Movement-evoked Pain versus Pain at Rest in Postsurgical Clinical Trials and in Meta-analyses: An Updated Systematic Review.

BACKGROUND: Given the widespread recognition that postsurgical movement-evoked pain is generally more intense, and more functionally relevant, than pain at rest, the authors conducted an update to a previous 2011 review to re-evaluate the assessment of pain at rest and movement-evoked pain in more recent postsurgical analgesic clinical trials. METHODS: The authors searched MEDLINE and Embase for postsurgical pain randomized controlled trials and meta-analyses published between 2014 and 2023 in the setting of thoracotomy, knee arthroplasty, and hysterectomy using methods consistent with the original 2011 review. Included trials and meta-analyses were characterized according to whether they acknowledged the distinction between pain at rest and movement-evoked pain and whether they included pain at rest and/or movement-evoked pain as a pain outcome. For trials measuring movement-evoked pain, pain-evoking maneuvers used to assess movement-evoked pain were tabulated. RESULTS: Among the 944 included trials, 504 (53%) did not measure movement-evoked pain (vs. 61% in 2011), and 428 (45%) did not distinguish between pain at rest and movement-evoked pain when defining the pain outcome (vs. 52% in 2011). Among the 439 trials that measured movement-evoked pain, selection of pain-evoking maneuver was highly variable and, notably, was not even described in 139 (32%) trials (vs. 38% in 2011). Among the 186 included meta-analyses, 94 (51%) did not distinguish between pain at rest and movement-evoked pain (vs. 71% in 2011). CONCLUSIONS: This updated review demonstrates a persistent limited proportion of trials including movement-evoked pain as a pain outcome, a substantial proportion of trials failing to distinguish between pain at rest and movement-evoked pain, and a lack of consistency in the use of pain-evoking maneuvers for movement-evoked pain assessment. Future postsurgical trials need to (1) use common terminology surrounding pain at rest and movement-evoked pain, (2) assess movement-evoked pain in virtually every trial if not contraindicated, and (3) standardize movement-evoked pain assessment with common, procedure-specific pain-evoking maneuvers. More widespread knowledge translation and mobilization are required in order to disseminate this message to current and future investigators.

Preoperative Patient Expectations of Postoperative Pain Are Associated with Moderate to Severe Acute Pain After VATS.

OBJECTIVE: The goal of this post hoc analysis of subjects from a prospective observational study was to identify the predictors of patients developing moderate to severe acute pain (mean numerical rating scale [NRS] ≥4, 0-10) during the first three days after video-assisted thoracoscopic surgery (VATS) from a comprehensive evaluation of demographic, psychosocial, and surgical factors. METHODS: Results from 82 patients who were enrolled one week before VATS and evaluated during the first three postoperative days are presented. The primary outcome variable of the current study was the presence of moderate to severe acute pain after VATS. RESULTS: Fifty-nine percent (95% confidence interval, 47-69%) of study subjects developed moderate to severe acute pain after VATS. Factors univariately associated with the presence of moderate to severe acute pain were greater average expected postoperative pain, greater pain to a suprathreshold cold stimulus, and longer durations of surgery and hospital stay (P < 0.05). When considered in the multiple logistic regression models, the patients' preoperative average intensity of expected postoperative pain (NRS, 0-10) was the only measure associated with the moderate to severe acute pain. Average intensity of postoperative pain expected by patients when questioned preoperatively mediated the effect of reported intensity of pain to the suprathreshold cold stimulus for moderate to severe acute pain levels. Preoperative patient expectations had greater predictive value than other assessed variables including psychosocial factors such as catastrophizing or anxiety assessed one week before surgery. CONCLUSIONS: None of the preoperative psychosocial measures were associated with the moderate to severe acute pain after VATS. Average expected postoperative pain was the only measure associated with the development of moderate to severe acute pain after VATS.

Effect of Thoracic Epidural Anesthesia in a Rat Model of Phrenic Motor Inhibition after Upper Abdominal Surgery.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: One important example of impaired motor function after surgery is diaphragmatic dysfunction after upper abdominal surgery. In this study, the authors directly recorded efferent phrenic nerve activity and determined the effect of the upper abdominal incision. The authors hypothesized that phrenic motor output would be decreased after the upper abdominal incision; it was also hypothesized that blocking sensory input from the incision using thoracic epidural anesthesia would diminish this incision-induced change in phrenic motor activity. METHODS: Efferent phrenic activity was recorded 1 h to 10 days after upper abdominal incision in urethane-anesthetized rats. Ventilatory parameters were measured in unanesthetized rats using whole-body plethysmography at multiple time points after incision. The authors then determined the effect of thoracic epidural anesthesia on phrenic nerve activity and ventilatory parameters after incision. RESULTS: Phrenic motor output remained reduced by approximately 40% 1 h and 1 day after incision, but was not different from the sham group by postoperative day 10. One day after incision (n = 9), compared to sham-operated animals (n = 7), there was a significant decrease in spike frequency area-under-the-curve (median [interquartile range]: 54.0 [48.7 to 84.4] vs. 97.8 [88.7 to 130.3]; P = 0.0184), central respiratory rate (0.71 [0.63 to 0.79] vs. 0.86 [0.82 to 0.93]/s; P = 0.0460), and inspiratory-to-expiratory duration ratio (0.46 [0.44 to 0.55] vs. 0.78 [0.72 to 0.93]; P = 0.0023). Unlike humans, a decrease, not an increase, in breathing frequency has been observed after the abdominal incision in whole-body plethysmography. Thoracic epidural anesthesia attenuated the incision-induced changes in phrenic motor output and ventilatory parameters. CONCLUSIONS: Upper abdominal incision decreased phrenic motor output and ventilatory parameters, and this incision-induced impairment was attenuated by thoracic epidural anesthesia. The authors' results provide direct evidence that afferent inputs from the upper abdominal incision induce reflex inhibition of phrenic motor activity.

A Prospective Study of Chronic Pain after Thoracic Surgery.

BACKGROUND: The goal of this study was to detect the predictors of chronic pain at 6 months after thoracic surgery from a comprehensive evaluation of demographic, psychosocial, and surgical factors. METHODS: Thoracic surgery patients were enrolled 1 week before surgery and followed up 6 months postsurgery in this prospective, observational study. Comprehensive psychosocial measurements were assessed before surgery. The presence and severity of pain were assessed at 3 and 6 months after surgery. One hundred seven patients were assessed during the first 3 days after surgery, and 99 (30 thoracotomy and 69 video-assisted thoracoscopic surgery, thoracoscopy) patients completed the 6-month follow-up. Patients with versus without chronic pain related to thoracic surgery at 6 months were compared. RESULTS: Both incidence (P = 0.37) and severity (P = 0.97) of surgery-related chronic pain at 6 months were similar after thoracotomy (33%; 95% CI, 17 to 53%; 3.3 ± 2.1) and thoracoscopy (25%; 95% CI, 15 to 36%; 3.3 ± 1.7). Both frequentist and Bayesian multivariate models revealed that the severity of acute pain (numerical rating scale, 0 to 10) is the measure associated with chronic pain related to thoracic surgery. Psychosocial factors and quantitative sensory testing were not predictive. CONCLUSIONS: There was no difference in the incidence and severity of chronic pain at 6 months in patients undergoing thoracotomy versus thoracoscopy. Unlike other postsurgical pain conditions, none of the preoperative psychosocial measurements were associated with chronic pain after thoracic surgery.

Hydrogen Peroxide Induces Muscle Nociception via Transient Receptor Potential Ankyrin 1 Receptors.

BACKGROUND: H2O2 has a variety of actions in skin wounds but has been rarely studied in deep muscle tissue. Based on response to the transient receptor potential ankyrin 1 antagonists after plantar incision, we hypothesized that H2O2 exerts nociceptive effects via the transient receptor potential ankyrin 1 in muscle. METHODS: Nociceptive behaviors in rats (n = 269) and mice (n = 16) were evaluated after various concentrations and volumes of H2O2 were injected into the gastrocnemius muscle or subcutaneous tissue. The effects of H2O2 on in vivo spinal dorsal horn neuronal activity and lumbar dorsal root ganglia neurons in vitro were evaluated from 26 rats and 6 mice. RESULTS: Intramuscular (mean ± SD: 1,436 ± 513 s) but not subcutaneous (40 ± 58 s) injection of H2O2 (100 mM, 0.6 ml) increased nociceptive time. Conditioned place aversion was evident after intramuscular (-143 ± 81 s) but not subcutaneous (-2 ± 111 s) injection of H2O2. These H2O2-induced behaviors were blocked by transient receptor potential ankyrin 1 antagonists. Intramuscular injection of H2O2 caused sustained in vivo activity of dorsal horn neurons, and H2O2 activated a subset of dorsal root ganglia neurons in vitro. Capsaicin nerve block decreased guarding after plantar incision and reduced nociceptive time after intramuscular H2O2. Nociceptive time after intramuscular H2O2 in transient receptor potential ankyrin 1 knockout mice was shorter (173 ± 156 s) compared with wild-type mice (931 ± 629 s). CONCLUSIONS: The greater response of muscle tissue to H2O2 may help explain why incision that includes deep muscle but not skin incision alone produces spontaneous activity in nociceptive pathways.

The ACTTION-APS-AAPM Pain Taxonomy (AAAPT) Multidimensional Approach to Classifying Acute Pain Conditions.

Objective: With the increasing societal awareness of the prevalence and impact of acute pain, there is a need to develop an acute pain classification system that both reflects contemporary mechanistic insights and helps guide future research and treatment. Existing classifications of acute pain conditions are limiting, with a predominant focus on the sensory experience (e.g., pain intensity) and pharmacologic consumption. Consequently, there is a need to more broadly characterize and classify the multidimensional experience of acute pain. Setting: Consensus report following expert panel involving the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION), American Pain Society (APS), and American Academy of Pain Medicine (AAPM). Methods: As a complement to a taxonomy recently developed for chronic pain, the ACTTION public-private partnership with the US Food and Drug Administration, the APS, and the AAPM convened a consensus meeting of experts to develop an acute pain taxonomy using prevailing evidence. Key issues pertaining to the distinct nature of acute pain are presented followed by the agreed-upon taxonomy. The ACTTION-APS-AAPM Acute Pain Taxonomy will include the following dimensions: 1) core criteria, 2) common features, 3) modulating factors, 4) impact/functional consequences, and 5) putative pathophysiologic pain mechanisms. Future efforts will consist of working groups utilizing this taxonomy to develop diagnostic criteria for a comprehensive set of acute pain conditions. Perspective: The ACTTION-APS-AAPM Acute Pain Taxonomy (AAAPT) is a multidimensional acute pain classification system designed to classify acute pain along the following dimensions: 1) core criteria, 2) common features, 3) modulating factors, 4) impact/functional consequences, and 5) putative pathophysiologic pain mechanisms. Conclusions: Significant numbers of patients still suffer from significant acute pain, despite the advent of modern multimodal analgesic strategies. Mismanaged acute pain has a broad societal impact as significant numbers of patients may progress to suffer from chronic pain. An acute pain taxonomy provides a much-needed standardization of clinical diagnostic criteria, which benefits clinical care, research, education, and public policy. For the purposes of the present taxonomy, acute pain is considered to last up to seven days, with prolongation to 30 days being common. The current understanding of acute pain mechanisms poorly differentiates between acute and chronic pain and is often insufficient to distinguish among many types of acute pain conditions. Given the usefulness of the AAPT multidimensional framework, the AAAPT undertook a similar approach to organizing various acute pain conditions.

Effect of deep tissue incision on pH responses of afferent fibers and dorsal root ganglia innervating muscle.

BACKGROUND: Understanding the mechanisms underlying deep tissue pain in the postoperative period is critical to improve therapies. Using the in vitro plantar flexor digitorum brevis muscle-nerve preparation and patch clamp recordings from cultured dorsal root ganglia neurons innervating incised and unincised muscle, the authors investigated responses to various pH changes. METHODS: Incision including the plantar flexor digitorum brevis muscle or sham operation was made in the rat hind paw. On postoperative day 1, in vitro single-fiber recording was undertaken. On the basis of previous studies, the authors recorded from at least 40 fibers per group. Also DiI-labeled dorsal root ganglia innervating muscle from rats undergoing incision and a sham operation were cultured and tested for acid responses, using whole cell patch clamp recordings. RESULTS: The prevalence of responsive group IV afferents to lactic acid pH 6.5 in the incision group (15 of 67; 22.3%) was greater than that in the control group (2 of 35; 5.7%; P=0.022). In dorsal root ganglia neurons innervating muscle, incision increased mean current amplitudes of acid-evoked currents; the acid-sensing ion channel blocker, amiloride 300 µM, inhibited more than 75% of the acid-evoked current, whereas, the transient receptor vanilloid receptor 1 blocker (AMG9810 1 µM) did not cause significant inhibition. CONCLUSION: The authors' experiments demonstrated that incision increases the responses of flexor digitorum brevis muscle afferent fibers to weak acid solutions, and increased acid-evoked currents in dorsal root ganglia innervating muscle. The authors' data suggest that up-regulation of acid-sensing ion channels might underlie this increased chemosensitivity caused by surgery.

Wound hypoxia in deep tissue after incision in rats.

Our previous studies using rat models of incisional pain have shown that tissue lactate levels increase and pH decreases for several days after incision, suggesting the presence of an ischemic-like condition. The purpose of this study was to evaluate the time course and the extent of tissue hypoxia that develops in incised muscle and skin. We directly measured oxygen tension at several time points after incisions of the gastrocnemius muscle, the paraspinal skin, and the plantar hindpaw in anesthetized rats using an oxygen-sensitive microelectrode. In vivo hypoxia of the incised tissues was also evaluated immunohistochemically using a hypoxia marker, pimonidazole hydrochloride. To minimize intersubject variability, unincised contralateral tissues were used as a control. Tissue oxygen tension was decreased in both skeletal muscle and skin compared with control, for several days after incision. When measured directly, oxygen tension decreased immediately and remained low for several days after incisions. Pimonidazole immunostaining revealed hypoxic areas in incised muscle and skin for several days. By postoperative day 10, tissue oxygen tension recovered to that of control tissue. These results support the evidence that a hypoxic condition is present in deep tissue after incisions and that an ischemic-like mechanism may contribute to postoperative pain.

Gene expression in skin, muscle, and dorsal root ganglion after plantar incision in the rat.

BACKGROUND: Treating postoperative pain remains a significant challenge for perioperative medicine. Recent studies have shown that nerve growth factor is up-regulated and contributes to incisional pain. To date, few studies have examined expression of other neurotrophin-related mediators that may contribute to the development and/or maintenance of incisional pain. METHODS: Male Sprague-Dawley rats underwent a plantar incision, and pain behaviors were examined (n = 6). In a separate group of rats, expression of neurotrophic factors were studied. At various times after incision (n = 4) or sham surgery (n = 4), the skin, muscle, and dorsal root ganglia were harvested and total RNA isolated. Real-time reverse transcription polymerase chain reaction was performed and the fold change in gene expression was analyzed using significance analysis of microarrays. RESULTS: Several genes were changed (P < 0.05) as early as 1 h after incision. Expression of artemin and nerve growth factor were increased in both incised skin and muscle. Brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-5 were all down-regulated in the skin but up-regulated in the muscle 48 h after incision. Few genes changed in the dorsal root ganglion. Most changes in expression occurred in the first 48 h after incision, a timeframe when pain behavior was the greatest. CONCLUSION: Surgical incision is associated with pain-related gene expression changes in skin, muscle, and, to a lesser extent, dorsal root ganglion. The gene expression profile provides clues as to mediators that are involved in peripheral sensitization and pain transmission after surgical incision and also suggest mechanisms for resolution of postoperative pain when more persistent pain syndromes like neuropathic pain continue.

Increased local concentration of complement C5a contributes to incisional pain in mice.

BACKGROUND: In our previous study, we demonstrated that local injection of complement C5a and C3a produce mechanical and heat hyperalgesia, and that C5a and C3a activate and sensitize cutaneous nociceptors in normal skin, suggesting a contribution of complement fragments to acute pain. Other studies also have shown that the complement system can be activated by surgical incision, and the systemic blockade of C5a receptor (C5aR) reduces incision-induced pain and inflammation. In this study, we further examined the possible contribution of wound area C5a to incisional pain. METHODS: Using of a hind paw incisional model, the effects of a selective C5aR antagonist, PMX53, on nociceptive behaviors were measured after incision in vivo. mRNA levels of C5 and C5aR in skin, dorsal root ganglia (DRG) and spinal cord, and C5a protein levels in the skin were quantified after incision. The responses of nociceptors to C5a were also evaluated using the in vitro skin-nerve preparation. RESULTS: Local administration of PMX53 suppressed heat hyperalgesia and mechanical allodynia induced by C5a injection or after hind paw incision in vivo. mRNA levels of C5 and C5aR in the skin, but not DRG and spinal cord, were dramatically increased after incision. C5a protein in the skin was also increased after incision. In vitro C5a did not increase the prevalence of fibers with ongoing activity in afferents from incised versus control, unincised skin. C5a sensitized C-fiber afferent responses to heat; however, this was less evident in afferents adjacent to the incision. PMX53 blocked sensitization of C-fiber afferents to heat by C5a but did not by itself influence ongoing activity or heat sensitivity in afferents innervating control or incised skin. The magnitude of mechanical responses was also not affected by C5a in any nociceptive fibers innervating incised or unincised skin. CONCLUSIONS: This study demonstrates that high locally generated C5a levels are present in wounds for at least 72 hours after incision. In skin, C5a contributes to hypersensitivity after incision, but increased responsiveness of cutaneous nociceptors to C5a was not evident in incised skin. Thus, high local concentrations of C5a produced in wounds likely contribute to postoperative pain.

The pathophysiology of acute pain: animal models.

PURPOSE OF REVIEW: Trauma, surgery, and burns are three common clinical scenarios that are associated with significant acute pain. This review describes the pathophysiology of acute pain utilizing three preclinical models: surgery, burn, and fracture. RECENT FINDINGS: In general, there is greater interest directed toward peripheral mediators of acute pain. Studies indicate that treatment against nerve growth factor, interleukins, and ischemic-like mediators may provide valuable avenues for treatment of acute pain. By targeting the periphery, analgesic therapies may have reduced side-effects. SUMMARY: Peripheral mediators of acute pain can vary depending upon the type of injury. Treatment aimed toward those mediators specific to the injury may improve acute pain management in the future. It will be important to translate these findings into clinical trials in the future.

AAAPT Diagnostic Criteria for Acute Thoracic Surgery Pain.

Patients undergoing thoracic surgery experience particular challenges for acute pain management. Availability of standardized diagnostic criteria for identification of acute pain after thoracotomy and video assisted thoracic surgery (VATS) would provide a foundation for evidence-based management and facilitate future research. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the United States Food and Drug Administration, the American Pain Society (APS), and the American Academy of Pain Medicine (AAPM) formed the ACTTION-APS-AAPM Pain Taxonomy (AAAPT) initiative to address absence of acute pain diagnostic criteria. A multidisciplinary working group of pain experts was invited to develop diagnostic criteria for acute thoracotomy and VATS pain. The working group used available studies and expert opinion to characterize acute pain after thoracotomy and VATS using the 5-dimension taxonomical structure proposed by AAAPT (i.e., core diagnostic criteria, common features, modulating factors, impact/functional consequences, and putative mechanisms). The resulting diagnostic criteria will serve as the starting point for subsequent empirically validated criteria. PERSPECTIVE ITEM: This article characterizes acute pain after thoracotomy and VATS using the 5-dimension taxonomical structure proposed by AAAPT (ie, core diagnostic criteria, common features, modulating factors, impact and/or functional consequences, and putative mechanisms).

Guarding pain and spontaneous activity of nociceptors after skin versus skin plus deep tissue incision.

BACKGROUND: Guarding pain after rat plantar incision is similar to pain at rest in postoperative patients. Spontaneous activity (SA) in nociceptive pathways quite likely transmits such ongoing pain. This study examined the extent of tissue injury by incision on pain behaviors and nociceptor SA. METHODS: Rat pain behaviors were measured after a sham procedure, skin incision, or skin plus deep tissue incision. Separate groups of rats underwent in vivo single-fiber recording 1 day after a sham procedure, skin, or skin plus deep tissue incision or 7 days after skin plus deep tissue incision. RESULTS: Compared with the control procedure, skin incision induced moderate guarding on the day of incision only, whereas skin plus deep tissue incision caused guarding for 5 days. Mechanical and heat hyperalgesia were similar in both incised groups, except that mechanical hyperalgesia lasted longer after skin plus deep tissue incision. On Postoperative Day 1, skin incision (18.2%) produced a similar prevalence of SA in nociceptors as in controls (13.0%), whereas skin plus deep tissue incision generated a greater prevalence of SA (61.0%); SA rate also tended to be greater (6.1 vs. 10.0 imp/s) after skin plus deep tissue incision. Seven days after skin plus deep tissue incision, the SA prevalence was similar (13.6%) as in controls. CONCLUSIONS: These data demonstrated that incised deep tissue rather than skin had a central role in the genesis of guarding behavior and nociceptor SA. Understanding the responses of deep tissue to incision and the mechanisms for deep tissue pain will improve postoperative pain management.

Chemosensitivity and mechanosensitivity of nociceptors from incised rat hindpaw skin.

BACKGROUND: The authors have demonstrated a decrease in pH in the incisional wound environment, suggesting a possible contribution of low pH to postsurgical pain. In this study, the authors characterized the acid-responsiveness of nociceptors innervating the plantar aspect of the rat hind paw 1 day after plantar incision and compared this to plantar skin from unincised control rats. METHODS: Using the rat glabrous in vitro skin-tibial nerve preparation, afferent nerve activities from single mechanosensitive nociceptors were recorded. Differences in mechanosensitivity, spontaneous activity, and chemosensitivity of units were evaluated. For chemosensitivity, acid-responsiveness of nociceptors to lactic acid (pH 5.5 to 6.5) was studied. RESULTS: C-fibers showed dose-dependent, sustained responses to lactic acid. A greater proportion of C-fibers from 2 mm or less from the incision was activated by pH 6.0 lactic acid (52.9%) compared to control (14.3%). Total evoked potentials during acid exposure were greater in C-fibers innervating 2 mm or less from the incision compared to those in unincised skin. The prevalence of acid responses and total evoked potentials during acid exposure in C-fibers innervating more than 2 mm from the incision were not different from control. Few A-fibers responded to lactic acid, with a range of pH 5.5 to 6.5 in both incision and control groups. Increased spontaneous activity and mechanosensitivity were also evident. CONCLUSIONS: C-fibers in the vicinity of the incision showed qualitatively and quantitatively greater chemosensitivity to pH 6.0 lactic acid compared to control. This change was localized to 2 mm or less from the incision, suggesting increased chemosensitivity of nociceptive C-fibers 1 day after plantar incision.

Expression profile of nerve growth factor after muscle incision in the rat.

BACKGROUND: Previous studies have demonstrated that nerve growth factor (NGF) is an important mediator of pathologic pain. Many studies have focused on cutaneous mechanisms for NGF-induced hyperalgesia; few have examined its contribution in deeper tissues like muscle. This study examined pain behaviors and the expression of NGF in incised hind paw flexor digitorum brevis muscle. METHODS: Adult Sprague-Dawley rats were pretreated with anti-NGF peptibody and underwent skin or skin plus deep fascia and muscle incision. Guarding pain behaviors were measured. Muscle NGF messenger RNA (mRNA) was measured by reverse-transcriptase polymerase chain reaction. Changes in NGF protein expression were measured using Western blot, enzyme-linked immunosorbent assay, and immunohistochemistry. In situ hybridization for NGF mRNA was also performed. RESULTS: Pretreatment with anti-NGF peptibody (100 mg/kg) decreased the guarding behavior caused by deep fascia and muscle incision. Muscle NGF mRNA increased abruptly 2 h after incision and was the same as control by postoperative day 1. NGF protein increased from 4 h after incision and was sustained for several days. NGF was localized in many calcitonin gene-related peptide-positive axons, few N52-positive axons, but not isolectin B4-positive axons in incised muscle. The sources of NGF mRNA included keratinocytes in epidermis and fibroblasts in deeper tissues. CONCLUSION: Fibroblasts adjacent to the injury are sources of NGF in incised muscle. NGF is upregulated by incision of muscle and contributes to guarding pain behavior.

Ketoprofen produces modality-specific inhibition of pain behaviors in rats after plantar incision.

BACKGROUND: Postoperative pain remains a significant problem despite optimal treatment with current drugs. Nonsteroidal antiinflammatory drugs reduce inflammation and provide analgesia but are associated with adverse side effects. METHODS: We tested low doses (0.5-5 mg/kg) of parenteral ketoprofen against pain-related behaviors after plantar incision in rats. To further evaluate the potential sites of action of ketoprofen in our model, a novel, sustained-release microparticle formulation of ketoprofen was placed into the wound, and tested for its effects on pain behaviors. Intrathecal ketoprofen (150 microg) was also studied. Plasma samples were assayed for drug concentrations. RESULTS: We found that low doses of parenterally administered ketoprofen produced a modality-specific effect on pain behaviors; guarding after incision was decreased, whereas no inhibition of exaggerated responses to heat or mechanical stimuli was evident. Very low doses, 0.5 mg/kg, could produce inhibition of guarding. The locally applied sustained-release ketoprofen-eluting microparticles and intrathecally administered ketoprofen also produced a modality-specific effect on pain behaviors after incision, inhibiting only guarding. Plasma levels of ketoprofen after parenteral or local administration were in the range of therapeutic blood levels in postoperative patients. CONCLUSIONS: This study demonstrates that ketoprofen is an effective analgesic for nonevoked guarding in rats after plantar incision. There was no effect on mechanical or heat responses, which highlights the importance of multiple-modality testing of pain behaviors for drug evaluation. We found efficacy at doses used clinically in postoperative patients.

Deep Tissue Incision Enhances Spinal Dorsal Horn Neuron Activity During Static Isometric Muscle Contraction in Rats.

Translational correlates to pain with activities after deep tissue injury have been rarely studied. We hypothesized that deep tissue incision causes greater activation of nociception-transmitting neurons evoked by muscle contraction. In vivo neuronal activity was recorded in 203 dorsal horn neurons (DHNs) from 97 rats after sham, skin-only, or skin + deep muscle incision. We evaluated DHN responses to static, isometric muscle contractions induced by direct electrical stimulation of the muscle. The effect of pancuronium on DHN response to contractions was also examined. Approximately 50% of DHNs with receptive fields in the hindpaw were excited during muscle contraction. One-second .5- and 1.0-g muscle contractions produced greater DHN activity after skin + deep muscle incision (median [interquartile range], 32 [5-39] impulses, P = .021; and 36 [26-46] impulses, P = .006, respectively) than after sham (6 [0-21] and 15 [8-32] impulses, respectively). Neuromuscular blockade with pancuronium inhibited the muscle contractions and DHN activation during electrical stimulation, demonstrating contraction-induced activation. The greater response of spinal DHNs to static muscle contraction after skin + deep muscle incision may model and inform mechanisms of dynamic pain after surgery. PERSPECTIVE: Completion of various activities is an important milestone for recovery and hospital discharge after surgery. Skin + deep muscle incision caused greater activation of nociception-transmitting DHNs evoked by muscle contraction compared with skin-only incision. This result suggests an important contribution of deep muscle injury to activity-evoked hyperalgesia after surgery.