Showing papers in "Pain in 2007"

Pharmacologic management of neuropathic pain: evidence-based recommendations.

Abstract: Patients with neuropathic pain (NP) are challenging to manage and evidence-based clinical recommendations for pharmacologic management are needed. Systematic literature reviews, randomized clinical trials, and existing guidelines were evaluated at a consensus meeting. Medications were considered for recommendation if their efficacy was supported by at least one methodologically-sound, randomized clinical trial (RCT) demonstrating superiority to placebo or a relevant comparison treatment. Recommendations were based on the amount and consistency of evidence, degree of efficacy, safety, and clinical experience of the authors. Available RCTs typically evaluated chronic NP of moderate to severe intensity. Recommended first-line treatments include certain antidepressants (i.e., tricyclic antidepressants and dual reuptake inhibitors of both serotonin and norepinephrine), calcium channel alpha2-delta ligands (i.e., gabapentin and pregabalin), and topical lidocaine. Opioid analgesics and tramadol are recommended as generally second-line treatments that can be considered for first-line use in select clinical circumstances. Other medications that would generally be used as third-line treatments but that could also be used as second-line treatments in some circumstances include certain antiepileptic and antidepressant medications, mexiletine, N-methyl-D-aspartate receptor antagonists, and topical capsaicin. Medication selection should be individualized, considering side effects, potential beneficial or deleterious effects on comorbidities, and whether prompt onset of pain relief is necessary. To date, no medications have demonstrated efficacy in lumbosacral radiculopathy, which is probably the most common type of NP. Long-term studies, head-to-head comparisons between medications, studies involving combinations of medications, and RCTs examining treatment of central NP are lacking and should be a priority for future research.

Spinal cord stimulation versus conventional medical management for neuropathic pain: a multicentre randomised controlled trial in patients with failed back surgery syndrome.

Abstract: Patients with neuropathic pain secondary to failed back surgery syndrome (FBSS) typically experience persistent pain, disability, and reduced quality of life. We hypothesised that spinal cord stimulation (SCS) is an effective therapy in addition to conventional medical management (CMM) in this patient population. We randomised 100 FBSS patients with predominant leg pain of neuropathic radicular origin to receive spinal cord stimulation plus conventional medical management (SCS group) or conventional medical management alone (CMM group) for at least 6 months. The primary outcome was the proportion of patients achieving 50% or more pain relief in the legs. Secondary outcomes were improvement in back and leg pain, health-related quality of life, functional capacity, use of pain medication and non-drug pain treatment, level of patient satisfaction, and incidence of complications and adverse effects. Crossover after the 6-months visit was permitted, and all patients were followed up to 1 year. In the intention-to-treat analysis at 6 months, 24 SCS patients (48%) and 4 CMM patients (9%) (p<0.001) achieved the primary outcome. Compared with the CMM group, the SCS group experienced improved leg and back pain relief, quality of life, and functional capacity, as well as greater treatment satisfaction (p

Studying sex and gender differences in pain and analgesia: a consensus report

Abstract: In September 2006, members of the Sex, Gender and Pain Special Interest Group of the International Association for the Study of Pain met to discuss the following: (1) what is known about sex and gender differences in pain and analgesia; (2) what are the "best practice" guidelines for pain research with respect to sex and gender; and (3) what are the crucial questions to address in the near future? The resulting consensus presented herein includes input from basic science, clinical and psychosocial pain researchers, as well as from recognized experts in sexual differentiation and reproductive endocrinology. We intend this document to serve as a utilitarian and thought-provoking guide for future research on sex and gender differences in pain and analgesia, both for those currently working in this field as well as those still wondering, "Do I really need to study females?"

The incidence of complex regional pain syndrome: a population-based study.

Abstract: The complex regional pain syndrome (CRPS) is a painful disorder that can occur in an extremity after any type of injury, or even spontaneously. Data on the incidence of CRPS are scarce and mostly hospital based. Therefore the size of the problem and its burden on health care and society are unknown. The objective of the present study was to estimate the incidence of CRPS in the general population. A retrospective cohort study was conducted during 1996–2005 in the Integrated Primary Care Information (IPCI) project, a general practice research database with electronic patient record data from 600,000 patients throughout the Netherlands. Potential CRPS cases were identified by a sensitive search algorithm including synonyms and abbreviations for CRPS. Subsequently, cases were validated by electronic record review, supplemented with original specialist letters and information from an enquiry of general practitioners. The estimated overall incidence rate of CRPS was 26.2 per 100,000 person years (95% CI: 23.0–29.7). Females were affected at least three times more often than males (ratio: 3.4). The highest incidence occurred in females in the age category of 61–70 years. The upper extremity was affected more frequently than the lower extremity and a fracture was the most common precipitating event (44%). The observed incidence rate of CRPS is more as four times higher than the incidence rate observed in the only other population-based study, performed in Olmsted County, USA. Postmenopausal woman appeared to be at the highest risk for the development of CRPS. 2006 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Systematic review of observational (behavioral) measures of pain for children and adolescents aged 3 to 18 years.

Abstract: Observational (behavioral) scales of pain for children aged 3 to 18 years were systematically reviewed to identify those recommended as outcome measures in clinical trials. This review was commissioned by the Pediatric Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (www.immpact.org). In an extensive literature search, 20 observational pain scales were identified for review including behavior checklists, behavior rating scales, and global rating scales. These scales varied in their reliance on time sampling and inclusion of physiological items, facial and postural items, as well as their inclusion of multiple dimensions of assessment (e.g., pain and distress). Each measure was evaluated based on its reported psychometric properties and clinical utility. Scales were judged to be indicated for use in specific acute pain contexts rather than for general use. Two scales were recommended for assessing pain intensity associated with medical procedures and other brief painful events. Two scales were recommended for post-operative pain assessment, one for use in hospital and the other at home. Another scale was recommended for use in critical care. Finally, two scales were recommended for assessing pain-related distress or fear. No observational measures were recommended for assessing chronic or recurrent pain because the overt behavioral signs of chronic pain tend to habituate or dissipate as time passes, making them difficult to observe reliably. In conclusion, no single observational measure is broadly recommended for pain assessment across all contexts. Directions for further research and scale development are offered.

Development and validation of the Current Opioid Misuse Measure.

Abstract: Clinicians recognize the importance of monitoring aberrant medication-related behaviors of chronic pain patients while being prescribed opioid therapy. The purpose of this study was to develop and validate the Current Opioid Misuse Measure (COMM) for those pain patients already on long-term opioid therapy. An initial pool of 177 items was developed with input from 26 pain management and addiction specialists. Concept mapping identified six primary concepts underlying medication misuse, which were used to develop an initial item pool. Twenty-two pain and addiction specialists rated the items on importance and relevance, resulting in selection of a 40-item alpha COMM. Final item selection was based on empirical evaluation of items with patients taking opioids for chronic, noncancer pain (N=227). One-week test-retest reliability was examined with 55 participants. All participants were administered the alpha version of the COMM, the Prescription Drug Use Questionnaire (PDUQ) interview, and submitted a urine sample for toxicology screening. Physician ratings of patient aberrant behaviors were also obtained. Of the 40 items, 17 items appeared to adequately measure aberrant behavior, demonstrating excellent internal consistency and test-retest reliability. Cutoff scores were examined using ROC curve analysis and reasonable sensitivity and specificity were established. To evaluate the COMM’s ability to capture change in patient status, it was tested on a subset of patients (N = 86) that were followed and reassessed three months later. The COMM was found to have promise as a brief, self-report measure of current aberrant drug-related behavior. Further cross-validation and replication of these preliminary results is pending.

Mental disorders among persons with chronic back or neck pain: results from the World Mental Health Surveys.

Abstract: This paper reports cross-national data concerning back or neck pain comorbidity with mental disorders. We assessed (a) the prevalence of chronic back/neck pain, (b) the prevalence of mental disorders among people with chronic back/neck pain, (c) which mental disorder had strongest associations with chronic back/neck pain, and (d) whether these associations are consistent across countries. Population surveys of community-dwelling adults were carried out in 17 countries in Europe, the Americas, the Middle East, Africa, Asia, and the South Pacific (N=85,088). Mental disorders were assessed with the Composite International Diagnostic Interview, third version (CIDI 3.0): anxiety disorders (generalized anxiety disorder, panic disorder/agoraphobia, posttraumatic stress disorder, and social anxiety disorder), mood disorders (major depression and dysthymia), and alcohol abuse or dependence. Back/neck pain was ascertained by self-report. Between 10% and 42% reported chronic back/neck pain in the previous 12 months. After adjusting for age and sex, mental disorders were more common among persons with back/neck pain than among persons without. The pooled odds ratios were 2.3 [95% CI=2.1-2.5] for mood disorders, 2.2 [95% CI=2.1-2.4] for anxiety disorders, and 1.6 [95% CI=1.4-1.9] for alcohol abuse/dependence in people with versus without chronic back/neck pain. Although prevalence rates of back/neck pain were generally lower than in previous reports, mental disorders were associated with chronic back/neck pain. The strength of association was stronger for mood and anxiety disorders than for alcohol abuse/dependence. The association of mental disorders with back/neck pain showed a consistent pattern across both developed and developing countries.

Using screening tools to identify neuropathic pain

Abstract: 1 IntroductionIt is widely accepted that the unique painful and non-painful sensations in neuropathic pain are the result of particular mechanisms, and that specific management strategies for neuropathic pain should be applied to tackle them. Ideally, the treatment of chronic pain should be directed

The impact of patient expectations on outcomes in four randomized controlled trials of acupuncture in patients with chronic pain

Abstract: In a pooled analysis of four randomized controlled trials of acupuncture in patients with migraine, tension-type headache, chronic low back pain, and osteoarthritis of the knee we investigated the influence of expectations on clinical outcome. The 864 patients included in the analysis received either 12 sessions of acupuncture or minimal (i.e. sham) acupuncture (superficial needling of non-acupuncture points) over an 8 week period. Patients were asked at baseline whether they considered acupuncture to be an effective therapy in general and what they personally expected from the treatment. After three acupuncture sessions patients were asked how confident they were that they would benefit from the treatment strategy they were receiving. Patients were classified as responders if the respective main outcome measure improved by at least fifty percent. Both univariate and multivariate analyses adjusted for potential confounders (such as condition, intervention group, age, sex, duration of complaints, etc.) consistently showed a significant influence of attitudes and expectations on outcome. After completion of treatment, the odds ratio for response between patients considering acupuncture an effective or highly effective therapy and patients who were more sceptical was 1.67 (95% confidence interval 1.20-2.32). For personal expectations and confidence after the third session, odds ratios were 2.03 (1.26-3.26) and 2.35 (1.68-3.30), respectively. Results from the 6-month follow-up were similar. In conclusion, in our trials a significant association was shown between better improvement and higher outcome expectations.

Mediators, moderators, and predictors of therapeutic change in cognitive-behavioral therapy for chronic pain.

Abstract: Although cognitive-behavioral therapies (CBT) have been demonstrated to be effective for a variety of chronic pain problems, patients vary in their response and little is known about patient characteristics that predict or moderate treatment effects. Furthermore, although cognitive-behavioral theory posits that changes in patient beliefs and coping mediate the effects of CBT on patient outcomes, little research has systematically tested this. Therefore, we examined mediators, moderators, and predictors of treatment effects in a randomized controlled trial of CBT for chronic temporomandibular disorder (TMD) pain. Pre- to post-treatment changes in pain beliefs (control over pain, disability, and pain signals harm), catastrophizing, and self-efficacy for managing pain mediated the effects of CBT on pain, activity interference, and jaw use limitations at one year. In individual mediator analyses, change in perceived pain control was the mediator that explained the greatest proportion of the total treatment effect on each outcome. Analyzing the mediators as a group, self-efficacy had unique mediating effects beyond those of control and the other mediators. Patients who reported more pain sites, depressive symptoms, non-specific physical problems, rumination, catastrophizing, and stress before treatment had higher activity interference at one year. The effects of CBT generally did not vary according to patient baseline characteristics, suggesting that all patients potentially may be helped by this therapy. The results provide further support for cognitive-behavioral models of chronic pain and point to the potential benefits of interventions to modify specific pain-related beliefs in CBT and in other health care encounters.

Risk factors for clinically recognized opioid abuse and dependence among veterans using opioids for chronic non-cancer pain.

Abstract: A central question in prescribing opioids for chronic non-cancer pain (CNCP) is how to best balance the risk of opioid abuse and dependence with the benefits of pain relief. To achieve this balance, clinicians need an understanding of the risk factors for opioid abuse, an issue that is only partially understood. We conducted a secondary data analysis of regional VA longitudinal administrative data (years 2000-2005) for chronic users of opioids for CNCP (n=15,160) to investigate risk factors for the development of clinically recognized (i.e., diagnosed) opioid abuse or dependence among these individuals. We analyzed four broad groups of possible risk factors: (i) non-opioid substance abuse disorders, (ii) painful physical health disorders, (iii) mental health disorders, and (iv) socio-demographic factors. In adjusted models, a diagnosis of non-opioid substance abuse was the strongest predictor of opioid abuse/dependence (OR=2.34, p<0.001). Mental health disorders were moderately strong predictors (OR=1.46, p=0.005) of opioid abuse/dependence. However, the prevalence of mental health disorders was much higher than the prevalence of non-opioid substance abuse disorders (45.3% vs. 7.6%) among users of opioids for CNCP, suggesting that mental health disorders account for more of the population attributable risk for opioid abuse than does non-opioid substance abuse. Males, younger adults, and individuals with greater days supply of prescription opioids dispensed in 2002 were more likely to develop opioid abuse/dependence. Clinicians need to carefully screen for substance abuse and mental health disorders in candidates for opioid therapy and facilitate appropriate treatment of these disorders.

A meta-analysis of the analgesic effects of omega-3 polyunsaturated fatty acid supplementation for inflammatory joint pain

Abstract: Between 40% and 60% of Americans use complementary and alternative medicine to manage medical conditions, prevent disease, and promote health and well-being. Omega-3 polyunsaturated fatty acids (x-3 PUFAs) have been used to treat joint pain associated with several inflammatory conditions. We conducted a meta-analysis of 17 randomized, controlled trials assessing the pain relieving effects of x-3 PUFAs in patients with rheumatoid arthritis or joint pain secondary to inflammatory bowel disease and dysmenorrhea. Meta-analysis was conducted with Cochrane Review Manager 4.2.8. for six separate outcomes using standardized mean differences (SMDs) as a measure of effect size: (1) patient assessed pain, (2) physician assessed pain, (3) duration of morning stiffness, (4) number of painful and/or tender joints, (5) Ritchie articular index, and (6) nonselective nonsteroidal anti-inflammatory drug consumption. Supplementation with x-3 PUFAs for 3–4 months reduces patient reported joint pain intensity (SMD: 0.26; 95% CI: 0.49 to 0.03, p = 0.03), minutes of morning stiffness (SMD: 0.43; 95% CI: 0.72 to 0.15, p = 0.003), number of painful and/or tender joints (SMD: 0.29; 95% CI: 0.48 to 0.10, p = 0.003), and NSAID consumption (SMD: 0.40; 95% CI: 0.72 to 0.08, p = 0.01). Significant effects were not detected for physician assessed pain (SMD: 0.14; 95% CI: 0.49 to 0.22, p = 0.45) or Ritchie articular index (SMD: 0.15; 95% CI: 0.19 to 0.49, p = 0.40) at 3–4 months. The results suggest that x-3 PUFAs are an attractive adjunctive treatment for joint pain associated with rheumatoid arthritis, inflammatory bowel disease, and dysmenorrhea. 2007 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Comparison of general exercise, motor control exercise and spinal manipulative therapy for chronic low back pain: A randomized trial

Abstract: Practice guidelines recommend various types of exercise and manipulative therapy for chronic back pain but there have been few head-to-head comparisons of these interventions. We conducted a randomized controlled trial to compare effects of general exercise, motor control exercise and manipulative therapy on function and perceived effect of intervention in patients with chronic back pain. Two hundred and forty adults with non-specific low back pain 3months were allocated to groups that received 8weeks of general exercise, motor control exercise or spinal manipulative therapy. General exercise included strengthening, stretching and aerobic exercises. Motor control exercise involved retraining specific trunk muscles using ultrasound feedback. Spinal manipulative therapy included joint mobilization and manipulation. Primary outcomes were patient-specific function (PSFS, 3-30) and global perceived effect (GPE, -5 to 5) at 8weeks. These outcomes were also measured at 6 and 12months. Follow-up was 93% at 8weeks and 88% at 6 and 12months. The motor control exercise group had slightly better outcomes than the general exercise group at 8weeks (between-group difference: PSFS 2.9, 95% CI: 0.9-4.8; GPE 1.7, 95% CI: 0.9-2.4), as did the spinal manipulative therapy group (PSFS 2.3, 95% CI: 0.4-4.2; GPE 1.2, 95% CI: 0.4-2.0). The groups had similar outcomes at 6 and 12months. Motor control exercise and spinal manipulative therapy produce slightly better short-term function and perceptions of effect than general exercise, but not better medium or long-term effects, in patients with chronic non-specific back pain.

The roles of sodium channels in nociception: Implications for mechanisms of pain

Abstract: Understanding the role of voltage-gated sodium channels in nociception may provide important insights into pain mechanisms Voltage-gated sodium channels are critically important for electrogenesis and nerve impulse conduction, and a target for important clinically relevant analgesics such as lidocaine Furthermore, within the last decade studies have shown that certain sodium channel isoforms are predominantly expressed in peripheral sensory neurons associated with pain sensation, and that the expression and functional properties of voltage-gated sodium channels in peripheral sensory neurons can be dynamically regulated following axonal injury or peripheral inflammation These data suggest that specific voltage-gated sodium channels may play crucial roles in nociception Experiments with transgenic mice lines have clearly implicated Nav17, Nav18 and Nav19 in inflammatory, and possibly neuropathic, pain However the most convincing and perhaps most exciting results regarding the role of voltage-gated sodium channels has come out recently from studies on human inherited disorders of nociception Point mutations in Nav17 have been identified in patients with two distinct autosomal dominant severe chronic pain syndromes Electrophysiological experiments indicate that these pain-associated mutations cause small yet significant changes in the gating properties of voltage-gated sodium channels that are likely to contribute substantially to the development of chronic pain Equally exciting, a recent study has indicated that recessive mutations in Nav17 that eliminate functional current can result in an apparent complete, and possibly specific, indifference to pain in humans, suggesting that isoform specific blockers could be very effective in treating pain In this review we will examine what is known about the roles of voltage-gated sodium channels in nociception

Opioid dependence and addiction during opioid treatment of chronic pain.

Abstract: Throughout the long history of opioid drug use by humans, it has been known that opioids are powerful analgesics, but they can cause addiction. It has also been observed, and is now substantiated by multiple reports and studies, that during opioid treatment of severe and short-term pain, addiction arises only rarely. However, when opioids are extended to patients with chronic pain, and therapeutic opioid use is not confined to patients with severe and short-lived pain, compulsive opioid seeking and addiction arising directly from opioid treatment of pain become more visible. Although the epidemiological evidence base currently available is rudimentary, it appears that problematic opioid use arises in some fraction of opioid-treated chronic pain patients, and that problematic behaviors and addiction are problems that need to be addressed. Since the potentially devastating effects of addiction can substantially offset the benefits of opioid pain relief, it seems timely to reexamine addiction mechanisms and their relevance to the practice of long-term opioid treatment for pain. This article reviews the neurobiological and genetic basis of addiction, its terminology and diagnosis, the evidence on addiction rates during opioid treatment of chronic pain and the implications of biological mechanisms in formulating rational opioid treatment regimes.

Sativex successfully treats neuropathic pain characterised by allodynia: A randomised, double-blind, placebo-controlled clinical trial

Abstract: Cannabinoids are known to have analgesic properties. We evaluated the effect of oro-mucosal sativex, (THC: CBD), an endocannabinoid system modulator, on pain and allodynia, in 125 patients with neuropathic pain of peripheral origin in a five-week, randomised, double-blind, placebo-controlled, parallel design trial. Patients remained on their existing stable analgesia. A self-titrating regimen was used to optimise drug administration. Sixty-three patients were randomised to receive sativex and 62 placebo. The mean reduction in pain intensity scores (primary outcome measure) was greater in patients receiving sativex than placebo (mean adjusted scores -1.48 points vs. -0.52 points on a 0-10 Numerical Rating Scale (p=0.004; 95% CI: -1.59, -0.32). Improvements in Neuropathic Pain Scale composite score (p=0.007), sleep NRS (p=0.001), dynamic allodynia (p=0.042), punctate allodynia (p=0.021), Pain Disability Index (p=0.003) and Patient's Global Impression of Change (p<0.001) were similarly greater on sativex vs. placebo. Sedative and gastrointestinal side effects were reported more commonly by patients on active medication. Of all participants, 18% on sativex and 3% on placebo withdrew during the study. An open-label extension study showed that the initial pain relief was maintained without dose escalation or toxicity for 52 weeks.

Modulation of pain by estrogens.

Abstract: It has become increasingly apparent that women suffer a disproportionate amount of pain during their lifetime compared to men. Over the past 15 years, a growing number of studies have suggested a variety of causes for this sex difference, from cellular to psychosocial levels of analysis. From a biological perspective, sexual differentiation of pain appears to occur similarly to sexual differentiation of other phenomena: it results in large part from organizational and activational effects of gonadal steroid hormones. The focus of this review is the activational effects of a single group of ovarian hormones, the estrogens, on pain in humans and animals. The effects of estrogens (estradiol being the most commonly examined) on experimentally induced acute pain vs. clinical pain are summarized. For clinical pain, the review is limited to a few syndromes for which there is considerable evidence for estrogenic involvement: migraine, temporomandibular disorder (TMD) and arthritis. Because estrogens can modulate the function of the nervous, immune, skeletal, and cardiovascular systems, estrogenic modulation of pain is an exceedingly complex, multi-faceted phenomenon, with estrogens producing both pro- and antinociceptive effects that depend on the extent to which each of these systems of the body is involved in a particular type of pain. Forging a more complete understanding of the myriad ways that estrogens can ameliorate vs. facilitate pain will enable us to better prevent and treat pain in both women and men.

Usefulness and limitations of quantitative sensory testing : Clinical and research application in neuropathic pain states

Abstract: a Dept. of Neurosurgery, Pain Center, Karolinska University Hospital and Dept. of Molecular Medicine and Surgery, Section of Clinical Pain research, Karolinska Institutet, 171 76 Stockholm, Sweden b Department of Neurology H6/570, University of Wisconsin Hospital, Madison, WI 53792, USA c INSERM U-792, CHU Ambroise Pare, APHP, Boulogne-Billancourt F-92100, France d Université Versailles-Saint-Quentin, Versailles F-78035, France

Worry and chronic pain: a misdirected problem solving model

Abstract: An important human faculty is our ability to verbally ruminate on possible negative outcomes and plot methods of avoidance or escape. In his novel ‘Saturday’ Ian McEwan succinctly captures the features of worry that make it psychologically relevant to our consideration of chronic pain. First, worry is related to the perceived threat of danger; second, we worry not about what was but about what might be (it is future orientated); third, it functions to promote avoidance; fourth, it is exacerbated when external competition for attention is low (e.g., at night) and finally, it can be hard to control, going unchecked by reason, logic, or self-persuasion. In this topical review we argue that worry is a valuable construct for investigation of the cognitive reality of chronic pain. We begin by defining the construct of worry and map its boundaries within the larger field of fear and anxiety. Next, we apply worry to chronic pain describing how it operates within the context of pain and dis-

Body perception disturbance: a contribution to pain in complex regional pain syndrome (CRPS).

Abstract: In spite of pain in the CRPS limb, clinical observations show patients pay little attention to, and fail to care for, their affected limb as if it were not part of their body. Literature describes this phenomenon in terms of neurological neglect-like symptoms. This qualitative study sought to explore the nature of the phenomenon with a view to providing insights into central mechanisms and the relationship with pain. Twenty-seven participants who met the IASP CRPS classification were interviewed using qualitative methods to explore feelings and perceptions about their affected body parts. These semi-structured interviews were analysed utilising principles of grounded theory. Participants revealed bizarre perceptions about a part of their body and expressed a desperate desire to amputate this part despite the prospect of further pain and functional loss. A mismatch was experienced between the sensation of the limb and how it looked. Anatomical parts of the CRPS limb were erased in mental representations of the affected area. Pain generated a raised consciousness of the limb yet there was a lack of awareness as to its position. These feelings were about the CRPS limb only as the remaining unaffected body was felt to be normal. Findings suggest that there is a complex interaction between pain, disturbances in body perception and central remapping. Clinically, findings support the use of treatments that target cortical areas, which may reduce body perception disturbance and pain. We propose that body perception disturbance is a more appropriate term than 'neglect-like' symptoms to describe this phenomenon.

Exploring joint effects of genes and the clinical efficacy of morphine for cancer pain: OPRM1 and COMT gene

Abstract: Pain is a complex human trait. It is likely that the interaction of multiple genes, each with a small individual effect, along with the effect of environmental factors, influences the clinical efficacy of opioids rather than a single gene alone. Polymorphisms in genes coding for the mu-opioid receptor (A118G) and catechol-O-methyl transferase (Val158Met) may be important modulators of opioid efficacy. We assessed joint effects of the OPRM1 and COMT genes in predicting morphine dose for cancer pain relief. We used genotype and clinical data from a pharmacokinetic study of morphine in 207 inpatients treated with stable morphine dose for at least 3 days by Palliative Medicine Specialists. Results showed significant variation in morphine dose requirement by genotype groups: carriers of COMT Val/Val and Val/Met genotype required 63% and 23%, respectively, higher morphine dose compared to carriers of Met/Met genotype (p=0.02). Carriers of OPRM1 GG genotype required 93% higher morphine dose compared to carriers of AA genotypes (p=0.012). When we explored for joint effects, we found that carriers of the OPRM1 AA and COMT Met/Met genotype required the lowest morphine dose to achieve pain relief (87 mg/24 h; 95%CI=57,116) and those with neither Met/Met nor AA genotype needed the highest morphine dose (147 mg/24 h; 95%CI=100,180). The significant joint effects for the Met/Met and AA genotypes (p<0.012) persisted, even after controlling for demographic and clinical variables in the multivariable analyses. Future studies are needed to further characterize the joint effects of multiple genes, along with demographic and clinical variables, in predicting opioid dose.

Mast cell degranulation activates a pain pathway underlying migraine headache.

Abstract: Intracranial headaches such as that of migraine are generally accepted to be mediated by prolonged activation of meningeal nociceptors but the mechanisms responsible for such nociceptor activation are poorly understood In this study, we examined the hypothesis that meningeal nociceptors can be activated locally through a neuroimmune interaction with resident mast cells, granulated immune cells that densely populate the dura mater Using in vivo electrophysiological single unit recording of meningeal nociceptors in the rat we observed that degranulation of dural mast cells using intraperitoneal administration of the basic secretagogue agent compound 48/80 (2 mg/kg) induced a prolonged state of excitation in meningeal nociceptors Such activation was accompanied by increased expression of the phosphorylated form of the extracellular signal-regulated kinase (pERK), an anatomical marker for nociceptor activation Mast cell-induced nociceptor interaction was also associated with downstream activation of the spinal trigeminal nucleus as indicated by an increase in c-fos expression Our findings provide evidence linking dural mast cell degranulation to prolonged activation of the trigeminal pain pathway believed to underlie intracranial headaches such as that of migraine

The role of mindfulness in a contextual cognitive-behavioral analysis of chronic pain-related suffering and disability

Abstract: An increasing number of studies consider the specific processes by which distressing sensations, thoughts, and emotional experiences exert their influence on the daily functioning of those who suffer with chronic pain. Clinical methods of mindfulness and the processes that underlie them appear to have clear implications in this area, but have not been systematically investigated to this point in time. The purpose of the present study was to examine mindfulness in relation to the pain, emotional, physical, and social functioning of individuals with chronic pain. The present study included 105 consecutive patients attending a clinical assessment for treatment of chronic pain. Each completed a standardized battery of questionnaires, including a measure of mindfulness, the Mindful Attention Awareness Scale [Brown KW, Ryan RM. The benefits of being present: mindfulness and its role in psychological well-being. J Pers Soc Psychol 2003;84:822-48]. Correlation analyses indicated that mindfulness was unrelated to age, gender, education, or chronicity of pain, but was significantly related to multiple measures of patient functioning. In multiple regression analyses, after controlling for patient background variables, pain intensity, and pain-related acceptance, mindfulness accounted for significant variance in measures of depression, pain-related anxiety; physical, psychosocial, and "other" disability. In each instance greater mindfulness was associated with better functioning. The combined increments of variance explained from acceptance of pain and mindfulness were at least moderate and, in some cases, appeared potentially meaningful. The behavioral processes of mindfulness and their accessibility to scientific study are considered.

The facial expression of pain in patients with dementia

Abstract: The facial expression of pain has emerged as an important pain indicator in demented patients, who have difficulties in providing self-report ratings. In a few clinical studies an increase of facial responses to pain was observed in demented patients compared to healthy controls. However, it had to be shown that this increase can be verified when using experimental methods, which also allows for testing whether the facial responses in demented patients are still typical for pain. We investigated facial responses in 42 demented patients and 54 aged-matched healthy controls to mechanically induced pain of various intensities. The face of the subject was videotaped during pressure stimulation and was later analysed using the Facial Action Coding System. Besides facial responses we also assessed self-report ratings. Comparable to previous findings, we found that facial responses to noxious stimulation were significantly increased in demented patients compared to healthy controls. This increase was mainly due to an increase of pain-indicative facial responses in demented patients. Moreover, facial responses were closely related to the intensity of stimulation, especially in demented patients. Regarding self-report ratings, we found no significant group differences; however, the capacity to provide these self-report ratings was diminished in demented patients. The preserved pain typicalness of facial responses to noxious stimulation suggests that pain is reflected as validly in the facial responses of demented patients as it is in healthy individuals. Therefore, the facial expression of pain has the potential to serve as an alternative pain assessment tool in demented patients, even in patients who are verbally compromised.

Habituation to painful stimulation involves the antinociceptive system.

Abstract: The perception of pain results from an interaction between nociceptive and antinociceptive mechanisms. A better understanding of the neural circuitry underlying these physiological interactions provides an important opportunity to develop better treatment strategies for and ultimately even prevent pain. Here, we investigated how repeated painful stimulation over several days is processed, perceived and finally modulated in the healthy human brain. Twenty healthy subjects were stimulated daily with a 20min pain paradigm for 8 consecutive days, and functional MRI performed on days 1, 8 and 22. Repeated painful stimulation over several days resulted in substantially decreased pain ratings to identical painful stimuli. The decreased perception of pain over time is reflected in decreased BOLD responses to nociceptive stimuli in classical pain areas, including thalamus, insula, SII and the putamen. In contrast to this finding, we found that pain-related responses in the rACC, specifically the subgenual anterior cingulate cortex (sgACC), significantly increased over time. Given this area's predominant role in endogenous pain control, this response pattern suggests that habituation to pain is at least in part mediated by increased antinociceptive activity.

Striatal grey matter increase in patients suffering from fibromyalgia – A voxel-based morphometry study

Abstract: Fibromyalgia (FM), among other chronic pain syndromes, such as chronic tension type headache and atypical face pain, is classified as a so-called dysfunctional pain syndrome. Patients with fibromyalgia suffer from widespread, "deep" muscle pain and often report concomitant depressive episodes, fatigue and cognitive deficits. Clear evidence for structural abnormalities within the muscles or soft tissue of fibromyalgia patients is lacking. There is growing evidence that clinical pain in fibromyalgia has to be understood in terms of pathological activity of central structures involved in nociception. We applied MR-imaging and voxel-based morphometry, to determine whether fibromyalgia is associated with altered local brain morphology. We investigated 20 patients with the diagnosis of primary fibromyalgia and 22 healthy controls. VBM revealed a conspicuous pattern of altered brain morphology in the right superior temporal gyrus (decrease in grey matter), the left posterior thalamus (decrease in grey matter), in the left orbitofrontal cortex (increase in grey matter), left cerebellum (increase in grey matter) and in the striatum bilaterally (increase in grey matter). Our data suggest that fibromyalgia is associated with structural changes in the CNS of patients suffering from this chronic pain disorder. They might reflect either a consequence of chronic nociceptive input or they might be causative to the pathogenesis of fibromyalgia. The affected areas are known to be both, part of the somatosensory system and part of the motor system.

Differential expression patterns of cytokines in complex regional pain syndrome

Abstract: Complex regional pain syndromes (CRPS) are characterized by persistent and severe pain after trauma or surgery. Neuro-immune alterations are assumed to play a pathophysiological role. Here we set out to investigate whether patients with CRPS have altered systemic pro- and anti-inflammatory cytokine profiles compared to controls on mRNA and protein level. We studied blood cytokine mRNA and protein levels of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF), interleukin-2 (IL-2) and IL-8 and the anti-inflammatory cytokines IL-4, IL-10, and transforming growth factor-beta1 (TGF beta 1) in 40 prospectively recruited patients with CRPS I, two patients with CRPS II, and 34 controls. Quantitative real-time PCR and enzyme linked immunosorbent assay were used. Additionally, the patients underwent quantitative sensory testing and were assessed with the McGill pain questionnaire and the Hospital anxiety and depression scale. Patients with CRPS had higher blood TNF and IL-2 mRNA levels (p=0.005; p=0.04) and lower IL-8 mRNA levels (p<0.001) than controls. The mRNA for the anti-inflammatory cytokines IL-4 and IL-10 was reduced in the patient group (p=0.004; p=0.006), whereas TGF beta 1 mRNA levels did not differ between groups. These results were paralleled by serum protein levels, except for TGF beta 1, which was reduced in patients with CRPS, and for IL-8, which gave similar protein values in both groups. Sensory testing showed a predominant loss of small fiber-related modalities in the patient group. The shift towards a pro-inflammatory cytokine profile in patients with CRPS suggests a potential pathogenic role in the generation of pain.

Descending analgesia – When the spine echoes what the brain expects

Abstract: Changes in pain produced by psychological factors (e.g., placebo analgesia) are thought to result from the activity of specific cortical regions. However, subcortical nuclei, including the periaqueductal gray and the rostroventral medulla, also show selective activation when subjects expect pain relief. These brainstem regions send inhibitory projections to the spine and produce diffuse analgesic responses. Regrettably the precise contribution of spinal mechanisms in predicting the strength of placebo analgesia is unknown. Here, we show that expectations regarding pain radically change the strength of spinal nociceptive responses in humans. We found that contrary to expectations of analgesia, expectations of hyperalgesia completely blocked the analgesic effects of descending inhibition on spinal nociceptive reflexes. Somatosensory-evoked brain potentials and pain ratings further confirmed changes in spino-thalamo-cortical responses consistent with expectations and with changes in the spinal response. These findings provide direct evidence that the modulation of pain by expectations is mediated by endogenous pain modulatory systems affecting nociceptive signal processing at the earliest stage of the central nervous system. Expectation effects, therefore, depend as much about what takes place in the spine as they do about what takes place in the brain. Furthermore, complete suppression of the analgesic response normally produced by descending inhibition suggests that anti-analgesic expectations can block the efficacy of pharmacologically valid treatments which has important implications for clinical practice.

Fear of movement and (re)injury in chronic musculoskeletal pain: Evidence for an invariant two-factor model of the Tampa Scale for Kinesiophobia across pain diagnoses and Dutch, Swedish, and Canadian samples

Abstract: The aims of the current study were twofold. First, the factor structure, reliability (i.e., internal consistency), and validity (i.e., concurrent criterion validity) of the Tampa Scale for Kinesiophobia (TSK), a measure of fear of movement and (re)injury, were investigated in a Dutch sample of patients with work-related upper extremity disorders (study 1). More specifically, examination of the factor structure involved a test of three competitive models: the one-factor model of all 17 TSK items, a one-factor model of the TSK (Woby SR, Roach NK, Urmston M, Watson P. Psychometric properties of the TSK-11: a shortened version of the Tampa Scale for Kinesiophobia. Pain 2005;117:137-44.), and a two-factor model of the TSK-11. Second, invariance of the aforementioned TSK models was examined in patients with chronic musculoskeletal pain conditions (i.e., work-related upper extremity disorders, chronic low back pain, fibromyalgia, osteoarthritis) from The Netherlands, Sweden, and Canada was assessed (study 2). Results from study 1 showed that the two-factor model of the TSK-11 consisting of 'somatic focus' (TSK-SF) and 'activity avoidance' (TSK-AA) had the best fit. The TSK factors showed reasonable internal consistency, and were modestly but significantly related to disability, supporting the concurrent criterion validity of the TSK scales. Results from study 2 showed that the two-factor model of the TSK-11 was invariant across pain diagnoses and Dutch, Swedish, and Canadian samples. Altogether, we consider the TSK-11 and its two subscales a psychometrically sound instrument of fear of movement and (re)injury and recommend to use this measure in future research as well as in clinical settings.

Heritability of low back pain and the role of disc degeneration

Abstract: Twin studies suggest that both disc degeneration and back pain have a genetic component. We were interested in estimating the heritability of low back pain in men and examining whether genetic influences on back pain are mediated through genetic influences on disc degeneration. Thus, we conducted a classic twin study with multivariate quantitative genetic models to estimate the degree to which genetic (or environmental) effects on back pain were correlated with genetic (or environmental) effects on disc degeneration. Subjects included 147 monozygotic and 153 dizygotic male twin pairs ( N = 600 subjects) from the population-based Finnish Twin Cohort. All subjects underwent lumbar magnetic resonance imaging and completed an extensive interview, including back pain history and exposure to suspected risk factors. Disc height narrowing was the degenerative finding most associated with pain history, and was used to index disc degeneration in the models. Statistically significant genetic correlations were found for disc height narrowing and different definitions of back pain, such as duration of the worst back pain episode ( r g = 0.46) and hospitalization for back problems ( r g = 0.49), as well as disability in the previous year from back pain ( r g = 0.33). The heritability estimates for these back pain variables ranged from 30% to 46%. There also were statistically significant, but weaker, environmental correlations for disc height narrowing with back symptoms over the prior year. A substantial minority of the genetic influences on pain was due to the same genetic influences affecting disc degeneration. This suggests that disc degeneration is one pathway through which genes influence back pain.