Showing papers in "Pain in 2012"

Fear-avoidance model of chronic musculoskeletal pain: 12 years on

Abstract: It is widely acknowledged that pain is a universal experience that affects human beings across the life span, serving an important protective function. Typical protective behaviors are the withdrawal from the noxious stimulus, nonverbal expressions that signal others for impending harm, and verbal utterances. Some of these occur involuntarily, as a reflex, whereas other behaviors are more deliberate. However, there is accumulating evidence that it is not pain itself, but the meaning of pain that predicts the extent to which individuals engage in these protective behaviors [1,3]. About a decade ago, we summarized the research evidence supporting the role of fear of pain in the development of chronic pain disability, presented a model incorporating basic mechanisms, but also noted a number of unresolved issues that called for further scientific attention [39] (Fig. 1). In the last decade, the number of studies on this subject has increased exponentially [21], and novel directions are being proposed [6]. Two main stances have emerged. First, although pain has intrinsic threatening features, the threat value of similar pain stimulus may vary across contexts and individuals. Second, protective responding may be adaptive in the short term, but may paradoxically worsen the problem in the long term. In the current updated review, we briefly summarize the progress made since, and highlight a selected number of remaining challenges and areas for future research.

A systematic literature review of 10 years of research on sex/gender and experimental pain perception - part 1: are there really differences between women and men?

Abstract: The purpose of this systematic review was to summarize and critically appraise the results of 10 years of human laboratory research on pain and sex/gender. An electronic search strategy was designed by a medical librarian and conducted in multiple databases. A total of 172 articles published between 1998 and 2008 were retrieved, analyzed, and synthesized. The first set of results (122 articles), which is presented in this paper, examined sex difference in the perception of laboratory-induced thermal, pressure, ischemic, muscle, electrical, chemical, and visceral pain in healthy subjects. This review suggests that females (F) and males (M) have comparable thresholds for cold and ischemic pain, while pressure pain thresholds are lower in F than M. There is strong evidence that F tolerate less thermal (heat, cold) and pressure pain than M but it is not the case for tolerance to ischemic pain, which is comparable in both sexes. The majority of the studies that measured pain intensity and unpleasantness showed no sex difference in many pain modalities. In summary, 10 years of laboratory research have not been successful in producing a clear and consistent pattern of sex differences in human pain sensitivity, even with the use of deep, tonic, long-lasting stimuli, which are known to better mimic clinical pain. Whether laboratory studies in healthy subjects are the best paradigm to investigate sex differences in pain perception is open to question and should be discussed with a view to enhancing the clinical relevance of these experiments and developing new research avenues.

Conditioned pain modulation predicts duloxetine efficacy in painful diabetic neuropathy

Abstract: This study aims to individualize the selection of drugs for neuropathic pain by examining the potential coupling of a given drug's mechanism of action with the patient's pain modulation pattern. The latter is assessed by the conditioned pain modulation (CPM) and temporal summation (TS) protocols. We hypothesized that patients with a malfunctioning pain modulation pattern, such as less efficient CPM, would benefit more from drugs augmenting descending inhibitory pain control than would patients with a normal modulation pattern of efficient CPM. Thirty patients with painful diabetic neuropathy received 1 week of placebo, 1 week of 30 mg/d duloxetine, and 4 weeks of 60 mg/d duloxetine. Pain modulation was assessed psychophysically, both before and at the end of treatment. Patient assessment of drug efficacy, assessed weekly, was the study's primary outcome. Baseline CPM was found to be correlated with duloxetine efficacy (r=0.628, P<.001, efficient CPM is marked negative), such that less efficient CPM predicted efficacious use of duloxetine. Regression analysis (R(2)=0.673; P=.012) showed that drug efficacy was predicted only by CPM (P=.001) and not by pretreatment pain levels, neuropathy severity, depression level, or patient assessment of improvement by placebo. Furthermore, beyond its predictive value, the treatment-induced improvement in CPM was correlated with drug efficacy (r=-0.411, P=.033). However, this improvement occurred only in patients with less efficient CPM (16.8±16.0 to -1.1±15.5, P<.050). No predictive role was found for TS. In conclusion, the coupling of CPM and duloxetine efficacy highlights the importance of pain pathophysiology in the clinical decision-making process. This evaluative approach promotes personalized pain therapy.

A systematic literature review of 10 years of research on sex/gender and pain perception – Part 2: Do biopsychosocial factors alter pain sensitivity differently in women and men?

Abstract: This systematic review summarizes the results of 10 years of laboratory research on pain and sex/gender. An electronic search strategy was designed by a medical librarian to access multiple databases. A total of 172 articles published between 1998 and 2008 were retrieved, analyzed, and synthesized. The second set of results presented in this review (129 articles) examined various biopsychosocial factors that may contribute to differences in pain sensitivity between healthy women and men. The results revealed that the involvement of hormonal and physiological factors is either inconsistent or absent. Some studies suggest that temporal summation, allodynia, and secondary hyperalgesia may be more pronounced in women than in men. The evidence to support less efficient endogenous pain inhibitory systems in women is mixed and does not necessarily apply to all pain modalities. With regard to psychological factors, depression may not mediate sex differences in pain perception, while the role of anxiety is ambiguous. Cognitive and social factors appear to partly explain some sex-related differences. Finally, past individual history may be influential in female pain responses. However, these conclusions must be treated with much circumspection for various methodological reasons. Furthermore, some factors/mechanisms remain understudied in the field. There is also a need to assess and improve the ecological validity of findings from laboratory studies on healthy subjects, and perhaps a change of paradigm needs to be considered at this point in time to better understand the factors that influence the experience of women and men who suffer from acute or chronic pain.

An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee.

Abstract: The effect of PF-04457845, a potent and selective fatty acid amide hydrolase-1 (FAAH1) inhibitor, on pain due to osteoarthritis of the knee was investigated in a randomised placebo and active-controlled clinical trial. The trial involved 2 periods (separated by a 2-week washout) consisting of a 1-week wash-in phase followed by 2weeks double-blind treatment. Patients received single-blind placebo throughout the wash-in and washout periods. Patients were randomised to receive either 4mg q.d. PF-04457845 followed by placebo (or vice versa), or 500mg b.i.d. naproxen followed by placebo (or vice versa). The primary end point was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score. The trial had predefined decision rules based on likelihood that PF-04457845 was better or worse than the standard of care (considered to be a 1.8 reduction in WOMAC pain score compared to placebo). A total of 74 patients were randomised to 1 of 4 treatment sequences. The mean differences (80% confidence intervals) from placebo in WOMAC pain score were 0.04 (-0.63 to 0.71) for PF-04457845 and -1.13 (-1.79 to -0.47) for naproxen, indicating that whilst naproxen seemed efficacious, PF-04457845 was not differentiated from placebo. The study was stopped at the interim analysis for futility. PF-04457845 decreased FAAH activity by >96% and substantially increased 4 endogenous substrates (fatty acid amides). PF-04457845 was well tolerated in osteoarthritis patients, and there was no evidence of cannabinoid-type adverse events. The lack of analgesic effect of FAAH1 inhibition in humans is in contrast to data from animal models. This apparent disconnect between species needs further study.

Prevalence and Aetiology of Neuropathic Pain in Cancer Patients: A Systematic Review

Abstract: Pain in cancer patients remains common and is often associated with insufficient prescribing of targeted analgesia. An explanation for undertreatment could be the failure to identify neuropathic pain mechanisms, which require additional prescribing strategies. We wanted to identify the prevalence of neuropathic mechanisms in patients with cancer pain to highlight the need for detailed assessment and to support the development of an international classification system for cancer pain. We searched for studies that included adult and teenage patients (age above 12 years), with active cancer and who reported pain, and in which a clinical assessment of their pain had been made. We found 22 eligible studies that reported on 13,683 patients. Clinical assessment methods varied, and only 14 studies reported confirmatory testing for either sensory abnormality or diagnostic lesion to corroborate a diagnosis of neuropathic pain. We calculated that the prevalence of patients with neuropathic pain (95% confidence interval) varied from a conservative estimate of 19% (9.4% to 28.4%) to a liberal estimate of 39.1% (28.9% to 49.5%) when patients with mixed pain were included. The prevalence of pain with a neuropathic mechanism (95% confidence interval) ranged from a conservative estimate of 18.7% (15.3% to 22.1%) to a liberal estimate of 21.4% (15.2% to 27.6%) of all recorded cancer pains. The proportion of pain caused by cancer treatment was higher in neuropathic pain compared with all types of cancer pain. A standardised approach or taxonomy used for assessing neuropathic pain in patients with cancer is needed to improve treatment outcomes.

Persistent postsurgical pain in a general population: Prevalence and predictors in the Tromsø study

Abstract: 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.

Considerations for improving assay sensitivity in chronic pain clinical trials: IMMPACT recommendations.

Abstract: A number of pharmacologic treatments examined in recent randomized clinical trials (RCTs) have failed to show statistically significant superiority to placebo in conditions in which their efficacy had previously been demonstrated. Assuming the validity of previous evidence of efficacy and the comparability of the patients and outcome measures in these studies, such results may be a consequence of limitations in the ability of these RCTs to demonstrate the benefits of efficacious analgesic treatments vs placebo ("assay sensitivity"). Efforts to improve the assay sensitivity of analgesic trials could reduce the rate of falsely negative trials of efficacious medications and improve the efficiency of analgesic drug development. Therefore, an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus meeting was convened in which the assay sensitivity of chronic pain trials was reviewed and discussed. On the basis of this meeting and subsequent discussions, the authors recommend consideration of a number of patient, study design, study site, and outcome measurement factors that have the potential to affect the assay sensitivity of RCTs of chronic pain treatments. Increased attention to and research on methodological aspects of clinical trials and their relationships with assay sensitivity have the potential to provide the foundation for an evidence-based approach to the design of analgesic clinical trials and expedite the identification of analgesic treatments with improved efficacy and safety.

Nav1.8 expression is not restricted to nociceptors in mouse peripheral nervous system.

Abstract: A vast diversity of salient cues is sensed by numerous classes of primary sensory neurons, defined by specific neuropeptides, ion channels, or cytoskeletal proteins. Recent evidence has demonstrated a correlation between the expression of some of these molecular markers and transmission of signals related to distinct sensory modalities (eg, heat, cold, pressure). Voltage-gated sodium channel Na(v)1.8 has been reported to be preferentially expressed in small-diameter unmyelinated sensory afferents specialized for the detection of noxious stimuli (nociceptors), and Na(v)1.8-Cre mice have been widely used to investigate gene function in nociceptors. However, the identity of neurons in which Cre-mediated recombination occurs in these animals has not been resolved, and whether expression of Na(v)1.8 in these neurons is dynamic during development is not known, rendering interpretation of conditional knockout mouse phenotypes problematic. Here, we used genetics, immunohistochemistry, electrophysiology, and calcium imaging to precisely characterize the expression of Na(v)1.8 in the peripheral nervous system. We demonstrate that 75% of dorsal root ganglion (DRG) neurons express Na(v)1.8-Cre, including >90% of neurons expressing markers of nociceptors and, unexpectedly, a large population (∼40%) of neurons with myelinated A fibers. Furthermore, analysis of DRG neurons' central and peripheral projections revealed that Na(v)1.8-Cre is not restricted to nociceptors but is also expressed by at least 2 types of low-threshold mechanoreceptors essential for touch sensation, including those with C and Aβ fibers. Our results indicate that Na(v)1.8 underlies electrical activity of sensory neurons subserving multiple functional modalities, and call for cautious interpretation of the phenotypes of Na(v)1.8-Cre-driven conditional knockout mice.

Pain perception in athletes compared to normally active controls: a systematic review with meta-analysis.

Abstract: This study systematically reviewed differences in pain perception between athletes and normally active controls. We screened MEDLINE, Sport-Discus, EMBASE, Web of Science, PsycINFO, PSYNDEX, and the citations of original studies and systematic reviews. All studies on experimentally induced pain that compared pain perception between athletes and normally active controls were eligible. The main outcome measures were pain tolerance and pain threshold. Effects are described as standardized mean differences and were pooled using random-effects models. Fifteen studies including 899 subjects met the inclusion criteria. Twelve of these studies assessed pain tolerance, and 9 studies examined pain threshold. A meta-analysis of these studies revealed that athletes possessed higher pain tolerance compared to normally active controls (effect size calculated as Hedges' g=0.87, 95% confidence interval [CI(95)] 0.53-1.21; P<0.00001), whereas available data on pain threshold were less uniform (Hedges' g=0.69, CI(95) 0.16-1.21; P=0.01). After exclusion of studies with high risk of bias, differences between groups in pain threshold were not significant any longer. Our data suggest that regular physical activity is associated with specific alterations in pain perception. Psychological and biological factors that may be responsible for these alterations are discussed.

Unpacking the burden: Understanding the relationships between chronic pain and comorbidity in the general population

Abstract: SummaryAccumulated comorbid load is independently associated with chronic pain. Comorbid physical conditions increase risk additively, while anxiety/depression interacts with 2 specific conditions, increasing risk synergistically.AbstractWe investigated the association of chronic pain with physical

Changes in regional gray matter volume in women with chronic pelvic pain: a voxel-based morphometry study.

Abstract: Chronic pelvic pain (CPP) is a highly prevalent pain condition, estimated to affect 15%-20% of women in the United States. Endometriosis is often associated with CPP, however, other factors, such as preexisting or concomitant changes of the central pain system, might contribute to the development of chronic pain. We applied voxel-based morphometry to determine whether women with CPP with and without endometriosis display changes in brain morphology in regions known to be involved in pain processing. Four subgroups of women participated: 17 with endometriosis and CPP, 15 with endometriosis without CPP, 6 with CPP without endometriosis, and 23 healthy controls. All patients with endometriosis and/or CPP were surgically confirmed. Relative to controls, women with endometriosis-associated CPP displayed decreased gray matter volume in brain regions involved in pain perception, including the left thalamus, left cingulate gyrus, right putamen, and right insula. Women with CPP without endometriosis also showed decreases in gray matter volume in the left thalamus. Such decreases were not observed in patients with endometriosis who had no CPP. We conclude that CPP is associated with changes in regional gray matter volume within the central pain system. Although endometriosis may be an important risk factor for the development of CPP, acting as a cyclic source of peripheral nociceptive input, our data support the notion that changes in the central pain system also play an important role in the development of chronic pain, regardless of the presence of endometriosis.

Inflammation-induced decrease in voluntary wheel running in mice: a nonreflexive test for evaluating inflammatory pain and analgesia.

Abstract: Inflammatory pain impacts adversely on the quality of life of patients, often resulting in motor disabilities. Therefore, we studied the effect of peripheral inflammation induced by intraplantar administration of complete Freund's adjuvant (CFA) in mice on a particular form of voluntary locomotion, wheel running, as an index of mobility impairment produced by pain. The distance traveled over 1 hour of free access to activity wheels decreased significantly in response to hind paw inflammation, peaking 24 hours after CFA administration. Recovery of voluntary wheel running by day 3 correlated with the ability to support weight on the inflamed limb. Inflammation-induced mechanical hypersensitivity, measured with von Frey hairs, lasted considerably longer than the impaired voluntary wheel running and is not driving; therefore, the change in voluntary behavior. The CFA-induced decrease in voluntary wheel running was dose-dependently reversed by subcutaneous administration of antiinflammatory and analgesic drugs, including naproxen (10-80 mg/kg), ibuprofen (2.5-20mg/kg), diclofenac (1.25-10mg/kg), celecoxib (2.5-20mg/kg), prednisolone (0.62-5mg/kg), and morphine (0.06-0.5mg/kg), all at much lower doses than reported in most rodent models. Furthermore, the doses that induced recovery in voluntary wheel running did not reduce CFA-induced mechanical allodynia, indicating a greater sensitivity of the former as a surrogate measure of inflammatory pain. We conclude that monitoring changes in voluntary wheel running in mice during peripheral inflammation is a simple, observer-independent objective measure of functional changes produced by inflammation, likely more aligned to the global level of pain than reflexive measures, and much more sensitive to analgesic drug effects.

Cognitive Behavioral Therapy increases pain-evoked activation of the prefrontal cortex in patients with fibromyalgeia

Abstract: Interventions based on Cognitive Behavioral Therapy (CBT) are widely used to treat chronic pain, but the brain mechanisms responsible for these treatment effects are poorly understood. The aim of this study was to validate the relevance of the cortical control theory in response to an exposure-based form of CBT, Acceptance and Commitment Therapy, in patients with chronic pain. Forty-three female patients diagnosed with fibromyalgia syndrome were enrolled in a randomized, 12-week, waiting-list controlled clinical trial (CBT n=25; controls n=18). CBT was administered in groups of six patients during 12 weekly sessions. Functional magnetic resonance imaging (fMRI) during pressure-evoked pain was assessed before and after treatment or the 12-week period. Self-report questionnaires of depression and anxiety were administered pre- and posttreatment as well as 3 months following end of treatment. Patients treated with CBT reported larger improvement of fibromyalgia on the Patient Global Impression of Change measure, and improved depression and anxiety symptoms, compared to the waiting-list controls. However, there were no effects on clinical pain or pain sensitivity measures. An analysis of fMRI scans revealed that CBT led to increased activations in the ventrolateral prefrontal/lateral orbitofrontal cortex; regions associated with executive cognitive control. We suggest that CBT changes the brain's processing of pain through an altered cerebral loop between pain signals, emotions, and cognitions; leading to increased access to executive regions for reappraisal of pain. Our data thereby support our hypothesis about the activation of a cortical control mechanism in response to CBT treatment in chronic pain.

Impact of pain on the course of depressive and anxiety disorders

Abstract: The combination of pain and depression or anxiety is commonly seen in clinical practice. Little is known about the influence of pain on psychopathology over time, as previous studies have been mainly cross-sectional. The objectives of this study are to determine the impact of pain on the course of depressive and/or anxiety disorders, and investigate to what extent the association between pain and course of these mental disorders is mediated by psychiatric characteristics. Data from the Netherlands Study of Depression and Anxiety (NESDA), collected between 2004 and 2009, were used. A total of 1209 participants with a depressive and/or anxiety disorder at baseline were followed up for 2 years. Baseline pain was assessed by location, duration, use of pain medication, and severity (based on Chronic Pain Grade). Course of depressive and anxiety disorders was assessed by Composite International Diagnostic Interview (CIDI) and Life Chart Interview. A higher number of pain locations (OR=1.10; P=.008), joint pain (OR=1.64; P<.001), ≥ 90 days of pain (OR=1.40; P=.009), daily use of pain medication (OR=1.57; P=.047), and a higher Chronic Pain Grade score (OR=1.27; P<.001) were associated with worse course of depressive and anxiety disorders. These associations were largely mediated by baseline severity of the mental disorder. However, joint pain remained associated with a worse course independent of baseline psychiatric characteristics. This study shows that patients with pain are more prone to a chronic course of depressive and anxiety disorders. More attention to pain seems to be necessary when diagnosing and treating these disorders. Future research should focus on treatment modalities for this co-occurrence, with joint pain in particular.

Functional abdominal pain patient subtypes in childhood predict functional gastrointestinal disorders with chronic pain and psychiatric comorbidities in adolescence and adulthood

Abstract: Although pediatric functional abdominal pain (FAP) has been linked to abdominal pain later in life, childhood predictors of long-term outcomes have not been identified. This study evaluated whether distinct FAP profiles based on patterns of pain and adaptation in childhood could be identified and whether these profiles predicted differences in clinical outcomes and central sensitization (wind-up) on average 9years later. In 843 pediatric FAP patients, cluster analysis was used to identify subgroups at initial FAP evaluation based on profiles of pain severity, gastrointestinal (GI) and non-GI symptoms, pain threat appraisal, pain coping efficacy, catastrophizing, negative affect, and activity impairment. Three profiles were identified: high pain dysfunctional, high pain adaptive, and low pain adaptive. Logistic regression analyses controlling for age and sex showed that, compared with pediatric patients with the low pain adaptive profile, those with the high pain dysfunctional profile were significantly more likely at long-term follow-up to meet criteria for pain-related functional gastrointestinal disorder (FGID) (odds ratio: 3.45, confidence interval: 1.95 to 6.11), FGID with comorbid nonabdominal chronic pain (odds ratio: 2.6, confidence interval: 1.45 to 4.66), and FGID with comorbid anxiety or depressive psychiatric disorder (odds ratio: 2.84, confidence interval: 1.35 to 6.00). Pediatric patients with the high pain adaptive profile had baseline pain severity comparable to that of the high pain dysfunctional profile, but had outcomes as favorable as the low pain adaptive profile. In laboratory pain testing at follow-up, high pain dysfunctional patients showed significantly greater thermal wind-up than low pain adaptive patients, suggesting that a subgroup of FAP patients has outcomes consistent with widespread effects of heightened central sensitization.

Sensory signs in complex regional pain syndrome and peripheral nerve injury

Abstract: This study determined patterns of sensory signs in complex regional pain syndrome (CRPS) type I and II and peripheral nerve injury (PNI). Patients with upper-limb CRPS-I (n=298), CRPS-II (n=46), and PNI (n=72) were examined with quantitative sensory testing according to the protocol of the German Research Network on Neuropathic Pain. The majority of patients (66%-69%) exhibited a combination of sensory loss and gain. Patients with CRPS-I had more sensory gain (heat and pressure pain) and less sensory loss than patients with PNI (thermal and mechanical detection, hypoalgesia to heat or pinprick). CRPS-II patients shared features of CRPS-I and PNI. CRPS-I and CRPS-II had almost identical somatosensory profiles, with the exception of a stronger loss of mechanical detection in CRPS-II. In CRPS-I and -II, cold hyperalgesia/allodynia (28%-31%) and dynamic mechanical allodynia (24%-28%) were less frequent than heat or pressure hyperalgesia (36%-44%, 67%-73%), and mechanical hypoesthesia (31%-55%) was more frequent than thermal hypoesthesia (30%-44%). About 82% of PNI patients had at least one type of sensory gain. QST demonstrates more sensory loss in CRPS-I than hitherto considered, suggesting either minimal nerve injury or central inhibition. Sensory profiles suggest that CRPS-I and CRPS-II may represent one disease continuum. However, in contrast to recent suggestions, small fiber deficits were less frequent than large fiber deficits. Sensory gain is highly prevalent in PNI, indicating a better similarity of animal models to human patients than previously thought. These sensory profiles should help prioritize approaches for translation between animal and human research.

Demographic and medical parameters in the development of complex regional pain syndrome type 1 (CRPS1): prospective study on 596 patients with a fracture.

Abstract: Limited data are available on the incidence of complex regional pain syndrome type 1 (CRPS1) and on demographic and medical risk factors for the development of CRPS1. The objective of this study was to investigate the incidence of CRPS1 in patients with a fracture using 3 sets of diagnostic criteria and to evaluate the association between demographic/medical factors and the development of CRPS1 diagnosed with the Harden and Bruehl criteria. A prospective multicenter cohort study of 596 patients (ages 18 years and older) with a single fracture of the wrist, scaphoid, ankle, or metatarsal V, recruited patients from the emergency rooms of 3 Dutch hospitals. Of the 596 participants, 42 (7.0%) were diagnosed with CRPS1 according to the Harden and Bruehl criteria, 289 (48.5%) according to the International Association for the Study of Pain criteria, and 127 (21.3%) according to the criteria of Veldman. An analysis of the medical and demographic differences revealed that patients in whom CRPS1 later developed more often had intra-articular fractures, fracture dislocations, rheumatoid arthritis, or musculoskeletal comorbidities. An ankle fracture, dislocation, and an intra-articular fracture contributed significantly to the prediction of the development of CRPS1. No CRPS1 patients were symptom free at 12 months (T3). At baseline, patients with CRPS1 had significantly more pain than patients without CRPS1 (P < .001). The incidence of the diagnosis of CRPS1 after a single fracture depends to a large extent on the diagnostic criteria used. After a fracture, 7% of the patients developed CRPS1 and none of the patients were free of symptoms at 1-year follow-up.

Microneurographic identification of spontaneous activity in C-nociceptors in neuropathic pain states in humans and rats.

Abstract: C-nociceptors do not normally fire action potentials unless challenged by adequate noxious stimuli. However, in pathological states nociceptors may become hyperexcitable and may generate spontaneous ectopic discharges. The aim of this study was to compare rat neuropathic pain models and to assess their suitability to model the spontaneous C-nociceptor activity found in neuropathic pain patients. Studies were performed in normal rats (n=40), healthy human subjects (n=15), peripheral neuropathic pain patients (n=20), and in five rat neuropathic pain models: nerve crush (n=24), suture (n=14), chronic constriction injury (n=12), STZ-induced diabetic neuropathy (n=56), and ddC-induced neuropathy (n=15). Microneurographic recordings were combined with electrical stimulation to monitor activity in multiple C fibers. Stimulation at 0.25 Hz allowed spontaneous impulses to be identified by fluctuations in baseline latency. Abnormal latency fluctuations could be produced by several mechanisms, and spontaneous activity was most reliably identified by the presence of unexplained latency increases corresponding to two or more additional action potentials. Spontaneous activity was present in a proportion of mechano-insensitive C-nociceptors in the patients and all rat models. The three focal traumatic nerve injury models provided the highest proportion (59.5%), whereas the two polyneuropathy models had fewer (18.6%), and the patients had an intermediate proportion (33.3%). Spontaneously active mechano-sensitive C-nociceptors were not recorded. Microneurographic recordings of spontaneous activity in diseased C-nociceptors may be useful for both short- and long-term drug studies, both in animals and in humans.

The influence of children's pain memories on subsequent pain experience.

Abstract: Healthy children are often required to repeatedly undergo painful medical procedures (eg, immunizations). Although memory is often implicated in children's reactions to future pain, there is a dearth of research directly examining the relationship between the 2. The current study investigated the influence of children's memories for a novel pain stimulus on their subsequent pain experience. One hundred ten healthy children (60 boys) between the ages of 8 and 12 years completed a laboratory pain task and provided pain ratings. Two weeks later, children provided pain ratings based on their memories as well as their expectancies about future pain. One month following the initial laboratory visit, children again completed the pain task and provided pain ratings. Results showed that children's memory of pain intensity was a better predictor of subsequent pain reporting than their actual initial reporting of pain intensity, and mediated the relationship between initial and subsequent pain reporting. Children who had negatively estimated pain memories developed expectations of greater pain prior to a subsequent pain experience and showed greater increases in pain ratings over time than children who had accurate or positively estimated pain memories. These findings highlight the influence of pain memories on healthy children's expectations of future pain and subsequent pain experiences and extend predictive models of subsequent pain reporting.

Pain coping skills training and lifestyle behavioral weight management in patients with knee osteoarthritis: a randomized controlled study.

Abstract: Overweight and obese patients with osteoarthritis (OA) experience more OA pain and disability than patients who are not overweight. This study examined the long-term efficacy of a combined pain coping skills training (PCST) and lifestyle behavioral weight management (BWM) intervention in overweight and obese OA patients. Patients (n=232) were randomized to a 6-month program of: 1) PCST+BWM; 2) PCST-only; 3) BWM-only; or 4) standard care control. Assessments of pain, physical disability (Arthritis Impact Measurement Scales [AIMS] physical disability, stiffness, activity, and gait), psychological disability (AIMS psychological disability, pain catastrophizing, arthritis self-efficacy, weight self-efficacy), and body weight were collected at 4 time points (pretreatment, posttreatment, and 6 months and 12 months after the completion of treatment). Patients randomized to PCST+BWM demonstrated significantly better treatment outcomes (average of all 3 posttreatment values) in terms of pain, physical disability, stiffness, activity, weight self-efficacy, and weight when compared to the other 3 conditions (Ps<0.05). PCST+BWM also did significantly better than at least one of the other conditions (ie, PCST-only, BWM-only, or standard care) in terms of psychological disability, pain catastrophizing, and arthritis self-efficacy. Interventions teaching overweight and obese OA patients pain coping skills and weight management simultaneously may provide the more comprehensive long-term benefits.

Randomized control trial of topical clonidine for treatment of painful diabetic neuropathy.

Abstract: A length-dependent neuropathy with pain in the feet is a common complication of diabetes (painful diabetic neuropathy). It was hypothesized that pain may arise from sensitized-hyperactive cutaneous nociceptors, and that this abnormal signaling may be reduced by topical administration of the α(2)-adrenergic agonist, clonidine, to the painful area. This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. Nociceptor function was measured by determining the painfulness of 0.1% topical capsaicin applied to the pretibial area of each subject for 30minutes during screening. Subjects were then randomized to receive 0.1% topical clonidine gel (n=89) or placebo gel (n=90) applied 3 times a day to their feet for 12weeks. The difference in foot pain at week 12 in relation to baseline, rated on a 0-10 numerical pain rating scale (NPRS), was compared between groups. Baseline NPRS was imputed for missing data for subjects who terminated the study early. The subjects treated with clonidine showed a trend toward decreased foot pain compared to the placebo-treated group (the primary endpoint; P=0.07). In subjects who felt any level of pain to capsaicin, clonidine was superior to placebo (P<0.05). In subjects with a capsaicin pain rating ⩾2 (0-10, NPRS), the mean decrease in foot pain was 2.6 for active compared to 1.4 for placebo (P=0.01). Topical clonidine gel significantly reduces the level of foot pain in painful diabetic neuropathy subjects with functional (and possibly sensitized) nociceptors in the affected skin as revealed by testing with topical capsaicin. Screening for cutaneous nociceptor function may help distinguish candidates for topical therapy for neuropathic pain.

Too sick for school? Parent influences on school functioning among children with chronic pain

Abstract: Parental responses to children with chronic pain have been shown to influence the extent of the child’s functional disability, but these associations have not been well studied in relation to children’s pain-related school functioning. The current study tests the hypothesis that parental pain catastrophizing and parental protective responses to child pain influence the extent of school impairment in children with chronic pain. A mediational model was tested to determine whether parental protective behaviors serve a mediating role between parental pain catastrophizing and child school impairment. Study participants were a clinical sample of 350 children ages 8–17 years with chronic pain and their parents. Measures of pain characteristics, demographic characteristics, child depressive symptoms, school attendance rates, overall school functioning, parental pain catastrophizing, and parental protective responses to pain were collected. Results show that, controlling for the known influences of pain intensity and child depressive symptoms, parental pain catastrophizing and parental protective responses to child pain each independently predict child school attendance rates and reports of overall school impairment. Parental protectiveness was found to mediate the association between parental cognitions (i.e., parent pain catastrophizing) and child school functioning outcomes. These findings underscore the importance of intervening with parents to foster parental responses to child pain that help children engage and succeed in the school environment despite pain.

Effects of mitochondrial poisons on the neuropathic pain produced by the chemotherapeutic agents, paclitaxel and oxaliplatin

Abstract: The dose-limiting side effect of taxane, platinum-complex, and other kinds of anticancer drugs is a chronic, distal, bilaterally symmetrical, sensory peripheral neuropathy that is often accompanied by neuropathic pain. Work with animal models of these conditions suggests that the neuropathy is a consequence of toxic effects on mitochondria in primary afferent sensory neurons. If this is true, then additional mitochondrial insult ought to make the neuropathic pain worse. This prediction was tested in rats with painful peripheral neuropathy due to the taxane agent, paclitaxel, and the platinum-complex agent, oxaliplatin. Rats with established neuropathy were given 1 of 3 mitochondrial poisons: rotenone (an inhibitor of respiratory Complex I), oligomycin (an inhibitor of adenosine triphosphate synthase), and auranofin (an inhibitor of the thioredoxin-thioredoxin reductase mitochondrial antioxidant defense system). All 3 toxins significantly increased the severity of paclitaxel-evoked and oxaliplatin-evoked mechano-allodynia and mechano-hyperalgesia while having no effect on the mechano-sensitivity of chemotherapy-naive rats. Chemotherapy-evoked painful peripheral neuropathy is associated with an abnormal spontaneous discharge in primary afferent A fibers and C fibers. Oligomycin, at the same dose that exacerbated allodynia and hyperalgesia, significantly increased the discharge frequency of spontaneously discharging A fibers and C fibers in both paclitaxel-treated and oxaliplatin-treated rats, but did not evoke any discharge in naive control rats. These results implicate mitochondrial dysfunction in the production of chemotherapy-evoked neuropathic pain and suggest that drugs that have positive effects on mitochondrial function may be of use in its treatment and prevention.

Estimate at your peril: Imputation methods for patient withdrawal can bias efficacy outcomes in chronic pain trials using responder analyses

Abstract: a Pain Research and Nuffield Division of Anaesthetics, Department of Clinical Neurosciences, University of Oxford, The Churchill Hospital, Oxford, UK b Department of Occupational, Social and Environmental Medicine, University Medical Center Göttingen, Göttingen, Germany c Centre for Pain Research, The University of Bath, Bath, UK d The UK Cochrane Centre, NHS R&D Programme, Summertown Pavilion, Middle Way, Oxford, UK e Pain Clinic/Regional Centre of Excellence in Palliative Care, Haukeland University Hospital, Bergen, Norway f Pain Clinic, Department of Anaesthesiology and Intensive Care Medicine, Helsinki University Central Hospital, Meilahti Hospital, Helsinki, Finland g College of Human and Health Sciences, Swansea University, Swansea, Wales, UK

A randomized controlled evaluation of an online chronic pain self management program.

Abstract: Internet-based educational and therapeutic programs (e-health applications) are becoming increasingly popular for a variety of psychological and physical disorders. We tested the efficacy of an online Chronic Pain Management Program, a comprehensive, fully self-directed and self-paced system that integrates social networking features and self-management tools into an interactive learning environment. Of 305 adult participants (196 women, 109 men), a total of 162 individuals with chronic pain were randomly assigned unsupervised access to the program for approximately 6 weeks; 143 were assigned to the wait-listed control group with treatment as usual. A comprehensive assessment was administered before the study and approximately 7 and 14 weeks thereafter. All recruitment, data collection, and participant involvement took place online. Participation was fully self-paced, permitting the evaluation of program effectiveness under real-world conditions. Intent-to-treat analysis that used linear growth models was used as the primary analytic tool. Results indicated that program utilization was associated with significant decreases in pain severity, pain-related interference and emotional burden, perceived disability, catastrophizing, and pain-induced fear. Further, program use led to significant declines in depression, anxiety, and stress. Finally, as compared to the wait-listed control group, the experimental group displayed a significant increase in knowledge about the principles of chronic pain and its management. Study limitations are considered, including the recognition that not all persons with chronic pain are necessarily good candidates for self-initiated, self-paced, interactive learning.

The prevalence and management of low back pain across adulthood: Results from a population based cross-sectional study (the MUSICIAN study).

Abstract: The aim of the current study was to determine: the prevalence of low back pain (LBP) and associated disability; the frequency of consultation to general practice; whether there were differences in management by age We conducted a cross-sectional population study in Aberdeen city and Cheshire County, UK Participants were 15,272 persons aged 25 years and older The 1-month period prevalence of LBP was 285% It peaked at age 41-50 years, but at ages over 80 years was reported by 1 in 4 persons Older persons were more likely to consult, and the prevalence of severe LBP continued to increase with age Management by general practitioners differed by age of the patient Older persons (> 70 vs ≤ 40 years) were more likely to only have been prescribed painkillers (odds ratio [OR] 174, 95% confidence interval [CI] 128-235) or only pain killers with other medications (OR 145, 95% CI 107-198) They were less likely to be prescribed physiotherapy or exercise (OR 063, 95% CI 046-085) or to be referred to a specialist (OR 077, 95% CI 057-104) Older persons were more likely to have previously received exercise therapy for pain, were less likely to be enthusiastic about receiving it now (P<00001), and were less likely to think it would result in improved symptoms (P<00001) It is important that older persons, who have the highest prevalence of LBP with disability and are most likely to consult, are receiving optimal pharmacological and nonpharmacological management

High spontaneous activity of C-nociceptors in painful polyneuropathy.

Abstract: Polyneuropathy can be linked to chronic pain but also to reduced pain sensitivity. We investigated peripheral C-nociceptors in painful and painless polyneuropathy patients to identify pain-specific changes. Eleven polyneuropathy patients with persistent spontaneous pain and 8 polyneuropathy patients without spontaneous pain were investigated by routine clinical methods. For a specific examination of nociceptor function, action potentials from single C-fibres including 214 C-nociceptors were recorded by microneurography. Patients with and without pain were distinguished by the occurrence of spontaneous activity and mechanical sensitization in C-nociceptors. The mean percentage of C-nociceptors being spontaneously active or mechanically sensitized was significantly higher in patients with pain (mean 40.5% and 14.6%, respectively, P=.02). The difference was mainly due to more spontaneously active mechanoinsensitive C-nociceptors (operationally defined by their mechanical insensitivity and their axonal characteristics) in the pain patients (19 of 56 vs 6 of 43; P=.02). The percentage of sensitized mechanoinsensitive C-nociceptors correlated to the percentage of spontaneously active mechanoinsensitive C-nociceptors (Kendall's tau=.55, P=.004). Moreover, spontaneous activity of mechanoinsensitive C-nociceptors correlated to less pronounced activity-dependent slowing of conduction (Kendall's tau=-.48, P=.009), suggesting that axons were included in the sensitization process. Hyperexcitability in mechanoinsensitive C-nociceptors was significantly higher in patients with polyneuropathy and pain compared to patients with polyneuropathy without pain, while the difference was much less prominent in mechanosensitive (polymodal) C-nociceptors. This hyperexcitability may be a major underlying mechanism for the pain experienced by patients with painful peripheral neuropathy.

Predictors of postoperative movement and resting pain following total knee replacement

Abstract: This study determined preoperative predictors of movement and resting pain following total knee replacement (TKR). We hypothesized that younger patients with higher preoperative pain intensity, pain sensitivity, trait anxiety, pain catastrophizing, and depression would be more likely to experience higher postoperative movement pain than older patients with lower scores on these variables prior to surgery, and that predictors would be similar for resting pain. Demographics, analgesic intake, anxiety, depression, pain catastrophizing, resting pain, movement pain (ie, during active knee range of motion), and quantitative sensory tests were performed preoperatively on 215 participants scheduled for a unilateral TKR. On postoperative day 2, analgesic intake, resting pain, and movement pain were again assessed. Significant predictors of moderate or severe movement pain were higher preoperative movement pain, von Frey pain intensity, and heat pain threshold. People with severe movement pain preoperatively were 20 times more likely to have severe movement pain postoperatively. When the influence of preoperative movement pain was removed, depression became a predictor. Significant predictors of moderate to severe resting pain were higher preoperative resting pain, depression, and younger age. These results suggest that patients with higher preoperative pain and depression are more likely to have higher pain following TKR, and younger patients may have higher resting pain. Cutaneous pain sensitivity predicted movement pain but not resting pain, suggesting that mechanisms underlying movement pain are different from resting pain. Aggressive management of preoperative pain, pain sensitivity, and depression prior to surgery may facilitate postoperative recovery.

Pain, affective symptoms, and cognitive deficits in patients with cerebral dopamine dysfunction.

Abstract: Converging preclinical, and human epidemiological, neuroimaging, and genetic evidence suggests a central role for dopamine neurotransmission in modulating pain perception and analgesia. Dysregulation in dopamine signaling may modulate the experience of pain both directly, by enhancing or diminishing the propagation of nociceptive signals, and indirectly, by influencing affective and cognitive processes, which affect the expectation, experience, and interpretation of nociceptive signals. Hypersensitivity to pain and high rates of comorbid chronic pain are common in disorders linked with deficits in dopamine system function, including disorders of mood and affect, substance abuse, and Parkinson disease. Hyposensitivity to pain, however, is common in patients with schizophrenia, which has been linked with excessive dopamine neurotransmission. Although patients are typically affected most by the primary symptoms of their disorders, alterations in pain perception may further increase the burden of their illness, compromising their quality of life. The present review focuses on this relationship, and discusses clinical and potential therapeutic implications for both patients with dopamine-related disorders and those with chronic pain syndromes.