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Abstract: The COVID-19 pandemic has had a tremendous impact, including on individuals with chronic pain. The social distancing policies necessary to slow the spread of SARS-CoV-2 have involved increased levels of social isolation. This cross-sectional survey study examined pain severity and interference among individuals with chronic pain during an early phase of social distancing mandates and identified characteristics of individuals who were most impacted. Approximately 4 to 8 weeks after social distancing mandates commenced in the state of Massachusetts, 150 patients with fibromyalgia, chronic spine, and postsurgical pain completed demographic, pain, social distancing, and validated psychosocial questionnaires. Patients self-reported an overall significant increase in pain severity and pain interference, compared with before social distancing, although both pain severity and interference were quite variable among individuals under conditions of social distancing. Several demographic, socioeconomic, and psychosocial factors were associated with greater pain severity and interference during social distancing. Multivariable linear regression demonstrated that female sex, nonwhite race, lower education, disability, fibromyalgia, and higher pain catastrophizing were independently associated with greater pain severity, while female sex and pain catastrophizing were independently associated greater pain interference. The findings suggest that individual differences among patients with chronic pain should be considered in the planning, development, and prioritization of interventions to improve pain care and to prevent worsening of symptoms during the continuing COVID-19 pandemic., (Copyright © 2020 International Association for the Study of Pain.)

Insufficient perioperative pain treatment is known as a highly predictive risk factor for the development of chronic postoperative pain. Remifentanil is an ultrashort-acting opioid that provides quick and efficient analgesia but is associated with the induction of opioid-induced hyperalgesia. Despite these well-known characteristics, this substance is being increasingly used in anesthesia and in a variety of medical fields, such as intensive-care medicine and obstetrics. The aim of our study was to reveal whether remifentanil influences postoperative pain, the requirement for postoperative analgesics, and requirement of antiemetics (as indirect indicator of postoperative nausea and vomiting), as well as the effects on time to extubation and length of stay in the postanesthesia care unit in daily clinical routine. From an electronic medical records database of 55,693 anesthesias, we analyzed data from all patients receiving intraabdominal surgery (visceral, gynecological, and urological) under general anesthesia or combined general-epidural anesthesia by propensity score matching. The administration of remifentanil was associated with higher postoperative pain scores despite a higher requirement of postoperative analgesics. Additional epidural analgesia was not able to avoid this finding. The intraoperative use of remifentanil is associated with a deterioration of pain levels and postoperative analgesic requirement, wherefore the potential benefit of this substance seems to be outweighed by its potential disadvantages. Especially in operative procedures in which high postoperative pain scores are expected, the unreflective use should be critically questioned.

Pain and physical activity are tightly intertwined. Although their relationship has been explored in chronic pain conditions, we know little about the pattern of recovery in activity and its short- and long-term relationship with pain after surgery. We recruited 103 women undergoing elective cesarean delivery and acquired daily pain assessments and hourly steps in 98 of them for 2 months after surgery. Compliance was good, with 78% of subjects missing less than 7 days of activity. Study personnel required daily checking for compliance and 20 minutes per subject per week in study. Activity increased over the first 2 postoperative months in a log(time) manner. The slope of each modeled individual curve for activity was inversely correlated (r = -0.54; P < 0.0001) with worst daily pain. After removing these 2-month trends, pain and activity within an individual day were negatively associated with each point increase in pain being inversely associated with -119 steps (95% confidence interval [CI] = -214 to -25; P = 0.013). A patient's previous experience of pain was not associated with current activity as well as current activity was not associated with future pain scores. These data, although limited by the study of a single operation in a unique social circumstance with low risk of chronic postsurgical pain, demonstrate feasibility of measuring hourly activity for 2 months after surgery. Recovery from pain and inactivity are tightly correlated, and the negative relationship between within-day pain and activity without interday carryover relationships is in stark contrast to findings in chronic pain conditions.

Although chronic postsurgical pain (CPSP) is a major health care problem, pain-related functional interference has rarely been investigated. Using the PAIN OUT registry, we evaluated patients' pain-related outcomes on the first postoperative day, and their pain-related interference with daily living (Brief Pain Inventory) and neuropathic symptoms (DN4: douleur neuropathique en 4 questions) at 6 months after surgery. Endpoints were pain interference total scores (PITS) and their association with pain and DN4 scores. Furthermore, possible risk factors associated with impaired function at M6 were analyzed by ordinal regression analysis with PITS groups (no to mild, moderate, and severe interference) as a dependent three-stage factor. Odds ratios with 95% confidence intervals were calculated. Of 2322 patients, 15.3% reported CPSP with an average pain score ≥3 (numeric rating scale 0-10). Risk for a higher PITS group increased by 190% (odds ratio [95% confidence interval]: 2.9 [2.7-3.2]; P < 0.001) in patients with CPSP, compared to without CPSP. A positive DN4 independently increased risk by 29% (1.3 [1.12-1.45]; P < 0.001). Preexisting chronic pain (3.6 [2.6-5.1]; P < 0.001), time spent in severe acute pain (2.9 [1.3-6.4]; P = 0.008), neurosurgical back surgery in males (3.6 [1.7-7.6]; P < 0.001), and orthopedic surgery in females (1.7 [1.0-3.0]; P = 0.036) were the variables with strongest association with PITS. Pain interference total scores might provide more precise information about patients' outcomes than pain scores only. Because neuropathic symptoms increase PITS, a suitable instrument for their routine assessment should be defined.

Residual lower-limb pain after low back surgery (postsurgical sciatica) and complex regional pain syndrome (CRPS) involving a lower limb are separate conditions but may share some mechanisms (eg, tissue inflammation, neuroimmune disturbances, and central neuroplasticity). As adrenergically evoked pain contributes, in part, to CRPS, whether an adrenergic mechanism also contributes to postsurgical sciatica was investigated in this study. Immunohistochemistry was used to identify α1-adrenoceptors (α1-AR) on nerve fibres and other targets in the affected and contralateral skin of 25 patients with postsurgical sciatica, and α1-AR expression was investigated in relation to pain and pinprick hyperalgesia after intradermal injection of the α1-AR agonist phenylephrine. In addition, quantitative sensory testing was performed on all 4 limbs and on each side of the forehead. α1-AR expression was greater in keratinocytes (but not blood vessels or nerve fibres) in the symptomatic than contralateral leg, and dermal nerve fibre density was reduced in both legs. However, distal adrenergic involvement in pain in postsurgical sciatica seems unlikely, as neither heightened α1-AR expression in keratinocytes nor reduced dermal nerve fibre density were associated with pain or hyperalgesia to intradermal phenylephrine injection. Sensitivity to pressure-pain, pinprick, and cold-pain was greater in the ipsilateral than contralateral forehead of the entire cohort, but sensory disturbances were most pronounced in patients with additional CRPS-like features. Together, these findings suggest that bilateral distal neuropathy and central neuroplastic changes are involved not only in the pathophysiology of CRPS but also in postsurgical sciatica. This may have treatment implications for patients with postsurgical sciatica.

In this randomized, double-blind, placebo-controlled crossover study, we investigated whether a peripheral nerve block could temporarily eliminate phantom and stump pain after amputation. Amputees with constant postamputation pain were included and randomized to receive a nerve block with lidocaine 2% with adrenaline or saline in a crossover design. Spontaneous phantom and stump pain and evoked responses were assessed at baseline and at fixed time-points until 120 minutes after lidocaine or saline injection. The primary outcome was the difference in absolute change between worst pain intensity, either phantom or stump pain, at baseline and at 30 minutes after lidocaine or saline injection. Twelve amputees were randomized and 9 patients were included in the analysis. The absolute change in median worst pain intensity between lidocaine and saline injection was -2.0 (interquartile range, -4.0 to 0.0) (n = 9, P = 0.12). Nine of 9 patients reported at least some pain relief after lidocaine injection compared with only 2 of 9 patients after saline injection (P = 0.02). Phantom pain intensity was significantly reduced after lidocaine compared with saline injection (P = 0.04), whereas there was no significant change in stump pain intensity between the 2 interventions (P = 0.17). In all 9 amputees, evoked responses were eliminated after lidocaine injection. Thus, our findings suggest that afferent input from the peripheral nervous system plays an important role in postamputation pain.

Noxious stimulation at critical stages of development has long-term consequences on somatosensory processing in later life, but it is not known whether this developmental plasticity is restricted to nociceptive pathways. Here, we investigate the effect of repeated neonatal noxious or innocuous hind paw stimulation on adult spinal dorsal horn cutaneous mechanical sensitivity. Neonatal Sprague-Dawley rats of both sexes received 4 unilateral left hind paw needle pricks (NPs, n = 13) or 4 tactile (cotton swab touch) stimuli, per day (TC, n = 11) for the first 7 days of life. Control pups were left undisturbed (n = 17). When adult (6-8 weeks), lumbar wide-dynamic-range neuron activity in laminae III-V was recorded using in vivo extracellular single-unit electrophysiology. Spike activity evoked by cutaneous dynamic tactile (brush), pinch and punctate (von Frey hair) stimulation, and plantar receptive field areas were recorded, at baseline and 2 and 5 days after left plantar hind paw incision. Baseline brush receptive fields, von Frey hair, and pinch sensitivity were significantly enhanced in adult NP and TC animals compared with undisturbed controls, although effects were greatest in NP rats. After incision, injury sensitivity of adult wide-dynamic-range neurons to both noxious and dynamic tactile hypersensitivity was significantly greater in NP animals compared with TC and undisturbed controls. We conclude that both repeated touch and needle-prick stimulation in the neonatal period can alter adult spinal sensory neuron sensitivity to both innocuous and noxious mechanical stimulation. Thus, spinal sensory circuits underlying touch and pain processing are shaped by a range of early-life somatosensory experiences.

Persistent postoperative pain (PPP) has been described as a complication of cardiac surgery (CS). We aimed to study PPP after CS (PPPCS) by conducting a systematic review of the literature regarding its incidence, intensity, location, and the presence of neuropathic pain, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The review comprised 3 phases: a methodological assessment of 6 different databases identifying potential articles and screening for inclusion criteria by 2 independent reviewers; data extraction; and study quality assessment. Meta-analysis was used to estimate the pooled incidence rates using a random effects model. We have identified 442 potentially relevant studies through database searching. A total of 23 studies (involving 11,057 patients) met our inclusion criteria. Persistent postoperative pain affects 37% patients in the first 6 months after CS, and it remains present more than 2 years after CS in 17%. The reported incidence of PPP during the first 6 months after CS increased in recent years. Globally, approximately half of the patients with PPPCS reported moderate to severe pain. Chest is the main location of PPPCS followed by the leg; neuropathic pain is present in the majority of the patients. This is the first systematic review and meta-analysis to provide estimates regarding incidence and intensity of PPPCS, which elucidates its relevance. There is an urgent need for adequate treatment and follow-up in patients with PPPCS.

Widespread hyperalgesia has been found in patients with painful hip osteoarthritis (OA) which can be normalized after total hip arthroplasty (THA) if patients have no residual postoperative pain. This study characterized the preoperative somatosensory profiles and provided possible interpretation of underlying pain mechanisms that might influence the development of postoperative pain. Forty hip OA patients with unilateral pain were assessed before and 6 weeks post-THA and compared with 40 asymptomatic control subjects. Hip pain intensity at rest and while walking was assessed on a visual analogue scale (VAS). Bilateral cuff algometry from the thighs was used to assess the cuff pressure pain thresholds, pressure values at VAS scores equal with 6 cm (PVAS6), cuff pressure tolerance, and temporal summation of pain (TSP) quantified by an increase in VAS scores to repeated phasic cuff stimulations. Correlations between hip pain VAS post-THA and preoperative quantitative sensory testing results were analyzed. Post-THA hip pain VAS scores decreased (P < 0.05) compared with pre-THA. The cuff pressure pain threshold, PVAS6, and cuff pressure tolerance were significantly lower bilaterally in both patients with pre-THA and post-THA compared with controls (P < 0.05). Temporal summation of pain was facilitated bilaterally in patients with pre-THA compared with controls and normalized after THA in postoperative pain-free patients (P < 0.05). Postoperative hip pain VAS scores correlated with preoperative ipsilateral TSP (r = 0.44, P < 0.05). Bilateral pressure pain hypersensitivity and facilitated TSP were demonstrated in patients with preoperative hip OA. Although persistent postoperative pain is known as multifactorial, greater preoperative TSP was associated with greater pain and less reduction in pain after THA.

Chronic postoperative pain after total knee replacement (TKR) in knee osteoarthritis (KOA) implies clinical challenges. Widespread hyperalgesia, facilitated temporal summation of pain (TSP), and impaired conditioned pain modulation (CPM) have been found in painful KOA. This exploratory study investigated postoperative pain relief 12 months after TKR in 4 subgroups of patients preoperatively profiled by mechanistic quantitative sensory testing. In 103 patients with KOA, pressure pain detection threshold (PDT) and tolerance thresholds (PTT) were assessed at the lower leg using cuff algometry. Temporal summation of pain was measured as an increase in pain intensity scores during 10 repeated (2 seconds intervals) painful cuff stimuli. Conditioned pain modulation was calculated as the relative increase in PDT during painful conditioning stimulation. The grand averages of TSP and CPM were calculated and values below or above were used for subgrouping: facilitated TSP/impaired CPM (group A, N = 16), facilitated TSP/normal CPM (group B, N = 15), normal TSP/impaired CPM (group C, N = 44), and normal TSP/normal CPM (group D, N = 28). Clinical VAS pain intensity scores were collected before and 12 months after TKR surgery and the pain relief calculated. Less pain relief was found in group A (52.0% ± 14.0% pain relief) than in group B (81.1% ± 3.5%, P = 0.023) and group C (79.6% ± 4.4%, P = 0.007), but not group D (69.4% ± 7.9%, P = 0.087). Low preoperative PDT was associated with a less postoperative pain relief (R = -0.222, P = 0.034), whereas TSP or CPM alone showed no associations with postoperative pain relief. This explorative study indicated that patients with osteoarthritis with facilitated TSP together with impaired CPM are more vulnerable to experience less pain relief after TKR.

Local injections of botulinum toxins have been reported to be useful not only for the treatment of peripheral neuropathic pain and migraine but also to cause long-lasting muscle paralysis, a potentially serious side effect. Recently, a botulinum A-based molecule ("BiTox") has been synthesized that retains neuronal silencing capacity without triggering muscle paralysis. In this study, we examined whether BiTox delivered peripherally was able to reduce or prevent the increased nociceptive sensitivity found in animal models of inflammatory, surgical, and neuropathic pain. Plasma extravasation and edema were also measured as well as keratinocyte proliferation. No motor deficits were seen and acute thermal and mechanical nociceptive thresholds were unimpaired by BiTox injections. We found reduced plasma extravasation and inflammatory edema as well as lower levels of keratinocyte proliferation in cutaneous tissue after local BiTox injection. However, we found no evidence that BiTox was transported to the dorsal root ganglia or dorsal horn and no deficits in formalin-elicited behaviors or capsaicin or formalin-induced c-Fos expression within the dorsal horn. In contrast, Bitox treatment strongly reduced A-nociceptor-mediated secondary mechanical hyperalgesia associated with either complete Freund's adjuvant (CFA)-induced joint inflammation or capsaicin injection and the hypersensitivity associated with spared nerve injury. These results imply that although local release of neuromodulators from C-fibers was inhibited by BiTox injection, C-nociceptive signaling function was not impaired. Taken together with recent clinical data the results suggest that BiTox should be considered for treatment of pain conditions in which A-nociceptors are thought to play a significant role.

Number-based assessment tools are used to evaluate pain perception in patients and determine the effect of pain management. The aim of this study was to determine the ability of chronic and acute pain patients to score their response to randomly applied noxious stimuli and assess the effect of opioid treatment. Thirty-seven healthy controls, 30 fibromyalgia patients, and 62 postoperative patients with acute pain received random heat pain (Hp) and electrical pain (Ep) stimuli. All subjects rated their pain on an 11-point numerical rating scale (NRS). The data were analyzed using a penalty score system, based on the assumption that stimuli of higher intensity are scored with a greater NRS, and stratified into cohorts corresponding to "good," "mediocre," and "poor" scoring. Healthy controls were well able to score pain with 73% (Hp) and 81% (Ep) of subjects classified into cohort "good." Fibromyalgia had a negative effect on scoring with 45% (Hp, P = 0.03 vs controls) and 67% (Ep) of patients in cohort "good." In controls, scoring deteriorated during opioid administration leaving just 40% (Hp, P = 0.015 vs baseline) and 70% (Ep) of subjects in the cohort "good." Similar observations were made in fibromyalgia patients (P = 0.02) but not in surgical patients with postoperative pain. Consistency to grade pain using an NRS is high in healthy volunteers but deteriorates in chronic pain and during opioid administration to volunteers and chronic pain patients but not to acute pain patients.

Over 1 million children undergo inpatient surgery annually in the United States. Emerging research indicates that many children have longer-term problems with pain. However, limited data exist on the course of pain over time and the impact of pain recovery on long-term health outcomes. We sought to prospectively characterize children's postsurgical pain trajectories using repeated assessments over 12 months. In addition, we identified presurgical child and parent psychological risk factors associated with persistent pain and examined relationships between pain trajectories and long-term health outcomes. Sixty children aged 10 to 18 years undergoing major surgery and their parent/guardian were enrolled. Participants completed assessments at 5 time points: presurgery, inhospital, 2 weeks, 4 months, and 1 year postsurgery. Child and parent pain catastrophizing was assessed during the week before surgery. Children completed daily monitoring with an electronic pain diary and reported on pain characteristics, health-related quality of life, and activity limitations. Group-based longitudinal modeling revealed 2 distinct trajectories of postsurgical pain: early recovery (n = 49, 82%) and late recovery (n = 11, 18%). In a logistic regression model controlling for age and sex, parental pain catastrophizing before surgery significantly predicted membership in the late recovery group (odds ratio = 1.11, P = 0.03), whereas child catastrophizing and baseline pain did not (Ps < 0.05). In a multivariate regression controlling for age and sex, late pain recovery was significantly associated with poorer health-related quality of life (β = -10.7, P = 0.02) and greater activity limitations (β = 3.6, P = 0.04) at 1 year. Our findings suggest that preoperative interventions that modify parent behaviors and cognitions might be beneficial in this population.

Preclinical assessment of pain has typically relied on measuring animal responses to evoked stimulation. Because of inherent limitations of these assays, there is a need to develop measures of animal pain/discomfort that are objective, not experimentally evoked, and mimic the human condition. Patients with chronic pain manifest a variety of co-morbidities, one of which is disturbances in sleep. We used electroencephalography to objectively assess 4 rat models of pain (inflammatory/complete Freund's adjuvant [CFA], neuropathic/chronic constriction injury [CCI], postoperative/skin incision, osteoarthritis/monosodium iodoacetate [MIA]) for the occurrence of sleep disturbances. Four different measures of slow-wave sleep (SWS) were examined: amplitude of 1- to 4-Hz waves, total time spent in SWS, time spent in SWS-1, and time spent in SWS-2. Bilateral injuries were more likely to induce a sleep disturbance than unilateral injuries in the CFA, CCI, and skin incision assays. Sleep disturbances occurred in the deeper stage of SWS, as the amplitude of 1- to 4-Hz waves and time spent in SWS-2 were significantly decreased in all models except the osteoarthritis model. Sleep disturbances lasted for approximately 3 to 14days, depending on the model, and were resolved despite continued hypersensitivity to evoked stimulation. Morphine, gabapentin, diclofenac, and ABT-102 (TRPV1 antagonist) all improved sleep in the bilateral CFA assay at doses that did not significantly alter SWS in uninjured rats. Preclinical assessment of compounds should follow the path of clinical studies and take into account diverse aspects of the "pain condition." This would include evaluating nociceptive thresholds as well as other endpoints, such as cognition and sleep, that may be affected by the pathological state., (Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Persistent postsurgical pain (PPSP) is a frequent and often disabling complication of many surgical procedures. Nerve injury-induced neuropathic pain (NeuP) has repeatedly been proposed as a major cause of PPSP. However, there is a lack of uniformity in NeuP assessment across studies, and the prevalence of NeuP may differ after various surgeries. We performed a systematic search of the PubMed, CENTRAL, and Embase databases and assessed 281 studies that investigated PPSP after 11 types of surgery. The prevalence of PPSP in each surgical group was examined. The prevalence of NeuP was determined by applying the recently published NeuP probability grading system. The prevalence of probable or definite NeuP was high in patients with persistent pain after thoracic and breast surgeries-66% and 68%, respectively. In patients with PPSP after groin hernia repair, the prevalence of NeuP was 31%, and after total hip or knee arthroplasty it was 6%. The results suggest that the prevalence of NeuP among PPSP cases differs in various types of surgery, probably depending on the likelihood of surgical iatrogenic nerve injury. Because of large methodological variability across studies, a more uniform approach is desirable in future studies for evaluating persistent postsurgical NeuP., (Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Population-based data on the prevalence of persistent postsurgical pain are scarce. This study aimed to assess the prevalence of persistent postsurgical pain in a general population and to describe associated physical, social, and psychological factors, including symptoms of nerve injury and sensitization. A cross-sectional survey was performed in northern Norway with questionnaire items covering surgery, pain, and sensory abnormalities in the area of surgery. Of the 12,982 participants, 24.0% (3111) had undergone one or more surgical procedures during the 3 years preceding the survey. Of these, 2043 had the surgery performed more than 3 months before the investigation. Persistent pain in the area of surgery was reported by 40.4% of the patients (826 of 2043), moderate or severe pain by 18.3% (373 of 2043). Hypoesthesia, hyperesthesia, or both was reported by 24.5% (501 of 2043). There were strong associations between sensory abnormalities and persistent pain, increasingly with higher pain intensities; odds ratios were 2.68 for hypoesthesia and 6.27 for hyperesthesia. Of the 826 individuals reporting persistent pain in the anatomical area of surgery, 51.0% reported chronic pain when questioned without specific reference to the surgery. The present study supports evidence from clinical studies of persistent postsurgical pain, indicating a high prevalence, but reveals large discrepancies in report of pain, depending on the questions asked and the context in which the questions are presented. Strong associations between sensory abnormalities and pain indicate neuropathic mechanisms in a major proportion of cases., (Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Several studies have shown that placebo analgesia effects can be obtained in healthy volunteers, as well as patients suffering from acute postoperative pain and chronic pain conditions such as irritable bowel syndrome. However, it is unknown whether placebo analgesia effects can be elicited in chronic pain conditions with a known pathophysiology such as a nerve injury. Nineteen patients who had developed neuropathic pain after thoracotomy were exposed to a placebo manipulation in which they received either open or hidden administrations of lidocaine. Before the treatment, the patients rated their levels of spontaneous pain and expected pain and completed a questionnaire on their emotional feelings (Positive Affect Negative Affect Schedule) and went through quantitative sensory testing of evoked pain (brush and cold allodynia, heat pain tolerance, area of pinprick hyperalgesia, wind-up-like pain after pinprick stimulation). The placebo manipulation significantly reduced the area of pinprick hyperalgesia (P=.027), and this placebo effect was significantly related to low levels of negative affect (P=.008; R(2)=0.362) but not to positive affect or expected pain levels. No placebo effect was observed in relation to spontaneous pain or evoked pain, which is most likely due to low pain levels resulting in floor effects. This is the first study to demonstrate a placebo effect in neuropathic pain. The possible mechanisms underlying the placebo effects in hyperalgesia are discussed, and implications for treatment are outlined., (Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Postoperative pain is often stated to be a significant contributor to a sympathetic stress response after surgery. However, hardly any evidence has been published to support this assumption. Hence it was the aim of this trial to investigate the relationship between postoperative pain and hemodynamic, endocrine, and autonomic parameters. A total of 85 postoperative patients in the recovery room were repeatedly asked to rate their pain on a numeric rating scale (NRS). Concurrently, the parameters of heart rate variability (HRV) were analysed, and mean arterial pressure (MAP), heart rate (HR) and respiration rate (RR) were recorded. Pain was categorized into no, mild, moderate, and severe. Blood samples were taken for epinephrine (EPI) and norepinephrine (NE) plasma level assessment at the time of recovery room admission and discharge, and each time pain was found decreased in categorized severity. A total of 239 pain readings were obtained. None of the investigated parameters correlated with NRS scores. NE was higher at NRS 5 to 10 vs. NRS 0 to 4 (mean [SEM]: 1009 [73] pg/mL vs. 872 [65] pg/mL; P<0.01). This was also found for MAP, but not for EPI or the parameters of HRV, HR, and RR. In contrast to common belief, the severity of postoperative pain does not appear to be associated with the degree of sympathetic stress response after surgery, and other factors such as surgical trauma may be more important. Importantly, the absence of signs of sympathetic stimulation cannot be seen as a guarantee for the absence of significant pain., (Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Consistent evidence supports a significant association between lower positive affect and higher negative affect and increased pain and disability in adults with chronic pain. However, examining this relation in surgical populations has received little empirical consideration. The primary purpose of this study was to determine whether preoperative and postoperative positive and negative affect predict pain, disability, and functional status after spine surgery. A secondary objective was to assess the relation of depression to postoperative outcomes compared with positive and negative affect. Participants were 141 patients treated by spine surgery for lumbar or cervical degeneration. Data collection occurred at baseline and 6 weeks and 3 months postoperatively. Affect was measured with the Positive and Negative Affect Schedule. Multivariable mixed-model linear regression analyses found that preoperative variables were not predictive of postoperative pain, disability and functional status. However, multivariable postoperative analysis found that 6-week positive affect predicted functional status, and 6-week negative affect predicted pain interference and pain-related disability at 3 months following surgery. Postoperative depression demonstrated statistically significant and stronger associations with pain intensity, pain interference, and pain-related disability at 3-month follow-up, as compared with negative affect. Results suggest that positive affect and depression are important variables to target when seeking to improve postoperative outcomes in a spine surgery population. Recommendations include postoperative screening for positive affect and depression, and treating depression as well as focusing on rehabilitation strategies to bolster positive affect so as to improve functional outcomes after spine surgery., (Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Persistent postoperative pain is a common complication of surgery, including surgical interventions for cancer. So far, there is limited information about the prevalence and clinical characteristics of pain after lymph node biopsy and dissection in patients with malignant melanoma. In this study, a questionnaire was sent out to all surviving patients (n=402) after surgery for cutaneous malignant melanoma at the Aalborg Hospital Department of Plastic Surgery, Aalborg, Denmark. Of patients responding, sentinel node biopsy (SNB) and/or lymph node dissection (LND) was performed in 175 patients. All patients with pain and a control group were invited to a clinical examination. Altered sensation and pain were significantly more common after LND (82% and 34%, respectively) than after SNB (32% and 14%, respectively). In patients with LND, 12% reported at least moderate pain and 14% impact of pain on quality of life, while in patients with SNB, 3% reported at least moderate pain and 2% pain impact on quality of life. The most important predictor of pain was sensory abnormalities. At the clinical follow-up, 10 out of 12 patients with pain both met the criteria of the recently proposed grading system for probable neuropathic pain and used descriptors on the DN4 questionnaire suggestive of neuropathic pain. Different patterns of sensory profiles were observed in single patients, suggesting heterogeneous sensory processing within single patients. This study suggested that nerve injury was the main underlying mechanism of persistent pain after lymph node excision., (Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

The present study examined the prospective value of response expectancies (ie, pain, sleep) and behavioral outcome expectancies (ie, return to function) in the prediction of pain severity and functional limitations 12 months after total knee arthroplasty (TKA). The study sample consisted of 120 individuals (73 women, 47 men) with osteoarthritis of the knee who were scheduled for TKA. Measures of expectancies, pain severity, pain catastrophizing, pain-related fears of movement, and depression were completed prior to surgery. Participants also completed measures of pain severity and functional limitations 12 months following surgery. Analyses revealed that behavioral outcome expectancies were stronger predictors of follow-up pain and functional limitations than response expectancies. Consistent with previous research, analyses also revealed that pain catastrophizing, pain-related fear of movement, and depression predicted follow-up pain and function. In a multivariate analysis, only pain catastrophizing contributed significant unique variance to the prediction of follow-up pain and function. Behavioral outcome expectancies partially mediated the relation between catastrophizing and follow-up pain and function. The relation between catastrophizing and follow-up pain severity and functional limitations remained significant even when controlling for behavioral outcome expectancies. The results suggest that interventions designed to specifically target behavioral outcome expectancies and catastrophizing might improve post-surgical outcomes., (Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Previous studies on sensory function in persistent postherniotomy pain (PPP) have only identified pressure pain threshold to be significantly different from pain-free patients despite several patients reporting cutaneous pain and wind-up phenomena. However the limited number of patients studied hinders evaluation of potential subgroups for further investigation and/or treatment allocation. Thus we used a standardized QST protocol to evaluate sensory functions in PPP and pain-free control patients, to allow individual sensory characterization of pain patients from calculated Z-values. Seventy PPP patients with pain related impairment of everyday activities were compared with normative data from 40 pain-free postherniotomy patients operated>1 year previously. Z-values showed a large variation in sensory disturbances ranging from pronounced detection hypoesthesia (Z=6, cold) to pain hyperalgesia (Z=-8, pressure). Hyperalgesia for various modalities were found in 80% of patients, with pressure hyperalgesia in approximately 65%, and cutaneous (mechanical or thermal) hyperalgesia in approximately 35% of patients. The paradoxical combination of tactile hypoesthesia and hyperalgesia was seen in approximately 25% of patients. Increased pain from repetitive tactile and/or brush stimulation was found in 51%, suggesting a role of altered central nociceptive function in this subpopulation. A high incidence (26%) of pressure hyperalgesia was found in the contralateral groin, with a significant correlation (rho=0.58, p=0.002) to the hyperalgesic level on the painful side, again suggesting central nervous mechanisms in PPP. In conclusion, this study shows that a standardized trauma results in heterogeneous combinations of hypo- and hyperalgesia. Z-score evaluation of sensory function identifies subpopulations in PPP, which may be used in selecting surgical and/or pharmacological treatment strategies., (Copyright (c) 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Individual differences in sensitivity to fentanyl, a widely used opioid analgesic, can hamper effective pain treatment. Still controversial is whether the single nucleotide polymorphisms (SNPs) of the human OPRM1 gene encoding the mu-opioid receptor influence the analgesic effects of opioids. We examined associations between fentanyl sensitivity and the two SNPs, A118G and IVS3+A8449G, in the human OPRM1 gene in 280 Japanese patients undergoing painful orofacial cosmetic surgery, including bone dissection. Regarding the A118G SNP in exon 1, in a cold pressor-induced pain test before surgery, less analgesic effects of fentanyl were shown in subjects carrying the minor G allele of the A118G SNP (median of difference between pain perception latencies before and after fentanyl injection [PPLpost-PPLpre]: 12s) compared with subjects not carrying this allele (PPLpost-PPLpre: 15s, p=0.046). Furthermore, the IVS3+A8449G SNP in intron 3, which represents a complete linkage disequilibrium block with more than 30 SNPs from intron 3 to the 3' untranslated region, was associated with 24-h postoperative fentanyl requirements. Subjects carrying the minor G allele of the IVS3+A8449G SNP required significantly less fentanyl for 24-h postoperative pain control (median: 1.5microg/kg) compared with subjects not carrying this allele (median: 2.5microg/kg, p=0.010). Although further validation is needed, the present findings shed light on the involvement of OPRM1 3' untranslated region polymorphisms in fentanyl sensitivity in addition to the A118G SNP and open new avenues for personalized pain treatment with fentanyl.

Substance P (SP) signaling facilitates nociceptive sensitization in various inflammatory and chronic pain models and we postulated that SP signaling might also contribute to the development of post-incisional hyperalgesia. These studies used mice with a deletion of the pre-protachykinin A gene (ppt-A(-/-)) which codes for SP to determine the role of SP signaling in post-incisional pain and in the increased cytokine and nerve growth factor (NGF) expression observed in the incised skin. SP deficient ppt-A(-/-) mice displayed reduced mechanical allodynia and heat hyperalgesia compared to the wild-type (wt) mice at all post-incision time points, despite similar baseline values (p<0.001). Furthermore, the NK-1 receptor antagonist LY303870 attenuated mechanical allodynia produced by incision in the wt mice (p<0.001). Incision also up-regulated IL-6, TNF-alpha and KC levels but not IL-1beta after 2h in the wt mice skin. However, ppt-A(-/-) mice had more skin NGF levels 2h post-incision. Subcutaneous hind paw SP injection produced acute and transient elevations of IL-1beta, IL-6, and KC but modest elevations in TNF-alpha levels in the wt mice. Systemic LY303870 reversed the SP-induced elevations of these cytokines. Hind paw injection of IL-6 and NGF dose dependently produced less mechanical allodynia in the ppt-A(-/-) compared to wt mice. Additionally, SP produced mechanical allodynia in a dose-dependent fashion in wt mice. Therefore, SP supports nociceptive sensitization after hind paw incision and potentially participates directly in modulating the intensity of inflammatory response in peri-incisional tissue.

Surgery injures both skin and deep tissue causing pain at rest and evoked pain with activities. In this study, we examined the extent of injury by incision and dorsal horn neuron (DHN) spontaneous activity (SA) in rats that underwent a sham operation, skin incision or skin plus deep tissue incision. Pain behaviors were measured 1 day later followed by DHN recordings in the same rats. On postoperative day (POD) 1, guarding pain, assessed with an abbreviated pain score, was increased in the skin plus deep tissue incision group (7.0+/-0.7 vs. 0.1+/-0.6 in control, P<0.001), but not in the skin incision group (1.8+/-1.0); yet, mechanical and heat hyperalgesia were similar in both incised groups. In the rats that underwent skin plus deep tissue incision, more DHNs expressed SA (78.1% vs. 35.7% in control, P<0.01) and SA rate also tended to be greater (13.8+/-2.9 vs. 5.6+/-2.0 imp/s). Bupivacaine infiltration into the incision decreased SA in both skin incision and skin plus deep tissue incision (POD1) groups to the same level as in the sham-operated rats. In a separate group of rats that underwent skin plus deep tissue incision, guarding pain was not present (0.1+/-0.6) on POD7 and the percentage and rate of DHN SA were the same as in the sham control. These data demonstrate that incised deep tissue rather than skin is critical for the development of guarding pain and increased SA of DHNs. Skin incision alone is sufficient for primary mechanical and heat hyperalgesia.

Further understanding of pathophysiology of postoperative acute pain is necessary for its better management. The methodology of current threshold (CT) determination by using sine-wave stimuli at 3 frequencies has been used to selectively and quantitatively analyze the function of the subsets of fibers (i.e., frequency of 5, 250, and 2000Hz recruits C-, Adelta-, and Abeta-fibers, respectively). This study investigated how surgical incision would affect the CTs, and then assessed the efficacy of intrathecal pharmacotherapy. The CT required to evoke a paw withdrawal response was assessed over time at stimulus frequencies of 5Hz (CT5), 250Hz (CT250), and 2000Hz (CT2000) in rats that had undergone surgical incision of the plantar skin and muscle. The CTs at all frequencies significantly decreased immediately after the incision. The decreased thresholds gradually recovered during the first week post-surgery. CT5 and CT250 (but not CT2000) remained significantly low even on day 7 post-surgery. Morphine at 5microg/10microL i.t. significantly reversed CT5 and CT250. NBQX (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid [AMPA]/kainate receptor antagonist) at 1.9 or 3.8microg/10microL i.t. significantly increased the thresholds over the pre-surgery threshold levels at all frequencies. MK-801 (N-methyl d-aspartate [NMDA] receptor antagonist) up to 13.5microg/10microL i.t. did not significantly affect CTs at any frequencies. In conclusion, a broad spectrum of sensory fibers (Abeta, Adelta, and C) is sensitized at the spinal and/or peripheral level in the postoperative acute pain state. Spinal AMPA/kainate receptors but not NMDA receptors play a significant role in this sensitization.

Ralfinamide is analgesic when applied as a single dose in rodent models of stimulus-evoked chronic pain. However, it is unknown whether its chronic application after nerve injury can suppress spontaneous chronic pain, the main symptom driving patients to seek treatment. In this study ralfinamide was administered to rats at doses producing plasma levels similar to those causing analgesia in pain patients. The analgesic effect was tested on autotomy, a behavior of self-mutilation of a denervated paw that models spontaneous neuropathic pain. Sprague-Dawley male rats (N=10-20/group) underwent transection of the sciatic and saphenous nerves unilaterally. Ralfinamide or its vehicle were administered per os for 7 days preoperatively (80 mg/kg; bid), followed by the vehicle or Ralfinamide, until postoperative d42. Autotomy was scored daily until d63. Lasting 'preemptive analgesia' was found in rats treated with ralfinamide preoperatively, expressed by delayed autotomy onset (P=0.009) and reduced scores on d63 (P=0.01). Rats treated with ralfinamide (30 or 60 mg/kg; bid) from the operation till d42, but not preoperatively, also showed delayed autotomy (P=0.05, P=0.006), and reduced autotomy scores lasting till d63 (P=0.02, P=0.01), for the two doses, respectively. Combining ralfinamide treatments for 7 days preoperatively and 42 days postoperatively also resulted in significantly suppressed scores on d42 and d63 (P=0.005, P=0.001, respectively). Suppression of neuropathic pain-related behavior was likely caused by a combination of mechanisms reported for ralfinamide, including inhibition of Na+ and Ca++ currents in Nav1.3, Nav1.7, Nav1.8, and Cav2.2 channels in rat DRG neurons, inhibition of substance P release from spinal cord synaptosomes, NMDA receptor antagonism and neuroprotection.

Inguinal herniotomy is one of the most frequent surgical procedures and chronic pain affecting everyday activities is reported in approximately 10% of patients. However, the neurophysiological changes and underlying pathophysiological mechanisms of postherniotomy pain are not known in detail, thereby precluding advances in treatment strategies and prophylaxis. Therefore, we examined forty-six patients reporting moderate to severe postherniotomy pain affecting daily activities for more than a year postoperatively, and compared them with a control group of patients without pain 1 yr postoperatively. A quantitative sensory testing protocol was used, assessing sensory dysfunction type, location and severity. We assessed the protocol test-retest variability using data from healthy control subjects. All patients (pain and pain-free) had signs of nerve damage, seen as sensory dysfunction. Detection thresholds for tactile and warmth stimulation were significantly increased while cold detection and pressure pain detection thresholds were significantly decreased in pain patients compared to controls. Repetitive punctuate and brush stimulation resulted in significantly more frequent and intense pain on the painful side than on the unaffected side in pain patients, and was not observed in controls. Our findings showed large and small fiber dysfunction in both pain and pain-free patients but more profound in pain patients and with signs of central sensitization (abnormal temporal summation). The specific finding of reduced pain detection threshold over the external inguinal annulus is consistent with damage to the cutaneous innervation territory of nervous structures in the inguinal region. The correspondence between pain location and sensory disturbance suggests that the pain is neuropathic in nature. Whether the underlying pathophysiological mechanisms are related to direct intraoperative nerve injury or nerve injury due to an inflammatory mesh response remains to be determined.

Various surgical procedures, e.g. thoracotomy and inguinal hernia repair, frequently evoke persistent pain lasting for many months following the initial surgery. The essential prolonged tissue retraction required during such surgeries may account for the persistence and high incidence of postoperative pain in these patient populations. This study describes a new rat model of persistent postoperative pain evoked by skin/muscle incision and retraction (SMIR), akin to a clinical procedure. Under anaesthesia, skin and superficial muscle of the medial thigh were incised and a small pair of retractors inserted. This tissue was retracted for 1h causing potential stretch of the saphenous nerve. SMIR surgery evoked persistent significant mechanical hypersensitivity to von Frey stimulation of the plantar ipsilateral hindpaw, compared to either pre-surgery responses or concurrent responses of sham-operated rats. SMIR-evoked mechanical hypersensitivity was observed by postoperative day 3, most prominent between postoperative days 10 and 13, persisted until at least postoperative day 22 and had dissipated by postoperative day 32. Overall, mechanical sensitivity of the SMIR contralateral paw and the sham ipsilateral paw did not significantly change from pre-surgery responses. SMIR did not evoke significant heat hyperalgesia or cold allodynia. Light microscopy of saphenous nerve sections did not show degeneration or oedema in the saphenous nerve at, or proximally or distally to, the surgical site. In addition, very little to no degeneration was detected with ATF3 staining in DRG from SMIR-operated rats. These data suggest that prolonged retraction of superficial tissue evokes a persistent pain syndrome that is not driven by neuronal damage.

Pregabalin has anticonvulsant, antihyperalgesic, and anxiolytic properties. In this study we evaluated the control of pain after perioperative administration of pregabalin 300 or 600 mg, compared with diazepam 10mg. Altogether 91 women scheduled for laparoscopic hysterectomy were randomized to receive diazepam 10mg (D10), pregabalin 150 mg (P300) or 300 mg (P600) for premedication, and the dose was repeated after 12h, except for the D10 group, in which the patients received placebo. Up until the 1st postoperative morning, analgesia was provided by oxycodone using patient controlled analgesia. The visual analogue scale scores for pain and side effects, and the amounts of the analgesics were recorded for three days after surgery. The doses of oxycodone during hours 0-12 after surgery were similar in the three groups, whereas the dose of oxycodone during hours 12-24 after surgery was smaller in the P600 group than in the P300 group (0.09 vs. 0.16 mg kg(-1); P=0.025). The total dose of oxycodone (0-24h after surgery) was smaller in the P600 group than in the D10 group (0.34 vs. 0.45 mg kg(-1); P=0.046). The incidence of dizziness (70% vs. 35%; P=0.012), blurred vision (63% vs. 14%; P=0.002) and headache (31% vs. 7%; P=0.041) were higher in the P600 group than in the D10 group. In conclusion, perioperative administration of pregabalin 600 mg decreases oxycodone consumption compared with diazepam 10mg, but is associated with an increased incidence of adverse effects.

The contribution of endothelin-1 (ET-1), acting via endothelin-A receptors (ET(A)), on post-incisional pain was examined in a rat model of incision through the hairy skin of the lumbar dorsum. Post-incisional mechanical hyperesthesia was evaluated by cutaneous trunci muscle reflexes (CTMR) of subcutaneous muscles responding to stimulation with von Frey filaments near the wound (primary responses) and at a distance, especially on the contralateral dorsum (secondary responses, involving spinal circuits). The role of ET(A) was determined by pre-incisional, subcutaneous injection of the selective receptor antagonist BQ-123 at the incision site, 15 min or 24h before surgery. Control incisions showed both primary tactile allodynia and hyperalgesia, and a weaker secondary hyperesthesia, peaking 3-4h after surgery and lasting at least 24h. Primary allodynia, but not hyperalgesia, was dose-dependently suppressed by 15 min pre-incisional BQ-123. In contrast, both secondary allodynia and hyperalgesia were inhibited by local BQ-123. The suppression of primary allodynia by local antagonist disappeared in 24h, but that of secondary hyperesthesia remained strong for at least 24h. Systemically delivered BQ-123 was without effect on any post-incisional hyperesthesia, and if the antagonist was locally injected 24h before surgery there was no difference on hyperesthesia compared to vehicle injected at that time. We conclude that ET-1, released from skin by incision, activates nociceptors to cause primary allodynia and to sensitize spinal circuits through central sensitization. Blockade of ET(A) in the immediate peri-operative period prevents the later development of central sensitization.

Spinally released dynorphin contributes to hypersensitivity from nerve injury, inflammation, and sustained morphine treatment, but its role in post-operative pain has not been tested. Intrathecal injection of dynorphin activates cyclooxygenase (COX)-1 and -2 to induce hypersensitivity. Spinal COX-1 expression and activity increase following incisional paw surgery in rats, although the stimulus for this increase is not known. In the current study we tested whether spinal dynorphin expression increases after incisional surgery and induces hypersensitivity in this setting, and whether dynorphin stimulates COX-1 activity in spinal cord microglia. Paw incision resulted in increased prodynorphin immunoreactivity in laminae I, IIo, and V in the L4-L6 spinal cord dorsal horn ipsilateral to surgery. Change in prodynorphin expression did not parallel that of mechanical hypersensitivity. Repeated intrathecal dynorphin A antiserum injection failed to alter mechanical hypersensitivity after incisional surgery, although it was effective against mechanical hypersensitivity following spinal nerve ligation. Paw incision increased COX-1 immunoreactivity in the L4-L6 ipsilateral spinal cord, and these cells were confirmed to be microglia by co-localization with OX-42. Spinal cord microglia in culture expressed COX-1 immunoreactivity and released PGE2, but dynorphin A failed to increase release of PGE2 in these cultures. These results suggest that increased COX-1 expression occurs in spinal cord microglia following incisional surgery. Although prodynorphin immunoreactivity also increases, it likely does not drive COX-1 expression or mechanical hypersensitivity in this setting.

Antisense (AS) oligodeoxynucleotides (ODNs) targeting the Nav 1.8 sodium channel have been reported to decrease inflammatory hyperalgesia and L5/L6 spinal nerve ligation-induced mechanical allodynia in rats. The present studies were conducted to further characterize Nav 1.8 AS antinociceptive profile in rats to better understand the role of Nav 1.8 in different pain states. Consistent with earlier reports, chronic intrathecal Nav 1.8 AS, but not mismatch (MM), ODN decreased TTX-resistant sodium current density (by 60.5+/-10.2% relative to MM; p<0.05) in neurons from L4 to L5 dorsal root ganglia and significantly attenuated mechanical allodynia following intraplantar complete Freund's adjuvant. In addition, 10 days following chronic constriction injury of the sciatic nerve, Nav 1.8 AS, but not MM, ODN also attenuated mechanical allodynia (54.3+/-8.2% effect, p<0.05 vs. MM) 2 days after initiation of ODN treatment. The anti-allodynic effects remained for the duration of the AS treatment, and CCI rats returned to an allodynic state 4 days after discontinuing AS. In contrast, Nav 1.8 AS ODN failed to reduce mechanical allodynia in the vincristine chemotherapy-induced neuropathic pain model or a skin-incision model of post-operative pain. Finally, Nav 1.8 AS, but not MM, ODN treatment produced a small but significant attenuation of acute noxious mechanical sensitivity in naïve animals (17.6+/-6.2% effect, p<0.05 vs. MM). These data demonstrate a greater involvement of Nav 1.8 in frank nerve injury and inflammatory pain as compared to acute, post-operative or chemotherapy-induced neuropathic pain states.

To determine the incidence of pain related sexual dysfunction 1 year after inguinal herniorrhaphy and to assess the impact pain has on sexual function. In contrast to the well-described about 10% risk of chronic wound related pain after inguinal herniorrhaphy, chronic genital pain, dysejaculation, and sexual dysfunction have only been described sporadically. The aim was therefore to describe these symptoms in a questionnaire study. A nationwide detailed questionnaire study in September 2004 of pain related sexual dysfunction in all men aged 18-40 years undergoing inguinal herniorrhaphy between October 2002 and June 2003 (n=1015) based upon the nationwide Danish Hernia Database collaboration. The response rate was 68.4%. Combined frequent and moderate or severe pain from the previous hernia site during activity was reported by 187 patients (18.4%). Pain during sexual activity was reported by 224 patients (22.1%), of which 68 (6.7%) had moderate or severe pain occurring every third time or more. Genital or ejaculatory pain was found in 125 patients (12.3%), and 28 (2.8%) patients reported that the pain impaired their sexual activity to a moderate or severe degree. Pain during sexual activity and subsequent sexual dysfunction represent a clinically significant problem in about 3% of younger male patients with a previous inguinal herniorrhaphy. Intraoperative nerve damage and disposition to other chronic pain conditions are among the most likely pathogenic factors.

Although systemic lidocaine has been shown to suppress postoperative pain in a clinical setting, the mechanisms of action of lidocaine have not been elucidated. The present study was therefore designed to determine the relative contribution of central and peripheral sites to the action of lidocaine on incision-induced hyperexcitation of spinal dorsal horn (SDH) neurons in the rat. Receptive field (RF) areas, spontaneous activities, and responses of single wide-dynamic-range (WDR) neurons of the SDH to nonnoxious and noxious stimuli were recorded before and after longitudinal incisions of 1cm through the skin, fascia, and muscle had been made in the center of their RFs of the hindquarters. Significant increases in spontaneous activities, RF sizes, and responses of WDR neurons to both nonnoxious and noxious stimuli were observed at 30 min after the incision (P<0.001). Systemic administration of lidocaine (1 mg/kg bolus plus 0.5 mg/kg/h and 2 mg/kg bolus plus 1 mg/kg/h) and QX-314 (1mg/kg bolus plus 0.5 mg/kg/h and 2 mg/kg bolus plus 1 mg/kg/h) significantly but temporarily suppressed and reversed the increases in spontaneous activity, responses to nonnoxious, and noxious stimuli and RF sizes (P<0.01). Systemic administration of the same doses of lidocaine and QX-314 did not affect responses of WDR neurons to nonnoxious or noxious stimuli or their RF sizes in sham-operated animals in which an incision had not been made. The results suggest that systemic administration of lidocaine has suppressive effects on postoperative pain mainly through peripheral sites of action.

The psychometric properties of pain intensity scales for the assessment of postoperative pain across the adult lifespan have not been reported. The objective of this study was to compare the feasibility and validity of the Numeric Rating Scale (NRS), Verbal Descriptor Scale (VDS), and Visual Analog Scale (horizontal (VAS-H) and vertical (VAS-V) line orientation) for the assessment of pain intensity in younger and older surgical patients. At 24h following surgery, 504 patients, who were receiving i.v. morphine via patient-controlled analgesia, completed the pain intensity measures and the McGill Pain Questionnaire (MPQ) in a randomized order. They were asked which scale was easiest to complete, the most accurate measure, and which they would most prefer to complete in the future, as an index of face validity. The amount of opioid self-administered was recorded. Age differences in postoperative pain intensity were not found. However, elderly patients obtained lower MPQ scores and self-administered less morphine than younger people. Psychometric analyses suggested that the NRS was the preferred pain intensity scale. It had low error rates, and higher face, convergent, divergent and criterion validity than the other scales. Most importantly, its properties were not age-related. The VDS also had a favourable profile with low error rates and good face, convergent and criterion validity. Finally, difficulties with VAS use among the elderly were identified, including high rates of unscorable data and low face validity. Its use with elderly postoperative patients should be discouraged.

Acutely, nerve growth factor (NGF) exerts profound effects on nociceptive transmission and produces pain and hyperalgesia. In the present study, we sought to determine the tissue levels and role of NGF after a plantar incision. A substantial increase in NGF protein expression occurred in skin 4-h, 1-day and 2-days and 5-days after incision comparing contralateral uninjured skin. Plantar incision did not change NGF levels in the tibial nerve and L4-L6 dorsal root ganglia. The therapeutic effect of a monoclonal antibody against endogenous NGF was evaluated by intraperitoneal administration of a single preoperative dose of anti-NGF. Of three different doses of anti-NGF used, the highest dose 2.8 mg/kg anti-NGF attenuated or almost abolished guarding pain scores at 4-h, 1-day (>80% decrease) and 2-days after incision. This effect is dose dependent in that lower doses (1, 0.1 mg/kg) were effective only at 1-day after incision. Anti-NGF also attenuated heat hyperalgesia at 1-day and 2-days after incision when the highest dose was used. However, treatment by anti-NGF did not affect C-fibers sensitized 1-day after incision in a glabrous skin-tibial nerve in vitro preparation. In conclusion, increased NGF was present in skin after plantar incision. NGF contributes to some incision-induced pain behaviors, guarding and heat hyperalgesia. Anti-NGF did not affect the extent of sensitization of C-fibers observed in vitro.

Postoperative pain significantly impacts patient recovery. However, postoperative pain management remains suboptimal, perhaps because treatment strategies are based mainly on studies using inflammatory pain models. We used a recently developed mouse model of incisional pain to investigate peripheral and spinal mechanisms contributing to heat hyperalgesia after incision. Behavioral experiments involving TRPV1 KO mice demonstrate that, as previously observed in inflammatory models, TRPV1 is necessary for heat (but not mechanical) hyperalgesia after incision. However, in WT mice, neither the proportion of TRPV1 immunoreactive neurons in the DRG nor the intensity of TRPV1 staining in the sciatic nerve was different from that in controls up to 4 days after incision. This result was corroborated by immunoblot analysis of sciatic nerve in rats subjected to an incision, and is distinct from that following inflammation of the rat hind paw, a situation in which TRPV1 expression levels in sciatic nerve increases. In the absence of heat exposure, spinal c-Fos staining was similar between incised TRPV1 KO and WT mice. However, differences in c-Fos staining between heat exposed TRPV1 KO and WT mice after incision suggest that the incision-mediated enhancement of heat-evoked signaling to the spinal cord involves a TRPV1-dependent mechanism. Finally, heat hyperalgesia after incision was reversed by antagonism of spinal non-NMDA receptors, unlike inflammatory hyperalgesia, which is mediated via NMDA receptors . Thus, TRPV1 is important for the generation of thermal hyperalgesia after incision. Our observations suggest that all experimental pain models may not be equally appropriate to guide the development of postoperative pain therapies.

Surgery commonly causes pain and neural plasticity that are unique compared to other persistent pain problems. To more precisely study central sensitization and plasticity, we examined the role of ionotropic EAA receptors in dorsal horn neuron sensitization early after incision. Sensitization, in the form of increased background activity, increased mechanosensitivity or pinch receptive field expansion, was induced by plantar incision 1 h later in 30 neurons. (+)-5-Methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine (MK-801) or 1 mM 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo[f]quinoxaline-7-sulfonamide (NBQX) was administered through a microdialysis fiber to block NMDA and nonNMDA EAA receptors, respectively. Dorsal horn neuron sensitization was reexamined 1 h later. Spinal administration of NBQX blocked AMPA-induced excitation but did not affect excitation by NMDA. NBQX decreased background activity in the neurons that developed sustained increased activity after incision. The median decrease caused by NBQX was from 2.3 to 0.0 imp/s. Spinal administration of 5 mM MK-801 blocked NMDA-induced excitation but did not affect excitation by AMPA. The median change (from 2.6 to 1.1 imp/s) in background activity increased by incision was not significantly affected by MK-801. The responses to mechanical stimuli were enhanced after incision in wide dynamic range (WDR) neurons. NBQX eliminated these responses but MK-801 had no effect. The pinch receptive field (RF) expansion into uninjured areas of the paw and hindquarters occurred after incision. Only 1 of 13 neurons exhibited RF expansion after spinal NBQX administration; 9 of 12 neurons had RF expansion remaining after MK-801. Thus, nonNMDA receptors are critical and NMDA-independent factors influence the increased responsiveness of dorsal horn neurons that occur early after incision.

Does pain or tissue damage in early life lead to hyperalgesia persisting into childhood? We performed a cross-sectional study in 164 infants to investigate whether major surgery within the first 3 months of life increases pain sensitivity to subsequent surgery and to elucidate whether subsequent surgery in the same dermatome or in a different dermatome leads to differences in pain sensitivity. All infants received standard intraoperative and postoperative pain management, with rescue analgesia guided by a treatment algorithm. Differences in pain sensitivity during surgery were assessed by the intraoperative fentanyl intake and by (nor)epinephrine plasma concentrations. Differences in postoperative pain sensitivity were assessed by the observational pain measures COMFORT and VAS, and by morphine intake and (nor)epinephrine plasma concentrations. Infants previously operated upon in the same dermatome needed more intraoperative fentanyl, had higher COMFORT and VAS scores, had greater (nor)epinephrine plasma concentrations, and needed also more morphine than did infants with no prior surgery. In contrast, infants who previously underwent surgery in another dermatome had only significant higher postoperative analgesic requirements and norepinephrine plasma concentrations in comparison with infants with no prior surgery. These preliminary differences may indicate the occurrence of spinal and supraspinal changes following neonatal surgery. We conclude that the long-term consequences of surgery in early infancy are greater in areas of prior tissue damage and that these effects may portend limited clinical but important neurobiological differences.

The long-term consequences of neonatal noxious stimulation on adulthood pain behavior were investigated in male and female mice. On the day of birth, mouse pups were exposed to a laparotomy under cold anesthesia followed by an analgesic dose of morphine (10 mg/kg) post-operatively, or a saline control. An additional group of subjects was exposed to the non-noxious aspects of the surgical procedure (cold exposure, separation from the dam, injection) comprising a 'sham' surgery control group, whereas another group of control subjects was administered an injection of saline or morphine, but was otherwise undisturbed. Behavioral observations of the pups immediately following the procedure indicated that the laparotomy produced increased distress vocalizations in the ultrasonic range (40 kHz) compared to both groups of control subjects. During 90 min observations periods following the surgery and 1-week later, maternal care did not vary among treatment conditions. In adulthood, offspring were tested for nociceptive sensitivity on the hot-plate (HP; 53 degrees C), tail-withdrawal (TW; 50 degrees C) and acetic acid abdominal constriction test (AC). On both the TW and the AC tests, neonatal surgery decreased pain behavior relative to both groups of control subjects, an effect that was reversed by post-operative morphine treatment. On the HP test, both groups of subjects exposed to the stressful aspects of neonatal surgery (laparotomy or sham surgery) exhibited decreased pain behavior in adulthood. These findings suggest that early exposure to noxious and/or stressful stimuli may induce long-lasting changes in pain behavior, perhaps mediated by alterations in the stress-axis and antinociceptive circuitry.

Pain after surgery results in significant morbidity, and systemic opioids often fail to provide adequate analgesia without marked sedation and respiratory depression. Intrathecal morphine provides better analgesia, but is limited by delayed respiratory depression. Intrathecal injection of the cyclooxygenase inhibitor, ketorolac, has recently entered clinical trials, and the current study examined the interaction between intrathecal morphine and ketorolac to treat postoperative pain. We also sought to compare these treatments on a commonly used assessment of withdrawal threshold and a new assessment of spontaneous behavior after surgery. Male Sprague Dawley rats and underwent hind paw incision or subcostal laparotomy surgery. Intrathecal morphine, ketorolac, or their combination were injected on the first postoperative day, with outcome measure being return to pre-surgery withdrawal threshold with von Frey filament testing of the paw after paw incision, or return to pre-surgery exploratory activity after laparotomy. Intrathecal morphine completely reversed the effects of surgery in both models, but intrathecal ketorolac only partially reversed them. Ketorolac enhanced the potency of morphine several fold in both models, and did so synergistically after paw incision. In all cases drug potency was greater for spontaneous than elicited responses. These data confirm that spinal opioid receptor and cyclooxygenase enzyme inhibition diminish elicited tactile hypersensitivity after surgery, and that they similarly return spontaneous behavior to normal. Differences in drug potency could reflect fundamental differences in outcome measures or in the surgical procedures themselves. These data support combination study of intrathecal morphine and ketorolac for postoperative pain.

Ketamine, an N-methyl-D-aspartate receptor antagonist, is known to be analgesic and to induce psychomimetic effects. Benefits and risks of ketamine for the control of postoperative pain are not well understood. We systematically searched for randomised comparisons of ketamine with inactive controls in surgical patients, reporting on pain outcomes, opioid sparing, and adverse effects. Data were combined using a fixed effect model. Fifty-three trials (2839 patients) from 25 countries reported on a large variety of different ketamine regimens and surgical settings. Sixteen studies tested prophylactic intravenous ketamine (median dose 0.4 mg/kg, range (0.1-1.6)) in 850 adults. Weighted mean difference (WMD) for postoperative pain intensity (0-10 cm visual analogue scale) was -0.89 cm at 6 h, -0.42 at 12 h, -0.35 at 24 h and -0.27 at 48 h. Cumulative morphine consumption at 24 h was significantly decreased with ketamine (WMD -15.7 mg). There was no difference in morphine-related adverse effects. The other 37 trials tested in adults or children, prophylactic or therapeutic ketamine orally, intramuscularly, subcutaneously, intra-articulary, caudally, epidurally, transdermally, peripherally or added to a PCA device; meta-analyses were deemed inappropriate. The highest risk of hallucinations was in awake or sedated patients receiving ketamine without benzodiazepine; compared with controls, the odds ratio (OR) was 2.32 (95%CI, 1.09-4.92), number-needed-to-harm (NNH) 21. In patients undergoing general anaesthesia, the incidence of hallucinations was low and independent of benzodiazepine premedication; OR 1.49 (95%CI 0.18-12.6), NNH 286. Despite many published randomised trials, the role of ketamine, as a component of perioperative analgesia, remains unclear.

The aim of the study was to evaluate post-operative pain and analgesic use after pre-operative or post-incisional i.v. fentanyl plus low dose i.v. ketamine vs. a standard treatment receiving i.v. fentanyl but not ketamine. Men undergoing radical prostatectomy under general anesthesia were randomly assigned in a double-blinded manner to one of three groups. Patients received i.v. fentanyl before incision followed by an i.v. bolus dose (0.2 ml kg(-1)) and an i.v. infusion (0.0025 ml kg(-1)min(-1)) of 1 mg ml(-1) ketamine (group 1) or normal saline (groups 2 and 3). Seventy minutes after incision, patients received i.v. fentanyl followed by an i.v. bolus dose (0.2 ml kg(-1)) and an i.v. infusion (0.0025 ml kg(-1)min(-1)) of saline (groups 1 and 3) or ketamine (group 2). Pain, von Frey pain thresholds, and cumulative morphine consumption using patient-controlled analgesia (PCA) were assessed up to 72 h after surgery. 143 patients completed the study (group 1, n = 47, group 2, n = 50, group 3, n = 46). Cumulative PCA morphine (mean+/-SD) did not differ significantly among groups (group 1, 92.3+/-45.9 mg; group 2, 107.2+/-58.4 mg; group 3, 103.6+/-50.4 mg; P = 0.08 for groups 1 vs. 2, and groups 1 vs. 3). On day 3, the hourly rate (mean+/-SEM) of morphine consumption was significantly lower (p < 0.0009) in group 1 (0.61+/-0.013 mg h(-1)) than group 2 (0.86+/-0.011 mg h(-1)) and group 3 (0.89+/-0.008 mg h(-1)). Pain scores and von Frey pain thresholds did not differ significantly among groups. Two-week and 6-month follow-ups did not reveal significant group differences in pain incidence, intensity, disability or mental health. Pre-operative, low-dose administration of i.v. ketamine did not result in a clinically meaningful reduction in pain or morphine consumption when compared with post-incisional administration of ketamine or a saline control condition.