Development Of Persistent Postsurgical Pain Research Articles

The mechanisms and management of persistent postsurgical pain.

An estimated 10%-50% of patients undergoing a surgical intervention will develop persistent postsurgical pain (PPP) lasting more than 3 months despite adequate acute pain management and the availability of minimally invasive procedures. The link between early and late pain outcomes for surgical procedures remains unclear-some patients improve while others develop persistent pain. The elective nature of a surgical procedure offers a unique opportunity for prophylactic or early intervention to prevent the development of PPP and improve our understanding of its associated risk factors, such as pre-operative anxiety and the duration of severe acute postoperative pain. Current perioperative pain management strategies often include opioids, but long-term consumption can lead to tolerance, addiction, opioid-induced hyperalgesia, and death. Pre-clinical models provide the opportunity to dissect mechanisms underpinning the transition from acute to chronic, or persistent, postsurgical pain. This review highlights putative mechanisms of PPP, including sensitisation of peripheral sensory neurons, neuroplasticity in the central nervous system and nociceptive signalling along the neuro-immune axis.

Kristin Schreiber, M.D., Ph.D., a Recipient of the 2022 James E. Cottrell, M.D., Presidential Scholar Award

Kristin Schreiber, M.D., Ph.D., a Recipient of the 2022 James E. Cottrell, M.D., Presidential Scholar Award

Different than Your Mother's Pain: Postsurgical Pain Modulation by Psychosocial Factors among Younger and Older Breast Cancer Patients

Younger age is a risk factor for worse outcomes following breast cancer surgery, including acute pain, development of persistent post-surgical pain, physical symptoms (arm disability), and greater psychological distress (depression). The biopsychosocial model of pain emphasizes the importance of considering the psychosocial context of pain experience, in addition to biological factors (age). Potentially, younger women's worse psychosocial adjustment after breast cancer surgery may explain their greater pain-related functional disability. We investigated the longitudinal relationship between age and pain-related functioning three months post-surgery among women with breast cancer. Further, we examined whether early postoperative psychosocial distress, reported two weeks postoperatively, mediated the association between age and subsequent pain-related functioning. This prospective, observational longitudinal study recruited women (N:161, age:54, range: 26-81) undergoing breast cancer surgery. Validated psychosocial assessments (anxiety, depression, sleep disturbance) were assessed two weeks postoperatively, and impact of surgical pain on cognitive/emotional and physical functioning was assessed three months postoperatively. Bivariate correlations tested associations among age, psychosocial factors, and pain-related functioning. Parallel mediation analyses tested whether the relationship between age and pain-related functioning three months postoperatively was mediated by psychosocial factors reported two weeks postoperatively. Younger age was significantly associated with greater impact of pain on cognitive/emotional and physical functioning. Younger age was associated with greater severity of depressive and anxiety symptoms, and greater sleep disturbance (ps<.001). The association between younger age and greater impact of pain on cognitive/emotional functioning was mediated by greater severity of anxiety. The association between younger age and greater impact of pain on physical functioning was mediated by greater sleep disturbance. Findings suggest that anxiety and sleep disturbance that occur early after breast cancer surgery may help explain greater chronic pain-related functional disability in younger patients. Anxiety and sleep disturbance are potentially modifiable, to some degree, with behavioral interventions, making them potential perioperative therapeutic targets. Grant support from NIH/NIGMS: K23 GM110540.

Enhanced Recovery After Surgery: Opioid Sparing Strategies After Discharge: A Review.

PURPOSEOF REVIEW: Many surgical subspecialties have developed enhanced recovery after surgery (ERAS) protocols that focus on multimodal analgesia to limit opioid use during a hospital stay and improve patient recovery. Unfortunately, ERAS protocols do not extend to post-discharge patient care, and opioids continue to be over prescribed. The primary reason seems to be a lack of good quality research evaluating extended use of a multimodal analgesic approach. This review was undertaken to evaluate available evidence for non-opioid analgesics in the postoperative period after discharge, utilizing Pubmed, Scopus, and Google Scholar. RECENT FINDINGS: Several studies have explored strategies to reduce the overprescribing of opioids after surgery without worsening postoperative pain scores or complications. However, these studies do not necessarily reflect on situations where an ultra-restrictive protocol may fail, leading to breakthrough pain. Ultra-restrictive opioid protocols, therefore, could risk undertreatment of acute pain and the development of persistent post-surgical pain, highlighting the need for a review of non-opioid strategies. Our findings show that little research has been conducted on the efficacy of non-opioid therapies post-discharge including acetaminophen, NSAIDs, gabapentin, duloxetine, venlafaxine, tizanidine, valium, and oral ketamine. Further studies are warranted to more precisely evaluate the utility of these agents, specifically for their side effect profile and efficacy in improving pain-control and function while limiting opioid use.

The Effect of Preoperative Serratus Anterior Muscle Plane Block on Persistent Postsurgical Pain After Video-assisted Thoracic Surgery: A Retrospective Cohort Study.

Acute pain intensity is a strong indicator for the occurrence of persistent postsurgical pain (PPP) after video-assisted thoracic surgery (VATS). The effect of preoperative serratus anterior muscle plane block (SAPB) on PPP was investigated. In this retrospective cohort study, data of 148 patients who underwent VATS for lung nodules in 2019 were collected. Seventy-four patients received a single-shot of SAPB with 0.33% ropivacaine 30 mL after anesthesia induction and another 74 patients received intercostal blocks using 1% ropivacaine 10 mL at the fifth to seventh intercostal spaces after surgery. Postoperative analgesia was accomplished by continuous infusion of flurbiprofen (8 mg/h), and intravenous oxycodone rescue (1 mg) given on demand. Pain intensity was recorded at 24 and 48 hours after surgery and all patients were followed up 3 months after surgery investigating the occurrence of PPP. Intraoperative sufentanil in the SAPB group was significantly decreased in comparison with Control group (0.34±0.09 vs. 0.43±0.14 ug/kg, P<0.001). The incidence of PPP was comparable between 2 groups (20.2% [15/74] vs. 14.8% [11/74], P=0.078). All patients who experienced PPP rated their PPP as mild, except 1 patient in Control group rated her pain as moderate. Multivariate logistic regression showed that pain score at 24 hours (odds ratio 1.646, 95% confidence interval [1.058, 2.560], P=0.027) and female (odds ratio 3.711, 95% confidence interval [1.274, 10.810], P=0.026) were independent risk factors for the development of PPP. When SAPB was combined with continuous infusion of nonsteroidal anti-inflammatory drugs, no patient had moderate chronic pain. Pain score at 24 hours after surgery and female were risk factors for PPP after VATS.

Predicting long-term postsurgical pain by examining the evolution of acute pain.

Increased acute postoperative pain intensity has been associated with the development of persistent postsurgical pain (PPP) in mechanistic and clinical investigations, but it remains unclear which aspects of acute pain explain this linkage. We analysed clinical postoperative pain intensity assessments using symbolic aggregate approximations (SAX), a graphical way of representing changes between pain states from one patient evaluation to the next, to visualize and understand how pain intensity changes across sequential assessments are associated with the intensity of postoperative pain at 1 (M1) and 6 (M6) months after surgery. SAX-based acute pain transition patterns were compared using cosine similarity, which indicates the degree to which patterns mirror each other. This single-centre prospective cohort study included 364 subjects. Patterns of acute postoperative pain sequential transitions differed between the 'None' and 'Severe' outcomes at M1 (cosine similarity 0.44) and M6 (cosine similarity 0.49). Stratifications of M6 outcomes by preoperative pain intensity, sex, age group, surgery type and catastrophising showed significant heterogeneity of pain transition patterns within and across strata. Severe-to-severe acute pain transitions were common, but not exclusive, in patients with moderate or severe pain intensity at M6. Clinically, these results suggest that individual pain-state transitions, even within patient or procedural strata associated with PPP, may not alone offer good predictive information regarding PPP. Longitudinal observation in the immediate postoperative period and consideration of patient- and surgery-specific factors may help indicate which patients are at increased risk of PPP. Symbolic aggregate approximations of clinically obtained, acute postoperative pain intraday time series identify different motifs in patients suffering moderate to severe pain 6months after surgery.

Incidence and risk factors for development of persistent postsurgical pain following total knee arthroplasty: A retrospective cohort study.

Persistent postsurgical pain (PPP) is defined as the discomfort that lasts >3 months postoperatively. The primary aim of this retrospective study was to estimate the risk of developing moderate-to-severe PPP after primary total knee arthroplasty (TKA). The secondary goal was to explore potential predictors of this outcome.Data were collected via hospital arthroplasty registry and chart review. The risk of moderate-to-severe PPP, defined as ≥4 on the numerical rating scale (NRS) at minimum of 3 months post-surgery, was calculated. Multivariable logistic regression was used to estimate the association of patient demographics, diagnoses, length of hospital stay, and preoperative NRS with the odds of developing PPP. Exploratory, simple logistic regression was used to estimate the association of perioperative factors with the odds of developing PPP on a subset of patients (n = 72).The risk of PPP after TKA was 31.3% (95% confidence interval [CI]: 27.5–35.0) (n = 578). Every 2-point increase in baseline NRS was associated with 1.66 (95% CI: 1.37–2.03) times the odds of developing PPP (P < .001). African-Americans (vs whites) had 1.82 (95% CI: 1.03–3.22) times the odds of developing PPP (P = .040). Exploratory analysis suggested that the adductor canal saphenous nerve (vs femoral nerve) blocks were associated with 2.87 (95% CI: 1.00–8.26) times the odds of developing PPP (P = .049).This study estimated a high risk (31.3%) of moderate-to-severe PPP after primary TKA. This study suggested that higher preoperative pain scores might be associated with greater odds of developing PPP. Moreover, this study suggested the possibility that racial differences and types of peripheral nerve blocks might be associated with greater odds of developing moderate-to-severe PPP after TKA surgery. However, the evidence obtained from our exploratory analysis of limited data certainly requires further exploration in large-scale studies.

Factors Associated With Acute Pain Estimation, Postoperative Pain Resolution, Opioid Cessation, and Recovery

Acute postoperative pain is associated with the development of persistent postsurgical pain, but it is unclear which aspect is most estimable. To identify patient clusters based on acute pain trajectories, preoperative psychosocial characteristics associated with the high-risk cluster, and the best acute pain predictor of remote outcomes. A secondary analysis of the Stanford Accelerated Recovery Trial randomized, double-blind clinical trial was conducted at a single-center, tertiary, referral teaching hospital. A total of 422 participants scheduled for thoracotomy, video-assisted thoracoscopic surgery, total hip replacement, total knee replacement, mastectomy, breast lumpectomy, hand surgery, carpal tunnel surgery, knee arthroscopy, shoulder arthroplasty, or shoulder arthroscopy were enrolled between May 25, 2010, and July 25, 2014. Data analysis was performed from January 1 to August 1, 2018. Patients were randomized to receive gabapentin (1200 mg, preoperatively, and 600 mg, 3 times a day postoperatively) or active placebo (lorazepam, 0.5 mg preoperatively, inactive placebo postoperatively) for 72 hours. A modified Brief Pain Inventory prospectively captured 3 surgical site pain outcomes: average pain and worst pain intensity over the past 24 hours, and current pain intensity. Within each category, acute pain trajectories (first 10 postoperative pain scores) were compared using a k-means clustering algorithm. Fifteen descriptors of acute pain were compared as predictors of remote postoperative pain resolution, opioid cessation, and full recovery. Of the 422 patients enrolled, 371 patients (≤10% missing pain scores) were included in the analysis. Of these, 146 (39.4%) were men; mean (SD) age was 56.67 (11.70) years. Two clusters were identified within each trajectory category. The high pain cluster of the average pain trajectory significantly predicted prolonged pain (hazard ratio [HR], 0.63; 95% CI, 0.50-0.80; P < .001) and delayed opioid cessation (HR, 0.52; 95% CI, 0.41-0.67; P < .001) but was not a predictor of time to recovery in Cox proportional hazards regression (HR, 0.89; 95% CI, 0.69-1.14; P = .89). Preoperative risk factors for categorization to the high average pain cluster included female sex (adjusted relative risk [ARR], 1.36; 95% CI, 1.08-1.70; P = .008), elevated preoperative pain (ARR, 1.11; 95% CI, 1.07-1.15; P < .001), a history of alcohol or drug abuse treatment (ARR, 1.90; 95% CI, 1.42-2.53; P < .001), and receiving active placebo (ARR, 1.27; 95% CI, 1.03-1.56; P = .03). Worst pain reported on postoperative day 10 was the best predictor of time to pain resolution (HR, 0.83; 95% CI, 0.78-0.87; P < .001), opioid cessation (HR, 0.84; 95% CI, 0.80-0.89; P < .001), and complete surgical recovery (HR, 0.91; 95% CI, 0.86-0.96; P < .001). This study has shown a possible uniform predictor of remote postoperative pain, opioid use, and recovery that can be easily assessed. Future work is needed to replicate these findings. ClinicalTrials.gov Identifier: NCT01067144.

Propofol attenuates postoperative hyperalgesia via regulating spinal GluN2B-p38MAPK/EPAC1 pathway in an animal model of postoperative pain.

Total intravenous anesthesia with propofol has been shown to reduce postoperative pain in some clinical studies, but knowledge of its underlying analgesic mechanism remains limited. In this study, we compared the analgesic effects of propofol versus isoflurane in an animal model of postoperative pain and evaluated its underlying molecular mechanisms. Plantar incision was made in the hind paws of rats under general anesthesia with 2.5% of inhalational isoflurane (isoflurane group) or intravenous infusion of propofol (1.5mgkg-1 min-1 , propofol group). Mechanical allodynia was assessed by paw withdrawal threshold before and after incision. Spinal dorsal horns (L3-L5) were harvested 1hr after incision to assess the level of phosphorylated GluN2B, p38MAPK, ERK, JNK, and EPAC using Western blot and immunofluorescence. Mechanical allodynia induced by plantar incision peaked at 1hr and lasted for 3days after incision. It was significantly less in the propofol group compared with the isoflurane group in the first 2hr following incision. The incision-induced increases in phosphorylated GluN2B, p38MAPK, and EPAC1 were significantly reduced in the propofol group. The number of spinal dorsal neurons co-expressed with EPAC1 and c-Fos after the incision was significantly lower in the propofol group. Propofol reduced pain responses in an animal model of postoperative pain and suppressed the spinal GluN2B-p38MAPK/EPAC1 signaling pathway. Since the p38MAPK/EPAC pathway plays a critical role in the development of postoperative hyperalgesia, our results provide evidence-based behavioral, molecular, and cellular mechanisms for the analgesic effects of propofol when used for general anesthesia. These findings may provide a new mechanism for the postsurgical analgesic effect of propofol, which is particularly interesting during the subacute period after surgery as it is the critical period for the development of persistent postsurgical pain.

Persistent Postsurgical Pain: Pathophysiology and Preventative Pharmacologic Considerations.

The development of chronic pain is considered a major complication after surgery. Basic science research in animal models helps us understand the transition from acute to chronic pain by identifying the numerous molecular and cellular changes that occur in the peripheral and central nervous systems. It is now well recognized that inflammation and nerve injury lead to long-term synaptic plasticity that amplifies and also maintains pain signaling, a phenomenon referred to as pain sensitization. In the context of surgery in humans, pain sensitization is both responsible for an increase in postoperative pain via the expression of wound hyperalgesia and considered a critical factor for the development of persistent postsurgical pain. Using specific drugs that block the processes of pain sensitization reduces postoperative pain and prevents the development of persistent postoperative pain. This narrative review of the literature describes clinical investigations evaluating different preventative pharmacologic strategies that are routinely used by anesthesiologists in their daily clinical practices for preventing persistent postoperative pain. Nevertheless, further efforts are needed in both basic and clinical science research to identify preclinical models and novel therapeutics targets. There remains a need for more patient numbers in clinical research, for more reliable data, and for the development of the safest and the most effective strategies to limit the incidence of persistent postoperative pain.

Machine-learned selection of psychological questionnaire items relevant to the development of persistent pain after breast cancer surgery

BackgroundPrevention of persistent pain after breast cancer surgery, via early identification of patients at high risk, is a clinical need. Psychological factors are among the most consistently proposed predictive parameters for the development of persistent pain. However, repeated use of long psychological questionnaires in this context may be exhaustive for a patient and inconvenient in everyday clinical practice. MethodsSupervised machine learning was used to create a short form of questionnaires that would provide the same predictive performance of pain persistence as the full questionnaires in a cohort of 1000 women followed up for 3 yr after breast cancer surgery. Machine-learned predictors were first trained with the full-item set of Beck's Depression Inventory (BDI), Spielberger's State–Trait Anxiety Inventory (STAI), and the State–Trait Anger Expression Inventory (STAXI-2). Subsequently, features were selected from the questionnaires to create predictors having a reduced set of items. ResultsA combined seven-item set of 10% of the original psychological questions from STAI and BDI, provided the same predictive performance parameters as the full questionnaires for the development of persistent postsurgical pain. The seven-item version offers a shorter and at least as accurate identification of women in whom pain persistence is unlikely (almost 95% negative predictive value). ConclusionsUsing a data-driven machine-learning approach, a short list of seven items from BDI and STAI is proposed as a basis for a predictive tool for the persistence of pain after breast cancer surgery.

Epidurals in Pancreatic Resection Outcomes (E-PRO) study: protocol for a randomised controlled trial

IntroductionEpidural analgesia provides an important synergistic method of pain control. In addition to reducing perioperative opioid consumption, the deliverance of analgesia into the epidural space, effectively creating a sympathetic blockade,...

Continuous regional anesthesia: a review of perioperative outcome benefits.

Routine use of regional anesthesia for patients having surgery is supported by general safety and proven effectiveness as a targeted modality in the prevention and treatment of acute pain. Recently, perioperative physicians have become much more interested in improving long-term outcomes after surgery rather than focusing on the well-established short-term benefits of regional anesthesia. This interest has raised important questions regarding the potential influence of regional anesthesia on morbidity and mortality, persistent pain and cancer prognosis. Tissue injury is responsible for the inflammatory reaction and physiologic stress response observed during the perioperative period and can influence a patient's recovery trajectory. Regional anesthesia can modulate the inflammatory response through the direct anti-inflammatory effect of local anesthetics, blocking neural afferents, and blunting sympathetic activation. Moreover, continuous techniques (e.g., epidural and perineural catheters) that provide longer duration and titratable pain relief in the perioperative period may be protective against the development of persistent post-surgical pain by providing effective acute pain management and decreasing exposure to opioids. To maximize the potential for long-term outcome benefits to surgical patients, continuous regional anesthesia techniques are preferred over single injection techniques. Although the data are not yet definitive, some studies have demonstrated better functional recovery after joint replacement and lower rates of cancer recurrence in patients treated with continuous regional anesthesia. Future research studies in regional anesthesia will have to focus on these long-term patient-centered outcomes and may need to incorporate novel study designs and analyses of big data.

Spinal AMPA Receptor GluA1 Ser831 Phosphorylation Controls Chronic Alcohol Consumption-Produced Prolongation of Postsurgical Pain.

Previous studies have shown that excessive alcohol drinking is associated with chronic pain development; however, the molecular mechanism underlying this association is poorly understood. In this study, we investigated the effect of chronic alcohol consumption on plantar incision-induced postsurgical pain. We observed that 4-week ethanol drinking significantly prolonged plantar incision-induced mechanical pain, but not thermal pain. The chronic alcohol consumption enhanced plantar incision-produced α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluA1 phosphorylation at the Ser831 site in the spinal cord. The targeted mutation of the GluA1 phosphorylation site in GluA1 S831A mutant mice significantly inhibited the incisional pain prolongation produced by chronic alcohol consumption. Moreover, chronic alcohol consumption combined with plantar incision markedly increased AMPA receptor-mediated miniature excitatory postsynaptic currents in the spinal dorsal horn neurons, and this effect was diminished significantly in the GluA1 S831A mutant mice. Our results suggest that chronic alcohol consumption may promote the development of persistent postsurgical pain by enhancing AMPA receptor GluA1 Ser831 phosphorylation. We identified chronic alcohol consumption as a risk factor for pain chronification after surgery.

Do depression and anxiety profiles over time predict persistent post-surgical pain? A study in cardiac surgery patients.

Rates of depression and anxiety in cardiac surgery patients are higher than in the general population. The development of persistent post-surgical pain (PPSP) in this population is also concerning. The objectives of this study were to (1) identify anxiety and depression trajectories of cardiac surgery patients over a 2-year period; (2) examine demographic and clinical characteristics associated with trajectory memberships and (3) determine if anxiety and/or depression trajectories predict PPSP. A total of 1071 patients completed questionnaires before cardiac surgery and 7days, 3, 6, 12 and 24months thereafter. Models were run using growth mixture modelling. Both anxiety and depression models yielded a 3-trajectory solution. A minority of patients (<10%) had unremitted major depression, almost one-third of patients had remitted minor depression and the remaining patients had no depression over the 2-year period. <10% of patients had unremitted elevated anxiety, almost 40% of patients had unremitted mild anxiety symptoms, whereas half of patients did not experience anxiety over the same time period. Patients with unremitted elevated anxiety were more likely to report PPSP; the association between depression and PPSP was not significant. The results' novelty lies in the identification of a homogeneous patient subgroup presenting with unremitted elevated anxiety which predicted the presence of PPSP up to 2years following cardiac surgery. Unlike anxiety, depression subgroups were not predictive of PPSP status. This article presents the relationship between anxiety and depression profiles over 2years in cardiac surgery patients and persistent post-surgical pain. These results suggest the importance of evaluating how early identification and treatment of high-risk patients could prevent PPSP. These results provide potential detection and prevention avenues of chronic pain for high-risk patients based on their anxiety trajectory.

Postoperative Pain Management: Clinical Practice Guidelines

OVER THE PAST 2 decades, there has been an increased emphasis on the need for effective management of acute pain. The focus on pain management was sharpened when the Joint Commission on Accreditation of Healthcare Organizations integrated the requirement for pain assessment and management into their standards in 2000. 1 Berry P.H. Dahl J.L. The new JCAHO pain standards: Implications for pain management nurses. Pain Manag Nurs. 2000; 1: 3-12 Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar Acute postoperative pain, however, continues to be inadequately controlled. Among patients who have had surgical procedures, 80% experience postoperative pain and 75% or more of them report pain that is at a moderate, severe, or extreme level. 2 Gan T.J. Habib A.S. Miller T.E. White W. Apfelbaum J.L. Incidence, patient satisfaction, and perceptions of post-surgical pain: Results from a US national survey. Curr Med Res Opin. 2014; 30: 149-160 Crossref PubMed Scopus (454) Google Scholar Inadequately treated acute pain is associated with the risk for the development of persistent postsurgical pain. 3 Clarke H. Bonin R.P. Orser B.A. Englesakis M. Wijeysundera D.N. Katz J. The prevention of chronic postsurgical pain using gabapentin and pregabalin: A combined systematic review and meta-analysis. Anesth Analg. 2012; 115: 428-442 Crossref PubMed Scopus (298) Google Scholar , 4 Page M.G. Katz J. Romero Escobar E.M. et al. Distinguishing problematic from nonproblematic postsurgical pain: A pain trajectory analysis after total knee arthroplasty. Pain. 2015; 156: 460-468 Crossref PubMed Scopus (68) Google Scholar Poor pain control has significant physiological consequences that can ultimately result in impaired recovery, decreased function, and reduced quality of life. 2 Gan T.J. Habib A.S. Miller T.E. White W. Apfelbaum J.L. Incidence, patient satisfaction, and perceptions of post-surgical pain: Results from a US national survey. Curr Med Res Opin. 2014; 30: 149-160 Crossref PubMed Scopus (454) Google Scholar , 5 Argoff C.E. Recent management advances in acute postoperative pain. Pain Pract. 2014; 14: 477-487 PubMed Google Scholar Maureen F. Cooney, DNP, FNP-BC, is a Nurse Practitioner, Pain Management, Westchester Medical Center, Valhalla, NY

Pain management in knee arthroplasty: an overview

Perioperative pain management after knee arthroplasty has undergone a conceptual revolution in the last decade. Along with other exciting innovations, including minimally invasive techniques, computer-assisted procedures and a significant stride in tribology, understanding pain modulation and drug action at a molecular level is recognized as the game changer in arthroplasty surgeries. While most patients usually recover and experience pain relief within 3 mo after TKA, about 20% (10–34%) of the patients are left with an unfavorable long-term pain outcome. Fifty-two percent of patients report moderate pain and 16% report severe pain at rest 30 days after TKA, while pain at movement affects as much as 78% of the patients. Inability to adequately control postoperative pain causes undue suffering, inability to participate in fast-track rehabilitation programs, sleep disturbance (44% patients first 3 nights), delayed discharge, and the development of persistent postsurgical pain. The goal of this review article is to give an overview of the fundamental concept of surgical pain, the molecular mechanism of action of different drugs, evolution of the concept of preventive analgesia, and state of the art for current pain management. When combined and standardized, these factors allow arthroplasty surgeons to offer outpatient arthroplasty procedures.

Henrik Kehlet, M.D., Ph.D., recipient of the 2014 Excellence in Research Award.

Henrik Kehlet, M.D., Ph.D., recipient of the 2014 Excellence in Research Award.

Pathophysiology of Pain

The experience of pain is a subjective one and more than a simple sensation. Pain is commonly defined as an unpleasant sensory and emotional experience due to actual or potential tissue damage or described in such terms. Pain may be broadly classified into physiological and pathological pain. Nociceptive and inflammatory pains are physiological pain states, as they are protective and adaptive, whereas pathological pain is nonprotective and maladaptive. Nociception is the result of suprathreshold stimulation of peripheral nociceptors. Inflammatory pain follows release of various chemical mediators after tissue injury including surgery leading to peripheral sensitization. Nociceptive input is then transmitted to the spinal cord via primary afferents. Modulation of the nociceptive input occurs in the dorsal horn of the spinal cord, influenced by descending inhibitory systems. Central sensitization is a neuromodulatory change that results in the development of secondary hyperalgesia. The modulated nociceptive input then travels up the ascending tracts, mainly via the spinothalamic tract to the thalamus and subsequently to the higher centers of the brain. Pathological pain such as neuropathic pain and central nervous system dysfunctional pain are the result of neuroplasticity of the peripheral and central nervous system. Abnormal ectopic firing of neurons in the absence of a stimulus, increased neuronal hypersensitivity, changes within ion channels, and even alteration in gene expression and changes in the cortical representation are involved in the pathogenesis of these pain states. The development of persistent postsurgical pain is an example for this complex process.

Associations Between Cytokine Gene Variations and Severe Persistent Breast Pain in Women Following Breast Cancer Surgery

Persistent pain following breast cancer surgery is a significant clinical problem. Although immune mechanisms may play a role in the development and maintenance of persistent pain, few studies have evaluated for associations between persistent breast pain following breast cancer surgery and variations in cytokine genes. In this study, associations between previously identified extreme persistent breast pain phenotypes (ie, no pain vs severe pain) and single nucleotide polymorphisms (SNPs) spanning 15 cytokine genes were evaluated. In unadjusted analyses, the frequency of 13 SNPs and 3 haplotypes in 7 genes differed significantly between the no pain and severe pain classes. After adjustment for preoperative breast pain and the severity of average postoperative pain, 1 SNP (ie, interleukin [IL] 1 receptor 2 rs11674595) and 1 haplotype (ie, IL10 haplotype A8) were associated with pain group membership. These findings suggest a role for cytokine gene polymorphisms in the development of persistent breast pain following breast cancer surgery. PerspectiveThis study evaluated for associations between cytokine gene variations and the severity of persistent breast pain in women following breast cancer surgery. Variations in 2 cytokine genes were associated with severe breast pain. The results suggest that cytokines play a role in the development of persistent postsurgical pain.