Incidence Of Persistent Post-surgical Pain Research Articles

Introduction of an enhanced recovery program for young adults undergoing posterior spinal fusion surgery for idiopathic scoliosis: a single-centre pilot study evaluating short term outcomes

Background: The large surgical incision and extensive tissue trauma in posterior spinal fusion for adolescent idiopathic scoliosis causes severe acute postoperative pain. Furthermore, posterior spinal fusion is associated with a risk of persistent postsurgical pain. Six months after posterior spinal fusion, the incidence of persistent postsurgical pain is as high as 22% of the patients. Optimizing pain management therefore remains crucial, but challenging. Objective: The study objective is to design and implement an enhanced recovery pathway for patients with adolescent idiopathic scoliosis undergoing posterior spinal fusion integrating all aspects of biopsychosocial care. Its outcomes are assessed, including its effect on postoperative pain and early mobilization. Design and settings: A prospective cohort study was performed at the Antwerp University Hospital. Methods: In December 2019, a prospective cohort study was set up in which an enhanced recovery pathway substitutes more than the patient controlled intravenous analgesia containing morphine postoperatively. This pathway consists of m/eHealth based psychological screening questionnaires, patient education, early mobilization, and a multimodal analgesia protocol consisting of preemptive gabapentin, an intraoperatively given single dose of methadone (0.2 mg kg-1), non-steroidal anti-inflammatory drugs, and acetaminophen. Results: We treated 25 adolescents (10 males and 15 females) with the developed enhanced recovery pathway with a mean age of 16.5 years (range 12-22). The mean number of spinal levels fused was 10 (range 6-13). Mean numerical rating scale scores were 4.17 at postoperative day 1, 4.46 at postoperative day 2, and 3.74 at postoperative day 3 in enhanced recovery pathway treated patients. Mean bladder catheterization duration was 3.04 days and enhanced recovery pathway patients stayed in the hospital for an average of 7.4 days. Conclusions: Using an enhanced recovery pathway for patients undergoing posterior spinal fusion could not only reduce the acute and chronic opioid consumption and its side effects, but could also result in less postoperative pain, shorter hospital stay and higher patient satisfaction. Further reevaluation and improvement focused on these variables will likely further improve the effectiveness of enhanced recovery pathways. Trial registration: ClinicalTrials.gov NCT04038229.

Identifying Risk Factors, Patient-Reported Experience and Outcome Measures, and Data Capture Tools for an Individualized Pain Prediction Tool in Pediatrics: Focus Group Study.

The perioperative period is a data-rich environment with potential for innovation through digital health tools and predictive analytics to optimize patients' health with targeted prehabilitation. Although some risk factors for postoperative pain following pediatric surgery are already known, the systematic use of preoperative information to guide personalized interventions is not yet widespread in clinical practice. Our long-term goal is to reduce the incidence of persistent postsurgical pain (PPSP) and long-term opioid use in children by developing personalized pain risk prediction models that can guide clinicians and families to identify targeted prehabilitation strategies. To develop such a system, our first objective was to identify risk factors, outcomes, and relevant experience measures, as well as data collection tools, for a future data collection and risk modeling study. This study used a patient-oriented research methodology, leveraging parental/caregiver and clinician expertise. We conducted virtual focus groups with participants recruited at a tertiary pediatric hospital; each session lasted approximately 1 hour and was composed of clinicians or family members (people with lived surgical experience and parents of children who had recently undergone a procedure requiring general anesthesia) or both. Data were analyzed thematically to identify potential risk factors for pain, as well as relevant patient-reported experience and outcome measures (PREMs and PROMs, respectively) that can be used to evaluate the progress of postoperative recovery at home. This guidance was combined with a targeted literature review to select tools to collect risk factor and outcome information for implementation in a future study. In total, 22 participants (n=12, 55%, clinicians and n=10, 45%, family members) attended 10 focus group sessions; participants included 12 (55%) of 22 persons identifying as female, and 12 (55%) were under 50 years of age. Thematic analysis identified 5 key domains: (1) demographic risk factors, including both child and family characteristics; (2) psychosocial risk factors, including anxiety, depression, and medical phobias; (3) clinical risk factors, including length of hospital stay, procedure type, medications, and pre-existing conditions; (4) PREMs, including patient and family satisfaction with care; and (5) PROMs, including nausea and vomiting, functional recovery, and return to normal activities of daily living. Participants further suggested desirable functional requirements, including use of standardized and validated tools, and longitudinal data collection, as well as delivery modes, including electronic, parent proxy, and self-reporting, that can be used to capture these metrics, both in the hospital and following discharge. Established PREM/PROM questionnaires, pain-catastrophizing scales (PCSs), and substance use questionnaires for adolescents were subsequently selected for our proposed data collection platform. This study established 5 key data domains for identifying pain risk factors and evaluating postoperative recovery at home, as well as the functional requirements and delivery modes of selected tools with which to capture these metrics both in the hospital and after discharge. These tools have been implemented to generate data for the development of personalized pain risk prediction models.

Phantom Limb Pain on Post-Surgical Amputation Osteosarcoma Children Patient

Osteosarcoma is a musculoskeletal malignancy that often occurs in pediatric patients requiring multidisciplinary management. Management in the form of amputation surgery (limb-salvage surgery) with a combination of chemotherapy or radiotherapy. Post-amputation complications that are often experienced by patient is postsurgical pain. Persistent Postsurgical Pain (PPSP) in pediatric patients is influenced by risk factors such as age, gender, preoperative preparation (pain intensity, anxiety, pain efficacy), intraoperative measures (site of surgery, potential for nerve damage, administration of analgesia regimens, technique of anesthesia), and postoperative management. The incidence of PPSP in osteosarcoma postamputation patients is related to Phantom Limb Syndrome with varying incidence and duration. This syndrome is a phenomenon that often occurs after post-amputation procedures in the form of sensation (Phantom Limb Sensation) or pain (Phantom Limb Pain) due to loss of part of the body. Phantom Limb Pain (PLP) is an effect and complication that occurs after amputation surgery in pediatric osteosarcoma patients. The PLP pathomechanism is related to the interaction of the Central Nervous System (Cortical Remapping Theory and Proprioceptive Theory) and the Peripheral Nervous System (Dorsal Root Ganglia and nocireceptor stimulation). Management of PLP consists of neuropathic pain medications such as antidepressants, opioids, anticonvulsants, N-methyl-D-aspartate (NMDA) receptor antagonists and other anesthetic agents.

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.

Characterisation of pragmatic postoperative PAin Trajectories over seven days and their association with CHronicity after 3 months: a prospective, pilot cohort study (PATCH study)

BackgroundReliable outcome measurement providing information both on early and late postoperative pain outcomes are still lacking. The purpose of this study was: 1) to characterise postoperative pain trajectories according to an innovative pragmatic concept: ideal pain trajectory (rapid and sustained pain relief) vs non-ideal pain trajectories (late, transient, or no pain relief); and 2) to assess the incidence of persistent post-surgical pain (PPSP) and the potential association between non-ideal pain trajectories and PPSP. MethodsThis prospective observational pilot cohort study was performed from March until June 2016. A total of 344 patients undergoing major general surgery were invited to complete a self-assessment of pain intensity using numerical rating scale (NRS; 0 = no pain to 10 = worst pain) from day 1 until day 7 after surgery, in order to establish their pain trajectory. Three months after surgery, patients were screened for PPSP. ResultsRest pain score was analysed in 308 participants. Among them, 210 (68% - 95% CI: 63–73) had an “ideal” pain trajectory, while 98 (32% - 95% CI: 27–37) had “non-ideal” pain trajectories. Three months after surgery, 31% (95% CI: 26–37) reported PPSP. Multivariable analysis showed that “non-ideal” pain trajectories [OR 2.25; (95% CI: 1.26–4.01) P = 0.006] were significantly associated with PPSP. ConclusionsThe present study proposes an innovative pragmatic concept of postoperative pain trajectories: ideal vs non-ideal pain trajectories, providing information both on acute postoperative pain resolution and early identification patients at risk for developing PPSP. Trial registrationNCT02599233; November, 6, 2015, with clinicaltrials.gov.

Dexmedetomidine infusion as an analgesic adjuvant during laparoscopic \u0441holecystectomy: a randomized controlled study

BackgroundDexmedetomidine (DEX) has sedative, sympatholytic and analgesic effects and might be beneficial if used as an adjuvant to: improve analgesia; modulate haemodynamic responses to intubation and pneumoperitoneum and; reduce the number of opioid-associated adverse events. The aim of this study was to evaluate the efficacy and safety of DEX infusion during elective laparoscopic cholecystectomy (LC).MethodsA randomized, single-centre, parallel-group, placebo-controlled study was carried out between May 2016 and June 2017. Adult patients (18–79 years) with American Society of Anesthesiology (ASA) physical status I–II were randomly assigned to 0.5 μg/kg/h DEX infusion from induction of anaesthesia to extubation (Group D; n = 30) or normal saline infusion (Group C; n = 30). The primary efficacy outcomes were postoperative morphine consumption. Secondary efficacy outcomes included: time to first use of rescue analgesia; postoperative morphine consumption; intraoperative fentanyl consumption; time from end of surgery to extubation; lengths of intensive care unit (ICU) and general ward stay; degree of postoperative pain 3, 6, 12 and 24 h after surgery; incidence of persistent post-surgical pain.ResultsDEX infusion was associated with a decrease in postoperative morphine consumption (p = 0.001), lower incidence of severe postoperative pain (odds ratio [OR] 9, 95% confidence interval [CI] 1.1–77, p = 0.04) and significantly longer time to first use of rescue analgesia (p = 0.001). Group D also had significantly lower fentanyl consumption both intraoperatively (p = 0.001) and in the time from end of surgery to extubation (p = 0.001) plus decreased incidence of persistent post-surgical pain (OR 14.5, 95% CI 1.7–122, p = 0.005). The incidence of postoperative nausea and vomiting was lower in Group D than Group C (OR 5, 95% CI 1.1–26, p = 0.005). Median pain intensity did not differ between the groups 3, 6, 12 or 24 h after surgery and there were no inter-group differences in the lengths of ICU stay or overall hospital stay between groups. The incidence of hypertension was significantly higher in Group C (OR 13.8, 95% CI 4–48, p < 0.0001); there were no inter-group differences in incidences of hypotension and bradycardia.ConclusionsIntraoperative DEX infusion is safe and effective for improving analgesia during and after elective LC. DEX appears to significantly reduce the number of patients with severe postoperative pain, postoperative morphine consumption and prolong time to first use of rescue analgesia.Trial registrationClinicalTrials.gov: Retrospectively registered on July 7, 2017, NCT03211871.

Predicting the pain continuum after adolescent idiopathic scoliosis surgery: A prospective cohort study.

Chronic postsurgical pain (CPSP) affects half a million children annually in the United States, with dire socioeconomic consequences, including long-term disability into adulthood. The few studies of CPSP in children are limited by sample size, follow-up duration, non-homogeneity of surgical procedure and factors evaluated. In a prospective study of 144 adolescents undergoing a single major surgery (spine fusion), we evaluated demographic, perioperative, surgical and psychosocial factors as predictors of a continuum of postsurgical pain: immediate, pain maintenance at 2-3months (chronic pain/CP) and persistence of pain a year (persistent pain/PP) after surgery. We found an incidence of 37.8% and 41.8% for CP and PP. CP and acute pain were both significant predictors for developing PP (p-value <0.001 and 0.003). Preoperative pain and higher postoperative opioid requirement was significantly associated with CP (p=0.015, p=0.002), while Childhood Anxiety Sensitivity Index (p=0.002) and surgical duration (p=0.014) predicted PP. The final regression models had reasonable predictive accuracy (c-statistic of 0.73 and 0.83 for CP and PP, respectively). Anxiety scores and catastrophizing for child and parent were found to be significantly correlated (p=0.005, p=0.013 respectively). Pain trajectories revealed that 65% of patients who developed PP reported CP and high pain trends; however, 33% of those who developed PP could not be identified using solely pain criteria. Persistent postsurgical pain in children is a significant problem. It can be predicted in part by combinations of psychological and clinical variables, which may provide evidence-based measures to prevent development of CPSP in the future. In a homogeneous cohort of adolescents undergoing spine fusion, we report a high incidence of persistent postsurgical pain (41.8%) predicted by child anxiety, perioperative pain, and surgical duration. Our results stress timely preventive and therapeutic strategies.

Prolonged Perioperative Low-Dose Ketamine Does Not Improve Short and Long-term Outcomes After Pediatric Idiopathic Scoliosis Surgery.

A randomized, double-blind, placebo-controlled study, with a six-month follow-up period. The aim of this study was to test the hypothesis that a 72-hour dose of subanesthetic ketamine in this surgical procedure reduces postoperative morphine use and to assess whether there are fewer adverse effects, if postoperative recovery is faster, if there is less peri-incisional hyperalgesia, or if there is lower incidence of persistent postsurgical pain. Tissue injury and high opioid requirements following posterior spinal fusion surgery produce central sensitization, which can in turn be associated with hyperalgesia and chronic pain. Clinical trials involving this type of procedure using subanesthetic ketamine doses have assessed pain and morphine requirements with contradictory results. The effects of prolonged subanesthetic ketamine doses on postoperative recovery, mechanical hyperalgesia, and the incidence of chronic pain are unknown. A total of 48 pediatric patients between 10 and 18 years diagnosed with idiopathic scoliosis were randomized to receive perioperative low-dose ketamine or placebo for 72 hours. They received general anesthesia, intraoperative remifentanil, and morphine postoperatively (patient-controlled analgesia). We measured morphine consumption, pain at rest and during movement (coughing), undesirable effects, and sedation during morphine treatment. The onset of oral intake, ambulation, and hospital stay were recorded. The extent of the peri-incisional hyperalgesia was measured at 72 hours and pain controls were conducted postsurgery. Primary endpoint results (total cumulative morphine consumption while admitted) were obtained in 44 patients. Results were 2.72 (SD 1.13) in the placebo group and 3.13 (SD 1.13) in the study group (P = 0.2903), with no significant differences. Moreover, differences were not found between the experimental group and the placebo group in the secondary endpoints analyzed. Our findings do not support the routine combining of prolonged subanesthetic ketamine doses with opioids in posterior fusion surgery in children with idiopathic scoliosis. 2.

Persistent postsurgical pain after video-assisted thoracic surgery--an observational study.

The risk of persistent postsurgical pain (PPP) and subsequent pain-related functional impairment may potentially be reduced by video-assisted thoracic surgery (VATS) compared to thoracotomy. The aim of the study was therefore to assess in detail the incidence and consequences on activities of daily living of PPP after VATS. Using a prospective observational design, 47 patients undergoing VATS completed both preoperative, early postoperative and 3 months follow-up. Preoperative pain, pain characteristics, psychological factors, pain-related functional impairment and quantitative sensory testing (QST) including nociceptive thresholds were compared with postoperative data. Only five (11%) patients developed PPP with NRS > 3 originating from the surgical area. However, about 30% of patients still reported some pain-related functional impairment from the surgical area within four well-defined domains of everyday activities. Psychological and sensory thermal tests did not predict persistent postoperative pain, except preoperative pin-prick sensitivity was higher in patients with PPP. Postoperative pain 7 days after surgery was significantly higher in PPP patients. Preoperative pain originating from remote areas did not predict PPP. The incidence of PPP, nerve damage (based on QST) and pain-related functional impairment following VATS was lower than reported following thoracotomy. No psychological or other factors predicted PPP. These findings call for further large-scale studies to support VATS to decrease PPP.

Interventional options for the management of refractory cancer pain--what is the evidence?

Pain is the most common symptom in cancer patients. Standard pain treatment according to the WHO three-step analgesic ladder provides effective pain management in approximately 70-90% of cancer patients. Refractory pain is defined as not responding to "standard" treatments. Interventional analgesic techniques can be used in an attempt to control refractory pain in patients in whom conventional analgesic strategies fail to provide effective pain relief or are intolerable due to severe adverse effects. This systematic review aims to provide the latest evidence on interventional refractory pain management in cancer patients. Systematic literature search in Cochrane, EMBASE and PubMed including reviews and randomised controlled trials (RCTs) and non-randomised controlled trials in the absence of reviews. Neuraxial analgesia may play a role in refractory cancer pain management. Paravertebral blocks decrease the incidence of persistent post-surgical pain after breast cancer. Coeliac plexus blocks improve pain scores in refractory pancreatic cancer pain for up to 4 weeks after the intervention with fewer burdensome side effects as compared to opioids. Cordotomy has mainly been studied in mesothelioma, and the case series suggest possible benefit for pain at the expense of a relatively high risk of side effects. Overall, very few RCTs have been conducted on interventional pain techniques. In reality, it is very difficult to undertake large controlled trials for a number of reasons. Therefore, today's best evidence for practice may be from large case series of comparable patients with careful response and toxicity evaluation and follow-up.

Risk factors for persistent pain after urological surgery

ObjectiveTen to 50% of patients with post-surgical pain develop chronic pain depending on the type of surgery. The objective of this study was to assess the incidence of persistent post-surgical pain (PPSP) and to identify risk factors following urology surgery. DesignRetrospective observational study. PatientsTwo hundred and twenty-eight patients scheduled for urology surgery. Reasons for non-inclusions: patients who underwent a procedure not defined as being associated with PPSP. MethodsSurgical urologic procedures potentially associated with PPSP were defined. All patients who had one of these procedures during the study period received a questionnaire by mail at least 3months after the surgery. The files of these patients were retrospectively studied. ResultsEight percent of the patients had preoperative pain. PPSP, assessed approximately 6months after the surgery, was reported by 24% of the patients. Twenty-five (36%) of them reported neuropathic pain. Patients with PPSP had significantly more preoperative pain and an increased postoperative morphine consumption. Postoperative NSAID administration led to less persistent pain. Multivariate logistic regression analysis identified two independent risk factors of developing persistent pain: preoperative pain (OR=21.6, 95% CI 6.7–69.5, P<0.0001), morphine consumption 48hours after surgery higher than 6mg (OR=2.3, 95% CI 1.2–4.3, P=0.0118). ConclusionThese findings confirm the role of preoperative pain and morphine consumption in the genesis of PPSP and call for establishing clinical perioperative pathways tailored to the patient.

Different effects of local anesthetics on extracellular signal-regulated kinase phosphorylation in rat dorsal horn neurons

Local anesthetics, which are widely known to be neuronal voltage-gated Na+ channel blockers, also affect a variety of other ion channels, N-methyl-d-asparate (NMDA) receptors and α-amino-3-hydroxy-5-methyl-4-izoxazolepropionic acid (AMPA) receptors. Glutamate, which is released from presynaptic fibers, activates extracellular signal-regulated kinase (ERK) through NMDA and AMPA receptors in spinal dorsal horn neurons. ERK plays a key role in central sensitization, which contributes to the chronicity of pain. We investigated the effects of four representative local anesthetics, lidocaine, tetracaine, levobupivacaine, and ropivacaine on ERK phosphorylation induced by capsaicin, which releases glutamate from presynaptic neurons, NMDA, AMPA, or ionomycin, a calcium ionophore, in dorsal neurons. We observed capsaicin-induced phosphorylation of ERK, which was suppressed by lidocaine, tetracaine, or ropivacaine, but not by levobupivacaine. NMDA-induced phosphorylation of ERK was suppressed by lidocaine, tetracaine, or levobupivacaine, but not by ropivacaine. AMPA-induced phosphorylation of ERK was suppressed by lidocaine or tetracaine, but not by levobupivacaine or ropivacaine. Finally, ionomycin-induced ERK phosphorylation was suppressed by lidocaine, tetracaine, or ropivacaine, but not by levobupivacaine. Our results suggest that local anesthetics contribute to the prevention of the incidence of persistent postsurgical pain with varying intensities and through different mechanisms of action.

Perioperative Intravenous Lidocaine Decreases the Incidence of Persistent Pain After Breast Surgery

Breast cancer surgery is associated with a high incidence of persistent postsurgical pain (PPSP). The aim of this study was to evaluate the impact of intravenous (IV) lidocaine on acute and PPSP, analgesic requirements, and sensation abnormalities in patients undergoing surgery for breast cancer. Thirty-six patients participated in this randomized, double-blinded study. Before induction of general anesthesia, patients received a bolus of intravenous lidocaine 1.5 mg/kg followed by a continuous infusion of lidocaine 1.5 mg/kgh (lidocaine group) or an equal volume of saline (control group). The infusion was stopped 1 hour after the skin closure. Pain scores and analgesic consumption were recorded at 2, 4, 24 hours, and then daily for 1 week postoperatively. Three months later, patients were assessed for PPSP and secondary hyperalgesia. Two (11.8%) patients in the lidocaine group and 9 (47.4%) patients in the control group reported PPSP at 3 months follow-up (P=0.031). McGill Pain Questionnaire revealed greater present pain intensity-visual analog scale in the control group (14.6 ± 22.5 vs. 2.6 ± 7.5; P=0.025). Secondary hyperalgesia (area of hyperalgesia/length of surgical incision) was significantly less in the lidocaine group compared with control group (0.2 ± 0.8 vs. 3.2 ± 4.5 cm; P=0.002). The 2 groups were similar in terms of analgesic consumption during the early postoperative period. Intravenous perioperative lidocaine decreases the incidence and severity of PPSP after breast cancer surgery. Prevention of the induction of central hyperalgesia is a potential mechanism.

Does Manipulating Local Surgical Wound Cytokines Improve Surgical Outcomes?

Surgical trauma produces complex local biochemical changes that contribute to inflammation and acute postoperative pain, and in some cases to chronic pain.1 Tissue injury induces an increase in the complex cascade of inflammatory cytokines that can induce peripheral and central nervous system sensitization, leading to hyperalgesia.2 In a set of articles in this issue of the journal, Hu et al.3,4 describe the role of one of these inflammatory cytokines, interleukin (IL)-1β, in postsurgical wound healing and acute postoperative pain. In a rodent model of incision pain, they demonstrated that the antiinflammatory cytokine, IL1ra, which antagonizes the binding of IL-1β to its receptor, decreases postoperative mechanical hypersensitivity when administered intraperitoneally. In addition, the concentration of other inflammatory cytokines, such as IL-6 and tumor necrosis factor (TNF)α, were reduced in wound skin tissue. This complements their human studies, which showed that IL-1β stimulated cytokine production, especially IL-8, in vitro in primary human keratinocytes, and that IL-1β and IL-8 levels were highly correlated in surgical wound exudates from both cesarean incisions and sunburn-induced blisters. The authors suggest that because a commercially available recombinant version of IL1ra, anakinra, is already in use in rheumatoid arthritis patients, a clinical trial to assess its value in improving wound healing and reducing pain when administered perioperatively can be considered. What are the main issues to consider before using any type of cytokine modulator to reduce inflammation and pain during the perioperative period? First, how serious a problem is wound healing and acute postoperative pain for each type of surgery being considered? Second, are some of the inflammatory immune mediators necessary as part of the normal defense of the surgical wound to prevent infection? With small incisions of skin and underlying muscle with minimal retraction, postoperative outcomes are usually good and recovery is uneventful. Therefore, cytokine manipulation may not be needed. However, for major types of surgery, e.g., joint replacement surgery, spine, or thoracotomy, acute postoperative pain may be severe and can delay rehabilitation. In addition, with procedures such as knee replacement surgery and thoracotomy, the incidence of persistent postsurgical pain is relatively high5; therefore, there are even more incentives to consider reducing postsurgical inflammation.1 The relative importance of each cytokine may differ depending on the type of surgery. With hip replacement surgery, concentrations of IL-1β, IL-6, and IL-8 increase in hip drain exudates, whereas TNFα levels decrease.6 Similarly, as described in this issue of the journal, in cesarean delivery, local inflammatory mediators such as substance P, IL-1, IL-6, IL-8, and IL-10 are increased.7 However, it is not known whether controlling surgical site IL-1β release or binding would be more important than suppressing IL-6 or IL-8 in improving wound healing and reducing pain. In the earlier stages of wound healing (up to 24 hours), neutrophils are the dominant cell type in the local immune response,8–10 and after hip replacement surgery, there is upregulation of gene expression for such inflammatory modulators as macrophage migration inhibitory factor, IL1ra itself, the chemokine CCL20, and receptors for IL-8 and IL-18 in neutrophils extracted from the wound drainage.11 Recent basic12 and clinical studies13 all point to IL-1 as the main local tissue receptor type correlated with postoperative analgesia. Choosing the correct dose of the IL-1 receptor blocker, anakinra, for a clinical trial affecting surgical outcomes may not be obvious, based on approved doses for rheumatoid arthritis. In the rodent incision model, the anakinra dose to reduce postoperative mechanical hypersensitivity was 100 mg/kg. However, the daily dose in rheumatoid arthritis patients is 100 mg,4,12 which is approximately 1 mg/kg. Whereas the antihyperalgesic doses in rodent pain models are often much larger than doses used clinically to reduce pain, it is possible that the maximum approved anakinra dose for patients may be inadequate to decrease postoperative pain. In a review of clinical trials using anakinra for chronic rheumatoid arthritis, the incidence of serious infections was 1.8% in the anakinra group versus 0.6% in the placebo group.14 Although for cutaneous wounds this may not be a real clinical issue, for major joint replacement surgery, an infected prosthesis could be detrimental. All of the above issues apply not just to anakinra, but to inflammatory cytokine modulators in general (e.g., TNFα inhibitors: etanercept, adalimumab, infliximab). The 2 articles in this journal,3,4 along with previous animal studies,15,16 provide a rationale for IL1ra administration in the perioperative setting. Nevertheless, it is important that the choice of surgery for an initial clinical trial is chosen judiciously. A key consideration is that the surgery in question be one in which surgical outcomes have a relatively high incidence of acute pain, and possibly chronic pain, so that a successful treatment will be clinically and statistically significant. In addition, the type of surgery chosen for study should be one in which infection would be relatively easy to treat, should one occur.