronic pain; however, cryoneurolysis is a promising modality that can provide analgesia for weeks to months.¹⁵ More profound and sustained analgesia is achieved with PNS, which can provide analgesia for up to 60 days and lead to potential positive effects even following treatment cessation.¹⁵ PNS utilizes the theory of gate control and neuromodulation to stimulate large-diameter afferent nerve fibers, thereby interrupting transmission of pain signals to the central nervous system. Initial studies have suggested that PNS has the potential to be an incredibly promising tool in the acute pain physician’s arsenal in the prevention of CPSP because of its duration of treatment and analgesic effect, titratability, and lack of motor blockade.

Unfortunately, significant evidence supporting the acute pain physician’s role in reducing the development of long term opioid use is generally lacking. However, it is well documented that exposure to high dose potent opioids such as fentanyl and remifentanil can increase the risk of acute opioid tolerance, hyperalgesia, and CPSP in a dose dependent fashion.^16-19 Therefore, minimizing these exposures might represent a reasonable initial mechanism to reduce postoperative opioid use; however, direct evidence of this association is lacking. Addressing persistent postoperative opioid use is an important consideration as this condition remains a common affliction following both major and minor surgery, and is associated with many of the same risk factors as CPSP.^20,21 For example, at least 3-6% of opioid naïve patients continue to consume opioids after any surgery, while 10-13% of opioid naïve patients continue to consume opioids following surgery associated with more severe pain, such as total hip arthroplasty or total knee arthroplasty.²² The most successful approaches associated with minimizing long-term opioid consumption appear to be proper perioperative opioid prescribing, reducing postoperative opioid overprescribing, and expectation management and shared decision making with patients.²³ Although large investigations are ongoing, the magnitude of acute pain intervention impact on reductions in chronic postsurgical opioid use awaits delineation.²⁴

In conclusion, it appears that the path for acute pain management providers to make a more profound impact in the prevention of CPSP and chronic postsurgical opioid use includes  an expanded focus on interventions of longer duration, (ie, PNS), proper opioid prescription habits, and an expanded clinical footprint beyond the operating room and hospital floor, such as a transitional pain clinic.²⁵

Anthony Machi, MD, is an assistant professor at the Department of Anesthesiology and Pain Management and the regional anesthesia and acute pain medicine fellowship director at the University of Texas Southwestern Medical Center.

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References

1. Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. Lancet. 2006;367(9522):1618-25. https://doi.org/10.1016/S0140-6736(06)68700-X
2. Buvanendran A, Della Valle CJ, Kroin JS, et al. Acute postoperative pain is an independent predictor of chronic postsurgical pain following total knee arthroplasty at 6 months: a prospective cohort study. Reg Anesth Pain Med. 2019;rapm-2018-100036. https://doi.org/10.1136/rapm-2018-100036
3. Johansen A, Romundstad L, Nielsen CS, Schirmer H, Stubhaug A. Persistent postsurgical pain in a general population: prevalence and predictors in the Tromsø study. Pain. 2012;153(7):1390-96. https://doi.org/10.1016/j.pain.2012.02.018
4. Glare P, Aubrey KR, Myles PS. Transition from acute to chronic pain after surgery. Lancet. 2019;393(10180):1537-46. https://doi.org/10.1016/S0140-6736(19)30352-6
5. Richebé P, Capdevila X, Rivat C. Persistent postsurgical pain: pathophysiology and preventative pharmacologic considerations. Anesthesiology. 2018;129(3):590-607. https://doi.org/10.1097/ALN.0000000000002238
6. Flor H, Elbert T, Knecht S, et al. Phantom-limb pain as a perceptual correlate of cortical reorganization following arm amputation. Nature. 1995;375(6531):482-4. https://doi.org/10.1038/375482a0
7. Andoh J, Milde C, Diers M, et al. Assessment of cortical reorganization and preserved function in phantom limb pain: a methodological perspective. Sci Rep. 2020;10(1):11504. https://doi.org/10.1038/s41598-020-68206-9
8. Katz J, Weinrib A, Fashler SR, et al. 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. https://doi.org/10.2147/JPR.S91924
9. Blichfeldt-Eckhardt MR. From acute to chronic postsurgical pain: the significance of the acute pain response. Dan Med J. 2018;65(3)B5326.
10. Lewis GN, Rice DA, McNair PJ, Kluger M. Predictors of persistent pain after total knee arthroplasty: a systematic review and meta-analysis. Br J Anaesth. 2015;114(4):551-61. https://doi.org/10.1093/bja/aeu441
11. Weinstein EJ, Levene JL, Cohen MS, et al. Local anaesthetics and regional anaesthesia versus conventional analgesia for preventing persistent postoperative pain in adults and children. Cochrane Database of Syst Rev. 2018;6(6):CD007105. https://doi.org/10.1002/14651858.CD007105.pub4
12. Borghi B, D'Addabbo M, White PF, et al. The use of prolonged peripheral neural blockade after lower extremity amputation: the effect on symptoms associated with phantom limb syndrome. Anesth Analg. 2010;111(5):1308-15. https://doi.org/10.1213/ANE.0b013e3181f4e848
13. Deruddre S, Combettes E, Estebe JP, et al. Effects of a bupivacaine nerve block on the axonal transport of Tumor Necrosis Factor-alpha (TNF-alpha) in a rat model of carrageenan-induced inflammation. Brain Behav Immun. 2010;24(4):652-9. https://doi.org/10.1016/j.bbi.2010.01.013
14. Gentili ME, Mazoit JX, Samii KK, Fletcher D. The effect of a sciatic nerve block on the development of inflammation in carrageenan injected rats. Anesth Analg. 1999;89(4):979-84. https://doi.org/10.1097/00000539-199910000-00029
15. Ilfeld BM, Finneran IV JJ. Cryoneurolysis and percutaneous peripheral nerve stimulation to treat acute pain: a narrative review. Anesthesiology. 2020;133(5):1127-49. https://doi.org/10.1097/ALN.0000000000003532
16. Guignard B, Bossard AE, Coste C, et al. Acute opioid tolerance: intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology. 2000;93(2):409-17. https://doi.org/10.1097/00000542-200008000-00019
17. Joly V, Richebe P, Guignard B, et al. Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Anesthesiology. 2005;103(1):147-55. https://doi.org/10.1097/00000542-200507000-00022
18. van Gulik L, Ahlers SJ, van de Garde EM, et al. Remifentanil during cardiac surgery is associated with chronic thoracic pain 1 yr after sternotomy. Br J Anaesth. 2012;109(4):616-22. https://doi.org/10.1093/bja/aes247
19. Chia YY, Liu K, Wang JJ, Kuo MC, Ho ST. Intraoperative high dose fentanyl induces postoperative fentanyl tolerance. Can J Anaesth. 1999;46(9):872-7. https://doi.org/10.1007/BF03012978
20. Brummett CM, Waljee JF, Goesling J, et al. New persistent opioid use after minor and major surgical procedures in US adults. JAMA Surg. 2017;152(6):e170504. https://doi.org/10.1001/jamasurg.2017.0504
21. Sun EC, Darnall BD, Baker LC, Mackey S. Incidence of and risk factors for chronic opioid use among opioid-naive patients in the postoperative period. JAMA Intern Med. 2016;176(9):1286-93. https://doi.org/10.1001/jamainternmed.2016.3298
22. Cook DJ, Kaskovich SW, Pirkle SC, Mica MAC, Shi LL, Lee MJ. Benchmarks of duration and magnitude of opioid consumption after total hip and knee arthroplasty: a database analysis of 69,368 patients. J Arthroplasty. 2019;34(4):638-44.e631. https://doi.org/10.1016/j.arth.2018.12.023
23. Neuman MD, Bateman BT, Wunsch H. Inappropriate opioid prescription after surgery. Lancet. 2019;393(10180):1547-57. https://doi.org/10.1016/S0140-6736(19)30428-3
24. Hah JM, Bateman BT, Ratliff J, Curtin C, Sun E. Chronic opioid use after surgery: implications for perioperative management in the face of the opioid epidemic. Anesth Analg. 2017;125(5):1733-40. https://doi.org/10.1213/ANE.0000000000002458
25. Huang A, Azam A, Segal S, et al. Chronic postsurgical pain and persistent opioid use following surgery: the need for a transitional pain service. Pain Manag. 2016;6(5):435-43. https://doi.org/10.2217/pmt-2016-0004