- Email: [email protected]
Characterization of persistent postoperative pain by quantitative sensory testing
European Journal of Pain Supplements 4 (2010) 203–207
Contents lists available at ScienceDirect
European Journal of Pain Supplements journal homepage: www.EuropeanJournalPain.com
Characterization of persistent postoperative pain by quantitative sensory testing Mads U. Werner a,⇑, Henrik Kehlet b a b
The Multidisciplinary Pain Centre 7612, Rigshospitalet, Copenhagen University Hospitals, Denmark Section of Surgical Pathophysiology 4074, Rigshospitalet, Copenhagen University Hospitals, Denmark
a r t i c l e Keywords: Postoperative pain Sensory assessments Acute pain Chronic pain Perception
i n f o
a b s t r a c t Postoperative pain remains inadequately treated, and it has been estimated that 5–10% undergoing surgery will develop moderate to severe persistent pain leading to chronic physical disability and psychosocial distress. Quantitative sensory testing (QST) is a graded, standardized activation of the sensory system either by mechanical, thermal or electrical stimuli, with assessment of the evoked psychophysical response. QST has been used in prospective assessments of how and why some individuals develop persistent postoperative pain. This comprehensive review describes, first, QST as a predictive research tool in studies investigating the correlation between responses to preoperatively applied experimental pain stimuli and clinical postoperative pain. Second, the use of QST as a valuable prognostic, sequential assessment tool in surgical procedure specific research is presented. Third, the implications of these findings for use of QST in future research are discussed. More rational design of predictive studies in PPP, based on surgical procedure specific approaches, is needed in order to improve our understanding of prevention and management of this debilitating postsurgical condition. Ó 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.
1. Introduction There are a number of incentives to improve our quest of knowledge in acute pain and in particular on its transition to persistent pain states. First, postoperative pain still remains inadequately treated (Gramke et al., 2007; Fletcher et al., 2008; Benhamou et al., 2008; Sommer et al., 2008). Second, it has been estimated that 5–10% of individuals undergoing surgery will develop moderate to severe persistent pain leading to chronic physical disability and psychosocial distress (Kehlet et al., 2006; Poleshuck and Green, 2008). Third, in a number of studies pre-existing pain and highintensity postoperative pain have been predictors of development of persistent pain following surgery (Bisgaard et al., 2005; Katz et al., 2005; Poleshuck et al., 2006; Pluijms et al., 2006; Peters et al., 2007; Steegers et al., 2007). Comprehensive reviews in these areas have been published recently (Kehlet et al., 2006; Rotbøll-Nielsen et al., 2007; Ip et al., 2009; Werner et al., 2010; Kehlet et al., 2010). Neurological evaluation includes quantitative sensory testing (QST) which is a graded, standardized activation of the peripheral ⇑ Corresponding author. Address: The Multidisciplinary Pain Centre 7612, Neuroscience Center Rigshospitalet, Copenhagen University Hospitals, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark. Tel.: +45 2825 7703; fax: +45 3545 3247. E-mail address: [email protected] (M.U. Werner).
nociceptive system either by mechanical (pressure, punctuate, vibratory, light touch), thermal (cold pain, cool, warm, heat pain) or electrical stimuli, with assessment of the psychophysical response (Arendt-Nielsen et al., 2007; Arendt-Nielsen and Yarnitsky, 2009). It is well-known that the inter-individual variation in pain perception is considerable (Edwards et al., 2005) and QST has been developed in an effort to minimize and control the intra-method error. It has rightfully been questioned if these methods in evoked pain research can replicate the sensory, emotional and cognitive dimensions of clinical pain (Gracely, 2007), and if results of QST are, indeed relevant for clinical pain (Edwards et al., 2005). A number of QST-studies have supplied important information about the mechanisms of pain and pain control, about normal and abnormal pain processing, about the trajectory of clinical pain in various disorders like peripheral neuropathies (Dreyer et al., 2004), central pain (Boivie, 2003), arthropathies (Hendiani et al., 2003), fibromyalgia (Desmeules et al., 2003), temporomandibular disorders (Ayesh et al., 2007), pelvic pain disorders (Granot et al., 2002), postmastectomy pain (Gottrup et al., 2000), postamputation pain (Nikolajsen and Jensen, 2006), and persistent postoperative pain (Mikkelsen et al., 2004). This article addresses a number of relevant aspects of QST. First, QST as a predictive research tool in studies investigating the correlation between responses to preoperatively applied experimental
1754-3207/$36.00 Ó 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.eujps.2010.09.004
204
M.U. Werner, H. Kehlet / European Journal of Pain Supplements 4 (2010) 203–207
pain stimuli and clinical postoperative pain is described. Second, the use of QST as a valuable prognostic, sequential assessment tool in surgical procedure specific research is presented. Third, the implications of these findings for use of QST in future research are discussed. 2. Quantitative sensory testing as a predictive experimental research tool To the authors´ knowledge, 18 predictive QST-based studies have been published, where the outcome parameters mainly have been postoperative pain intensity and postoperative requirements of analgesics. The experimental pain evoking stimulation methods have been the cold-pressor test (Bisgaard et al., 2001), heat immersion test (Yarnitsky et al., 2008), brief phasic (Granot et al., 2003; Pan et al., 2006; Martinez et al., 2007; Rudin et al., 2008; Weissman-Fogel et al., 2009; Rudin et al., 2010) or tonic heat stimulation (Strulov et al., 2006; Aasvang and Kehlet, 2010; Aasvang et al., 2010b), cutaneous electrical stimulation (Wilder-Smith et al., 2003; Nielsen et al., 2007; Lundblad et al., 2008; Aasvang et al., 2009; Hickey et al., 2010), pressure algometry (Nikolajsen et al., 2000; Hsu et al., 2005), punctuate mechanical stimulation (Martinez et al., 2007; Weissman-Fogel et al., 2009) and induction of an inflammatory injury (Werner et al., 2004). Contact thermodes were used in 10 of the studies (Granot et al., 2003; Werner et al., 2004; Pan et al., 2006; Strulov et al., 2006; Martinez et al., 2007; Yarnitsky et al., 2008; Rudin et al., 2008; Weissman-Fogel et al., 2009; Rudin et al., 2010; Aasvang et al., 2010b), hand immersion in ice water or hot water in 2 studies (Bisgaard et al., 2001; Yarnitsky et al., 2008), electrical stimulation with surface electrodes in 5 studies (Wilder-Smith et al., 2003; Nielsen et al., 2007; Lundblad et al., 2008; Aasvang et al., 2009; Hickey et al., 2010), a hand-hold pressure algometer (Nikolajsen et al., 2000; Hsu et al., 2005) and punctate stimulation with monofilaments (Martinez et al., 2007; Weissman-Fogel et al., 2009) were used in 2 studies, respectively. Predictive variables for acute and persistent postoperative pain were investigated in 15 studies (Nikolajsen et al., 2000; Bisgaard et al., 2001; Granot et al., 2003; Wilder-Smith et al., 2003; Werner et al., 2004; Hsu et al., 2005; Pan et al., 2006; Strulov et al., 2006; Nielsen et al., 2007; Yarnitsky et al., 2008; Rudin et al., 2008; Aasvang et al., 2009; Weissman-Fogel et al., 2009; Rudin et al., 2010; Aasvang et al., 2010b) and 6 studies (Nikolajsen et al., 2000; Martinez et al., 2007; Yarnitsky et al., 2008; Lundblad et al., 2008; Hickey et al., 2010; Aasvang et al., 2010b), respectively. Suprathreshold mechanical and thermal noxious stimulation had a better predictive performance than pain thresholds in regard to experience of clinical pain and requirement of analgesics (Edwards et al., 2005; Gracely 2006). In 7 (Granot et al., 2003; Werner et al., 2004; Pan et al., 2006; Strulov et al., 2006; Rudin et al., 2008; Rudin et al., 2010; Aasvang et al., 2010b) of 8 thermal QST studies an improved predictive power of suprathreshold stimulation was observed. The regression analyses demonstrated that preoperative QST measurements may predict 4–54% of the variance in acute postoperative pain experience and 13–59% of the variance in development of persistent postoperative pain1 (Nikolajsen et al., 2000; Werner et al., 2010; Aasvang et al., 2010b). Five studies evaluated the predictive power of QST on requirement of analgesics (Hsu et al., 2005; Pan et al., 2006; Martinez et al., 2007; Rudin et al., 2008; Rudin et al., 2010). In only one total knee arthroplasty study, preoperative heat hyperalgesia at the inflammatory changed surgical 1 The square of the correlation coefficient either q2 (Spearman’s correlation coefficient (rho) for non-parametric analyzes) or r2 (Pearson’s correlation coefficient for parametric analyzes) indicate the percentage of the variance of the dependent variable that is predicted by the independent variable(s).
area predicted 44% of the variance in postoperative morphine consumption by patient-controlled analgesia (Martinez et al., 2007). A number of studies, in addition to QST-assessments, also investigated the predictive potential of preoperative psychological variables (anxiety, depression, psychological vulnerability, catastrophizing behavior). Interestingly, by adding psychological variables to the QST-variables in multivariate regression analyses, the increase in predictive power of the model generally was very modest or even absent (Werner et al., 2010). In contrast, recent studies have reported that in particular preoperative anxiety (Munafo and Stevenson, 2001; Janssen et al., 2008b), but also depression (Ozalp et al., 2003), neuroticism (Borly et al., 1999; Cohen et al., 2005) and catastrophizing behavior (Granot and Ferber, 2005) seem associated with development of high-intensity postoperative pain (Rotbøll-Nielsen et al., 2007) and may have a negative effect on surgical outcome (Rosenberger et al., 2006). Thus, QST-assessments as research tools in studies with experimental preoperative pain have provided valuable information on the pre and postsurgical state of the pain system and on the predictive efficacy of different stimulation methods and testing paradigms. A main finding is that the results from the five elective cesarean section studies (Granot et al., 2003; Wilder-Smith et al., 2003; Pan et al., 2006; Strulov et al., 2006; Nielsen et al., 2007) suggest rather consistently that pain after this procedure can, at least in part, be predicted. Previous research, however, has demonstrated that the surgical procedure and technique may influence the intensity and the duration of postoperative pain (Kehlet et al., 2006; Janssen et al., 2008a). Therefore an important limitation of the predictive studies is, that in 18 studies, 11 different surgical procedures were performed, indicating an important source of data heterogeneity. In addition, in most studies the surgical procedure in regard to characteristics of skin incision and handling of nerves and muscles were only rudimentary described. Furthermore, it is not known if the pain mechanisms or pain trajectory may differ between inflammatory, neuropathic or visceral types of postoperative pain. The majority of the predictive studies are probably best considered hypothesis generating studies, although one high-powered study (n = 464) in inguinal herniotomy patients (Aasvang et al., 2010b) seems to bridge the gap to adequately powered procedure specific research. 3. Quantitative sensory testing in procedure specific research In order to overcome some of the major obstacles in postoperative pain research, the use of surgical procedure specific approaches have been advocated (Kehlet et al., 2007; Raja and Jensen, 2010). During the last years the research has rapidly accelerated in following procedures: inguinal herniotomy, thoracotomy and breast cancer surgery. 3.1. Inguinal herniotomy Persistent postoperative pain (PPP) leading to a severe impact on daily ambulatory functions, occurs in 5–8% of the patients following groin hernia repair (Kehlet, 2008). This high-volume, albeit minor, surgical procedure therefore generates a substantial number of chronic pain patients annually. The inguinal herniotomy is an ideal research model to study, since the patients seldom have any significant comorbidity interfering with PPP (Aasvang et al., 2008). Several perioperative risk factors have been identified: preoperative pain, surgical trauma, nerve lesions and acute postoperative pain (Kehlet et al., 2010). Neurophysiological characterization of herniotomy patients with QST has contributed to an increased understanding of the
M.U. Werner, H. Kehlet / European Journal of Pain Supplements 4 (2010) 203–207
underlying pathophysiology (Aasvang et al., 2008; Aasvang and Kehlet 2010; Aasvang et al., 2010a; Aasvang et al., 2010b). Importantly, it has been shown that pain-free herniotomy patients also demonstrate sensory disturbances (thermal and mechanical hypo-/hyperaesthesia, decreased algometry pain/tolerance thresholds) in the surgical area (Aasvang and Kehlet, 2010). Thus evaluation of QST-data from individuals with PPP should not only consider side-to-side data, compensating for cross-over effects or generalized sensitization phenomena, but also consider normative data from pain-free herniotomy patients (Aasvang et al., 2010a). When the sensory disturbances are compared in pain and pain-free postherniotomy patients, in patients with PPP 17% demonstrate cold hypoaesthesia, 30% warmth hypoaesthesia and 37–66% exhibit mechanical hyperaesthesia to deep tissue stimulation. The sensory changes are quite heterogeneously distributed, a finding that also has been described in other types of injury (Pappagallo et al., 2000; Gottrup et al., 2000). The combination of spontaneous or evoked pain, cutaneous sensory loss and increased pain thresholds is suggestive of a neuropathic component. Repetitive pin-prick or brush stimulation significantly increase pain intensity in 51% of PPP patients and in 15% of pain-free individuals (Aasvang and Kehlet, 2010; Aasvang et al., 2010a). This ‘‘wind-up like”, cutaneous phenomenon indicates central nervous sensitization and is identical to findings from PPP-states following amputation, mastectomy and thoracotomy procedures (Nikolajsen et al., 1996; Gottrup et al., 2000; Weissman-Fogel et al., 2009), corroborating the assumption of a neuropathic pain component. The observed mechanical hyperaesthesia to deep tissue stimulation is compatible with an ongoing inflammatory response to the mesh, either with or without secondary nerve dysfunction (Aasvang et al., 2008). 3.2. Thoracotomy The reported prevalence of PPP following anterolateral thoracotomy is 25–60% reflecting a wide variation in study design, methods and definitions (Wildgaard et al., 2009; Kehlet et al., 2010; Kristensen et al., 2010). Neurological assessments have included somatosensory-evoked responses, electrical stimulation thresholds, magnetic intercostal nervestimulation, intercostal nerve conduction analysis and intercostal motor evoked potentials (Benedetti et al., 1998; Rogers et al., 2002; Maguire et al., 2006). Very few studies have used a detailed neurophysiological characterization of persistent post-thoracotomy pain with QST (Kristensen et al., 2010). It has been suggested that post-thoracotomy pain is mainly of neuropathic origin, due to intercostal nerve transection, nerve ligation or rib retractor-induced traction or crush injury of neural tissue. A recent demographic study has questioned the neuropathic origin of the pain (Steegers et al., 2008), and it is a possibility that PPP may be generated from other structures in the rib cage traumatized during the procedure: intercostal muscles, ribs, and possibly costo-vertebral or costo-sternal joints. The first published QST study investigated adults (n = 88) who had thoracotomy performed during childhood or adolescence (Kristensen et al., 2010). Only three of the examined individuals had persistent pain 29–31 years after the surgical procedure. Hypo or hyperaesthesia to touch and tactile stimulation were demonstrated in nearly all participants. Tactile detection threshold and pressure (pinch) pain threshold were significantly increased in the surgical side compared to the contralateral side. In an interesting unpublished study, adults (n = 42), who had thoracotomy performed due to lung cancer, were investigated with QST-assessments three years after surgery (Wilgaard et al., submitted for publication). Eighteen of the patients had PPP while 24 pain-free patients served as controls. Patients with post-thoracotomy pain demonstrated significantly increased
205
side-to-side differences in mechanical and thermal detection thresholds, and heat pain threshold compared to controls. No difference was observed in regard to pressure pain and tolerance threshold, or in cold hypoaesthesia areas. The study concludes that nerve injury is a frequent finding following thoracotomy, both in pain and pain-free individuals. The pressure algometry findings do not support that pain is generated from deeper tissues. 3.3. Breast cancer surgery Persistent postoperative pain and sensory disturbances after breast cancer surgery is estimated to be 25–60% and 20–80%, respectively. A recent nationwide, cross-sectional questionnaire study (n = 3253) demonstrated that 47% of patients experience pain (13% reporting severe pain) and 58% experience sensory disturbances in the surgical region, one to three years after the procedure (Gärtner et al., 2009). Factors associated with persistent pain were young age, adjuvant radiotherapy and axillary lymph node resection compared to sentinel node technique. In breast cancer surgery only 3 studies have included QST-assessments (Gottrup et al., 2000; Vilholm et al., 2008; Vilholm et al., 2009). In the first study 15 patients with spontaneous PPP with sensory disturbances were compared with 11 pain-free women with sensory disturbances. Sensory thresholds to pinprick and thermal stimuli were significantly higher on the surgical side in patients and controls, while pressure pain threshold was significantly lower in pain patients on the surgical side compared to the contralateral side. Responses to repetitive pin-prick stimulation were increased on the surgical side in pain patients indicating sensitization of the nervous system. The second study was a pharmacological QST-study on the effect of levetiracetam, an anticonvulsant, on postmastectomy syndrome (Vilholm et al., 2008). The third study included patients with PPP (n = 55) and pain-free individuals (n = 27) acting as controls (Vilholm et al., 2009). In both groups higher thermal thresholds were demonstrated on the surgical side compared to the contralateral side. The side-to-side difference was significantly higher for warmth detection threshold in the pain group. The incidences of cold-allodynia and temporal summation with pin-prick were significantly more frequent in the pain group. The authors conclude that PPP after breast cancer surgery seems to be of neuropathic origin. These findings are consistent with data from other procedures (Mikkelsen et al., 2004; Jaaskelainen et al., 2004; Nikolajsen et al., 2009; Aasvang et al., 2010a). 4. Recommendations for study design in persistent postoperative pain Although an increasing number of QST studies are available to predict and characterize PPP-states, there is a need for prospective studies including all potential risk factors (pre, intra, and early and late postoperative assessments) in order to improve our understanding of the relative role of the different pathogenic mechanisms, thereby hopefully serving for more rational strategies for prevention and treatment. The application of sensory tests and psychometric questionnaires are in most cases a time consuming process, and not clinically feasible at this time. A simple electrical device was used in 2 of the studies (Nielsen et al., 2007; Aasvang et al., 2009) and although a multivariate model that includes seven clinically relevant variables (Kalkman et al., 2003; Janssen et al., 2008a; Janssen et al., 2008b), all easily obtained during the preoperative evaluation, has been proposed to predict severe postoperative pain, further research efforts in easily applicable and accurate methods are needed.
206
M.U. Werner, H. Kehlet / European Journal of Pain Supplements 4 (2010) 203–207
Table 1 Variables important to consider in design of studies of persistent postoperative pain (Kehlet and Rathmell, 2010). Preoperatively Characterization of pre-existing pain Opioid therapy Assessment of the functional consequences of pre-existing pain Psychosocial assessment Neurophysiologic assessment Analyses of ‘‘pain genes” Intraoperatively Type of anesthesia Descriptive characteristics of the surgical procedure: endoscopically assisted/open access skin incision handling of nerves and muscles implantation of prosthetic materials Surgical classification of the disease Early postoperatively Pain intensity and character Pain management Neurophysiologic assessment Late postoperatively Pain intensity and character Assessment of the functional consequences Neurophysiologic assessment Adjuvant therapies (radiotherapy, chemotherapy)
The variables involved in persisting postoperative pain may be divided into patient- and surgery-related variables (Table 1) (Kehlet and Rathmell, 2010). Pre-existing pain is considered a significant predictor of severe postoperative pain and development of chronic postoperative pain (Kehlet et al., 2006; Janssen et al., 2008a) and it is interesting that in only 6 of the previously mentioned 18 predictive QST-studies (Bisgaard et al., 2001; Martinez et al., 2007; Rudin et al., 2008; Lundblad et al., 2008; Rudin et al., 2010; Aasvang et al., 2010b) the prevalence of pre-existing pain was reported. The sensitization induced by pre-existing pain may be enhanced by opioid treatment, and could play an important role in the exaggerated postoperative pain response seen in chronic pain patients (Angst and Clark, 2006; Koppert, 2007). Assessments of the functional consequences of pre-existing pain on daily life, including the impact of psychosocial distress, are also important preoperative variables. Several gene candidates seem to correlate with the development of PPP (Lacroix-Fralish and Mogil, 2009), but since the combinations of different single nucleotide polymorphisms may reach an astronomically high number, new technologies like genome-wide association studies (GWAS) are needed (Mogil, 2009). Unfortunately this concept requires large-scale studies including 1000– 3000 individuals. The intraoperative variables include type of anesthesia, surgical approach, nerve identification, nerve injury and implantation of synthetic materials (i.e. mesh). For cancer surgery the intraoperative findings are important determinants in staging and classification of the disease, and in the planning of adjuvant therapies, all which may affect the risk of development of persistent postoperative pain (Katz and Seltzer, 2009). The postoperative variables include detailed descriptions of pain (intensity, character and duration), pain management, neurophysiologic changes, adjuvant therapies and the functional consequences of pain. Although a proposed criterion for PPP, according to the International Association of Pain (IASP) (Macrae and Davies, 1999), has been a duration of at least 2 months, data seem to indicate that after certain surgical procedures a continuous inflammatory response may develop, calling for assessments for at least 3–6 months postoperatively to provide reliable results (Kehlet and Rathmell, 2010). Very few studies have included such detailed long-time follow up of patients with PPP.
More rational design of predictive studies in PPP, based on surgical procedure specific approaches, is needed in order to improve our understanding of prevention and management of this prevalent postsurgical condition.
Conflict of interest statement The authors declare no conflict of interest.
Acknowledgements This review was supported by grants from the Lundbeck Foundation and is a part of the Europain project, funded by the Innovative Medicines Initiative Joint Undertaking (IMI JU)’ Grant No. 115007.
References Aasvang EK, Brandsborg B, Christensen B, Jensen TS, Kehlet H. Neurophysiological characterization of postherniotomy pain. Pain 2008;137:173–81. Aasvang EK, Brandsborg B, Jensen TS, Kehlet H. Heterogeneous sensory processing in persistent postherniotomy pain. Pain 2010a;150:237–42. Aasvang EK, Gmaehle E, Hansen JB, Gmaehle B, Forman JL, Schwarz J, et al. Predictive risk factors for persistent postherniotomy pain. Anesthesiology 2010b;112:957–69. Aasvang EK, Hansen JB, Kehlet H. Can preoperative electrical nociceptive stimulation predict acute pain after groin herniotomy? Eur J Pain 2009;13:1018–22. Aasvang EK, Kehlet H. Persistent sensory dysfunction in pain-free herniotomy. Acta Anaesthesiol Scand 2010;54:291–8. Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology 2006;104:570–87. Arendt-Nielsen L, Curatolo M, Drewes A. Human experimental pain models in drug development: translational pain research. Curr Opin Investig Drugs 2007;8:41–53. Arendt-Nielsen L, Yarnitsky D. Experimental and clinical applications of quantitative sensory testing applied to skin, muscles and viscera. J Pain 2009;10:556–72. Ayesh EE, Jensen TS, Svensson P. Somatosensory function following painful repetitive electrical stimulation of the human temporomandibular joint and skin. Exp Brain Res 2007;179:415–25. Benedetti F, Vighetti S, Ricco C, Amanzio M, Bergamasco L, Casadio C, et al. Neurophysiologic assessment of nerve impairment in posterolateral and muscle-sparing thoracotomy. J Thorac Cardiovasc Surg 1998;115:841–7. Benhamou D, Berti M, Brodner G, De AJ, Draisci G, Moreno-Azcoita M, et al. Postoperative analgesic therapy observational survey (PATHOS): a practice pattern study in 7 Central/Southern European countries. Pain 2008;136:134–41. Bisgaard T, Klarskov B, Rosenberg J, Kehlet H. Characteristics and prediction of early pain after laparoscopic cholecystectomy. Pain 2001;90:261–9. Bisgaard T, Rosenberg J, Kehlet H. From acute to chronic pain after laparoscopic cholecystectomy: a prospective follow-up analysis. Scand J Gastroenterol 2005;40:1358–64. Boivie J. Central pain and the role of quantitative sensory testing (QST) in research and diagnosis. Eur J Pain 2003;7:339–43. Borly L, Andersen IB, Christensen E, Sehested A, Kehlet H, Matzen P, et al. Preoperative prediction model of outcome after cholecystectomy for symptomatic gallstones. Scand J Gastroenterol 1999;34:1144–52. Cohen L, Fouladi RT, Katz J. Preoperative coping strategies and distress predict postoperative pain and morphine consumption in women undergoing abdominal gynecologic surgery. J Psychosom Res 2005;58:201–9. Desmeules JA, Cedraschi C, Rapiti E, Baumgartner E, Finckh A, Cohen P, et al. Neurophysiologic evidence for a central sensitization in patients with fibromyalgia. Arthritis Rheum 2003;48:1420–9. Dreyer M, Vucic S, Cros DP, Chong PS. Multiple painful sensory mononeuropathies (MPSM), a novel pattern of sarcoid neuropathy. J Neurol Neurosurg Psychiatry 2004;75:1645–6. Edwards RR, Sarlani E, Wesselmann U, Fillingim RB. Quantitative assessment of experimental pain perception: multiple domains of clinical relevance. Pain 2005;114:315–9. Fletcher D, Fermanian C, Mardaye A, Aegerter P. A patient-based national survey on postoperative pain management in France reveals significant achievements and persistent challenges. Pain 2008;137:441–51. Gartner R, Jensen MB, Nielsen J, Ewertz M, Kroman N, Kehlet H. Prevalence of and factors associated with persistent pain following breast cancer surgery. JAMA 2009;302:1985–92. Gottrup H, Andersen J, Arendt-Nielsen L, Jensen TS. Psychophysical examination in patients with post-mastectomy pain. Pain 2000;87:275–84.
M.U. Werner, H. Kehlet / European Journal of Pain Supplements 4 (2010) 203–207 Gracely RH. Studies of pain in human subjects. In: McMahon SB, Koltzenburg M, editors. Wall and Melzack´s textbook of Elsevier Churchill Livingstone, 2006. p. 267–89. Gracely RH. Stimulus response functions. In: Schmidt RF, Willis WD, editors. Encyclopedia of pain 2007;vol. 3. Berlin Heidelberg New York: Springer; 2007. p. 2321–4. Gramke HF, de Rijke JM, van KM, Raps F, Kessels AG, Peters ML, et al. The prevalence of postoperative pain in a cross-sectional group of patients after day-case surgery in a university hospital. Clin J Pain 2007;23:543–8. Granot M, Ferber SG. The roles of pain catastrophizing and anxiety in the prediction of postoperative pain intensity: a prospective study. Clin J Pain 2005;21:439–45. Granot M, Friedman M, Yarnitsky D, Zimmer EZ. Enhancement of the perception of systemic pain in women with vulvar vestibulitis. BJOG 2002;109:863–6. Granot M, Lowenstein L, Yarnitsky D, Tamir A, Zimmer EZ. Postcesarean section pain prediction by preoperative experimental pain assessment. Anesthesiology 2003;98:1422–6. Hendiani JA, Westlund KN, Lawand N, Goel N, Lisse J, McNearney T. Mechanical sensation and pain thresholds in patients with chronic arthropathies. J Pain 2003;4:203–11. Hickey OT, Burke SM, Hafeez P, Mudrakouski AL, Hayes ID, Keohane C, et al. Determinants of outcome for patients undergoing lumbar discectomy: a pilot study. Eur J Anaesthesiol 2010;27:696–701. Hsu YW, Somma J, Hung YC, Tsai PS, Yang CH, Chen CC. Predicting postoperative pain by preoperative pressure pain assessment. Anesthesiology 2005;103:613–8. Ip HY, Abrishami A, Peng PW, Wong J, Chung F. Predictors of postoperative pain and analgesic consumption: a qualitative systematic review. Anesthesiology 2009;111:657–77. Jaaskelainen SK, Teerijoki-Oksa T, Virtanen A, Tenovuo O, Forssell H. Sensory regeneration following intraoperatively verified trigeminal nerve injury. Neurology 2004;62:1951–7. Janssen KJ, Kalkman CJ, Grobbee DE, Bonsel GJ, Moons KG, Vergouwe Y. The risk of severe postoperative pain: modification and validation of a clinical prediction rule. Anesth Analg 2008a;107:1330–9. Janssen KJ, Moons KG, Kalkman CJ, Grobbee DE, Vergouwe Y. Updating methods improved the performance of a clinical prediction model in new patients. J Clin Epidemiol 2008b;61:76–86. Kalkman CJ, Visser K, Moen J, Bonsel GJ, Grobbee DE, Moons KG. Preoperative prediction of severe postoperative pain. Pain 2003;105:415–23. Katz J, Poleshuck EL, Andrus CH, Hogan LA, Jung BF, Kulick DI, et al. Risk factors for acute pain and its persistence following breast cancer surgery. Pain 2005;119:16–25. Katz J, Seltzer Z. Transition from acute to chronic postsurgical pain: risk factors and protective factors. Expert Rev Neurother 2009;9:723–44. Kehlet H, Macrae WA, Stubhaug A. Persistent postoperative pain pathogenic mechanisms and preventive strategies. In: Mogil JS, editor. Pain 2010. An updated review: refresher course syllabus. Seattle: IASP Press; 2010. p. 3–12. Kehlet H. Chronic pain after groin hernia repair. Br J Surg 2008;95:135–6. Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. Lancet 2006;367:1618–25. Kehlet H, Rathmell JP. Persistent postsurgical pain: the path forward through better design of clinical studies. Anesthesiology 2010;112:514–5. Kehlet H, Wilkinson RC, Fischer HB, Camu F. PROSPECT: evidence-based, procedurespecific postoperative pain management. Best Pract Res Clin Anaesthesiol 2007;21:149–59. Koppert W. Opioid-induced hyperalgesia – pathophysiology and clinical relevance. Acute Pain 2007;9:21–34. Kristensen AD, Pedersen TA, Hjortdal VE, Jensen TS, Nikolajsen L. Chronic pain in adults after thoracotomy in childhood or youth. Br J Anaesth 2010;104:75–9. Lacroix-Fralish ML, Mogil JS. Progress in genetic studies of pain and analgesia. Annu Rev Pharmacol Toxicol 2009;49:97–121. Lundblad H, Kreicbergs A, Jansson KA. Prediction of persistent pain after total knee replacement for osteoarthritis. J Bone Joint Surg Br 2008;90:166–71. Macrae WA, Davies HTO. Chronic postsurgical pain. In: Crombie IK, Linton S, Von Korff M, LeResche L, editors. Epidemiology of pain. Seattle: IASP Press; 1999. p. 125–42. Maguire MF, Latter JA, Mahajan R, Beggs FD, Duffy JP. A study exploring the role of intercostal nerve damage in chronic pain after thoracic surgery. Eur J Cardiothorac Surg 2006;29:873–9. Martinez V, Fletcher D, Bouhassira D, Sessler DI, Chauvin M. The evolution of primary hyperalgesia in orthopedic surgery: quantitative sensory testing and clinical evaluation before and after total knee arthroplasty. Anesth Analg 2007;105:815–21. Mikkelsen T, Werner MU, Lassen B, Kehlet H. Pain and sensory dysfunction 6 to 12 months after inguinal herniotomy. Anesth Analg 2004;99:146–51. Mogil JS. Are we getting anywhere in human pain genetics? Pain 2009;146:231–2. Munafo MR, Stevenson J. Anxiety and surgical recovery. Reinterpreting the literature. J Psychosom Res 2001;51:589–96. Nielsen PR, Norgaard L, Rasmussen LS, Kehlet H. Prediction of post-operative pain by an electrical pain stimulus. Acta Anaesthesiol Scand 2007;51:582–6. Nikolajsen L, Hansen CL, Nielsen J, Keller J, Arendt-Nielsen L, Jensen TS. The effect of ketamine on phantom pain: a central neuropathic disorder maintained by peripheral input. Pain 1996;67:69–77.
207
Nikolajsen L, Ilkjaer S, Jensen TS. Relationship between mechanical sensitivity and postamputation pain: a prospective study. Eur J Pain 2000;4:327–34. Nikolajsen L, Jensen TS. Phantom limb. In: McMahon SB, Koltzenburg M, editors. Wall and Melzack´s textbook of pain Elsevier Churchill Livingstone, 2006. p. 961–71. Nikolajsen L, Kristensen AD, Thillemann TM, Jurik AG, Rasmussen T, Kehlet H, et al. Pain and somatosensory findings in patients 3 years after total hip arthroplasty. Eur J Pain 2009;13:576–81. Ozalp G, Sarioglu R, Tuncel G, Aslan K, Kadiogullari N. Preoperative emotional states in patients with breast cancer and postoperative pain. Acta Anaesthesiol Scand 2003;47:26–9. Pan PH, Coghill R, Houle TT, Seid MH, Lindel WM, Parker RL, et al. Multifactorial preoperative predictors for postcesarean section pain and analgesic requirement. Anesthesiology 2006;104:417–25. Pappagallo M, Oaklander AL, Quatrano-Piacentini AL, Clark MR, Raja SN. Heterogenous patterns of sensory dysfunction in postherpetic neuralgia suggest multiple pathophysiologic mechanisms. Anesthesiology 2000;92: 691–8. Peters ML, Sommer M, de Rijke JM, Kessels F, Heineman E, Patijn J, et al. Somatic and psychologic predictors of long-term unfavorable outcome after surgical intervention. Ann Surg 2007;245:487–94. Pluijms WA, Steegers MA, Verhagen AF, Scheffer GJ, Wilder-Smith OH. Chronic postthoracotomy pain: a retrospective study. Acta Anaesthesiol Scand 2006;50:804–8. Poleshuck EL, Green CR. Socioeconomic disadvantage and pain. Pain 2008;136:235–8. Poleshuck EL, Katz J, Andrus CH, Hogan LA, Jung BF, Kulick DI, et al. Risk factors for chronic pain following breast cancer surgery: a prospective study. J Pain 2006;7:626–34. Raja SN, Jensen TS. Predicting postoperative pain based on preoperative pain perception: are we doing better than the weatherman? Anesthesiology 2010;112:1311–2. Rogers ML, Henderson L, Mahajan RP, Duffy JP. Preliminary findings in the neurophysiological assessment of intercostal nerve injury during thoracotomy. Eur J Cardiothorac Surg 2002;21:298–301. Rosenberger PH, Jokl P, Ickovics J. Psychosocial factors and surgical outcomes: an evidence-based literature review. J Am Acad Orthop Surg 2006;14: 397–405. Rotbøll-Nielsen P, Rudin A, Werner MU. Prediction of postoperative pain. Curr Anaesth Crit Care 2007;18:157–65. Rudin A, Eriksson L, Liedholm R, List T, Werner MU. Prediction of postoperative pain after mandibular third molar surgery. J Orofac Pain 2010;24:189–96. Rudin A, Wolner-Hanssen P, Hellbom M, Werner MU. Prediction of post-operative pain after a laparoscopic tubal ligation procedure. Acta Anaesthesiol Scand 2008;52:938–45. Sommer M, de Rijke JM, van KM, Kessels AG, Peters ML, Geurts JW, et al. The prevalence of postoperative pain in a sample of 1490 surgical inpatients. Eur J Anaesthesiol 2008;25:267–74. Steegers MA, Snik DM, Verhagen AF, van der Drift MA, Wilder-Smith OH. Only half of the chronic pain after thoracic surgery shows a neuropathic component. J Pain 2008;9:955–61. Steegers MA, van de LA, Noyez L, Scheffer GJ, Wilder-Smith OH. The role of angina pectoris in chronic pain after coronary artery bypass graft surgery. J Pain 2007;8:667–73. Strulov L, Zimmer EZ, Granot M, Tamir A, Jakobi P, Lowenstein L. Pain catastrophizing, response to experimental heat stimuli, and post-cesarean section pain. J Pain 2006;8:273–9. Vilholm OJ, Cold S, Rasmussen L, Sindrup SH. Effect of levetiracetam on the postmastectomy pain syndrome. Eur J Neurol 2008;15:851–7. Vilholm OJ, Cold S, Rasmussen L, Sindrup SH. Sensory function and pain in a population of patients treated for breast cancer. Acta Anaesthesiol Scand 2009;53:800–6. Weissman-Fogel I, Granovsky Y, Crispel Y, Ben-Nun A, Best LA, Yarnitsky D, et al. Enhanced presurgical pain temporal summation response predicts postthoracotomy pain intensity during the acute postoperative phase. J Pain 2009;10:628–36. Werner MU, Duun P, Kehlet H. Prediction of postoperative pain by preoperative nociceptive responses to heat stimulation. Anesthesiology 2004;100:115–9. Werner MU, Mjobo HN, Nielsen PR, Rudin A. Prediction of postoperative pain: a systematic review of predictive experimental pain studies. Anesthesiology 2010;112:1494–502. Wilder-Smith CH, Hill L, Dyer RA, Torr G, Coetzee E. Postoperative sensitization and pain after cesarean delivery and the effects of single im doses of tramadol and diclofenac alone and in combination. Anesth Analg 2003;97:526–33. Wildgaard K, Ravn J, Kehlet H. Chronic post-thoracotomy pain: a critical review of pathogenic mechanisms and strategies for prevention. Eur J Cardiothorac Surg 2009;36:170–80. Wilgaard K, Ringsted TK, Aasvang EK, Ravn J, Kehlet H. Neurophysiological characterization of persistent post-thoracotomy pain, submitted for publication. Yarnitsky D, Crispel Y, Eisenberg E, Granovsky Y, Ben-Nun B, Best LA, et al. Prediction of chronic post-operative pain: pre-operative DNIC testing identifies patients at risk. Pain 2008;138:22–8.
Contents lists available at ScienceDirect
European Journal of Pain Supplements journal homepage: www.EuropeanJournalPain.com
Characterization of persistent postoperative pain by quantitative sensory testing Mads U. Werner a,⇑, Henrik Kehlet b a b
The Multidisciplinary Pain Centre 7612, Rigshospitalet, Copenhagen University Hospitals, Denmark Section of Surgical Pathophysiology 4074, Rigshospitalet, Copenhagen University Hospitals, Denmark
a r t i c l e Keywords: Postoperative pain Sensory assessments Acute pain Chronic pain Perception
i n f o
a b s t r a c t Postoperative pain remains inadequately treated, and it has been estimated that 5–10% undergoing surgery will develop moderate to severe persistent pain leading to chronic physical disability and psychosocial distress. Quantitative sensory testing (QST) is a graded, standardized activation of the sensory system either by mechanical, thermal or electrical stimuli, with assessment of the evoked psychophysical response. QST has been used in prospective assessments of how and why some individuals develop persistent postoperative pain. This comprehensive review describes, first, QST as a predictive research tool in studies investigating the correlation between responses to preoperatively applied experimental pain stimuli and clinical postoperative pain. Second, the use of QST as a valuable prognostic, sequential assessment tool in surgical procedure specific research is presented. Third, the implications of these findings for use of QST in future research are discussed. More rational design of predictive studies in PPP, based on surgical procedure specific approaches, is needed in order to improve our understanding of prevention and management of this debilitating postsurgical condition. Ó 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.
1. Introduction There are a number of incentives to improve our quest of knowledge in acute pain and in particular on its transition to persistent pain states. First, postoperative pain still remains inadequately treated (Gramke et al., 2007; Fletcher et al., 2008; Benhamou et al., 2008; Sommer et al., 2008). Second, it has been estimated that 5–10% of individuals undergoing surgery will develop moderate to severe persistent pain leading to chronic physical disability and psychosocial distress (Kehlet et al., 2006; Poleshuck and Green, 2008). Third, in a number of studies pre-existing pain and highintensity postoperative pain have been predictors of development of persistent pain following surgery (Bisgaard et al., 2005; Katz et al., 2005; Poleshuck et al., 2006; Pluijms et al., 2006; Peters et al., 2007; Steegers et al., 2007). Comprehensive reviews in these areas have been published recently (Kehlet et al., 2006; Rotbøll-Nielsen et al., 2007; Ip et al., 2009; Werner et al., 2010; Kehlet et al., 2010). Neurological evaluation includes quantitative sensory testing (QST) which is a graded, standardized activation of the peripheral ⇑ Corresponding author. Address: The Multidisciplinary Pain Centre 7612, Neuroscience Center Rigshospitalet, Copenhagen University Hospitals, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark. Tel.: +45 2825 7703; fax: +45 3545 3247. E-mail address: [email protected] (M.U. Werner).
nociceptive system either by mechanical (pressure, punctuate, vibratory, light touch), thermal (cold pain, cool, warm, heat pain) or electrical stimuli, with assessment of the psychophysical response (Arendt-Nielsen et al., 2007; Arendt-Nielsen and Yarnitsky, 2009). It is well-known that the inter-individual variation in pain perception is considerable (Edwards et al., 2005) and QST has been developed in an effort to minimize and control the intra-method error. It has rightfully been questioned if these methods in evoked pain research can replicate the sensory, emotional and cognitive dimensions of clinical pain (Gracely, 2007), and if results of QST are, indeed relevant for clinical pain (Edwards et al., 2005). A number of QST-studies have supplied important information about the mechanisms of pain and pain control, about normal and abnormal pain processing, about the trajectory of clinical pain in various disorders like peripheral neuropathies (Dreyer et al., 2004), central pain (Boivie, 2003), arthropathies (Hendiani et al., 2003), fibromyalgia (Desmeules et al., 2003), temporomandibular disorders (Ayesh et al., 2007), pelvic pain disorders (Granot et al., 2002), postmastectomy pain (Gottrup et al., 2000), postamputation pain (Nikolajsen and Jensen, 2006), and persistent postoperative pain (Mikkelsen et al., 2004). This article addresses a number of relevant aspects of QST. First, QST as a predictive research tool in studies investigating the correlation between responses to preoperatively applied experimental
1754-3207/$36.00 Ó 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.eujps.2010.09.004
204
M.U. Werner, H. Kehlet / European Journal of Pain Supplements 4 (2010) 203–207
pain stimuli and clinical postoperative pain is described. Second, the use of QST as a valuable prognostic, sequential assessment tool in surgical procedure specific research is presented. Third, the implications of these findings for use of QST in future research are discussed. 2. Quantitative sensory testing as a predictive experimental research tool To the authors´ knowledge, 18 predictive QST-based studies have been published, where the outcome parameters mainly have been postoperative pain intensity and postoperative requirements of analgesics. The experimental pain evoking stimulation methods have been the cold-pressor test (Bisgaard et al., 2001), heat immersion test (Yarnitsky et al., 2008), brief phasic (Granot et al., 2003; Pan et al., 2006; Martinez et al., 2007; Rudin et al., 2008; Weissman-Fogel et al., 2009; Rudin et al., 2010) or tonic heat stimulation (Strulov et al., 2006; Aasvang and Kehlet, 2010; Aasvang et al., 2010b), cutaneous electrical stimulation (Wilder-Smith et al., 2003; Nielsen et al., 2007; Lundblad et al., 2008; Aasvang et al., 2009; Hickey et al., 2010), pressure algometry (Nikolajsen et al., 2000; Hsu et al., 2005), punctuate mechanical stimulation (Martinez et al., 2007; Weissman-Fogel et al., 2009) and induction of an inflammatory injury (Werner et al., 2004). Contact thermodes were used in 10 of the studies (Granot et al., 2003; Werner et al., 2004; Pan et al., 2006; Strulov et al., 2006; Martinez et al., 2007; Yarnitsky et al., 2008; Rudin et al., 2008; Weissman-Fogel et al., 2009; Rudin et al., 2010; Aasvang et al., 2010b), hand immersion in ice water or hot water in 2 studies (Bisgaard et al., 2001; Yarnitsky et al., 2008), electrical stimulation with surface electrodes in 5 studies (Wilder-Smith et al., 2003; Nielsen et al., 2007; Lundblad et al., 2008; Aasvang et al., 2009; Hickey et al., 2010), a hand-hold pressure algometer (Nikolajsen et al., 2000; Hsu et al., 2005) and punctate stimulation with monofilaments (Martinez et al., 2007; Weissman-Fogel et al., 2009) were used in 2 studies, respectively. Predictive variables for acute and persistent postoperative pain were investigated in 15 studies (Nikolajsen et al., 2000; Bisgaard et al., 2001; Granot et al., 2003; Wilder-Smith et al., 2003; Werner et al., 2004; Hsu et al., 2005; Pan et al., 2006; Strulov et al., 2006; Nielsen et al., 2007; Yarnitsky et al., 2008; Rudin et al., 2008; Aasvang et al., 2009; Weissman-Fogel et al., 2009; Rudin et al., 2010; Aasvang et al., 2010b) and 6 studies (Nikolajsen et al., 2000; Martinez et al., 2007; Yarnitsky et al., 2008; Lundblad et al., 2008; Hickey et al., 2010; Aasvang et al., 2010b), respectively. Suprathreshold mechanical and thermal noxious stimulation had a better predictive performance than pain thresholds in regard to experience of clinical pain and requirement of analgesics (Edwards et al., 2005; Gracely 2006). In 7 (Granot et al., 2003; Werner et al., 2004; Pan et al., 2006; Strulov et al., 2006; Rudin et al., 2008; Rudin et al., 2010; Aasvang et al., 2010b) of 8 thermal QST studies an improved predictive power of suprathreshold stimulation was observed. The regression analyses demonstrated that preoperative QST measurements may predict 4–54% of the variance in acute postoperative pain experience and 13–59% of the variance in development of persistent postoperative pain1 (Nikolajsen et al., 2000; Werner et al., 2010; Aasvang et al., 2010b). Five studies evaluated the predictive power of QST on requirement of analgesics (Hsu et al., 2005; Pan et al., 2006; Martinez et al., 2007; Rudin et al., 2008; Rudin et al., 2010). In only one total knee arthroplasty study, preoperative heat hyperalgesia at the inflammatory changed surgical 1 The square of the correlation coefficient either q2 (Spearman’s correlation coefficient (rho) for non-parametric analyzes) or r2 (Pearson’s correlation coefficient for parametric analyzes) indicate the percentage of the variance of the dependent variable that is predicted by the independent variable(s).
area predicted 44% of the variance in postoperative morphine consumption by patient-controlled analgesia (Martinez et al., 2007). A number of studies, in addition to QST-assessments, also investigated the predictive potential of preoperative psychological variables (anxiety, depression, psychological vulnerability, catastrophizing behavior). Interestingly, by adding psychological variables to the QST-variables in multivariate regression analyses, the increase in predictive power of the model generally was very modest or even absent (Werner et al., 2010). In contrast, recent studies have reported that in particular preoperative anxiety (Munafo and Stevenson, 2001; Janssen et al., 2008b), but also depression (Ozalp et al., 2003), neuroticism (Borly et al., 1999; Cohen et al., 2005) and catastrophizing behavior (Granot and Ferber, 2005) seem associated with development of high-intensity postoperative pain (Rotbøll-Nielsen et al., 2007) and may have a negative effect on surgical outcome (Rosenberger et al., 2006). Thus, QST-assessments as research tools in studies with experimental preoperative pain have provided valuable information on the pre and postsurgical state of the pain system and on the predictive efficacy of different stimulation methods and testing paradigms. A main finding is that the results from the five elective cesarean section studies (Granot et al., 2003; Wilder-Smith et al., 2003; Pan et al., 2006; Strulov et al., 2006; Nielsen et al., 2007) suggest rather consistently that pain after this procedure can, at least in part, be predicted. Previous research, however, has demonstrated that the surgical procedure and technique may influence the intensity and the duration of postoperative pain (Kehlet et al., 2006; Janssen et al., 2008a). Therefore an important limitation of the predictive studies is, that in 18 studies, 11 different surgical procedures were performed, indicating an important source of data heterogeneity. In addition, in most studies the surgical procedure in regard to characteristics of skin incision and handling of nerves and muscles were only rudimentary described. Furthermore, it is not known if the pain mechanisms or pain trajectory may differ between inflammatory, neuropathic or visceral types of postoperative pain. The majority of the predictive studies are probably best considered hypothesis generating studies, although one high-powered study (n = 464) in inguinal herniotomy patients (Aasvang et al., 2010b) seems to bridge the gap to adequately powered procedure specific research. 3. Quantitative sensory testing in procedure specific research In order to overcome some of the major obstacles in postoperative pain research, the use of surgical procedure specific approaches have been advocated (Kehlet et al., 2007; Raja and Jensen, 2010). During the last years the research has rapidly accelerated in following procedures: inguinal herniotomy, thoracotomy and breast cancer surgery. 3.1. Inguinal herniotomy Persistent postoperative pain (PPP) leading to a severe impact on daily ambulatory functions, occurs in 5–8% of the patients following groin hernia repair (Kehlet, 2008). This high-volume, albeit minor, surgical procedure therefore generates a substantial number of chronic pain patients annually. The inguinal herniotomy is an ideal research model to study, since the patients seldom have any significant comorbidity interfering with PPP (Aasvang et al., 2008). Several perioperative risk factors have been identified: preoperative pain, surgical trauma, nerve lesions and acute postoperative pain (Kehlet et al., 2010). Neurophysiological characterization of herniotomy patients with QST has contributed to an increased understanding of the
M.U. Werner, H. Kehlet / European Journal of Pain Supplements 4 (2010) 203–207
underlying pathophysiology (Aasvang et al., 2008; Aasvang and Kehlet 2010; Aasvang et al., 2010a; Aasvang et al., 2010b). Importantly, it has been shown that pain-free herniotomy patients also demonstrate sensory disturbances (thermal and mechanical hypo-/hyperaesthesia, decreased algometry pain/tolerance thresholds) in the surgical area (Aasvang and Kehlet, 2010). Thus evaluation of QST-data from individuals with PPP should not only consider side-to-side data, compensating for cross-over effects or generalized sensitization phenomena, but also consider normative data from pain-free herniotomy patients (Aasvang et al., 2010a). When the sensory disturbances are compared in pain and pain-free postherniotomy patients, in patients with PPP 17% demonstrate cold hypoaesthesia, 30% warmth hypoaesthesia and 37–66% exhibit mechanical hyperaesthesia to deep tissue stimulation. The sensory changes are quite heterogeneously distributed, a finding that also has been described in other types of injury (Pappagallo et al., 2000; Gottrup et al., 2000). The combination of spontaneous or evoked pain, cutaneous sensory loss and increased pain thresholds is suggestive of a neuropathic component. Repetitive pin-prick or brush stimulation significantly increase pain intensity in 51% of PPP patients and in 15% of pain-free individuals (Aasvang and Kehlet, 2010; Aasvang et al., 2010a). This ‘‘wind-up like”, cutaneous phenomenon indicates central nervous sensitization and is identical to findings from PPP-states following amputation, mastectomy and thoracotomy procedures (Nikolajsen et al., 1996; Gottrup et al., 2000; Weissman-Fogel et al., 2009), corroborating the assumption of a neuropathic pain component. The observed mechanical hyperaesthesia to deep tissue stimulation is compatible with an ongoing inflammatory response to the mesh, either with or without secondary nerve dysfunction (Aasvang et al., 2008). 3.2. Thoracotomy The reported prevalence of PPP following anterolateral thoracotomy is 25–60% reflecting a wide variation in study design, methods and definitions (Wildgaard et al., 2009; Kehlet et al., 2010; Kristensen et al., 2010). Neurological assessments have included somatosensory-evoked responses, electrical stimulation thresholds, magnetic intercostal nervestimulation, intercostal nerve conduction analysis and intercostal motor evoked potentials (Benedetti et al., 1998; Rogers et al., 2002; Maguire et al., 2006). Very few studies have used a detailed neurophysiological characterization of persistent post-thoracotomy pain with QST (Kristensen et al., 2010). It has been suggested that post-thoracotomy pain is mainly of neuropathic origin, due to intercostal nerve transection, nerve ligation or rib retractor-induced traction or crush injury of neural tissue. A recent demographic study has questioned the neuropathic origin of the pain (Steegers et al., 2008), and it is a possibility that PPP may be generated from other structures in the rib cage traumatized during the procedure: intercostal muscles, ribs, and possibly costo-vertebral or costo-sternal joints. The first published QST study investigated adults (n = 88) who had thoracotomy performed during childhood or adolescence (Kristensen et al., 2010). Only three of the examined individuals had persistent pain 29–31 years after the surgical procedure. Hypo or hyperaesthesia to touch and tactile stimulation were demonstrated in nearly all participants. Tactile detection threshold and pressure (pinch) pain threshold were significantly increased in the surgical side compared to the contralateral side. In an interesting unpublished study, adults (n = 42), who had thoracotomy performed due to lung cancer, were investigated with QST-assessments three years after surgery (Wilgaard et al., submitted for publication). Eighteen of the patients had PPP while 24 pain-free patients served as controls. Patients with post-thoracotomy pain demonstrated significantly increased
205
side-to-side differences in mechanical and thermal detection thresholds, and heat pain threshold compared to controls. No difference was observed in regard to pressure pain and tolerance threshold, or in cold hypoaesthesia areas. The study concludes that nerve injury is a frequent finding following thoracotomy, both in pain and pain-free individuals. The pressure algometry findings do not support that pain is generated from deeper tissues. 3.3. Breast cancer surgery Persistent postoperative pain and sensory disturbances after breast cancer surgery is estimated to be 25–60% and 20–80%, respectively. A recent nationwide, cross-sectional questionnaire study (n = 3253) demonstrated that 47% of patients experience pain (13% reporting severe pain) and 58% experience sensory disturbances in the surgical region, one to three years after the procedure (Gärtner et al., 2009). Factors associated with persistent pain were young age, adjuvant radiotherapy and axillary lymph node resection compared to sentinel node technique. In breast cancer surgery only 3 studies have included QST-assessments (Gottrup et al., 2000; Vilholm et al., 2008; Vilholm et al., 2009). In the first study 15 patients with spontaneous PPP with sensory disturbances were compared with 11 pain-free women with sensory disturbances. Sensory thresholds to pinprick and thermal stimuli were significantly higher on the surgical side in patients and controls, while pressure pain threshold was significantly lower in pain patients on the surgical side compared to the contralateral side. Responses to repetitive pin-prick stimulation were increased on the surgical side in pain patients indicating sensitization of the nervous system. The second study was a pharmacological QST-study on the effect of levetiracetam, an anticonvulsant, on postmastectomy syndrome (Vilholm et al., 2008). The third study included patients with PPP (n = 55) and pain-free individuals (n = 27) acting as controls (Vilholm et al., 2009). In both groups higher thermal thresholds were demonstrated on the surgical side compared to the contralateral side. The side-to-side difference was significantly higher for warmth detection threshold in the pain group. The incidences of cold-allodynia and temporal summation with pin-prick were significantly more frequent in the pain group. The authors conclude that PPP after breast cancer surgery seems to be of neuropathic origin. These findings are consistent with data from other procedures (Mikkelsen et al., 2004; Jaaskelainen et al., 2004; Nikolajsen et al., 2009; Aasvang et al., 2010a). 4. Recommendations for study design in persistent postoperative pain Although an increasing number of QST studies are available to predict and characterize PPP-states, there is a need for prospective studies including all potential risk factors (pre, intra, and early and late postoperative assessments) in order to improve our understanding of the relative role of the different pathogenic mechanisms, thereby hopefully serving for more rational strategies for prevention and treatment. The application of sensory tests and psychometric questionnaires are in most cases a time consuming process, and not clinically feasible at this time. A simple electrical device was used in 2 of the studies (Nielsen et al., 2007; Aasvang et al., 2009) and although a multivariate model that includes seven clinically relevant variables (Kalkman et al., 2003; Janssen et al., 2008a; Janssen et al., 2008b), all easily obtained during the preoperative evaluation, has been proposed to predict severe postoperative pain, further research efforts in easily applicable and accurate methods are needed.
206
M.U. Werner, H. Kehlet / European Journal of Pain Supplements 4 (2010) 203–207
Table 1 Variables important to consider in design of studies of persistent postoperative pain (Kehlet and Rathmell, 2010). Preoperatively Characterization of pre-existing pain Opioid therapy Assessment of the functional consequences of pre-existing pain Psychosocial assessment Neurophysiologic assessment Analyses of ‘‘pain genes” Intraoperatively Type of anesthesia Descriptive characteristics of the surgical procedure: endoscopically assisted/open access skin incision handling of nerves and muscles implantation of prosthetic materials Surgical classification of the disease Early postoperatively Pain intensity and character Pain management Neurophysiologic assessment Late postoperatively Pain intensity and character Assessment of the functional consequences Neurophysiologic assessment Adjuvant therapies (radiotherapy, chemotherapy)
The variables involved in persisting postoperative pain may be divided into patient- and surgery-related variables (Table 1) (Kehlet and Rathmell, 2010). Pre-existing pain is considered a significant predictor of severe postoperative pain and development of chronic postoperative pain (Kehlet et al., 2006; Janssen et al., 2008a) and it is interesting that in only 6 of the previously mentioned 18 predictive QST-studies (Bisgaard et al., 2001; Martinez et al., 2007; Rudin et al., 2008; Lundblad et al., 2008; Rudin et al., 2010; Aasvang et al., 2010b) the prevalence of pre-existing pain was reported. The sensitization induced by pre-existing pain may be enhanced by opioid treatment, and could play an important role in the exaggerated postoperative pain response seen in chronic pain patients (Angst and Clark, 2006; Koppert, 2007). Assessments of the functional consequences of pre-existing pain on daily life, including the impact of psychosocial distress, are also important preoperative variables. Several gene candidates seem to correlate with the development of PPP (Lacroix-Fralish and Mogil, 2009), but since the combinations of different single nucleotide polymorphisms may reach an astronomically high number, new technologies like genome-wide association studies (GWAS) are needed (Mogil, 2009). Unfortunately this concept requires large-scale studies including 1000– 3000 individuals. The intraoperative variables include type of anesthesia, surgical approach, nerve identification, nerve injury and implantation of synthetic materials (i.e. mesh). For cancer surgery the intraoperative findings are important determinants in staging and classification of the disease, and in the planning of adjuvant therapies, all which may affect the risk of development of persistent postoperative pain (Katz and Seltzer, 2009). The postoperative variables include detailed descriptions of pain (intensity, character and duration), pain management, neurophysiologic changes, adjuvant therapies and the functional consequences of pain. Although a proposed criterion for PPP, according to the International Association of Pain (IASP) (Macrae and Davies, 1999), has been a duration of at least 2 months, data seem to indicate that after certain surgical procedures a continuous inflammatory response may develop, calling for assessments for at least 3–6 months postoperatively to provide reliable results (Kehlet and Rathmell, 2010). Very few studies have included such detailed long-time follow up of patients with PPP.
More rational design of predictive studies in PPP, based on surgical procedure specific approaches, is needed in order to improve our understanding of prevention and management of this prevalent postsurgical condition.
Conflict of interest statement The authors declare no conflict of interest.
Acknowledgements This review was supported by grants from the Lundbeck Foundation and is a part of the Europain project, funded by the Innovative Medicines Initiative Joint Undertaking (IMI JU)’ Grant No. 115007.
References Aasvang EK, Brandsborg B, Christensen B, Jensen TS, Kehlet H. Neurophysiological characterization of postherniotomy pain. Pain 2008;137:173–81. Aasvang EK, Brandsborg B, Jensen TS, Kehlet H. Heterogeneous sensory processing in persistent postherniotomy pain. Pain 2010a;150:237–42. Aasvang EK, Gmaehle E, Hansen JB, Gmaehle B, Forman JL, Schwarz J, et al. Predictive risk factors for persistent postherniotomy pain. Anesthesiology 2010b;112:957–69. Aasvang EK, Hansen JB, Kehlet H. Can preoperative electrical nociceptive stimulation predict acute pain after groin herniotomy? Eur J Pain 2009;13:1018–22. Aasvang EK, Kehlet H. Persistent sensory dysfunction in pain-free herniotomy. Acta Anaesthesiol Scand 2010;54:291–8. Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology 2006;104:570–87. Arendt-Nielsen L, Curatolo M, Drewes A. Human experimental pain models in drug development: translational pain research. Curr Opin Investig Drugs 2007;8:41–53. Arendt-Nielsen L, Yarnitsky D. Experimental and clinical applications of quantitative sensory testing applied to skin, muscles and viscera. J Pain 2009;10:556–72. Ayesh EE, Jensen TS, Svensson P. Somatosensory function following painful repetitive electrical stimulation of the human temporomandibular joint and skin. Exp Brain Res 2007;179:415–25. Benedetti F, Vighetti S, Ricco C, Amanzio M, Bergamasco L, Casadio C, et al. Neurophysiologic assessment of nerve impairment in posterolateral and muscle-sparing thoracotomy. J Thorac Cardiovasc Surg 1998;115:841–7. Benhamou D, Berti M, Brodner G, De AJ, Draisci G, Moreno-Azcoita M, et al. Postoperative analgesic therapy observational survey (PATHOS): a practice pattern study in 7 Central/Southern European countries. Pain 2008;136:134–41. Bisgaard T, Klarskov B, Rosenberg J, Kehlet H. Characteristics and prediction of early pain after laparoscopic cholecystectomy. Pain 2001;90:261–9. Bisgaard T, Rosenberg J, Kehlet H. From acute to chronic pain after laparoscopic cholecystectomy: a prospective follow-up analysis. Scand J Gastroenterol 2005;40:1358–64. Boivie J. Central pain and the role of quantitative sensory testing (QST) in research and diagnosis. Eur J Pain 2003;7:339–43. Borly L, Andersen IB, Christensen E, Sehested A, Kehlet H, Matzen P, et al. Preoperative prediction model of outcome after cholecystectomy for symptomatic gallstones. Scand J Gastroenterol 1999;34:1144–52. Cohen L, Fouladi RT, Katz J. Preoperative coping strategies and distress predict postoperative pain and morphine consumption in women undergoing abdominal gynecologic surgery. J Psychosom Res 2005;58:201–9. Desmeules JA, Cedraschi C, Rapiti E, Baumgartner E, Finckh A, Cohen P, et al. Neurophysiologic evidence for a central sensitization in patients with fibromyalgia. Arthritis Rheum 2003;48:1420–9. Dreyer M, Vucic S, Cros DP, Chong PS. Multiple painful sensory mononeuropathies (MPSM), a novel pattern of sarcoid neuropathy. J Neurol Neurosurg Psychiatry 2004;75:1645–6. Edwards RR, Sarlani E, Wesselmann U, Fillingim RB. Quantitative assessment of experimental pain perception: multiple domains of clinical relevance. Pain 2005;114:315–9. Fletcher D, Fermanian C, Mardaye A, Aegerter P. A patient-based national survey on postoperative pain management in France reveals significant achievements and persistent challenges. Pain 2008;137:441–51. Gartner R, Jensen MB, Nielsen J, Ewertz M, Kroman N, Kehlet H. Prevalence of and factors associated with persistent pain following breast cancer surgery. JAMA 2009;302:1985–92. Gottrup H, Andersen J, Arendt-Nielsen L, Jensen TS. Psychophysical examination in patients with post-mastectomy pain. Pain 2000;87:275–84.
M.U. Werner, H. Kehlet / European Journal of Pain Supplements 4 (2010) 203–207 Gracely RH. Studies of pain in human subjects. In: McMahon SB, Koltzenburg M, editors. Wall and Melzack´s textbook of Elsevier Churchill Livingstone, 2006. p. 267–89. Gracely RH. Stimulus response functions. In: Schmidt RF, Willis WD, editors. Encyclopedia of pain 2007;vol. 3. Berlin Heidelberg New York: Springer; 2007. p. 2321–4. Gramke HF, de Rijke JM, van KM, Raps F, Kessels AG, Peters ML, et al. The prevalence of postoperative pain in a cross-sectional group of patients after day-case surgery in a university hospital. Clin J Pain 2007;23:543–8. Granot M, Ferber SG. The roles of pain catastrophizing and anxiety in the prediction of postoperative pain intensity: a prospective study. Clin J Pain 2005;21:439–45. Granot M, Friedman M, Yarnitsky D, Zimmer EZ. Enhancement of the perception of systemic pain in women with vulvar vestibulitis. BJOG 2002;109:863–6. Granot M, Lowenstein L, Yarnitsky D, Tamir A, Zimmer EZ. Postcesarean section pain prediction by preoperative experimental pain assessment. Anesthesiology 2003;98:1422–6. Hendiani JA, Westlund KN, Lawand N, Goel N, Lisse J, McNearney T. Mechanical sensation and pain thresholds in patients with chronic arthropathies. J Pain 2003;4:203–11. Hickey OT, Burke SM, Hafeez P, Mudrakouski AL, Hayes ID, Keohane C, et al. Determinants of outcome for patients undergoing lumbar discectomy: a pilot study. Eur J Anaesthesiol 2010;27:696–701. Hsu YW, Somma J, Hung YC, Tsai PS, Yang CH, Chen CC. Predicting postoperative pain by preoperative pressure pain assessment. Anesthesiology 2005;103:613–8. Ip HY, Abrishami A, Peng PW, Wong J, Chung F. Predictors of postoperative pain and analgesic consumption: a qualitative systematic review. Anesthesiology 2009;111:657–77. Jaaskelainen SK, Teerijoki-Oksa T, Virtanen A, Tenovuo O, Forssell H. Sensory regeneration following intraoperatively verified trigeminal nerve injury. Neurology 2004;62:1951–7. Janssen KJ, Kalkman CJ, Grobbee DE, Bonsel GJ, Moons KG, Vergouwe Y. The risk of severe postoperative pain: modification and validation of a clinical prediction rule. Anesth Analg 2008a;107:1330–9. Janssen KJ, Moons KG, Kalkman CJ, Grobbee DE, Vergouwe Y. Updating methods improved the performance of a clinical prediction model in new patients. J Clin Epidemiol 2008b;61:76–86. Kalkman CJ, Visser K, Moen J, Bonsel GJ, Grobbee DE, Moons KG. Preoperative prediction of severe postoperative pain. Pain 2003;105:415–23. Katz J, Poleshuck EL, Andrus CH, Hogan LA, Jung BF, Kulick DI, et al. Risk factors for acute pain and its persistence following breast cancer surgery. Pain 2005;119:16–25. Katz J, Seltzer Z. Transition from acute to chronic postsurgical pain: risk factors and protective factors. Expert Rev Neurother 2009;9:723–44. Kehlet H, Macrae WA, Stubhaug A. Persistent postoperative pain pathogenic mechanisms and preventive strategies. In: Mogil JS, editor. Pain 2010. An updated review: refresher course syllabus. Seattle: IASP Press; 2010. p. 3–12. Kehlet H. Chronic pain after groin hernia repair. Br J Surg 2008;95:135–6. Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. Lancet 2006;367:1618–25. Kehlet H, Rathmell JP. Persistent postsurgical pain: the path forward through better design of clinical studies. Anesthesiology 2010;112:514–5. Kehlet H, Wilkinson RC, Fischer HB, Camu F. PROSPECT: evidence-based, procedurespecific postoperative pain management. Best Pract Res Clin Anaesthesiol 2007;21:149–59. Koppert W. Opioid-induced hyperalgesia – pathophysiology and clinical relevance. Acute Pain 2007;9:21–34. Kristensen AD, Pedersen TA, Hjortdal VE, Jensen TS, Nikolajsen L. Chronic pain in adults after thoracotomy in childhood or youth. Br J Anaesth 2010;104:75–9. Lacroix-Fralish ML, Mogil JS. Progress in genetic studies of pain and analgesia. Annu Rev Pharmacol Toxicol 2009;49:97–121. Lundblad H, Kreicbergs A, Jansson KA. Prediction of persistent pain after total knee replacement for osteoarthritis. J Bone Joint Surg Br 2008;90:166–71. Macrae WA, Davies HTO. Chronic postsurgical pain. In: Crombie IK, Linton S, Von Korff M, LeResche L, editors. Epidemiology of pain. Seattle: IASP Press; 1999. p. 125–42. Maguire MF, Latter JA, Mahajan R, Beggs FD, Duffy JP. A study exploring the role of intercostal nerve damage in chronic pain after thoracic surgery. Eur J Cardiothorac Surg 2006;29:873–9. Martinez V, Fletcher D, Bouhassira D, Sessler DI, Chauvin M. The evolution of primary hyperalgesia in orthopedic surgery: quantitative sensory testing and clinical evaluation before and after total knee arthroplasty. Anesth Analg 2007;105:815–21. Mikkelsen T, Werner MU, Lassen B, Kehlet H. Pain and sensory dysfunction 6 to 12 months after inguinal herniotomy. Anesth Analg 2004;99:146–51. Mogil JS. Are we getting anywhere in human pain genetics? Pain 2009;146:231–2. Munafo MR, Stevenson J. Anxiety and surgical recovery. Reinterpreting the literature. J Psychosom Res 2001;51:589–96. Nielsen PR, Norgaard L, Rasmussen LS, Kehlet H. Prediction of post-operative pain by an electrical pain stimulus. Acta Anaesthesiol Scand 2007;51:582–6. Nikolajsen L, Hansen CL, Nielsen J, Keller J, Arendt-Nielsen L, Jensen TS. The effect of ketamine on phantom pain: a central neuropathic disorder maintained by peripheral input. Pain 1996;67:69–77.
207
Nikolajsen L, Ilkjaer S, Jensen TS. Relationship between mechanical sensitivity and postamputation pain: a prospective study. Eur J Pain 2000;4:327–34. Nikolajsen L, Jensen TS. Phantom limb. In: McMahon SB, Koltzenburg M, editors. Wall and Melzack´s textbook of pain Elsevier Churchill Livingstone, 2006. p. 961–71. Nikolajsen L, Kristensen AD, Thillemann TM, Jurik AG, Rasmussen T, Kehlet H, et al. Pain and somatosensory findings in patients 3 years after total hip arthroplasty. Eur J Pain 2009;13:576–81. Ozalp G, Sarioglu R, Tuncel G, Aslan K, Kadiogullari N. Preoperative emotional states in patients with breast cancer and postoperative pain. Acta Anaesthesiol Scand 2003;47:26–9. Pan PH, Coghill R, Houle TT, Seid MH, Lindel WM, Parker RL, et al. Multifactorial preoperative predictors for postcesarean section pain and analgesic requirement. Anesthesiology 2006;104:417–25. Pappagallo M, Oaklander AL, Quatrano-Piacentini AL, Clark MR, Raja SN. Heterogenous patterns of sensory dysfunction in postherpetic neuralgia suggest multiple pathophysiologic mechanisms. Anesthesiology 2000;92: 691–8. Peters ML, Sommer M, de Rijke JM, Kessels F, Heineman E, Patijn J, et al. Somatic and psychologic predictors of long-term unfavorable outcome after surgical intervention. Ann Surg 2007;245:487–94. Pluijms WA, Steegers MA, Verhagen AF, Scheffer GJ, Wilder-Smith OH. Chronic postthoracotomy pain: a retrospective study. Acta Anaesthesiol Scand 2006;50:804–8. Poleshuck EL, Green CR. Socioeconomic disadvantage and pain. Pain 2008;136:235–8. Poleshuck EL, Katz J, Andrus CH, Hogan LA, Jung BF, Kulick DI, et al. Risk factors for chronic pain following breast cancer surgery: a prospective study. J Pain 2006;7:626–34. Raja SN, Jensen TS. Predicting postoperative pain based on preoperative pain perception: are we doing better than the weatherman? Anesthesiology 2010;112:1311–2. Rogers ML, Henderson L, Mahajan RP, Duffy JP. Preliminary findings in the neurophysiological assessment of intercostal nerve injury during thoracotomy. Eur J Cardiothorac Surg 2002;21:298–301. Rosenberger PH, Jokl P, Ickovics J. Psychosocial factors and surgical outcomes: an evidence-based literature review. J Am Acad Orthop Surg 2006;14: 397–405. Rotbøll-Nielsen P, Rudin A, Werner MU. Prediction of postoperative pain. Curr Anaesth Crit Care 2007;18:157–65. Rudin A, Eriksson L, Liedholm R, List T, Werner MU. Prediction of postoperative pain after mandibular third molar surgery. J Orofac Pain 2010;24:189–96. Rudin A, Wolner-Hanssen P, Hellbom M, Werner MU. Prediction of post-operative pain after a laparoscopic tubal ligation procedure. Acta Anaesthesiol Scand 2008;52:938–45. Sommer M, de Rijke JM, van KM, Kessels AG, Peters ML, Geurts JW, et al. The prevalence of postoperative pain in a sample of 1490 surgical inpatients. Eur J Anaesthesiol 2008;25:267–74. Steegers MA, Snik DM, Verhagen AF, van der Drift MA, Wilder-Smith OH. Only half of the chronic pain after thoracic surgery shows a neuropathic component. J Pain 2008;9:955–61. Steegers MA, van de LA, Noyez L, Scheffer GJ, Wilder-Smith OH. The role of angina pectoris in chronic pain after coronary artery bypass graft surgery. J Pain 2007;8:667–73. Strulov L, Zimmer EZ, Granot M, Tamir A, Jakobi P, Lowenstein L. Pain catastrophizing, response to experimental heat stimuli, and post-cesarean section pain. J Pain 2006;8:273–9. Vilholm OJ, Cold S, Rasmussen L, Sindrup SH. Effect of levetiracetam on the postmastectomy pain syndrome. Eur J Neurol 2008;15:851–7. Vilholm OJ, Cold S, Rasmussen L, Sindrup SH. Sensory function and pain in a population of patients treated for breast cancer. Acta Anaesthesiol Scand 2009;53:800–6. Weissman-Fogel I, Granovsky Y, Crispel Y, Ben-Nun A, Best LA, Yarnitsky D, et al. Enhanced presurgical pain temporal summation response predicts postthoracotomy pain intensity during the acute postoperative phase. J Pain 2009;10:628–36. Werner MU, Duun P, Kehlet H. Prediction of postoperative pain by preoperative nociceptive responses to heat stimulation. Anesthesiology 2004;100:115–9. Werner MU, Mjobo HN, Nielsen PR, Rudin A. Prediction of postoperative pain: a systematic review of predictive experimental pain studies. Anesthesiology 2010;112:1494–502. Wilder-Smith CH, Hill L, Dyer RA, Torr G, Coetzee E. Postoperative sensitization and pain after cesarean delivery and the effects of single im doses of tramadol and diclofenac alone and in combination. Anesth Analg 2003;97:526–33. Wildgaard K, Ravn J, Kehlet H. Chronic post-thoracotomy pain: a critical review of pathogenic mechanisms and strategies for prevention. Eur J Cardiothorac Surg 2009;36:170–80. Wilgaard K, Ringsted TK, Aasvang EK, Ravn J, Kehlet H. Neurophysiological characterization of persistent post-thoracotomy pain, submitted for publication. Yarnitsky D, Crispel Y, Eisenberg E, Granovsky Y, Ben-Nun B, Best LA, et al. Prediction of chronic post-operative pain: pre-operative DNIC testing identifies patients at risk. Pain 2008;138:22–8.