The Journal of Pain - Articles in Press

Attentional Biases Toward Sensory Pain Words in Acute and Chronic Pain Patients - Corrected Proof

Sonia P. Haggman, Louise A. Sharpe, Michael K. Nicholas, Kathryn M. Refshauge — 2010-08-27

Abstract: Attentional biases towards pain-related words of chronic and acute low back pain (LBP) patients were compared with healthy pain-free controls. Specifically, the aims were to determine: 1) whether chronic LBP patients demonstrate attentional biases compared to pain-free controls; 2) whether observed biases are also present in those with acute LBP; and 3) whether observed biases are associated with pain-related fear among the pain groups. Four groups were recruited: 1) acute LBP patients; 2) chronic LBP patients from physiotherapy practices; 3) chronic LBP patients from a tertiary referral pain-management center; and 4) healthy pain-free controls. Participants were assessed on the dot-probe computer task for attentional bias to pain-related words. All 3 pain groups demonstrated biases compared to controls on sensory but not on affective, disability, or threat words. Among the pain groups, those with low and moderate levels of fear of (re)injury demonstrated biases towards sensory pain words that were absent in those with high levels of fear, which is counterintuitive to what the fear of (re)injury model suggests. These results suggest that the experience of pain, rather than duration, is the primary indicator of the presence of pain-related biases.Perspective: Attentional biases are present in chronic and acute pain. Biases towards sensory-pain stimuli were demonstrated regardless of pain duration; however, they were present in those with low and moderate levels of fear of (re)injury only and not those high in fear. These findings are not consistent with the fear of (re)injury model.

Topical Application of Compound Ibuprofen Suppresses Pain by Inhibiting Sensory Neuron Hyperexcitability and Neuroinflammation in a Rat Model of Intervertebral Foramen Inflammation - Corrected Proof

2010-08-27

Abstract: There is lack of evidence that topical application of an anti-inflammatory reagent could reduce pain due to intervertebral foramen (IVF) inflammation (IVFI). We investigated analgesic effects and underlying mechanisms of topical application of a compound ibuprofen cream (CIC) onto the surface of back skin covering the inflamed L5 IVF in a rat model. Repetitive CIC treatment (∼.54 g each treatment daily for 5 consecutive days) significantly reduces severity and duration of IVFI-induced thermal hyperalgesia and mechanical allodynia by 80 to 100% and 50 to 66%, respectively. Electrophysiological studies and Western blot analysis demonstrated that CIC treatment significantly inhibited hyperexcitability of the inflamed dorsal root ganglion (DRG) neurons and upregulation of Nav1.7 and Nav1.8 protein, respectively. Pathological manifestations of the inflamed DRG were also markedly improved following CIC treatment. Further, in the inflamed DRGs, phosphorylation and expression of transcription factor NF-κB and pro-inflammatory enzyme cyclooxygenase-2 (COX-2) were significantly increased, while a cytokine IL-1β level was increased. IVFI-induced upregulation of these molecules was significantly inhibited by CIC treatment. This study provides evidence that an anti-inflammatory reagent can be used topically to suppress pain due to IVFI and/or DRG inflammation through inhibition of sensory neuron hyperexcitability and the immune and inflammatory responses.Perspective: This study suggests a convenient and safe clinical intervention for treating pain due to intervertebral foramen inflammation and similar syndromes.

Median Nerve Small- and Large-Fiber Damage in Carpal Tunnel Syndrome: A Quantitative Sensory Testing Study - Corrected Proof

2010-08-27

Abstract: We explored the contribution of median nerve small (Aδ, C)-and large (Aβ)-fiber damage to the severity and topographic distribution of sensory symptoms in carpal tunnel syndrome (CTS) and the timing of fiber damage across CTS stages. We recruited 106 CTS patients. After selection, 49 patients were included. They underwent electrodiagnostic and quantitative sensory testing (QST) study and were asked on the severity of Boston Carpal Tunnel Questionnaire (BCTQ) Symptoms Severity Scale, daytime pain (DP), night pain and paresthesia, on the distribution of hand symptoms, and the presence of proximal symptoms. BCTQ Symptoms Severity Scale and DP severity was significantly correlated with Aδ-fiber damage. Small-fiber QST measures were impaired in electrodiagnostic-negative CTS patients and did not change across CTS neurographic stages. QST findings were not correlated to the topographical distribution of symptoms. Aδ-fiber damage contributes to CTS symptoms and in particular to DP. Night pain and paresthesia might be ascribed to ectopic fiber discharges secondary to median nerve enhanced mechanosensitivity. Small-fiber damage takes place earlier than large fiber. Median nerve fiber involvement does not directly contribute to extraterritorial symptoms spread. Our data may help understanding CTS pathophysiology and explain the well-known discrepancy between CTS symptoms and electrodiagnostic findings.Perspective: We explored the involvement of median nerve small and large fibers in carpal tunnel syndrome (CTS). We found a significant correlation between Aδ-fiber function and CTS symptoms. Small-fiber involvement took place in milder disease stages. These findings could help reconcile the discrepancy between CTS symptoms and electrodiagnostic data.

The Influence of Non-Nociceptive Factors on Hot-Plate Latency in Rats - Corrected Proof

Amanda Gunn, Erin N. Bobeck, Ceri Weber, Michael M. Morgan — 2010-08-27

Abstract: The hot plate is a widely used test to assess nociception. The effect of non-nociceptive factors (weight, sex, activity, habituation, and repeated testing) on hot-plate latency was examined. Comparison of body weight and hot-plate latency revealed a small but significant inverse correlation (light rats had longer latencies). Habituating rats to the test room for 1 hour prior to testing did not decrease hot-plate latency except for female rats tested on days 2 to 4. Hot-plate latency decreased with repeated daily testing, but this was not caused by a decrease in locomotor activity or learning to respond. Activity on the hot plate was consistent across all 4 trials, and prior exposure to a room-temperature plate caused a similar decrease in latency as rats tested repeatedly on the hot plate. Despite this decrease in baseline hot-plate latency, there was no difference in morphine antinociceptive potency. The present study shows that weight, habituation to the test room, and repeated testing can alter baseline hot-plate latency, but these effects are small and have relatively little impact on morphine antinociception.Perspective: This manuscript shows that non-nociceptive factors such as body weight, habituation, and repeated testing can alter hot-plate latency, but these factors do not alter morphine potency. In sum, the hot-plate test is an easy to use and reliable method to assess supraspinally organized nociceptive responses.

The Prevalence of Chronic Pain in United States Adults: Results of an Internet-based Survey - Corrected Proof

2010-08-27

Abstract: A cross-sectional, Internet-based survey was conducted in a nationally representative sample of United States (US) adults to estimate the point prevalence of chronic pain and to describe sociodemographic correlates and characteristics of chronic pain. The survey was distributed to 35,718 members (aged 18 years and older) of a Web-enabled panel that is representative of the US population, and 27,035 individuals responded. Crude and weighted prevalence estimates were calculated and stratified by age, sex, and type of chronic pain. The weighted point-prevalence of chronic pain (defined as chronic, recurrent, or long-lasting pain lasting for at least 6 months) was 30.7% (95% CI, 29.8–31.7). Prevalence was higher for females (34.3%) than males (26.7%) and increased with age. The weighted prevalence of primary chronic lower back pain was 8.1% and primary osteoarthritis pain was 3.9%. Half of respondents with chronic pain experienced daily pain, and average (past 3 months) pain intensity was severe (≥7 on a scale ranging from 0 to 10) for 32%. Multiple logistic regression analysis identified low household income and unemployment as significant socioeconomic correlates of chronic pain. Chronic pain is prevalent among US adults and is related to indicators of poorer socioeconomic status.Perspective: The results of this cross-sectional Internet-based survey suggest a considerable burden of chronic pain in US adults. Chronic pain, experienced by about a third of the population, was correlated with indicators of poorer socioeconomic status. Primary chronic pain was most commonly attributed to lower back pain, followed by osteoarthritis pain.

Does Chronic Pain Alter the Normal Interaction Between Cardiovascular and Pain Regulatory Systems? Pain Modulation in the Hypertensive-Monoarthritic Rat - Corrected Proof

2010-08-26

Abstract: Hypertension-associated hypoalgesia is widely recognized in acute pain conditions. In chronic pain states, however, the relationship between blood pressure and pain sensitivity is still ill-defined, with different authors reporting negative, positive, or even no relationship at all. This work addresses this issue, using complete Freund's adjuvant (CFA)-induced monoarthritis in different models of hypertension: Spontaneous (spontaneously hypertensive rats, SHR), induced by infusion of angiotensin II (ANG) or 1,3-dipropyl-8-sulfophenylxanthine (DPSPX, an adenosine receptors' antagonist), and renal artery ligation (RAL). Nociceptive responses associated with monoarthritis were evaluated by different behavioral tests (von Frey, ankle-bend and CatWalk) and by quantification of Fos expression at the dorsal horn upon noxious stimulation. In all hypertension models, higher von Frey thresholds and lower Fos expression were detected in hypertensive rats with chronic inflammatory pain, as compared to normotensive monoarthritic rats. In SHR and DPSPX, but not ANG or RAL models, hypertensive animals displayed lower inflammation than normotensives. Ankle-bend and CatWalk results indicated lower pain sensitivity in hypertensive rats only in SHR and DPSPX models. The present study shows the importance of using multiple models of hypertension, and evaluating pain responses by various methods, to better understand the complexity of the interactions between pain and cardiovascular regulatory systems.Perspective: This study used different models of hypertension to investigate whether chronic pain alters the normal integration of cardiovascular and pain regulatory systems. A complete understanding of the mechanisms underlying the complex interactions between these systems may disclose future therapeutic approaches to treat hypertension/chronic pain comorbidity states.

The Antinociceptive Effects of AR-A014418, a Selective Inhibitor of Glycogen Synthase Kinase-3 Beta, in Mice - Corrected Proof

2010-08-13

Abstract: We investigated the antinociceptive effects of AR-A014418, a selective inhibitor of glycogen synthase kinase-3β (GSK-3β) in mice. A 30-minute pretreatment with AR-A014418 (.1 and 1 mg/kg, intraperitoneal [ip]) inhibited nociception induced by an ip injection of acetic acid. AR-A014418 pretreatment (.1 and .3 mg/kg, ip) also decreased the late (inflammatory) phase of formalin-induced licking, without affecting responses of the first (neurogenic) phase. In a different set of experiments, AR-A014418 (.1–10 μg/site) coinjected intraplantarly (ipl) with formalin inhibited the late phase of formalin-induced nociception. Furthermore, AR-A014418 administration (1 and 10 ng/site, intrathecal [it]) inhibited both phases of formalin-induced licking. In addition, AR-A014418 coinjection (10 ng/site, it) inhibited nociception induced by glutamate, N-methyl-D-aspartate (NMDA), (±)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD), tumor necrosis factor-alpha (TNF-α), and interleukin-1beta (IL-1β) by 47 ± 12%, 48 ± 11%, 31 ± 8%, 46 ± 13%, and 44 ± 11%, respectively. In addition, a 30-minute pretreatment with NP031115 (3 and 10 mg/kg, ip), a different GSK-3 β inhibitor, also attenuated the late phase of formalin-induced nociception. Collectively, these results provide convincing evidence that AR-A014418, given by local, systemic, and central routes, produces antinociception in several mouse models of nociception. The AR-A014418-dependent antinociceptive effects were induced by modulation of the glutamatergic system through metabotropic and ionotropic (NMDA) receptors and the inhibition of the cytokine (TNF-α and IL-1β) signaling.Perspective: These results suggest that GSK-3β may be a novel pharmacological target for the treatment of pain.

Suprathreshold Heat Pain Response Is Associated With Clinical Pain Intensity for Patients With Shoulder Pain - Corrected Proof

Carolina Valencia, Roger B. Fillingim, Steven Z. George — 2010-08-09

Abstract: Quantitative sensory testing (QST) has become commonly used for the assessment of pain in subjects with clinical conditions. However, there is no consensus about which type of QST is the best predictor of clinical pain responses. The purposes of this study were to determine: a) the QST measure with the strongest association with clinical pain intensity; and b) if the QST measure continued to predict clinical pain intensity in a model including relevant psychological factors. Fifty-nine patients seeking treatment for shoulder pain underwent experimental pain assessment involving heat and pressure stimuli. The patients also completed validated questionnaires for pain intensity, pain catastrophizing, anxiety, and depression. The 5th pain rating in a series of suprathreshold heat pain stimuli accounted for a significant amount of variance in clinical pain intensity, with no other QST measure contributing to the model. The 5th pain rating remained a significant contributor to clinical pain intensity when psychological factors were included in the model. Furthermore, subjects with elevated 5th pain rating, pain catastrophizing, and depression scores had higher clinical pain intensity ratings in pre- and postoperative assessments. These data suggest that assessment of pain should include suprathreshold heat stimuli and psychological factors separately, and a combination of these factors may be predictive of pain intensity outcomes.Perspective: The current study provides evidence for a suprathreshold heat pain response as a clinically relevant QST measure for patients with shoulder pain, even after psychological factors were considered. The present findings suggest that the 5th pain rating from a series of suprathreshold stimuli, pain catastrophizing, and depression might play a role in predicting pain intensity outcomes.

Catechol O-Methyltransferase Haplotype Predicts Immediate Musculoskeletal Neck Pain and Psychological Symptoms After Motor Vehicle Collision - Corrected Proof

2010-08-06

Abstract: Genetic variations in the catechol-O-methyltransferase (COMT) gene have been associated with experimental pain and risk of chronic pain development, but no studies have examined genetic predictors of neck pain intensity and other patient characteristics after motor vehicle collision (MVC). We evaluated the association between COMT genotype and acute neck pain intensity and other patient characteristics in 89 Caucasian individuals presenting to the emergency department (ED) after MVC. In the ED in the hours after MVC, individuals with a COMT pain vulnerable genotype were more likely to report moderate-to-severe musculoskeletal neck pain (76 versus 41%, RR = 2.11 (1.33–3.37)), moderate or severe headache (61 versus 33%, RR = 3.15 (1.05–9.42)), and moderate or severe dizziness (26 versus 12%, RR = 1.97 (1.19–3.21)). Individuals with a pain vulnerable genotype also experienced more dissociative symptoms in the ED, and estimated a longer time to physical recovery (median 14 versus 7 days, P = .002) and emotional recovery (median 8.5 versus 7 days, P = .038). These findings suggest that genetic variations affecting stress response system function influence the somatic and psychological response to MVC, and provide the first evidence of genetic risk for clinical symptoms after MVC.Perspective: The association of COMT genotype with pain symptoms, psychological symptoms, and recovery beliefs exemplifies the pleiotropic effects of stress-related genes, which may provide the biological substrate for the biopsychosocial model of post-MVC pain. The identification of genes associated with post-MVC symptoms may also provide new insights into pathophysiology.

Progesterone Prevents Allodynia After Experimental Spinal Cord Injury - Corrected Proof

2010-08-05

Abstract: Chronic pain after spinal cord injury represents a therapeutic challenge. Progesterone, a neuroprotective steroid, has been shown to modulate nociceptive thresholds, whereas its effect on neuropathic pain needs to be further explored. In this study, we evaluated whether progesterone could ameliorate pain-associated behaviors in animals subjected to a spinal cord hemisection. The development of mechanical and cold allodynia was assessed in injured male rats treated with daily injections of progesterone or vehicle. The expression of N-methyl-D-aspartate receptor (NMDAR) subunits, protein kinase C gamma (PKCγ), preprodynorphin (ppD), and kappa opioid receptor (KOR), key players in chronic pain mechanisms, was determined in the dorsal spinal cord. Twenty-eight days after injury, all vehicle-treated animals presented allodynic behaviors and a marked increase in NMDAR subunits, PKCγ, and ppD mRNA levels, with no changes in KOR mRNA levels. Progesterone prevented the development of mechanical allodynia and reduced the painful responses to cold stimulation. In correlation with the attenuation of pain behaviors, the steroid prevented NMDAR subunits and PKCγ mRNAs upregulation, did not modify the elevated ppD mRNA levels, but increased KOR expression. In conclusion, progesterone modulates neuropathic pain after spinal cord injury, creating a favorable molecular environment that may decrease spinal nociceptive signaling.Perspective: The present study suggests that progesterone administration could represent an interesting strategy to modulate neuropathic pain circuits after spinal cord injury. Further studies are needed to investigate the potential progesterone receptors involved in these actions.

Varying Perceived Social Threat Modulates Pain Behavior in Male Mice - Corrected Proof

2010-08-05

Abstract: We previously demonstrated that male mice display significantly reduced pain behavior on the acetic acid abdominal constriction test when confined in close proximity to a stranger male mouse. We show here the testosterone-dependence (via castration and testosterone propionate replacement) of this phenomenon, likely a form of (social) stress-induced analgesia. However, when similar male dyads are separated by vertical metal bars, allowing only partial physical contact, we find that the mice exhibit hyperalgesia, not analgesia, in response to both acetic acid injection and noxious radiant heat, relative to testing in isolation. This finding is specific to same-sex male dyads, and no change in nociceptive sensitivity is observed when males are tested in the presence of a female conspecific. We propose that pain sensitivity varies with respect to the severity of the social threat: mild social threat produces hyperalgesia and more severe social threat produces analgesia.Perspective: This work highlights the importance of social threat in modulating pain behavior in a sex-specific manner. The findings add to a growing body of evidence that social factors affect pain behavior in mice, thus allowing the study of the mechanistic underpinnings of social modulation of pain in humans.

Laser-Evoked Potentials Habituation in Fibromyalgia - Corrected Proof

2010-08-05

Abstract: Abnormalities of central pain processing play an important role in the pathophysiology of fibromyalgia (FM). The aims of the present study were to: 1) evaluate habituation of laser-evoked potentials (LEP) to repeated painful stimulation of 1 tender and 2 nontender points; and 2) determine correlations between LEP abnormalities and major clinical features of FM. Fourteen consecutive FM outpatients and 13 normal controls were included. LEP were recorded from scalp designations Fz, Cz, Pz, T3, and T4. The dorsum of the right hand, the right supra-orbital zone, and the right knee (a tender point in all patients) were subjected to repeated CO2 laser stimuli. For each stimulation site, recordings were obtained for 3 consecutive series of 20 stimuli. The 3 main findings in FM patients were: 1) an increased amplitude of vertex LEP and subjective laser pain; 2) decreased habituation of vertex LEP and subjective laser pain; and 3) a correlation between reduced N2 wave habituation and the severity of self-reported depressive symptoms. As with other chronic pain syndromes, the pathophysiology of FM may involve a generalized increase in the perception of painful stimuli and reduced habituation of the sensory cortex.Perspective: Reduced habituation of cortical responses to laser stimuli in FM patients suggests alterations in the pattern of cortical excitability. This is facilitated by depressive symptoms and abnormalities in central neurotransmission. These findings provide further support for the use of medications with effects on the central nervous system in the management of FM.

A Multicenter, Randomized, Double-Blind, Controlled Dose Finding Study of NGX-4010, a High-Concentration Capsaicin Patch, for the Treatment of Postherpetic Neuralgia - Corrected Proof

2010-07-26

Abstract: Postherpetic neuralgia (PHN) is a painful complication of acute herpes zoster. This multicenter, double-blind, controlled study randomized 299 PHN patients to receive either NGX-4010, a high-concentration capsaicin (8%) patch, or a low-concentration capsaicin (0.04%) control patch for 30, 60, or 90 minutes. The mean percent reductions in NPRS score from baseline to weeks 2 through 8 were significantly greater in the total NGX-4010 group (26.5%, P = .0286) and the 90-minute NGX-4010 group (27.8%, P = .0438) compared to the pooled control group (17.3%). After review of the data suggested a difference between genders in reporting of pain scores and a higher proportion of males (61%) in the 60-minute NGX-4010 group, post hoc gender-stratified analyses were performed and showed that the 60-minute NGX-4010 group also had a significantly larger mean percent reduction in average pain scores (28.0%, P = .0331). Pain reduction in the 30-minute NGX-4010 group, although similar in magnitude to the other doses, was not significantly different from control in either of these analyses. Similar results were observed during weeks 2 through 12. Most treatment-emergent adverse events were application-site specific, transient and mostly mild to moderate in severity.Perspective: This article reports the safety and efficacy of NGX-4010 applied for 3 different durations (30, 60, or 90 minutes) in patients with PHN. The results identified the 60-minute duration as the dose to be evaluated in subsequent studies and identified a gender effect on reported changes in pain.

The Efficacy of Web-Based Cognitive Behavioral Interventions for Chronic Pain: A Systematic Review and Meta-Analysis - Corrected Proof

Debora Duarte Macea, Krzysztof Gajos, Yasser Armynd Daglia Calil, Felipe Fregni — 2010-07-23

Abstract: Our objective was to conduct a systematic review and meta-analysis to quantify the efficacy of web-based cognitive behavioral interventions for the treatment of patients with chronic pain. MEDLINE and other databases were searched as data sources. Reference lists were examined for other relevant articles. We included 11 studies that evaluated the effects of web-based interventions on chronic pain using specific scales of pain. The pooled effect size (standardized mean difference between intervention versus waiting-list group means) from a random effects model was .285 (95% confidence interval: .145–.424), favoring the web-based intervention compared with the waiting-list group, although the effect was small. In addition, these results were not driven by any particular study, as shown by sensitivity analysis. Results from funnel plot argue against publication bias. Finally, the average dropout rate was 26.6%. In our meta-analysis, we demonstrate a small effect of web-based interventions, when using pain scale as the main outcome. Despite the minor effects and high dropout rates, the decreased costs and minor risk of adverse effects compared with pharmacological treatments support additional studies in chronic pain patients using web-based interventions. Further studies will be important to confirm the effects and determine the best responders to this intervention.Perspective: Our findings suggest that web-based interventions for chronic pain result in small pain reductions in the intervention group compared with waiting-list control groups. These results advance the field of web-based cognitive behavioral interventions as a potential therapeutic tool for chronic pain and can potentially help clinicians and patients with chronic pain by decreasing treatment costs and side effects.

A Tropomyosine Receptor Kinase Inhibitor Blocks Spinal Neuroplasticity Essential for the Anti-Hypersensitivity Effects of Gabapentin and Clonidine in Rats With Peripheral Nerve Injury - Corrected Proof

Ken-ichiro Hayashida, James C. Eisenach — 2010-07-20

Abstract: Spinally released brain-derived nerve growth factor (BDNF) after nerve injury is essential to anatomic and functional changes in spinal noradrenergic and cholinergic systems, which are engaged or targeted by commonly used treatments for neuropathic pain. Since BDNF signals via tropomyosine receptor kinases (trks), we tested whether trk blockade by repeated spinal injection of the trk inhibitor K252a would reduce anatomical (spinal noradrenergic and cholinergic fiber density), functional (α2-adrenoceptor-mediated direct stimulation of spinal cholinergic terminals), and behavioral (anti-hypersensitivity from systemic gabapentin and spinal clonidine) plasticity, which depends on BDNF. Spinal K252a treatment did not alter hypersensitivity from spinal nerve ligation (SNL), but blocked the SNL-associated increase in dopamine-β-hydroxylase (DβH) fiber density in the spinal cord dorsal horn while reducing spinal choline acetyltransferase (ChAT)-immunoreactivity. K252a treatment also abolished the facilitatory effect of dexmedetomidine on KCl-evoked acetylcholine release in spinal cord synaptosomes and reduced the anti-hypersensitivity effects of oral gabapentin and spinal clonidine. These results suggest that spinal trk signaling is essential for the anatomic and functional plasticity in noradrenergic and cholinergic systems after nerve injury and consequently for the analgesia from drugs that rely on these systems.Perspective: Many drugs approved for neuropathic pain engage spinal noradrenergic and cholinergic systems for analgesia. This study demonstrates that spinal trk signaling after nerve injury is important to neuroplasticity of these systems, which is critical for the analgesic action of common treatments for neuropathic pain.

Complex Regional Pain Syndrome: What's in a Name? - Corrected Proof

Terence J. Coderre — 2010-07-16

Abstract: Within a 2-year period in the 1940s, 2 Boston physicians published dramatically opposing views on the underlying nature of a syndrome now known as complex regional pain syndrome (CRPS). Evans suggested, in several papers in 1946–1947, that sympathetic reflexes maintain pain and dystrophy in affected limbs. Foisie, in 1947, suggested arterial vasospasms were key in the etiology of this pain syndrome. Evans' hypothesis established the nomenclature for this syndrome for 60 years, and his term, “reflex sympathetic dystrophy,” guided clinical treatment and research activities over the same period. Foisie's proposed nomenclature was unrecognized, and had virtually no impact on the field. Recent evidence suggests that Evans' contribution to the field may have in fact led clinicians and researchers astray all those years. This focus article on CRPS compares recent observations with these 2 earlier theories and asks the question—what if we had adopted Foisie's nomenclature from the beginning?Perspective: This article discusses 2 opposing historical views on the etiology of what is now known as CRPS, and how they affected nomenclature, research, and clinical therapy in subsequent decades. This focus article may help researchers and clinicians realize the importance of syndrome names, and how they may inadvertently misdirect research and treatment.

Therapeutic Interactive Voice Response (TIVR) to Reduce Analgesic Medication Use for Chronic Pain Management - Corrected Proof

Magdalena R. Naylor, Shelly Naud, Francis J. Keefe, John E. Helzer — 2010-07-12

Abstract: This paper examines whether a telephone-based, automated maintenance enhancement program can help to reduce opioid and nonsteroidal anti-inflamatory drugs (NSAID) analgesic use in patients with chronic pain. Following 11 weeks of group cognitive-behavioral therapy (CBT), 51 subjects with chronic musculoskeletal pain were randomized to 1 of 2 study groups. Twenty-six subjects participated in 4 months of a Therapeutic Interactive Voice Response (TIVR) program in addition to standard follow-up care, while a control group of 25 subjects received standard follow-up care only. TIVR is an automated, telephone-based tool developed for the maintenance and enhancement of CBT skills. Opioid analgesic use decreased in the experimental group in both follow-ups: 4 and 8 months postCBT. In addition, at 8-month follow-up, 21% of the TIVR subjects had discontinued the use of opioid analgesics, 23% had discontinued NSAIDS, and 10% had discontinued antidepressant medications. In contrast, the control group showed increases in opioid and NSAIDS use. Analysis of covariance (ANCOVA) revealed significant between-group differences in opioid analgesic use at 8-month follow up (P = .004). We have previously demonstrated the efficacy of TIVR to decrease pain and improve coping; this analysis demonstrates that the use of TIVR may also result in concurrent reductions in opioid analgesic and NSAID medications use.Perspective: This article demonstrates that the Therapeutic Interactive Voice Response maintenance enhancement program can help to reduce opioid analgesic use in patients with chronic pain. This automated maintenance enhancement program could potentially assist patients not only to decrease pain and improve coping, but also to diminish the likelihood of opioid dependence.

Corticotropin-Releasing Factor in the Rat Amygdala Differentially Influences Sensory-Discriminative and Emotional-like Pain Response in Peripheral Neuropathy - Corrected Proof

Nora Bourbia, Osei B. Ansah, Antti Pertovaara — 2010-07-12

Abstract: The central nucleus of the amygdala (CeA) is involved in processing and regulation of pain. We determined whether amygdaloid corticotropin-releasing factor (CRF) contributes to pain modulation in the neuropathic rat. Emotional aspect of pain was assessed by an aversive place-conditioning test and sensory aspect of pain by determining monofilament-induced limb-withdrawal threshold. CRF6-33 (an inhibitor of CRF-binding protein) or CRF9-41, a nonselective CRF receptor antagonist, was microinjected to the left or right CeA or a control site in rats with spared nerve injury (SNI) or sham operation of the left hind limb. In SNI animals, CRF6-33 in the left or right CeA, but not in a control site, attenuated emotional painlike behavior and increased sensory pain. In sham controls, CRF6-33 in the right but not left CeA increased sensory aspect of pain, without influence on place-avoidance behavior. The effects induced by CRF6-33 were reversed by CRF9-41. The results indicate that endogenous CRF in the CeA, through action on CRF receptors, may differentially influence emotional and sensory aspects of pain in neuropathy. While the right CeA had a dominant role in modulation of pain-related responses in sham controls, left as well as right CeA contributed to pain modulation in neuropathic animals.Perspective: An increase in free endogenous corticotropin-releasing factor in the central nucleus of the amygdala was accompanied by increased cutaneous hypersensitivity and decreased emotional painlike behavior in neuropathic animals. This finding indicates that CRF in the amygdala may have differential effects on sensory and emotional aspects of neuropathic pain.

Do Intensity Ratings and Skin Conductance Responses Reliably Discriminate Between Different Stimulus Intensities in Experimentally Induced Pain? - Corrected Proof

2010-07-02

Abstract: The present study addresses the question whether pain-intensity ratings and skin conductance responses (SCRs) are able to detect different intensities of phasic painful stimuli and to determine the reliability of this discrimination. For this purpose, 42 healthy participants of both genders were assigned to either electrical, mechanical, or laser heat-pain stimulation (each n = 14). A whole range of single brief painful stimuli were delivered on the right volar forearm of the dominant hand in a randomized order. Pain-intensity ratings and SCRs were analyzed. Using generalizability theory, individual and gender differences were the main contributors to the variability of both intensity ratings and SCRs. Most importantly, we showed that pain-intensity ratings are a reliable measure for the discrimination of different pain stimulus intensities in the applied modalities. The reliability of SCR was adequate when mechanical and heat stimuli were tested but failed for the discrimination of electrical stimuli. Further studies are needed to reveal the reason for this lack of accuracy for SCRs when applying electrical pain stimuli.Perspective: Our study could help researchers to better understand the relationship between pain and activation of the sympathetic nervous system. Pain researchers are furthermore encouraged to consider individual and gender differences when measuring pain intensity and the concomitant SCRs in experimental settings.

Sequential Analyses of Daily Symptoms in Women With Fibromyalgia Syndrome - Corrected Proof

Akiko Okifuji, David H. Bradshaw, Gary W. Donaldson, Dennis C. Turk — 2010-07-02

Abstract: Fibromyalgia syndrome (FMS) is a chronic musculoskeletal pain disorder characterized by generalized pain, chronic fatigue, sleep disturbance, and a range of other symptoms having no definitive pathology. Consequently, patient evaluations rely on self-report. Ecological Momentary Assessment (EMA) allows frequent real-time collection of self-report measures, removing recall bias and increasing external validity. We studied 81 females with FMS aged 18 to 42 years. Participants carried EMA devices (Palm Pilot M100) programmed to request ratings to 8 FMS symptoms/conditions 3 times daily for 30 days. Completeness of response rates varied across participants and over time. Controlling for immediately previous fatigue (ie, fatigue rating from the immediately preceding rating), unit increases in immediately previous pain and immediately previous emotional distress predicted 9 and 7% increases, respectively, in current fatigue. Controlling for immediately previous emotional distress, a unit increase in immediately previous pain predicted 7% increase in current emotional distress. Controlled for immediately previous pain, a unit increase in immediately previous fatigue predicted a 7% increase in current pain, enhanced by prior diurnal effects; immediately previous emotional distress was not significant. Collectively these results suggest an asymmetry in which emotional stress and pain may increase fatigue, fatigue but not emotional distress may increase pain, and pain but not fatigue may increase emotional distress. Despite small effects and person-to-person variability, these findings suggest that longitudinal data collection by EMA may reveal sequential or causal explanatory patterns with important clinical implications.Perspective: Understanding how multiple symptoms covary in FMS is essential for optimal treatment planning. Our results show that small but significant temporal relations among pain, fatigue, and emotional distress. Our results also provide support for the use of EMA as a viable data collection method that allows longitudinal, real-time assessment of multiple FMS symptoms.

Assessing Pain in Older People With Persistent Pain: The NRS Is Valid But Only Provides Part of the Picture - Corrected Proof

Bradley M. Wood, Michael K. Nicholas, Fiona Blyth, Ali Asghari, Stephen Gibson — 2010-06-25

Abstract: This study examined the assessment of pain intensity and pain distress with the Numerical Rating Scale (NRS) in elderly patients (age >60 years) with persistent pain. A consecutive sample of 800 elderly patients were categorized by age into 3 groups: 61 to 70 years (n = 366), 71 to 80 years (n = 308), and 81 years and over (n = 126). Participants completed 3 Numerical Rating Scales assessing current pain intensity, and both the usual level of pain and average pain distress in the preceding week. The failure rate for scale completion was low for all scales for all age groups, but was significantly higher in the oldest group compared to the youngest group for the scales assessing current pain intensity and average pain distress in the preceding week. The NRS was shown to be a reliable and valid measure of pain intensity and pain distress in all these age groups. Distress related to pain appeared to be specific to the pain experience and was only weakly related to more generalized affective distress. These findings confirm that measures of pain intensity and pain distress, like the NRS, capture only part of the pain experience in older patients and should be supplemented by other measures in the assessment process.Perspective: This article confirms the utility of the Numerical Rating Scale (NRS) as a measure of pain intensity and pain distress in elderly patients with persistent pain. The use of a large sample increases confidence in the psychometric soundness of the NRS with this population.

Exploring Relations Among Traumatic, Posttraumatic, and Physical Pain Experiences in Methadone-Maintained Patients - Corrected Proof

2010-06-21

Abstract: Differences in lifetime trauma exposure and screened symptoms of posttraumatic stress disorder (PTSD) were examined in methadone maintenance treatment (MMT) patients with a variety of pain experiences. Parametric and nonparametric statistical tests were performed on data obtained from 150 patients currently enrolled in MMT. In comparison to MMT patients reporting no pain in the previous week, those with chronic severe pain (CSP) (ie, pain lasting at least 6 months with moderate to severe pain intensity or significant pain interference) exhibited comparable levels of trauma involving sexual assault but reported significantly higher levels of trauma involving physical assault, number of traumatic events, and screened symptoms of PTSD. A third group, non-CSP MMT patients reporting some pain in the past week, differed significantly from the CSP group on number of traumatic events but reported comparable levels of sexual assault and physical assault. In comparison to men, women reported higher levels of sexual assault and were more likely to score above the cutoff on the PTSD screener but reported comparable levels of physical assault and number of traumatic events. Pain-related differences in trauma and screened symptoms of PTSD exist in MMT patients and may have implications for program planning and outreach efforts.Perspective: This article demonstrates that trauma and screened symptoms of PTSD vary as a function of sex and pain status in methadone-maintained patients. Future studies may benefit from developing and assessing interventions that address chronic pain, PTSD, and opioid dependence in MMT.

The Differential Effect of Methadone Dose and of Chronic Pain on Pain Perception of Former Heroin Addicts Receiving Methadone Maintenance Treatment - Corrected Proof

Einat Peles, Shaul Schreiber, Tal Hetzroni, Miriam Adelson, Ruth Defrin — 2010-06-21

Abstract: The reports on pain perception among former heroin addicts receiving methadone maintenance treatment (MMT) vary with regard to pain and intolerance threshold, and perception of suprathreshold stimuli has not been previously evaluated. Our aim was to systematically assess perception of threshold and suprathreshold noxious and innocuous stimuli with special attention to the effect of MMT dose and the presence of chronic pain. Noxious and innocuous, thermal and mechanical thresholds and ratings of suprathreshold heat-pain stimuli were measured among 31 MMT subjects receiving high and low MMT dose, with and without chronic pain, and in 17 healthy controls. The characteristics of chronic pain were also evaluated. MMT dose and chronic pain differentially affected pain perception. Whereas MMT dose did not affect thresholds, chronic pain MMT subjects exhibited increased pain threshold and pain-free MMT subjects exhibited decreased pain threshold compared with controls. MMT in general was associated with decreased perception of suprathreshold pain; however, MMT subjects with chronic pain exhibited increased suprathreshold pain ratings. It appears that subjects receiving MMT are hyperalgesic but that chronic pain in these subjects interferes with threshold measurements, inducing an apparent hypoalgesia. On the other hand, chronic pain reduces the analgesic effect of methadone seen in pain-free MMT subjects, amplifying suprathreshold pain perception. Factors such as chronic pain and MMT dose should be taken into account in future studies on pain perception in this population.Perspective: We show that the presence of chronic pain and methadone dose significantly affects perception of pain in former heroin addicts receiving MMT. Studying the alteration in pain perception in these subjects may contribute to understanding the high rates of chronic pain among them and may promote better treatment.

Comparative Prospective Evaluation of the Responsiveness of Single-Item Pediatric Pain-Intensity Self-Report Scales and Their Uniqueness From Negative Affect in a Hospital Setting - Corrected Proof

Mark Connelly, Kathleen Neville — 2010-06-21

Abstract: Evaluating pain in verbal children in the hospital setting is done primarily through serial assessments of pain intensity using single-item measures. However, little remains known about intensity scales' relative responsiveness and uniqueness from negative affect in this clinical setting. In the present study, a total of 411 assessments using 3 common pediatric pain intensity measures (the Faces Pain Scale-Revised, a verbally presented numeric rating scale, and a visual analog scale) were obtained over a period of 3 days from 29 children ages 9 to 18 years following a relatively standardized surgical procedure. Hierarchical linear models were used to compare the 3 scales on responsiveness over postoperative recovery time, invariance across baseline variables (age, sex, and baseline mood), and distinctiveness from changes in negative affect. Results showed that all 3 pain-intensity measures were highly interrelated, varied similarly with age and baseline state anxiety, and were comparably related to contemporaneous changes in affect. However, patients tended to rate pain intensity higher on the Numerical Rating Scale, and only this scale failed to reflect a decreasing trend in pain scores with elapsed surgical recovery time. Potential implications for clinical practice are discussed.Perspective: This article presents data comparing the responsiveness over time and association with negative affect of 3 single-item pediatric pain-intensity scales commonly used in hospital settings. The results can help inform the selection of self-report measures when serially evaluating pain and treatment response in hospitalized children.

Analgesic Prescribing Errors and Associated Medication Characteristics - Corrected Proof

Howard S. Smith, Timothy S. Lesar — 2010-06-18

Abstract: Medication errors involving analgesics, including mistakes in prescribing, are a major contributor to suboptimal therapeutic outcomes and preventable adverse patient events. A systematic evaluation of 2,044 prevented (near-miss) analgesic prescribing errors detected in a teaching hospital was performed to better understand these errors and contributing error-prone analgesic medication characteristics. The overall detected error rate was 2.87 errors per 1,000 analgesic orders, with the error rate more than twice as high in pediatric patients than in adults. Error rates varied widely between drugs, dosage forms, and routes of administration, but there was general consistency of error rates within drug groups with similar characteristics. Commonly prescribed medications were associated with the most errors, but less frequently prescribed agents had higher error rates. A number of factors were found to contribute to errors, and the following characteristics contributed to 40% of errors: availability in dose forms for multiple routes of administration; modified dosage forms; atypical dosage regimens; sound-alike drug names; and analgesics used on an ongoing scheduled basis.Perspective: Identifiable analgesic product characteristics and uses are associated with higher risk for errors. The findings of this study can guide patient and caregiver education, and can be incorporated into medication safety strategies to reduce patient risk from analgesic errors.

Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase Inhibitors Produce Anti-Allodynic Effects in Mice Through Distinct Cannabinoid Receptor Mechanisms - Corrected Proof

Steven G. Kinsey, Jonathan Z. Long, Benjamin F. Cravatt, Aron H. Lichtman — 2010-06-17

Abstract: The endocannabinoids anandamide and 2-arachidonoylglycerol are predominantly regulated by the respective catabolic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). Inhibition of these enzymes elevates endocannabinoid levels and attenuates neuropathic pain. In the present study, CB1 and CB2 receptor-deficient mice were subjected to chronic constriction injury (CCI) of the sciatic nerve to examine the relative contribution of each receptor for the anti-allodynic effects of the FAAH inhibitor, PF-3845, and the MAGL inhibitor, JZL184. CCI caused marked hypersensitivity to mechanical and cold stimuli, which was not altered by deletion of either the CB1 or CB2 receptor, but was attenuated by gabapentin, as well as by each enzyme inhibitor. Whereas PF-3845 lacked anti-allodynic efficacy in both knockout lines, JZL184 did not produce anti-allodynic effects in CB1 (-/-) mice, but retained its anti-allodynic effects in CB2 (-/-) mice. These data indicate that FAAH and MAGL inhibitors reduce nerve injury-related hyperalgesic states through distinct cannabinoid receptor mechanisms of action. In conclusion, although endogenous cannabinoids do not appear to play a tonic role in long-term expression of neuropathic pain states, both FAAH and MAGL represent potential therapeutic targets for the development of pharmacological agents to treat chronic pain resulting from nerve injury.Perspective: This article presents data addressing the cannabinoid receptor mechanisms underlying the anti-allodynic actions of endocannabinoid catabolic enzyme inhibitors in the mouse sciatic nerve ligation model. Fatty acid amide hydrolase and monoacylglycerol lipase inhibitors reduced allodynia through distinct cannabinoid receptor mechanisms. These enzymes offer potential targets to treat neuropathic pain.

Are There Sex Differences in Affective Modulation of Spinal Nociception and Pain? - Corrected Proof

2010-06-17

Abstract: Sex differences in the processing and experience of emotion exist. The present study examined whether sex differences in emotion lead to sex differences in affective modulation of pain and spinal nociception (assessed by nociceptive flexion reflex, NFR). Participants were healthy men (n = 47) and women (n = 73). Prior to affective modulation testing, electrocutaneous pain sensitivity was assessed (NFR threshold, pain threshold, pain tolerance). Affective modulation of pain and NFR was then assessed by presenting pictures that vary in emotional valence and arousal (mutilation, attack, death, neutral, families, adventure, erotica) during which suprathreshold electrocutaneous stimulations were delivered. Subjective emotional reactions were assessed after every picture, and nociceptive reactions were assessed after every suprathreshold stimulus. Results indicated women had greater pain sensitivity and also responded more negatively to attack pictures and less positively to erotic pictures. But despite these differences, affective modulation of pain/NFR was not moderated by sex: erotic pictures inhibited pain/NFR and mutilation pictures enhanced pain/NFR. Together, this implies subjective emotional experience does not completely mediate picture-evoked modulation of pain/NFR, a supposition that was further supported by exploratory analyses that demonstrated picture-evoked modulation of pain/NFR was present even after controlling for intra- and inter-individual differences in emotional reactions to pictures. Implications and limitations of these findings are discussed.Perspective: Evidence suggests that women are more sensitive to experimental and clinical pain, but the mechanisms contributing to these sex differences are poorly understood. Affective processes are known to play a role in regulating pain signaling and pain experience; therefore, the present study examined whether sex differences in affective experience contribute to sex differences in pain. Results indicate that in healthy individuals affective processes may not contribute to sex differences in pain.

Analgesia Induced by 2- or 100-Hz Electroacupuncture in the Rat Tail-Flick Test Depends on the Activation of Different Descending Pain Inhibitory Mechanisms - Corrected Proof

Josie R.T. Silva, Marcelo L. Silva, Wiliam A. Prado — 2010-06-17

Abstract: We evaluated the effectiveness of intrathecal antagonists of α1- (WB4101) and α2- (idazoxan) adrenoceptors and serotonergic (methysergide), opioid (naloxone), muscarinic (atropine), GABAA (bicuculline) and GABAB (phaclofen) receptors in blocking 2- or 100-Hz electroacupuncture (EA)-induced analgesia (EAIA) in the rat tail-flick test. EA was applied bilaterally to the Zusanli and Sanyinjiao acupoints in lightly anesthetized rats. EA increased tail-flick latency, where the effect of 2-Hz EA lasted longer than that produced by 100-Hz EA. The 2-Hz EAIA was inhibited by naloxone or atropine, was less intense and shorter after WB4101 or idazoxan, and was shorter after methysergide, bicuculline, or phaclofen. The 100-Hz EAIA was less intense and shorter after naloxone and atropine, less intense and longer after phaclofen, shorter after methysergide or bicuculline, and remained unchanged after WB4101 or idazoxan. We postulate that the intensity of the effect of 2-Hz EA depends on noradrenergic descending mechanisms and involves spinal opioid and muscarinic mechanisms, whereas the duration of the effect depends on both noradrenergic and serotonergic descending mechanisms, and involves spinal GABAergic modulation. In contrast, the intensity of 100-Hz EAIA involves spinal muscarinic, opioid, and GABAB mechanisms, while the duration of the effects depends on spinal serotonergic, muscarinic, opioid, and GABAA mechanisms.Perspective: The results of this study indicate that 2- and 100-Hz EA induce analgesia in the rat tail-flick test activating different descending mechanisms at the spinal cord level that control the intensity and duration of the effect. The adequate pharmacological manipulation of such mechanisms may improve EA effectiveness for pain management.

Relationship Between Fibromyalgia and Obesity in Pain, Function, Mood, and Sleep - Corrected Proof

Akiko Okifuji, Gary W. Donaldson, Lynn Barck, Perry G. Fine — 2010-06-10

Abstract: Fibromyalgia syndrome (FMS) is a prevalent and disabling chronic pain disorder. Past research suggests that obesity is a common comorbidity and may be related to the severity of FMS. The main objective of the present study was to evaluate the relationships between FMS and obesity in the multiple FMS-related domains: hyperalgesia, symptoms, physical abilities, and sleep. A total of 215 FMS patients completed a set of self-report inventories to assess FMS-related symptoms and underwent the tender point (TP) examination, physical performance testing, and 7-day home sleep assessment. Forty-seven percent of our sample was obese and an additional 30% was overweight. Obesity was related significantly to greater pain sensitivity to TP palpation particularly in the lower body areas, reduced physical strength and lower-body flexibility, shorter sleep duration, and greater restlessness during sleep. The results confirmed that obesity is a prevalent comorbidity of FMS that may contribute to the severity of the problem. Potential mechanisms underlying the relationship are discussed.Perspective: This report presents how obesity may be interrelated to fibromyalgia pain, disability, and sleep. We found that obesity is common in FMS. Approximately half of our patients were obese and an additional 30% were overweight. We also found that obesity in FMS was associated with greater pain sensitivity, poorer sleep quality, and reduced physical strength and flexibility. The results suggest that obesity may aggregate FMS and weight management may need to be incorporated into treatments.

An Educational Strategy for Treating Chronic, Noncancer Pain With Opioids: A Pilot Test - Corrected Proof

Huda Elhwairis, Christopher B. Reznich — 2010-06-10

Abstract: Chronic pain is common and can be devastating to the patient and challenging to the health care provider. Despite the importance of the topic, pain management curricula are incomplete in health professionals' training. We developed a longitudinal curriculum to teach therapy for chronic noncancer pain over four units and pilot-tested the teaching of one unit (opioids) to internal medicine residents. The educational strategies we used included didactic sessions, write-up of a management plan following a model, case discussions, and role-play group activities. We pilot-tested one unit (opioid therapy) in March 2008. We performed learner evaluations, using a pretest and posttest, a write-up plan following a model, and a learner knowledge questionnaire. Results showed significant improvement in knowledge. Residents found the sessions and educational strategy to be excellent and reported higher confidence levels in managing patients with chronic noncancer pain.Perspective: This article demonstrates that multiple teaching modalities—including didactic lectures, case discussions, write-up of a management plan following a model, and role-play group activities—are effective methods of teaching internal medicine residents how to use opioids to manage chronic noncancer pain.

Psychological and Sensory Predictors of Experimental Thermal Pain: A Multifactorial Model - Corrected Proof

Christopher J. Starr, Timothy T. Houle, Robert C. Coghill — 2010-06-07

Abstract: Although large interindividual differences in pain exist, the underlying factors that contribute to these variations remain poorly understood. Consequently, being able to accurately explain variability in pain ratings in terms of its contributing factors could provide insights into developing a better understanding of individual differences in pain experience. In the present investigation, we show that a significant portion of the variability in experimental heat pain ratings may be predicted using simple quantitative sensory testing and a series of psychological questionnaires including State Trait and Anxiety Inventory (STAI), Center for Epidemiologic Studies – Depression Scale (CES-D), and Positive and Negative Affect Schedule – Expanded form (PANAS-X). A factor analysis was used to reduce individual predictors into sets of composite predictive factors. A multifactorial model that was generated from these factors can reliably predict a significant amount of the variability in heat pain sensitivity ratings (r2 = .537, P = .027). Moreover, individual variables including heat pain thresholds and self-assessment of pain sensitivity were found to be poor predictors of heat pain sensitivity. Taken together, these results suggest that a variety of factors underlie individual differences in pain experience and that a reliable model for predicting pain should be constructed from a combination of these factors.Perspective: The present study provides a way to predict subjects' experimental heat pain sensitivity using a multifactorial model generated from a combination of sensory and psychological factors. Future application of such a model in the studies of clinical pain could potentially improve the quality of care provided for patients in pain.

Assessing Pain Behaviors in Healthy Subjects Using the Critical-Care Pain Observation Tool (CPOT): A Pilot Study - Corrected Proof

Yannick Tousignant-Laflamme, Patricia Bourgault, Céline Gélinas, Serge Marchand — 2010-06-02

Abstract: The Critical-Care Pain Observation Tool (CPOT) is a behavioral scale recommended by experts for pain assessment in critically ill patients unable to verbally communicate. The main goal of this study was to determine the relationship between self-reports of pain intensity and the CPOT score, and establish the sensibility and the specificity of the CPOT to different levels of pain intensity in healthy subjects. A total of 18 healthy subjects participated in the study (mean age = 37.8 years). All subjects underwent a 2 minutes noxious cold pressor test (CPT) at 7°C. Verbal pain ratings were obtained with a visual analog scale (0-100) while pain behaviors were videotaped. Afterwards, 2 independent evaluators quantified pain behaviors using the CPOT. Interrater reliability was supported with an ICC of 0.963 (95%CI [0.904-0.986]). A moderate positive correlation between the CPOT scores and self-reports of pain intensity during the CPT was found (r = 0.52, p = 0.028). Such result indicates that subjects reporting high level of pain showed a higher number or more intense pain behaviors. A cut-off score >2.5/8 on the CPOT led to a sensibility of 64% and a specificity of 86%. Results from this pilot study support that an increase of CPOT score is correlated with moderate to high levels of pain intensity and further support the clinical use of the CPOT.Perspective: This article presents the psychometric properties of a behavioral pain scale called the CPOT which was developed to assess pain in critically ill adults unable to self-report. Our results in healthy subjects showed that the CPOT behavioral score is significantly correlated with the self-report of pain intensity and supports its clinical use.

Skin Incision Induces Expression of Axonal Regeneration-Related Genes in Adult Rat Spinal Sensory Neurons - Corrected Proof

2010-06-02

Abstract: Skin incision and nerve injury both induce painful conditions. Incisional and postsurgical pain is believed to arise primarily from inflammation of tissue and the subsequent sensitization of peripheral and central neurons. The role of axonal regeneration-related processes in development of pain has only been considered when there has been injury to the peripheral nerve itself, even though tissue damage likely induces injury of resident axons. We sought to determine if skin incision would affect expression of regeneration-related genes such as activating transcription factor 3 (ATF3) in dorsal root ganglion (DRG) neurons. ATF3 is absent from DRG neurons of the normal adult rodent, but is induced by injury of peripheral nerves and modulates the regenerative capacity of axons. Image analysis of immunolabeled DRG sections revealed that skin incision led to an increase in the number of DRG neurons expressing ATF3. RT-PCR indicated that other regeneration-associated genes (galanin, GAP-43, Gadd45a) were also increased, further suggesting an injury-like response in DRG neurons. Our finding that injury of skin can induce expression of neuronal injury/regeneration-associated genes may impact how clinical postsurgical pain is investigated and treated.Perspective: Tissue injury, even without direct nerve injury, may induce a state of enhanced growth capacity in sensory neurons. Axonal regeneration-associated processes should be considered alongside nerve signal conduction and inflammatory/sensitization processes as possible mechanisms contributing to pain, particularly the transition from acute to chronic pain.

PROMIS Pediatric Pain Interference Scale: An Item Response Theory Analysis of the Pediatric Pain Item Bank - Corrected Proof

2010-06-02

Abstract: An aim of the National Institutes of Health (NIH) Patient Reported Outcomes Measurement Information System (PROMIS) initiative is to develop item banks and computerized adaptive tests (CAT) that are applicable across a wide variety of chronic disorders. The PROMIS Pediatric Cooperative Group has concentrated on the development of pediatric self-report item banks for ages 8 through 17 years. The objective of the present study is to describe the Item Response Theory (IRT) analysis of the NIH PROMIS pediatric pain item bank and the measurement properties of the new unidimensional PROMIS Pediatric Pain Interference Scale. Test forms containing pediatric pain items were completed by a total of 3048 respondents. IRT analyses regarding scale dimensionality, item local dependence, and differential item functioning were conducted. A pain item pool was developed to yield scores on a T-score scale with a mean of 50 and standard deviation of 10. The recommended 8-item unidimensional short form for the PROMIS Pediatric Pain Interference Scale contains the item set which provides the maximum test information at the mean (50) on the T-score metric. A simulated CAT was computed that provides the most information at 5 possible score locations (30, 40, 50, 60, and 70 on the T-score metric).Perspective: The present study provides initial calibrations of the NIH PROMIS pediatric pain item bank and the creation of the PROMIS Pediatric Pain Interference Scale. It is anticipated that this new scale will have application in pediatric chronic and recurrent pain.

Salivary Cortisol Release and Hypothalamic Pituitary Adrenal Axis Feedback Sensitivity in Fibromyalgia Is Associated With Depression But Not With Pain - Corrected Proof

2010-06-02

Abstract: Results on HPA axis function in fibromyalgia are heterogeneous and studies that integrate psychological and biological mechanisms in the search for pathways to fibromyalgia are rare. The goal of the study was to evaluate cortisol release and HPA axis feedback regulation in fibromyalgia and its association with psychopathology and pain. Beneath assessment of pain thresholds and self-report of pain, salivary free cortisol release over the day before and after intake of 0.5 mg of dexamethasone was measured in 21 female patients with fibromyalgia and 26 control women. Depression was assessed by questionnaires and clinical interview. We found reduced feedback sensitivity and slightly enhanced cortisol release in patients with fibromyalgia compared with healthy control subjects. Post hoc analyses showed that these effects are exclusively found in those patients, who also had major depressive disorder. Patients with fibromyalgia had lower pain pressure threshold, whereas heat pain thresholds were comparable with control subjects. Pain pressure and heat pain thresholds were not associated with cortisol release. On the other hand measurements of affective pain experience and depression were positively correlated with salivary cortisol over the day. Our results support the hypotheses that HPA axis related alterations are associated with affective disturbances, for example, depression, in patients with fibromyalgia.Perspective: The presented data suggest depression to be an important factor in HPA axis–related dysfunction in fibromyalgia. This might be one explanation for equivocal findings in the literature.

Electroacupuncture Increases CB2 Receptor Expression on Keratinocytes and Infiltrating Inflammatory Cells in Inflamed Skin Tissues of Rats - Corrected Proof

2010-06-02

Abstract: Endogenous cannabinoids and peripheral cannabinoid CB2 receptors (CB2Rs) are involved in the antinociceptive effect of electroacupuncture (EA) on inflammatory pain. However, it remains unclear about how EA affects the expression and distribution patterns of peripheral CB2Rs in inflamed skin tissues. To study this, inflammatory pain was induced by local injection of complete Freund's adjuvant into the hindpaw of rats. The mRNA and protein levels of CB2Rs were quantified by using RTPCR and Western blotting, respectively. The distribution of CB2Rs on keratinocytes and immune cells recruited to the inflamed skin tissues was determined by using double-immunofluorescence labeling. Induction of tissue inflammation significantly increased the mRNA and protein levels of CB2Rs in the skin tissue. Also, both 2 Hz and 100 Hz EA, applied to GB30 and GB34, significantly increased the mRNA and protein levels of CB2Rs in inflamed tissues compared to the sham EA group. CB2Rimmunoreactivities were mainly distributed in keratinocytes, macrophages, and T-lymphocytes in the epidermis and dermis of the inflamed skin tissue. Inflammation caused a significant increase in the number of CB2R-immunoreactive keratinocytes, macrophages, and T-lymphocytes. Furthermore, compared to the sham EA group, EA at 2 or 100 Hz significantly increased the number of keratinocytes, macrophages, and T-lymphocytes with CB2R-immunoreactivity in the inflamed skin tissue. Therefore, our findings suggest that EA is associated with upregulation of local CB2Rs in the inflamed skin tissue. EA primarily potentiates the expression of CB2Rs on keratinocytes and infiltrating inflammatory cells at the site of inflammation.Perspective: This study shows that electroacupuncture increases the CB2 receptor expression on keratinocytes and infiltrating inflammatory cells in inflammatory skin tissues. This finding provides new evidence showing the potential role of CB2 receptors in the analgesic effect of acupuncture on inflammatory pain.

Dispositional Optimism Predicts Placebo Analgesia - Corrected Proof

2010-06-02

Abstract: Based on prior research identifying dispositional optimism as a predictor of placebo responding, the present study tested the hypothesis that individuals high in optimism would be more likely to respond to a placebo analgesic. Optimists and pessimists were randomly assigned to a placebo expectation condition or a no expectation condition before a cold pressor task. Blood pressure and heart rate were recorded before and during the cold pressor task, and participant ratings of pain and expectations were obtained immediately after the task. Analysis of the expectation manipulation revealed that the placebo instruction was successful in altering participant expectancy during the cold pressor. Supporting the main hypothesis, dispositional optimism was associated with lower pain ratings in the placebo condition but not in the control condition. Because dispositional optimism can alter placebo responding to laboratory pain, future studies should examine the potential role that this individual difference factor may play in patient responsivity to pharmacological and nonpharmacological treatments for clinical pain.Perspective: This study examined the possibility that individual differences can predict placebo analgesia. Participants were randomly assigned to receive either a placebo expectation or no expectation before a cold pressor task. Dispositional optimism was related to less cold pressor pain in the placebo condition as compared with the control condition.

Opioids, Chronic Pain, and Addiction in Primary Care - Corrected Proof

2010-06-02

Abstract: Research has largely ignored the systematic examination of physicians' attitudes towards providing care for patients with chronic noncancer pain. The objective of this study was to identify barriers and facilitators to opioid treatment of chronic noncancer pain patients by office-based medical providers. We used a qualitative study design using individual and group interviews. Participants were 23 office-based physicians in New England. Interviews were audiotaped, transcribed, and systematically coded by a multidisciplinary team using the constant comparative method. Physician barriers included absence of objective or physiological measures of pain; lack of expertise in the treatment of chronic pain and coexisting disorders, including addiction; lack of interest in pain management; patients' aberrant behaviors; and physicians' attitudes toward prescribing opioid analgesics. Physician facilitators included promoting continuity of patient care and the use of opioid agreements. Physicians' perceptions of patient-related barriers included lack of physician responsiveness to patients' pain reports, negative attitudes toward opioid analgesics, concerns about cost, and patients' low motivation for pain treatment. Perceived logistical barriers included lack of appropriate pain management and addiction referral options, limited information regarding diagnostic workup, limited insurance coverage for pain management services, limited ancillary support for physicians, and insufficient time. Addressing these barriers to pain treatment will be crucial to improving pain management service delivery.Perspective: This article demonstrates that perceived barriers to treating patients with chronic noncancer pain are common among office-based physicians. Addressing these barriers in physician training and in existing office-based programs might benefit both noncancer chronic pain patients and their medical providers.

Initial Psychometric Properties of the Pain Care Quality Survey (PainCQ) - Corrected Proof

2010-05-31

Abstract: This study examined the psychometric properties of the Pain Care Quality (PainCQ) survey, a new instrument to measure the quality of nursing and interdisciplinary care related to pain management. Hospitalized medical/surgical oncology patients with pain from 3 states completed the 44-item version of the PainCQ survey following completion of a nursing shift. Interdisciplinary items were evaluated over the entire hospital stay; nursing care was evaluated during the previous shift. The sample included 109 patients ranging in age from 20 to 84 (mean = 53.09). The sample was 58.7% female, 88% non-Hispanic white. Principal Axis Factoring with an oblimin rotation was used as factors were correlated. Two scales resulted. The PainCQ-Interdisciplinary scale included 11 items representing 2 constructs and explaining 47.1% of shared item variance: partnership with the health care team (k = 6 items; α = .85) and comprehensive interdisciplinary pain care (k = 5 items; α = .76). The PainCQ-Nursing scale measured three constructs and explained 60.8 % of shared item variance: being treated right (k = 15 items; α = .95), comprehensive nursing pain care (k = 3 items; α = .77), and efficacy of pain management (k =4 items; α = .87). Results supported the internal consistency reliability and structural validity of the PainCQ survey with 33 items.Perspective: This article presents the psychometric properties of a new tool to measure interdisciplinary and nursing care quality related to pain management from the patient's perspective. This tool can be used for research and as a clinical performance measure to monitor and improve quality of care and patient outcomes.

Topical Nifedipine for the Treatment of Localized Provoked Vulvodynia: A Placebo-Controlled Study - Corrected Proof

Jacob Bornstein, Ruba Tuma, Yaniv Farajun, Audrey Azran, Doron Zarfati — 2010-05-31

Abstract: Topical application of the calcium antagonist nifedipine has demonstrated effectiveness in treating chronic anal fissure, without adverse effects. Like chronic anal fissure, vulvodynia is associated with muscle hypertonicity and an inflammatory infiltrate. We conducted a double-blind placebo-controlled study to investigate the effectiveness of 2 concentrations of topical nifedipine cream in the treatment of vulvodynia. Thirty participants were alternately assigned to 3 topical treatment groups: .2% nifedipine, .4% nifedipine, and placebo. All administered the cream to the vestibule 4 times daily for 6 weeks. For all 3 treatment groups, mean pain intensity on vestibular touch, assessed by the Q-tipped cotton test, pain from speculum insertion, and reports of pain during sexual intercourse was reduced at post-treatment compared with pre-treatment. These improvements remained at 3 months' follow-up. The effectiveness of nifedipine in treating vulvodynia did not exceed that of placebo.Perspective: The topical application of both nifedipine and a placebo reduced pain in women with vulvodynia. This study highlights the need for controlled trials of treatments for vulvodynia and raises doubts about studies conducted without comparison to placebo.

Spatiotemporal Pattern of Concurrent Spinal and Supraspinal NF-κB Expression After Peripheral Nerve Injury - Corrected Proof

2010-05-31

Abstract: The expression of NF-κB in the spinal cord is associated with neuropathic pain. However, little is known about its expression beyond the spinal cord. Here we examined a spatial and temporal pattern of the NF-κB expression in both spinal and supraspinal regions. After chronic constriction injury (CCI) of the sciatic nerve, NF-κB (p65) expression was significantly increased in the ipsilateral spinal cord. In contrast, the NF-κB expression in the contralateral primary somatosensory cortex was decreased with no significant differences seen in the thalamus. In the contralateral anterior cingulate cortex, the NF-κB expression was increased significantly on day 14 as compared with the sham group. In the contralateral amygdala, the NF-κB expression showed a time-dependent downregulation after CCI, which became significant on day 14. MK-801 reduced nociceptive behaviors and reversed the direction of NF-κB expression. These results indicate that the CCI-induced expression of p65 NF-κB is both time-dependent and region-specific, in areas that process both sensory-discriminative and motivational-affective dimensions of pain.Perspective: This article presents a spatiotemporal mapping of the NF-κB expression in spinal and supraspinal regions after peripheral nerve injury. These findings point to an involvement of NF-κB beyond the spinal cord in both the sensory discriminative and emotional affective aspects of neuropathic pain processing.

Referred Pain from Muscle Trigger Points in the Masticatory and Neck-Shoulder Musculature in Women with Temporomandibular Disoders - Corrected Proof

2010-05-24

Abstract: Our aim was to describe the referred pain patterns and size of areas of trigger points (TrPs) in the masticatory and neck-shoulder muscles of women with myofascial temporomandibular disorders (TMD). Twenty-five women with myofascial TMD and 25 healthy matched women participated. Bilateral temporalis, deep masseter, superficial masseter, sternocleidomastoid, upper trapezius and suboccipital muscles were examined for TrPs by an assessor blinded to the subjects' condition. TrPs were identified with manual palpation and categorized into active and latent according to proposed criteria. The referred pain areas were drawn on anatomical maps, digitalized, and measured. The occurrence of active (P < .001) and latent TrPs (P = .04) were different between groups. In all muscles, there were significantly more active and latent TrP in patients than controls (P < .001). Significant differences in referred pain areas between groups (P < .001) and muscles (P < .001) were found: the referred pain areas were larger in patients (P < .001), and the referred pain area elicited by suboccipital TrPs was greater than the referred pain from other TrPs (P < .001). Referred pain areas from neck TrPs were greater than the pain areas from masticatory muscle TrPs (P < .01). Referred pain areas of masticatory TrPs were not different (P > .703). The local and referred pain elicited from active TrPs in the masticatory and neck-shoulder muscles shared similar pain pattern as spontaneous TMD, which supports the concept of peripheral and central sensitization mechanisms in myofascial TMD.Perspective: The current study showed the existence of multiple active muscle TrPs in the masticatory and neck-shoulder muscles in women with myofascial TMD pain. The local and referred pain elicited from active TrPs reproduced pain complaints in these patients. Further, referred pain areas were larger in TMD pain patients than in healthy controls. The results are also in accordance with the notion of peripheral and central sensitization mechanisms in patients with myofascial TMD.

Peripheral Formalin Injury Induces 2 Stages Of Microglial Activation in the Spinal Cord - Corrected Proof

Kai Li, Ting Lin, Ye Cao, Alan R. Light, Kai-Yuan Fu — 2010-05-21

Abstract: The formalin test produces 2 well-known acute phases of nociceptive behavior. Recently, we have shown that this same formalin test produces a third phase of nociceptive behavior consisting of prolonged thermal and mechanical hyperalgesia beginning days after formalin injection and lasting for at least 3 weeks. Here we investigated the activity of 3 MAPKs (p38, ERK and JNK) in the spinal dorsal horn following 5% formalin injection into rat hind paw. The p38 MAPK was rapidly activated in the spinal microglia minutes after injection and the activation persisted for 1 hour. In addition, this same injury induced a secondary increase of phospho-p38 expression in spinal microglia that was maximal 3 to 7 days postinjection. Intrathecal administration of p38 inhibitor SB203580 not only inhibited the early acute spontaneous nociceptive behaviors, but also inhibited the long-term formalin injury-induced mechanical hyperalgesia. Our results suggest that peripheral formalin injection induces 2 stages of microglial activation, and p38 activation in spinal microglia plays key roles in central pain modulation in formalin test respectively for the early acute phases and the late secondary long-term pain state as well.Perspective: This article presents unique properties of spinal microglial activation in a pain animal model. This finding could potentially help clinicians to further understand the contributions of spinal microglia to acute and chronic pain state.

High-Intensity Extended Swimming Exercise Reduces Pain-Related Behavior in Mice: Involvement of Endogenous Opioids and the Serotonergic System - Corrected Proof

2010-05-21

Abstract: The present study examined the hyponociceptive effect of swimming exercise in a chemical behavioral model of nociception and the mechanisms involved in this effect. Male mice were submitted to swimming sessions (30 min/d for 5 days). Twenty-four hours after the last session, we noticed that swimming exercise decreased the number of abdominal constriction responses caused by acetic acid compared with the nonexercised group. The hyponociception caused by exercise in the acetic acid test was significantly attenuated by intraperitoneal (i.p.) pretreatment of mice with naloxone (a nonselective opioid receptor antagonist, 1 mg/kg), ρ-chlorophenylalanine methyl ester (PCPA, an inhibitor of serotonin synthesis, 100 mg/kg once a day for 4 consecutive days), and by bilateral adrenalectomy. Collectively, the present results provide experimental evidences indicating for the first time that high-intensity extended swimming exercise reduces pain-related behavior in mice. The mechanisms involve an interaction with opioid and serotonin systems. Furthermore, endogenous opioids released by adrenal glands probably are involved in this effect.Perspective: Our results indicate that high-intensity extended exercise endogenously controls acute pain by activation of opioidergic and serotonergic pathways. Furthermore, these results support the use of exercise as a nonpharmacological approach for the management of acute pain.

Antagonistic Effects of Ondansetron and Tramadol? A Randomized Placebo and Active Drug Controlled Study - Corrected Proof

2010-05-20

Abstract: Opposing effects of ondansetron and tramadol on the serotonin pathway have been suggested which possibly increase tramadol consumption and emesis when co-administered. In a randomized, double-blinded study, 179 patients received intravenous ondansetron, metoclopramide, or placebo for emesis prophylaxis. Analgesic regimen consisted of tramadol intraoperative loading and subsequent patient-controlled analgesia. Tramadol consumption and response to antiemetic treatment were compared. Additionally, plasma concentrations of ondansetron and (+)O-demethyltramadol and CYP2D6 genetic variants were analyzed as possible confounders influencing analgesic and antiemetic efficacy. Tramadol consumption did not differ between the groups. Response rate to antiemetic prophylaxis was superior in patients receiving ondansetron (85.0%) compared with placebo (66.7%, P = .046), with no difference to metoclopramide (69.5%). Less vomiting was reported in the immediate postoperative hours in the verum groups (ondansetron 5.0%, metoclopramide 5.1%) compared with placebo (18.6%; P = .01). Whereas plasma concentrations of (+)O-demethyltramadol were significantly correlated to CYP2D6 genotype, no influence was detected for ondansetron. Co-administration of ondansetron neither increased tramadol consumption nor frequency of PONV in this postoperative setting.Perspective: Controversial findings were reported for efficacy of tramadol and ondansetron when co-administered due to their opposing serotonergic effects. Co-medication of these drugs neither increased postoperative analgesic consumption nor frequency of emesis in this study enrolling patients recovering from major surgery.

Large and Small Fiber Dysfunction in Peripheral Nerve Injuries With or Without Spontaneous Pain - Corrected Proof

Inge Petter Kleggetveit, Ellen Jørum — 2010-05-20

Abstract: Few data have been available on the functional role of small fiber damage in patients with peripheral nerve injuries with and without spontaneous pain. The aim of the present study was to investigate the function of large myelinated nerve fibers as well as small nerve fibers in a material of 60 patients with peripheral nerve injuries in upper or lower extremities, 30 patients with spontaneous pain, and 30 patients without pain. Patients were questioned about the characteristics of pain and investigated clinically with EMG/neurography and assessment of thermal thresholds in the innervation territory of the lesioned nerve as well as in the contralateral area. Sensation of touch and warmth and cold detection was significantly reduced in the injured side in both groups. There was a tendency, not significant, for heat pain thresholds to be more elevated in the affected side compared with the healthy side in the pain group only (47.8°C versus 45.1°C). There were no significant differences in thermal thresholds between the 2 groups of patients. The main finding was a high percentage of hyperphenomena (allodynia to light touch and reduced mechanical pain thresholds) in the pain group only.Perspective: Small fiber function did not significantly differ between patients with and without pain, indicating that elevated thermal thresholds alone will not reflect mechanisms responsible for the generation of pain. Hyperphenomena were present in the affected side of the pain group only.

Risk Factors Predicting the Development of Widespread Pain From Chronic Back or Neck Pain - Corrected Proof

Lindsay L. Kindler, Kim D. Jones, Nancy Perrin, Robert M. Bennett — 2010-05-20

Abstract: Emerging evidence suggests that some individuals with regional pain disorders go on to develop chronic widespread pain (CWP). However, the mechanism behind this transition and the nature of risk factors that predispose a person to develop CWP remain to be elucidated. The purpose of this study was to describe the frequency with which participants with chronic back or neck pain develop CWP and to determine the risk factors associated with this development. In a sample of 512 individuals, we found that nearly a quarter (22.6%) of subjects who presented with regional back or neck pain in 2001/2002 had developed CWP by 2007. Logistic regression indicated that 7 factors were associated with the transition to CWP: moderate or severe pain intensity, female gender, history of abuse, family history of CWP, severe interference with general activity, having 1 or more central sensitivity syndromes, and using more pain management strategies. History of abuse was not significant in multivariate analysis. Notably, number of depressive symptoms endorsed, pain duration, age, body mass index, number of medication classes used, and receipt of disability benefits were not significantly associated with this transition.Perspective: This study offers insight into risk factors associated with the development of CWP. This information not only offers clues as to the mechanism behind the expansion of pain sensitivity from a regional pain locus to a widespread pain disorder but also provides insight as to how clinicians might mitigate this transition.

Duloxetine Versus Placebo in Patients With Chronic Low Back Pain: A 12-Week, Fixed-Dose, Randomized, Double-Blind Trial - Corrected Proof

2010-05-17

Abstract: This randomized, double-blind, placebo-controlled study assessed efficacy and safety of duloxetine in patients with chronic low back pain (CLBP). Adults (n = 401) with a nonneuropathic CLBP and average pain intensity of ≥4 on an 11-point numerical scale (Brief Pain Inventory [BPI]) were treated with either duloxetine 60 mg once daily or placebo for 12 weeks. The primary measure was BPI average pain. Secondary endpoints included Patient's Global Impressions of Improvement (PGI-I), Roland Morris Disability Questionnaire (RMDQ-24), BPI-Severity (BPI-S), BPI-Interference (BPI-I), and response rates (either ≥30% or ≥50% BPI average pain reduction at endpoint). Health outcomes included Short Form-36, European Quality of Life–5 Dimensions, and the Work Productivity and Activity Impairment questionnaire. Safety and tolerability were assessed. Compared with placebo-treated patients, duloxetine-treated patients reported a significantly greater reduction in BPI average pain (P ≤ .001). Similarly, duloxetine-treated patients reported significantly greater improvements in PGI-I, BPI-S, BPI-I, 50% response rates, and some health outcomes. The RMDQ and 30% response rate showed numerical improvements with duloxetine treatment. Significantly more patients in the duloxetine group (15.2%) than patients in the placebo group (5.4%) discontinued because of adverse events (P = .002). Nausea and dry mouth were the most common treatment-emergent adverse events with rates significantly higher in duloxetine-treated patients.Perspective: This study provides clinical evidence of the efficacy and safety of duloxetine at a fixed dose of 60 mg once daily in the treatment of chronic low back pain (CLBP). As of December 2009, duloxetine has not received regulatory approval for the treatment of CLBP.

Central Sensitization and CaVα2δ Ligands in Chronic Pain Syndromes: Pathologic Processes and Pharmacologic Effect - Corrected Proof

2010-05-17

Abstract: Central sensitization is one form of long-term plasticity in the central nervous system. Sustained activation of primary sensory fibers supplying dorsal horn can induce long-lasting increases in the discharge amplitude of primary afferent synapses. This is similar to the long-term potentiation that occurs in many other CNS regions. Drugs that limit the short-duration wind-up component of central sensitization include sodium channel blockers, NMDA antagonists, fast-acting opioids and the calcium-channel ligands gabapentin and pregabalin (S-3-(aminomethyl)-5-methylhexanoic acid). Pregabalin, like gabapentin, binds selectively to the CaVα2δ auxiliary subunit of presynaptic voltage-gated calcium channels. The conformational changes induced by this binding inhibit abnormally intense neuronal activity by reducing the synaptic release of glutamate and other neurotransmitters. Recent identification in animal models of increased CaVα2δ protein expression in chronic pain, allodynia, and hyperalgesia have drawn additional interest to drugs that bind the CaVα2δ site. Experimental studies with animal models and healthy human volunteers have shown that pregabalin reduces nociceptive responses, particularly in conditions involving central sensitization. Since these actions occur with relatively modest effects on physiological and cognitive functions, pregabalin may be an important consideration in the pharmacotherapy of otherwise difficult-to-treat pain syndromes.Perspective: This focus article discusses how the central nervous system plasticity phenomenon, central sensitization, is established in the induction and maintenance of chronic pain, allodynia, and hyperalgesia. In addition, it explores the neurophysiologic actions of the calcium-channel ligands gabapentin and pregabalin in limiting pathological manifestations of central sensitization.

The Effect of Fibromyalgia and Widespread Pain on the Clinically Significant Temporomandibular Muscle and Joint Pain Disorders—A Prospective 18-Month Cohort Study - Corrected Proof

2010-05-13

Abstract: Although most cases of temporomandibular muscle and joint disorders (TMJD) are mild and self-limiting, about 10% of TMJD patients develop severe disorders associated with chronic pain and disability. It has been suggested that fibromyalgia and widespread pain play a significant role in TMJD chronicity. This paper assessed the effects of fibromyalgia and widespread pain on clinically significant TMJD pain (GCPS II-IV). Four hundred eighty-five participants recruited from the Minneapolis/St. Paul area through media advertisements and local dentists received examinations and completed the Graded Chronic Pain Scale (GCPS) at baseline and at 18 months. Baseline widespread pain (OR: 2.53, P = .04) and depression (OR: 5.30, P = .005) were associated with onset of clinically significant pain (GCPS II-IV) within 18 months after baseline. The risk associated with baseline fibromyalgia was moderate, but not significant (OR: 2.74, P = .09). Persistence of clinically significant pain was related to fibromyalgia (OR: 2.48, P = .02) and depression (OR: 2.48, P = .02). These results indicate that these centrally generated pain conditions play a role in the onset and persistence of clinically significant TMJD.Perspective: Fibromyalgia and widespread pain should receive important consideration when evaluating and developing a treatment plan for patients with TMJD.