- Email: [email protected]
The transition of acute postoperative pain to chronic pain: Part 1 – Risk factors for the development of postoperative acute persistent pain
Trends in Anaesthesia and Critical Care xxx (2014) 1e4
Contents lists available at ScienceDirect
Trends in Anaesthesia and Critical Care journal homepage: www.elsevier.com/locate/tacc
REVIEW
The transition of acute postoperative pain to chronic pain: Part 1 e Risk factors for the development of postoperative acute persistent pain Edward A. Shipton* Department of Anaesthesia, University of Otago, Corner of Riccarton and Hagley Avenues, Christchurch 8011, New Zealand
s u m m a r y Keywords: Perioperative risk factors Mechanisms of transition
Most patients will recover and return to their normal life after surgery, yet others will suffer chronic pain and long-lasting disabilities. Every chronic pain was once acute. The transition of acute perioperative pain to pathological chronic post-surgical pain (CPSP) is a complex and poorly understood process. Biological, psychological, and social-environmental factors and the known polymorphisms in human genes are all involved in perpetuating the pain. The Anaesthetist plays a pivotal role in the identification of factors that may lead to suboptimal pain control in the perioperative period. This review is based on an extensive search of the literature in relation to the topics covered without strict inclusion or exclusion criteria in the search strategy. The mechanisms of transition for acute perioperative to chronic postsurgical pain are explored. The identification of perioperative risk factors for developing CPSP is important as early interventions may prove beneficial. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction Most patients will recover and return to their normal life after surgery, yet others will suffer chronic pain and long-lasting disabilities.1 Every chronic pain was once acute. The transition of acute postoperative pain to pathological chronic post-surgical pain (CPSP) is a complex and poorly understood process. Biological, psychological, and social-environmental factors and the known polymorphisms in human genes are all involved in perpetuating the pain.2 The Anaesthetist plays a pivotal role in the identification of factors that may lead to suboptimal pain control in the perioperative period. This review is based on an extensive search of the literature in relation to the topics covered without strict inclusion or exclusion criteria in the search strategy. Chronic post-surgical pain (CPSP) is defined as pain attributable to the surgical procedure that persists for at least 2 months postoperatively, with exclusion of other causes and pre-existing problems.3e5 The frequency of occurrence ranges from 5% to 60% in all types of surgery.3 On average, one in five patients undergoing surgery will develop chronic post-surgical pain. One to three per cent of patients with CPSP will suffer from severe pain and pain-
* Tel.: þ64 3 3641642; fax: þ64 3 3572594. E-mail address: [email protected].
related interference with daily activities.3 The 1-year prevalence of adult CPSP typically ranges between 1.5% and 10%.6 About 13% of children report the existence of symptoms of chronic postoperative pain.7 The wide range of CPSP in the literature is due to varying definitions of chronic pain, different measurements of pain and different adjuvant treatments. Long-term painful sequelae of surgery occur following amputation of an extremity (in 30e50%),5 surgeries on abdominal visceral structures (10e14%),8 bone and joint surgery (about 20%),8 iliac crest bone harvest (in 19%),8 thoracotomy (in 30e 50%),9 herniorrhaphy (in 10%),10 hysterectomy (in 17%),11 and mastectomy (in 31e49%) (Table 1).5 In principle, all surgical procedures have the potential to cause CPSP.4 Recently, investigators evaluated postoperative pain in 50,523 patients from 105 German hospitals, and compared pain scores among 179 surgical groups. Surprisingly, pain was sometimes worse in the “minor” procedures (appendectomy, cholecystectomy, haemorrhoidectomy, and tonsillectomy).12 2. Mechanisms of transition for acute to chronic postsurgical pain Post-surgical pain arises from nociception (from sensory receptors on C fibres and A-delta fibres that respond to intense thermal or mechanical stimuli) and from the detection of inflammation by nociceptors (a consequence of trauma to peripheral
http://dx.doi.org/10.1016/j.tacc.2014.04.001 2210-8440/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Shipton EA, The transition of acute postoperative pain to chronic pain: Part 1 e Risk factors for the development of postoperative acute persistent pain, Trends in Anaesthesia and Critical Care (2014), http://dx.doi.org/10.1016/j.tacc.2014.04.001
2
E.A. Shipton / Trends in Anaesthesia and Critical Care xxx (2014) 1e4
Table 1 Examples of the incidence (estimated) of chronic postoperative pain after different surgical procedures. Type of surgery
Incidence of chronic postoperative pain (estimated) (%)
Hysterectomy Herniorrhaphy Mastectomy Thoracotomy Amputation of an extremity Surgeries on abdominal visceral structures Bone and Joint surgery Iliac crest bone harvest (See text for references)
17%11 10%10 31e49%5 30e50%9 30e50%5 10e14%8 20%8 19%8
tissues).13 Identifying the factors that contribute to the transition from acute, time-limited post-surgical pain to chronic pathological pain is essential if progress is to be made in preventing CPSP.13 After a surgical incision, inflammatory mediators are released by damaged tissue and trigger an inflammatory cascade. This inflammatory response reduces the threshold and increases the responsiveness of nociceptors to subsequent input in the damaged tissue.13 A variety of molecules, released at the periphery (prostaglandins, bradykinin, histamine, cytokines) act directly on the primary afferent terminals, decreasing their excitation threshold in a process known as peripheral sensitization.14 In particular, there is increased expression of the neuropeptides calcitonin-gene-related peptide (CGRP) and Substance P (Sub P) within the superficial dorsal horn.14 Similar sensitization processes can take place more centrally as a result of the ‘afferent barrage’ induced by activation of nociceptors in response to surgery. Central sensitization refers to an alteration in the response properties of central neurons (e.g. in the dorsal horn). Characteristics of central sensitization include an increased responsiveness to activation, reduced threshold, expanded receptive fields, and spontaneous activity following injury; all these contribute to increased pain after surgery.13 The mechanisms of peripheral and central sensitization that are initially protective then become maladaptive, with deleterious consequences. One manifestation of central sensitization is allodynia; here pain is experienced in a localized area that is not due to a painful stimulus but to a non-painful stimulus, such as touch. A second manifestation is known as secondary hyperalgesia, in which an increase in pain sensitivity occurs in non-injured areas beyond the area of primary injury.15 The extent and the duration of central sensitization and its importance in promoting pain chronicity may differ among individuals even after similar injury.1 Peripheral and central sensitization remains the essential mechanism of the development of pain chronicity.3 Long-term potentiation (LTP) of synaptic responses takes place in combination with impaired nociceptive inhibitory modulation, enhanced nociceptive facilitatory modulation, and central nervous system inflammatory changes triggered by injury-induced proliferation of immunologically active microglia and astrocytes.15 All seem to be critical in the development and maintenance of conditions of central sensitization and chronic pain.15 An individual’s state of endogenous pain-modulatory processes can influence the transition as well. Patients with poor inhibitory systems are more susceptible to develop CPSP after thoracotomy or major abdominal surgery.1 Patients with enhanced excitatory processes (i.e. with positive temporal summation) experience higher postoperative pain, and are more prone to CPSP.1 In addition ongoing translation of mRNA in the peripheral terminal of the
primary afferent nociceptor plays a role in the transition from acute to chronic pain.16 Hyperalgesic priming is used in the animal model to demonstrate the transition from acute to chronic pain. Hyperalgesic priming depends on the epsilon isoform of protein kinase C (PKC epsilon). Priming can be detected as an enhanced and prolonged hyperalgesic response to the proinflammatory cytokine prostaglandin E2 (PGE2). It can be explained by a switch in the intracellular signalling pathway mediating PGE2-induced hyperalgesia.16 If this occurs over a period of months, it is likely to be associated with the formation of a type of molecular memory in primary afferent nociceptors.16 Studies in the rat model confirm a switch to a G (i)-activated and PKC epsilon-dependent signalling pathway in primary mechanical hyperalgesia that is induced by stress or inflammation.17 The translation inhibitors, rapamycin and cordycepin at the peripheral terminal of the primed nociceptor have, however, been found to reverse priming in the rat model.16 It has recently been shown that cytoplasmic polyadenylation element binding protein (CPEB) expressed by isolectin B4-positive [IB4(þ)-nociceptors], a subset of nociceptors in which hyperalgesic priming occurs, can be co-immuno-precipitated with protein kinase C epsilon (PKCε).16 Down regulation of its expression by the intrathecal administration of antisense oligodeoxynucleotides prevents hyperalgesic priming.16
3. Perioperative risk factors Both postoperative pain and the risk for the development of chronic postoperative pain are determined by preoperative, intraoperative, and postoperative factors (Table 2). Risk factors for CPSP are mostly derived from small samples of surgical patients from single centres (often with less than 100 patients), and may not report the most accepted risk factors.18 A systematic review investigating predictors of CPSP have shown these to fall in five domains, namely, demographic, pain, clinical, surgery-related, and psychological.18 Early identification of patients at high risk of developing CPSP is practical, as early interventions can be beneficial to these patient populations.4
Table 2 Perioperative risk factors for developing chronic pain. Preoperative risk factors Preoperative pain state and demographics
Genetics
Younger age Female gender Preoperative pain distant from surgical site Preoperative pain at the surgical site Genetic polymorphisms Pharmacogenomics
Intraoperative risk factors Open versus minimally invasive surgery Site (e.g., thoracotomy, sternotomy, mastectomy, major limb amputation) Duration of surgery Damage to nerves occurs by surgical section, compression, stretching, ischaemia Low (compared to high) volume surgical unit Pericostal (versus intracostal) stitches Electrocautery Intravenous fluid excess Postoperative risk factors Exclude Red flags (infection, bleeding, organ rupture, compartment syndrome) Unrelieved and severe pain High postoperative use of analgesics Surgery performed in a previously injured area Radiation therapy and chemotherapy Repeated surgery in the same area
Please cite this article in press as: Shipton EA, The transition of acute postoperative pain to chronic pain: Part 1 e Risk factors for the development of postoperative acute persistent pain, Trends in Anaesthesia and Critical Care (2014), http://dx.doi.org/10.1016/j.tacc.2014.04.001
E.A. Shipton / Trends in Anaesthesia and Critical Care xxx (2014) 1e4
3.1. Preoperative risk factors The presence of preoperative pain, its intensity and duration are risk factors for the development of early severe acute postoperative pain, of acute pain in the days and weeks after surgery, and of longterm post-surgical pain.13,18 Preoperative pain at the surgical site may or may not be associated with plastic changes in the central nervous system.1 Chronic pain unrelated to the surgical site may be characterized by an underlying state of pain amplification, that is, central sensitization. This is observed in patients suffering idiopathic pain disorders. These include fibromyalgia, irritable bowel syndrome, chronic headaches, and back pain, amongst others.1 Studies have reported that female gender and younger age predict intense acute postoperative pain.17,19 Younger age is one of the most consistently reported factors associated with an increased risk of development of CPSP.18 Lower education and lower socioeconomic status have been identified as risk factors for CPSP as well.18,20 The evidence is mixed for other factors such as employment status, marital status, and for workers compensation.18,21 3.2. Intraoperative risk factors Surgery-related factors have been identified as increasing the risk of CPSP. These take account of factors such as the duration of surgery, and the specific surgical techniques used.22 Examples of surgical techniques include open versus laparoscopic or arthroscopic surgery, the type of implant, and the newer developments in minimally invasive surgery (such as natural orifice transluminal endoscopic surgery, single-incision laparoscopic surgery, or videoassisted lung resection).18,23 Minimally invasive surgery reduces the inflammatory response.24 Other intraoperative risk factors that are associated with an increased likelihood of developing chronic postsurgical pain include the following25: site (e.g., thoracotomy, sternotomy, mastectomy, major limb amputation); extent of surgery and incision type17,26; a low (compared to a high) volume surgical unit17,27; pericostal (versus intracostal) stitches; and intraoperative nerve damage.17,26 Damage to nerves occurs by surgical section, compression (in a suture or from clips, or following rib retraction), stretching, ischaemia, or infection.17,28 Mixed evidence is found for the role of the anaesthetic (e.g. regional anaesthesia) and for analgesic regimens (e.g. pre-emptive analgesia, epidural analgesia), and for the experience of the surgeon.21 Perioperative fluid management is important to improve outcomes, especially by avoiding fluid excess.23 3.3. Postoperative risk factors There should be an ongoing assessment of pain, both at rest and with movement. Red flags, such as infection, bleeding, organ rupture, and the onset of a compartment syndrome, need to be excluded. Postoperative risk factors include unrelieved and severe pain, high postoperative use of analgesics, surgery performed in a previously injured area, radiation therapy and chemotherapy, and repeated surgery in the same area.17 Acute postoperative pain remains one of the most consistent and strongest predictors of CPSP,29 especially the severity of acute postoperative pain in the days and weeks after surgery.13 Exposure to intense pain and stress during medical and nursing procedures can contribute to the transition from acute to chronic pain.15 Adequate postoperative analgesia allowing early mobilization is a prerequisite.23 The presence of large areas of secondary hyperalgesia in the early postoperative phase has been found to be a major predictor of CPSP.14 A longer assessment of postoperative pain that relies on the development of pain trajectories (e.g. from day 1 to day 5) is
3
needed.1 Multivariable predictors contribute to the prediction of CPSP. Such examples include capacity overloads, preoperative pain in the operating field, other chronic preoperative pain, postsurgical acute pain and co-morbid stress symptoms.4 Better clarification is needed on the underlying cause of the postoperative pain (i.e., infection versus mechanical versus neuropathic).13 3.4. Psychosocial risk factors The most common emotions experienced by patients scheduled for major surgery are fear and anxiety. High preoperative anxiety, surgical fear and depression are predictors of severe postoperative pain (Table 3).1,21 Other factors identified less frequently include somatization, hypochondriasis, avoidant coping, psychological vulnerability, neuroticism, and a low expectation of return to work.6 Many of these factors occur in the paediatric patient-related population as well.6 More recently, pain catastrophizing has been studied as a risk factor for CPSP (after knee arthroplasty and shoulder surgery).21 Pain hypervigilance, a strong attentional bias toward pain,1 and emotional numbing measured following hospital discharge, have been found to be predictive of subsequent CPSP and pain disability.13 Poorly relieved long-lasting postoperative pain not only has a negative psychological impact but contributes to maintaining an underlying central sensitization process. This interferes with rehabilitation. Most changes in health-related quality of life occur during the first weeks and months after surgery.1 Social and environmental factors have been associated with persistent postsurgical pain. These include stressful life events, solicitous responding from significant others, and social support.17 3.5. Genetic risk factors A patient’s gene expression profile can change rapidly in the post-injury period. Over 1000 genes are activated in the dorsal root ganglion alone after nerve injury.30 Much has been written about the association of genetic polymorphisms and the development of chronic pain.30 A few candidate gene polymorphisms have been linked to pain susceptibility, including catechol-O-methyltranferase (COMT). This gene modulates nociceptive and inflammatory pain, and has been linked to temporomandibular joint pain syndromes.30 Variants of the guanosine triphosphate cyclohydrolase 1/doparesponsive dystonia gene appear to regulate nociception.17 Other candidate genes are the transient receptor potential cation channel, subfamily 5 member 1 gene, and the melanocortin-1 receptor gene.17 The SCN9A gene has been studied as a marker of pain sensitivity. Mutations in this gene that codes for the alpha-subunit of a voltagegated sodium channel (Nav1.7), are known to result in alterations of
Table 3 Psychosocial factors for developing chronic pain. Preoperative risk factors
Postoperative risk factors
Social and environmental factors
High preoperative anxiety High preoperative surgical fear High preoperative depression Pain catastrophizing Pain hypervigilance Emotional numbing Low expectation of return to work Lower education Lower socioeconomic status Low self-rated health Stressful life events Solicitous responding from significant others Social support
Please cite this article in press as: Shipton EA, The transition of acute postoperative pain to chronic pain: Part 1 e Risk factors for the development of postoperative acute persistent pain, Trends in Anaesthesia and Critical Care (2014), http://dx.doi.org/10.1016/j.tacc.2014.04.001
4
E.A. Shipton / Trends in Anaesthesia and Critical Care xxx (2014) 1e4
pain perception; these have been noted in rare pain disorders such as erythromelalgia and in paroxysmal extreme pain disorder.30 SCN9A polymorphisms have been described in individuals who are insensitive to pain as well.30 Five hereditary sensory and autonomic neuropathy syndromes have been described.17 Epigenetics is the study of heritable modifications in gene expression and phenotype that do not require a change in genetic sequence to manifest their effects.30 DNA methylation, histone acetylation, and RNA interference can alter epigenetic processes. Epigenetic modifications potentially play an important role in inflammatory cytokine metabolism, in steroid responsiveness, and in opioid sensitivity; they are likely to be key factors in the development of chronic pain.30 At present there is an inability to prevent the epigenetic changes that occur following injury and surgery. 4. Preoperative experimental predictors Preoperative experimental stimulation methods have been used to test the correlation between preoperative responses to experimental pain stimuli and clinical postoperative pain. Examples include the cold-pressor test, the heat immersion test, cutaneous electrical stimulation, and pressure algometry.17 A systematic review found the predictive strength to be much higher than previously reported for single factor analyses of demographics and psychological factors.31 A recent study showed a correlation between the preoperative electrical pain thresholds and postoperative opioid consumption after percutaneous nephron lithotomy.32 5. Conclusion These are exciting times in acute pain medicine. Anaesthetists are in a unique position to assess all perioperative risk factors for persistent postsurgical pain. They can initiate multimodal analgesic pharmacotherapy and be at the forefront of targeting other mechanisms thereby reducing the neuro-inflammatory response.33 This will be discussed in Part 2 entitled: “Limiting the Transition”. Conflict of interest statement None. References 1. Lavand’homme P. The progression from acute to chronic pain. Curr Opin Anesthesiol 2011;24:545e50. 2. Walsh M, Woodhouse LJ, Thomas SG, Finch E. Strategies aimed at preventing chronic post-surgical pain: comprehensive perioperative pain management after total joint replacement surgery. Physiother Can 2011;63:289e304. 3. Gerbershagen HJ. Transition from acute to chronic postsurgical pain. Physiology, risk factors and prevention. Schmerz 2013;27:81e93. 4. Althaus A, Hinrichs-Rocker A, Chapman R, Arranz Becker O, Lefering R, Simanski C, et al. Development of a risk index for the prediction of chronic post-surgical pain. Eur J Pain 2012;16:901e10. 5. Macrae WA. Chronic pain after surgery. Br J Anaesth 2001;87:88e98. 6. Katz J, Pagé MG. Identification of risk and protective factors in the transition from acute to chronic post surgical pain. In: Lynch ME, Craig KD, Peng PWH, editors. Clinical pain management: a practical guide. Oxford: Wiley-Blackwell; 2010. p.32e41.
7. Fortier MA, Chou J, Maurer EL, Kain ZN. Acute to chronic postoperative pain in children: preliminary findings. J Pediatr Surg 2011;46:1700e5. 8. Haroutiunian S, Nikolajsen L, Finnerup NB, Jensen TS. The neuropathic component in persistent postsurgical pain: a systematic literature review. Pain 2013;154:95e102. 9. Wildgaard K, Ravn J, Nikolajsen L, Jakobsen E, Jensen TS, Kehlet H. Consequences of persistent pain after lung cancer surgery: a nationwide questionnaire study. Acta Anaesthesiol Scand 2011;55:60e8. 10. Poobalan AS, Bruce J, Smith WC, King PM, Krukowski ZH, Chambers WA. A review of chronic pain after inguinal herniorrhaphy. Clin J Pain 2003;19: 48e54. 11. Brandsborg B, Dueholm M, Nikolajsen L, Kehlet H, Jensen TS. A prospective study of risk factors for pain persisting 4 months after hysterectomy. Clin J Pain 2009;25:263e8. 12. Gerbershagen HJ, Aduckathil S, van Wijck AJ, Peelen LM, Kalkman CJ, Meissner W. Pain intensity on the first day after surgery: a prospective cohort study comparing 179 surgical procedures. Anesthesiology 2013;118:934e44. 13. Clarke H, 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: 289e304. 14. Deumens R, Steyaert A, Forget P, Schubert M, Lavand’homme P, Hermans E, et al. Prevention of chronic postoperative pain: cellular, molecular, and clinical insights for mechanism-based treatment approaches. Prog Neurobiol 2013;104: 1e37. 15. Kyranou M, Puntillo K. The transition from acute to chronic pain: might intensive care unit patients be at risk? Ann Intensive Care 2012;2:36. 16. Ferrari LF, Bogen O, Chu C, Levine JD. Peripheral administration of translation inhibitors reverses increased hyperalgesia in a model of chronic pain in the rat. J Pain 2013;14:731e8. 17. Shipton EA. Postoperative pain, persistent acute Pain. In: Schmidt RF, Willis WD, editors. Encyclopedic reference of pain. Berlin, Heidelburg: SpringerVerlag; 2013. pp. 3079e83. 18. VanDenKerkhof EG, Peters ML, Bruce J. Chronic pain after surgery: time for standardization? A framework to establish core risk factor and outcome domains for epidemiological studies. Clin J Pain 2013;29:2e8. 19. Clarke H, Kay J, Mitsakakis N, Katz J. Acute pain after total hip arthroplasty does not predict the development of chronic postsurgical pain 6 months later. J Anesth 2010;24:537e43. 20. Brandsborg B, Nikolajsen L, Kehlet H, Jensen TS. Chronic pain after hysterectomy. Acta Anaesthesiol Scand 2008;52:327e31. 21. Celestin J, Edwards RR, Jamison RN. Pretreatment psychosocial variables as predictors of outcomes following lumbar surgery and spinal cord stimulation: a systematic review and literature synthesis. Pain Med 2009;10:639e53. 22. Ahn ST, Kim JH, Park JY, Moon du G, Bae JH. Acute postoperative pain after ureteroscopic removal of stone: incidence and risk factors. Korean J Urol 2012;53:34e9. 23. Kehlet H, Slim K. The future of fast-track surgery. Br J Surg 2012;99:1025e6. 24. Kehlet H. Fast-track hip and knee arthroplasty. Lancet 2013;381:1600e2. 25. Katz J, Seltzer Z. Transition from acute to chronic postsurgical pain: risk factors and protective factors. Expert Rev Neurother 2009;9:723e44. 26. Liem MS, van Duyn EB, van der Graaf Y, van Vroonhoven TJ, Coala Trial Group. Recurrences after conventional anterior and laparoscopic inguinal hernia repair: a randomized comparison. Ann Surg 2003;237:136e41. 27. Tasmuth T, Blomqvist C, Kalso E. Chronic post-treatment symptoms in patients with breast cancer operated in different surgical units. Eur J Surg Oncol 1999;25:38e43. 28. Power I, McCormack JG, Myles PS. Regional anaesthesia and pain management. Anaesthesia 2010;65:38e47. 29. Powell R, Johnston M, Smith WC, King PM, Chambers WA, Krukowski Z, et al. Psychological risk factors for chronic post-surgical pain after inguinal hernia repair surgery: a prospective cohort study. Eur J Pain 2012;16:600e10. 30. Buchheit T, Van de Ven T, Shaw A. Epigenetics and the transition from acute to chronic pain. Pain Med 2012;13:1474e90. 31. Werner MU, Mjöbo HN, Nielsen PR, Rudin A. Prediction of postoperative pain: a systematic review of predictive experimental pain studies. Anesthesiology 2010;112:1494e502. 32. Pedersen KV, Olesen AE, Osther PJ, Arendt-Nielsen L, Drewes AM. Prediction of postoperative pain after percutaneous nephro lithotomy: can preoperative experimental pain assessment identify patients at risk? Urolithiasis 2013;41: 169e77. 33. Dickenson AH, Kehlet H. Can we stop pain before it starts? Pain 2014;155: 208e9.
Please cite this article in press as: Shipton EA, The transition of acute postoperative pain to chronic pain: Part 1 e Risk factors for the development of postoperative acute persistent pain, Trends in Anaesthesia and Critical Care (2014), http://dx.doi.org/10.1016/j.tacc.2014.04.001
Contents lists available at ScienceDirect
Trends in Anaesthesia and Critical Care journal homepage: www.elsevier.com/locate/tacc
REVIEW
The transition of acute postoperative pain to chronic pain: Part 1 e Risk factors for the development of postoperative acute persistent pain Edward A. Shipton* Department of Anaesthesia, University of Otago, Corner of Riccarton and Hagley Avenues, Christchurch 8011, New Zealand
s u m m a r y Keywords: Perioperative risk factors Mechanisms of transition
Most patients will recover and return to their normal life after surgery, yet others will suffer chronic pain and long-lasting disabilities. Every chronic pain was once acute. The transition of acute perioperative pain to pathological chronic post-surgical pain (CPSP) is a complex and poorly understood process. Biological, psychological, and social-environmental factors and the known polymorphisms in human genes are all involved in perpetuating the pain. The Anaesthetist plays a pivotal role in the identification of factors that may lead to suboptimal pain control in the perioperative period. This review is based on an extensive search of the literature in relation to the topics covered without strict inclusion or exclusion criteria in the search strategy. The mechanisms of transition for acute perioperative to chronic postsurgical pain are explored. The identification of perioperative risk factors for developing CPSP is important as early interventions may prove beneficial. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction Most patients will recover and return to their normal life after surgery, yet others will suffer chronic pain and long-lasting disabilities.1 Every chronic pain was once acute. The transition of acute postoperative pain to pathological chronic post-surgical pain (CPSP) is a complex and poorly understood process. Biological, psychological, and social-environmental factors and the known polymorphisms in human genes are all involved in perpetuating the pain.2 The Anaesthetist plays a pivotal role in the identification of factors that may lead to suboptimal pain control in the perioperative period. This review is based on an extensive search of the literature in relation to the topics covered without strict inclusion or exclusion criteria in the search strategy. Chronic post-surgical pain (CPSP) is defined as pain attributable to the surgical procedure that persists for at least 2 months postoperatively, with exclusion of other causes and pre-existing problems.3e5 The frequency of occurrence ranges from 5% to 60% in all types of surgery.3 On average, one in five patients undergoing surgery will develop chronic post-surgical pain. One to three per cent of patients with CPSP will suffer from severe pain and pain-
* Tel.: þ64 3 3641642; fax: þ64 3 3572594. E-mail address: [email protected].
related interference with daily activities.3 The 1-year prevalence of adult CPSP typically ranges between 1.5% and 10%.6 About 13% of children report the existence of symptoms of chronic postoperative pain.7 The wide range of CPSP in the literature is due to varying definitions of chronic pain, different measurements of pain and different adjuvant treatments. Long-term painful sequelae of surgery occur following amputation of an extremity (in 30e50%),5 surgeries on abdominal visceral structures (10e14%),8 bone and joint surgery (about 20%),8 iliac crest bone harvest (in 19%),8 thoracotomy (in 30e 50%),9 herniorrhaphy (in 10%),10 hysterectomy (in 17%),11 and mastectomy (in 31e49%) (Table 1).5 In principle, all surgical procedures have the potential to cause CPSP.4 Recently, investigators evaluated postoperative pain in 50,523 patients from 105 German hospitals, and compared pain scores among 179 surgical groups. Surprisingly, pain was sometimes worse in the “minor” procedures (appendectomy, cholecystectomy, haemorrhoidectomy, and tonsillectomy).12 2. Mechanisms of transition for acute to chronic postsurgical pain Post-surgical pain arises from nociception (from sensory receptors on C fibres and A-delta fibres that respond to intense thermal or mechanical stimuli) and from the detection of inflammation by nociceptors (a consequence of trauma to peripheral
http://dx.doi.org/10.1016/j.tacc.2014.04.001 2210-8440/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Shipton EA, The transition of acute postoperative pain to chronic pain: Part 1 e Risk factors for the development of postoperative acute persistent pain, Trends in Anaesthesia and Critical Care (2014), http://dx.doi.org/10.1016/j.tacc.2014.04.001
2
E.A. Shipton / Trends in Anaesthesia and Critical Care xxx (2014) 1e4
Table 1 Examples of the incidence (estimated) of chronic postoperative pain after different surgical procedures. Type of surgery
Incidence of chronic postoperative pain (estimated) (%)
Hysterectomy Herniorrhaphy Mastectomy Thoracotomy Amputation of an extremity Surgeries on abdominal visceral structures Bone and Joint surgery Iliac crest bone harvest (See text for references)
17%11 10%10 31e49%5 30e50%9 30e50%5 10e14%8 20%8 19%8
tissues).13 Identifying the factors that contribute to the transition from acute, time-limited post-surgical pain to chronic pathological pain is essential if progress is to be made in preventing CPSP.13 After a surgical incision, inflammatory mediators are released by damaged tissue and trigger an inflammatory cascade. This inflammatory response reduces the threshold and increases the responsiveness of nociceptors to subsequent input in the damaged tissue.13 A variety of molecules, released at the periphery (prostaglandins, bradykinin, histamine, cytokines) act directly on the primary afferent terminals, decreasing their excitation threshold in a process known as peripheral sensitization.14 In particular, there is increased expression of the neuropeptides calcitonin-gene-related peptide (CGRP) and Substance P (Sub P) within the superficial dorsal horn.14 Similar sensitization processes can take place more centrally as a result of the ‘afferent barrage’ induced by activation of nociceptors in response to surgery. Central sensitization refers to an alteration in the response properties of central neurons (e.g. in the dorsal horn). Characteristics of central sensitization include an increased responsiveness to activation, reduced threshold, expanded receptive fields, and spontaneous activity following injury; all these contribute to increased pain after surgery.13 The mechanisms of peripheral and central sensitization that are initially protective then become maladaptive, with deleterious consequences. One manifestation of central sensitization is allodynia; here pain is experienced in a localized area that is not due to a painful stimulus but to a non-painful stimulus, such as touch. A second manifestation is known as secondary hyperalgesia, in which an increase in pain sensitivity occurs in non-injured areas beyond the area of primary injury.15 The extent and the duration of central sensitization and its importance in promoting pain chronicity may differ among individuals even after similar injury.1 Peripheral and central sensitization remains the essential mechanism of the development of pain chronicity.3 Long-term potentiation (LTP) of synaptic responses takes place in combination with impaired nociceptive inhibitory modulation, enhanced nociceptive facilitatory modulation, and central nervous system inflammatory changes triggered by injury-induced proliferation of immunologically active microglia and astrocytes.15 All seem to be critical in the development and maintenance of conditions of central sensitization and chronic pain.15 An individual’s state of endogenous pain-modulatory processes can influence the transition as well. Patients with poor inhibitory systems are more susceptible to develop CPSP after thoracotomy or major abdominal surgery.1 Patients with enhanced excitatory processes (i.e. with positive temporal summation) experience higher postoperative pain, and are more prone to CPSP.1 In addition ongoing translation of mRNA in the peripheral terminal of the
primary afferent nociceptor plays a role in the transition from acute to chronic pain.16 Hyperalgesic priming is used in the animal model to demonstrate the transition from acute to chronic pain. Hyperalgesic priming depends on the epsilon isoform of protein kinase C (PKC epsilon). Priming can be detected as an enhanced and prolonged hyperalgesic response to the proinflammatory cytokine prostaglandin E2 (PGE2). It can be explained by a switch in the intracellular signalling pathway mediating PGE2-induced hyperalgesia.16 If this occurs over a period of months, it is likely to be associated with the formation of a type of molecular memory in primary afferent nociceptors.16 Studies in the rat model confirm a switch to a G (i)-activated and PKC epsilon-dependent signalling pathway in primary mechanical hyperalgesia that is induced by stress or inflammation.17 The translation inhibitors, rapamycin and cordycepin at the peripheral terminal of the primed nociceptor have, however, been found to reverse priming in the rat model.16 It has recently been shown that cytoplasmic polyadenylation element binding protein (CPEB) expressed by isolectin B4-positive [IB4(þ)-nociceptors], a subset of nociceptors in which hyperalgesic priming occurs, can be co-immuno-precipitated with protein kinase C epsilon (PKCε).16 Down regulation of its expression by the intrathecal administration of antisense oligodeoxynucleotides prevents hyperalgesic priming.16
3. Perioperative risk factors Both postoperative pain and the risk for the development of chronic postoperative pain are determined by preoperative, intraoperative, and postoperative factors (Table 2). Risk factors for CPSP are mostly derived from small samples of surgical patients from single centres (often with less than 100 patients), and may not report the most accepted risk factors.18 A systematic review investigating predictors of CPSP have shown these to fall in five domains, namely, demographic, pain, clinical, surgery-related, and psychological.18 Early identification of patients at high risk of developing CPSP is practical, as early interventions can be beneficial to these patient populations.4
Table 2 Perioperative risk factors for developing chronic pain. Preoperative risk factors Preoperative pain state and demographics
Genetics
Younger age Female gender Preoperative pain distant from surgical site Preoperative pain at the surgical site Genetic polymorphisms Pharmacogenomics
Intraoperative risk factors Open versus minimally invasive surgery Site (e.g., thoracotomy, sternotomy, mastectomy, major limb amputation) Duration of surgery Damage to nerves occurs by surgical section, compression, stretching, ischaemia Low (compared to high) volume surgical unit Pericostal (versus intracostal) stitches Electrocautery Intravenous fluid excess Postoperative risk factors Exclude Red flags (infection, bleeding, organ rupture, compartment syndrome) Unrelieved and severe pain High postoperative use of analgesics Surgery performed in a previously injured area Radiation therapy and chemotherapy Repeated surgery in the same area
Please cite this article in press as: Shipton EA, The transition of acute postoperative pain to chronic pain: Part 1 e Risk factors for the development of postoperative acute persistent pain, Trends in Anaesthesia and Critical Care (2014), http://dx.doi.org/10.1016/j.tacc.2014.04.001
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3.1. Preoperative risk factors The presence of preoperative pain, its intensity and duration are risk factors for the development of early severe acute postoperative pain, of acute pain in the days and weeks after surgery, and of longterm post-surgical pain.13,18 Preoperative pain at the surgical site may or may not be associated with plastic changes in the central nervous system.1 Chronic pain unrelated to the surgical site may be characterized by an underlying state of pain amplification, that is, central sensitization. This is observed in patients suffering idiopathic pain disorders. These include fibromyalgia, irritable bowel syndrome, chronic headaches, and back pain, amongst others.1 Studies have reported that female gender and younger age predict intense acute postoperative pain.17,19 Younger age is one of the most consistently reported factors associated with an increased risk of development of CPSP.18 Lower education and lower socioeconomic status have been identified as risk factors for CPSP as well.18,20 The evidence is mixed for other factors such as employment status, marital status, and for workers compensation.18,21 3.2. Intraoperative risk factors Surgery-related factors have been identified as increasing the risk of CPSP. These take account of factors such as the duration of surgery, and the specific surgical techniques used.22 Examples of surgical techniques include open versus laparoscopic or arthroscopic surgery, the type of implant, and the newer developments in minimally invasive surgery (such as natural orifice transluminal endoscopic surgery, single-incision laparoscopic surgery, or videoassisted lung resection).18,23 Minimally invasive surgery reduces the inflammatory response.24 Other intraoperative risk factors that are associated with an increased likelihood of developing chronic postsurgical pain include the following25: site (e.g., thoracotomy, sternotomy, mastectomy, major limb amputation); extent of surgery and incision type17,26; a low (compared to a high) volume surgical unit17,27; pericostal (versus intracostal) stitches; and intraoperative nerve damage.17,26 Damage to nerves occurs by surgical section, compression (in a suture or from clips, or following rib retraction), stretching, ischaemia, or infection.17,28 Mixed evidence is found for the role of the anaesthetic (e.g. regional anaesthesia) and for analgesic regimens (e.g. pre-emptive analgesia, epidural analgesia), and for the experience of the surgeon.21 Perioperative fluid management is important to improve outcomes, especially by avoiding fluid excess.23 3.3. Postoperative risk factors There should be an ongoing assessment of pain, both at rest and with movement. Red flags, such as infection, bleeding, organ rupture, and the onset of a compartment syndrome, need to be excluded. Postoperative risk factors include unrelieved and severe pain, high postoperative use of analgesics, surgery performed in a previously injured area, radiation therapy and chemotherapy, and repeated surgery in the same area.17 Acute postoperative pain remains one of the most consistent and strongest predictors of CPSP,29 especially the severity of acute postoperative pain in the days and weeks after surgery.13 Exposure to intense pain and stress during medical and nursing procedures can contribute to the transition from acute to chronic pain.15 Adequate postoperative analgesia allowing early mobilization is a prerequisite.23 The presence of large areas of secondary hyperalgesia in the early postoperative phase has been found to be a major predictor of CPSP.14 A longer assessment of postoperative pain that relies on the development of pain trajectories (e.g. from day 1 to day 5) is
3
needed.1 Multivariable predictors contribute to the prediction of CPSP. Such examples include capacity overloads, preoperative pain in the operating field, other chronic preoperative pain, postsurgical acute pain and co-morbid stress symptoms.4 Better clarification is needed on the underlying cause of the postoperative pain (i.e., infection versus mechanical versus neuropathic).13 3.4. Psychosocial risk factors The most common emotions experienced by patients scheduled for major surgery are fear and anxiety. High preoperative anxiety, surgical fear and depression are predictors of severe postoperative pain (Table 3).1,21 Other factors identified less frequently include somatization, hypochondriasis, avoidant coping, psychological vulnerability, neuroticism, and a low expectation of return to work.6 Many of these factors occur in the paediatric patient-related population as well.6 More recently, pain catastrophizing has been studied as a risk factor for CPSP (after knee arthroplasty and shoulder surgery).21 Pain hypervigilance, a strong attentional bias toward pain,1 and emotional numbing measured following hospital discharge, have been found to be predictive of subsequent CPSP and pain disability.13 Poorly relieved long-lasting postoperative pain not only has a negative psychological impact but contributes to maintaining an underlying central sensitization process. This interferes with rehabilitation. Most changes in health-related quality of life occur during the first weeks and months after surgery.1 Social and environmental factors have been associated with persistent postsurgical pain. These include stressful life events, solicitous responding from significant others, and social support.17 3.5. Genetic risk factors A patient’s gene expression profile can change rapidly in the post-injury period. Over 1000 genes are activated in the dorsal root ganglion alone after nerve injury.30 Much has been written about the association of genetic polymorphisms and the development of chronic pain.30 A few candidate gene polymorphisms have been linked to pain susceptibility, including catechol-O-methyltranferase (COMT). This gene modulates nociceptive and inflammatory pain, and has been linked to temporomandibular joint pain syndromes.30 Variants of the guanosine triphosphate cyclohydrolase 1/doparesponsive dystonia gene appear to regulate nociception.17 Other candidate genes are the transient receptor potential cation channel, subfamily 5 member 1 gene, and the melanocortin-1 receptor gene.17 The SCN9A gene has been studied as a marker of pain sensitivity. Mutations in this gene that codes for the alpha-subunit of a voltagegated sodium channel (Nav1.7), are known to result in alterations of
Table 3 Psychosocial factors for developing chronic pain. Preoperative risk factors
Postoperative risk factors
Social and environmental factors
High preoperative anxiety High preoperative surgical fear High preoperative depression Pain catastrophizing Pain hypervigilance Emotional numbing Low expectation of return to work Lower education Lower socioeconomic status Low self-rated health Stressful life events Solicitous responding from significant others Social support
Please cite this article in press as: Shipton EA, The transition of acute postoperative pain to chronic pain: Part 1 e Risk factors for the development of postoperative acute persistent pain, Trends in Anaesthesia and Critical Care (2014), http://dx.doi.org/10.1016/j.tacc.2014.04.001
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pain perception; these have been noted in rare pain disorders such as erythromelalgia and in paroxysmal extreme pain disorder.30 SCN9A polymorphisms have been described in individuals who are insensitive to pain as well.30 Five hereditary sensory and autonomic neuropathy syndromes have been described.17 Epigenetics is the study of heritable modifications in gene expression and phenotype that do not require a change in genetic sequence to manifest their effects.30 DNA methylation, histone acetylation, and RNA interference can alter epigenetic processes. Epigenetic modifications potentially play an important role in inflammatory cytokine metabolism, in steroid responsiveness, and in opioid sensitivity; they are likely to be key factors in the development of chronic pain.30 At present there is an inability to prevent the epigenetic changes that occur following injury and surgery. 4. Preoperative experimental predictors Preoperative experimental stimulation methods have been used to test the correlation between preoperative responses to experimental pain stimuli and clinical postoperative pain. Examples include the cold-pressor test, the heat immersion test, cutaneous electrical stimulation, and pressure algometry.17 A systematic review found the predictive strength to be much higher than previously reported for single factor analyses of demographics and psychological factors.31 A recent study showed a correlation between the preoperative electrical pain thresholds and postoperative opioid consumption after percutaneous nephron lithotomy.32 5. Conclusion These are exciting times in acute pain medicine. Anaesthetists are in a unique position to assess all perioperative risk factors for persistent postsurgical pain. They can initiate multimodal analgesic pharmacotherapy and be at the forefront of targeting other mechanisms thereby reducing the neuro-inflammatory response.33 This will be discussed in Part 2 entitled: “Limiting the Transition”. Conflict of interest statement None. References 1. Lavand’homme P. The progression from acute to chronic pain. Curr Opin Anesthesiol 2011;24:545e50. 2. Walsh M, Woodhouse LJ, Thomas SG, Finch E. Strategies aimed at preventing chronic post-surgical pain: comprehensive perioperative pain management after total joint replacement surgery. Physiother Can 2011;63:289e304. 3. Gerbershagen HJ. Transition from acute to chronic postsurgical pain. Physiology, risk factors and prevention. Schmerz 2013;27:81e93. 4. Althaus A, Hinrichs-Rocker A, Chapman R, Arranz Becker O, Lefering R, Simanski C, et al. Development of a risk index for the prediction of chronic post-surgical pain. Eur J Pain 2012;16:901e10. 5. Macrae WA. Chronic pain after surgery. Br J Anaesth 2001;87:88e98. 6. Katz J, Pagé MG. Identification of risk and protective factors in the transition from acute to chronic post surgical pain. In: Lynch ME, Craig KD, Peng PWH, editors. Clinical pain management: a practical guide. Oxford: Wiley-Blackwell; 2010. p.32e41.
7. Fortier MA, Chou J, Maurer EL, Kain ZN. Acute to chronic postoperative pain in children: preliminary findings. J Pediatr Surg 2011;46:1700e5. 8. Haroutiunian S, Nikolajsen L, Finnerup NB, Jensen TS. The neuropathic component in persistent postsurgical pain: a systematic literature review. Pain 2013;154:95e102. 9. Wildgaard K, Ravn J, Nikolajsen L, Jakobsen E, Jensen TS, Kehlet H. Consequences of persistent pain after lung cancer surgery: a nationwide questionnaire study. Acta Anaesthesiol Scand 2011;55:60e8. 10. Poobalan AS, Bruce J, Smith WC, King PM, Krukowski ZH, Chambers WA. A review of chronic pain after inguinal herniorrhaphy. Clin J Pain 2003;19: 48e54. 11. Brandsborg B, Dueholm M, Nikolajsen L, Kehlet H, Jensen TS. A prospective study of risk factors for pain persisting 4 months after hysterectomy. Clin J Pain 2009;25:263e8. 12. Gerbershagen HJ, Aduckathil S, van Wijck AJ, Peelen LM, Kalkman CJ, Meissner W. Pain intensity on the first day after surgery: a prospective cohort study comparing 179 surgical procedures. Anesthesiology 2013;118:934e44. 13. Clarke H, 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: 289e304. 14. Deumens R, Steyaert A, Forget P, Schubert M, Lavand’homme P, Hermans E, et al. Prevention of chronic postoperative pain: cellular, molecular, and clinical insights for mechanism-based treatment approaches. Prog Neurobiol 2013;104: 1e37. 15. Kyranou M, Puntillo K. The transition from acute to chronic pain: might intensive care unit patients be at risk? Ann Intensive Care 2012;2:36. 16. Ferrari LF, Bogen O, Chu C, Levine JD. Peripheral administration of translation inhibitors reverses increased hyperalgesia in a model of chronic pain in the rat. J Pain 2013;14:731e8. 17. Shipton EA. Postoperative pain, persistent acute Pain. In: Schmidt RF, Willis WD, editors. Encyclopedic reference of pain. Berlin, Heidelburg: SpringerVerlag; 2013. pp. 3079e83. 18. VanDenKerkhof EG, Peters ML, Bruce J. Chronic pain after surgery: time for standardization? A framework to establish core risk factor and outcome domains for epidemiological studies. Clin J Pain 2013;29:2e8. 19. Clarke H, Kay J, Mitsakakis N, Katz J. Acute pain after total hip arthroplasty does not predict the development of chronic postsurgical pain 6 months later. J Anesth 2010;24:537e43. 20. Brandsborg B, Nikolajsen L, Kehlet H, Jensen TS. Chronic pain after hysterectomy. Acta Anaesthesiol Scand 2008;52:327e31. 21. Celestin J, Edwards RR, Jamison RN. Pretreatment psychosocial variables as predictors of outcomes following lumbar surgery and spinal cord stimulation: a systematic review and literature synthesis. Pain Med 2009;10:639e53. 22. Ahn ST, Kim JH, Park JY, Moon du G, Bae JH. Acute postoperative pain after ureteroscopic removal of stone: incidence and risk factors. Korean J Urol 2012;53:34e9. 23. Kehlet H, Slim K. The future of fast-track surgery. Br J Surg 2012;99:1025e6. 24. Kehlet H. Fast-track hip and knee arthroplasty. Lancet 2013;381:1600e2. 25. Katz J, Seltzer Z. Transition from acute to chronic postsurgical pain: risk factors and protective factors. Expert Rev Neurother 2009;9:723e44. 26. Liem MS, van Duyn EB, van der Graaf Y, van Vroonhoven TJ, Coala Trial Group. Recurrences after conventional anterior and laparoscopic inguinal hernia repair: a randomized comparison. Ann Surg 2003;237:136e41. 27. Tasmuth T, Blomqvist C, Kalso E. Chronic post-treatment symptoms in patients with breast cancer operated in different surgical units. Eur J Surg Oncol 1999;25:38e43. 28. Power I, McCormack JG, Myles PS. Regional anaesthesia and pain management. Anaesthesia 2010;65:38e47. 29. Powell R, Johnston M, Smith WC, King PM, Chambers WA, Krukowski Z, et al. Psychological risk factors for chronic post-surgical pain after inguinal hernia repair surgery: a prospective cohort study. Eur J Pain 2012;16:600e10. 30. Buchheit T, Van de Ven T, Shaw A. Epigenetics and the transition from acute to chronic pain. Pain Med 2012;13:1474e90. 31. Werner MU, Mjöbo HN, Nielsen PR, Rudin A. Prediction of postoperative pain: a systematic review of predictive experimental pain studies. Anesthesiology 2010;112:1494e502. 32. Pedersen KV, Olesen AE, Osther PJ, Arendt-Nielsen L, Drewes AM. Prediction of postoperative pain after percutaneous nephro lithotomy: can preoperative experimental pain assessment identify patients at risk? Urolithiasis 2013;41: 169e77. 33. Dickenson AH, Kehlet H. Can we stop pain before it starts? Pain 2014;155: 208e9.
Please cite this article in press as: Shipton EA, The transition of acute postoperative pain to chronic pain: Part 1 e Risk factors for the development of postoperative acute persistent pain, Trends in Anaesthesia and Critical Care (2014), http://dx.doi.org/10.1016/j.tacc.2014.04.001