Showing papers in "Pain in 2016"

Neuropathic pain: An updated grading system for research and clinical practice

Abstract: The redefinition of neuropathic pain as "pain arising as a direct consequence of a lesion or disease affecting the somatosensory system," which was suggested by the International Association for the Study of Pain (IASP) Special Interest Group on Neuropathic Pain (NeuPSIG) in 2008, has been widely accepted. In contrast, the proposed grading system of possible, probable, and definite neuropathic pain from 2008 has been used to a lesser extent. Here, we report a citation analysis of the original NeuPSIG grading paper of 2008, followed by an analysis of its use by an expert panel and recommendations for an improved grading system. As of February, 2015, 608 eligible articles in Scopus cited the paper, 414 of which cited the neuropathic pain definition. Of 220 clinical studies citing the paper, 56 had used the grading system. The percentage using the grading system increased from 5% in 2009 to 30% in 2014. Obstacles to a wider use of the grading system were identified, including (1) questions about the relative significance of confirmatory tests, (2) the role of screening tools, and (3) uncertainties about what is considered a neuroanatomically plausible pain distribution. Here, we present a revised grading system with an adjusted order, better reflecting clinical practice, improvements in the specifications, and a word of caution that even the "definite" level of neuropathic pain does not always indicate causality. In addition, we add a table illustrating the area of pain and sensory abnormalities in common neuropathic pain conditions and propose areas for further research.

Do we need a third mechanistic descriptor for chronic pain states

Abstract: 1. IntroductionThe redefinition of neuropathic pain,23 which specifically excludes the concept of “dysfunction,” has left a large group of patients without a valid pathophysiological descriptor for their experience of pain. This group comprises people who have neither obvious activation of nocicepto

The fear-avoidance model of pain.

Abstract: This article describes the latest developments in the fear-avoidance model of pain and summarizes the research findings underpinning the model.

Trends and predictors of opioid use after total knee and total hip arthroplasty.

Abstract: Few studies have assessed postoperative trends in opioid cessation and predictors of persistent opioid use after total knee arthroplasty (TKA) and total hip arthroplasty (THA). Preoperatively, 574 TKA and THA patients completed validated, self-report measures of pain, functioning, and mood and were longitudinally assessed for 6 months after surgery. Among patients who were opioid naive the day of surgery, 8.2% of TKA and 4.3% of THA patients were using opioids at 6 months. In comparison, 53.3% of TKA and 34.7% of THA patients who reported opioid use the day of surgery continued to use opioids at 6 months. Patients taking >60 mg oral morphine equivalents preoperatively had an 80% likelihood of persistent use postoperatively. Day of surgery predictors for 6-month opioid use by opioid-naive patients included greater overall body pain (P = 0.002), greater affected joint pain (knee/hip) (P = 0.034), and greater catastrophizing (P = 0.010). For both opioid-naive and opioid users on the day of surgery, decreases in overall body pain from baseline to 6 months were associated with decreased odds of being on opioids at 6 months (adjusted odds ratio [aOR] = 0.72, P = 0.050; aOR = 0.62, P = 0.001); however, change in affected joint pain (knee/hip) was not predictive of opioid use (aOR = 0.99, P = 0.939; aOR = 1.00, P = 0.963). In conclusion, many patients taking opioids before surgery continue to use opioids after arthroplasty and some opioid-naive patients remained on opioids; however, persistent opioid use was not associated with change in joint pain. Given the growing concerns about chronic opioid use, the reasons for persistent opioid use and perioperative prescribing of opioids deserve further study.

Open-label placebo treatment in chronic low back pain: a randomized controlled trial

Abstract: Foundation for the Science of the Therapeutic Encounter (F-STE); National Center for Complementary and Integrative Health; U.S. National Institutes of Health

Pain and the global burden of disease.

Abstract: From time to time a major global research publication appears, which has profound implications for the pain research and clinical management community. The purpose of this article is to draw the attention of PAIN’s readership to one such article, The Global Burden of Disease (GBD) Study 2013, which was recently published in the Lancet. It comprises a comprehensive and extensive assessment of the global burden of disease down to country level. The GBD Study also documents changes in this burden over a 23-year period ending in 2013. Looking forward, there are plans for these data to be updated on an annual basis. In this article, we summarise, interpret, and contextualise the key aspects of theGBDStudy 2013 pertaining to pain.What is striking, and indeed highlighted in an accompanying commentary, about the morbidity and disability burden data is the high prominence of pain, and diseases associated with pain, as a global cause of disability in both the developed and developing countries. Furthermore, an important implication is that although some diseases have decreased in prevalence since 1990 (most notably some associated with acute infectious diseases), those burdens associated with chronic pain are in many cases increasing. This is at least partly because of powerful demographic forces such as the aging of populations in the developed countries and similarly increased survival into middle and old age in the developing countries, resulting both in growing population size and rising prevalence of chronic diseases. In GBD 2010, 40% of the overall disease burden in the developing countries was due to communicable diseases, 49% due to noncommunicable diseases, and 11% due to injuries, and the poorest people in the world were affectedat younger ages (40 andbelow). In developingcountries, populations are ageing at a much faster rate than occurred in developed countries: in theUnitedKingdom, it took45 years for the proportion of the population aged over 65 to double from 7% to 14%, whereas it is predicted to take only 14 years in Columbia. To quote Alex Kalache, “The developed world became rich before it became old. In developing countries, people are becoming old before they become rich.”

Reliability of conditioned pain modulation: a systematic review.

Abstract: A systematic literature review was undertaken to determine if conditioned pain modulation (CPM) is reliable. Longitudinal, English language observational studies of the repeatability of a CPM test paradigm in adult humans were included. Two independent reviewers assessed the risk of bias in 6 domains; study participation; study attrition; prognostic factor measurement; outcome measurement; confounding and analysis using the Quality in Prognosis Studies (QUIPS) critical assessment tool. Intraclass correlation coefficients (ICCs) less than 0.4 were considered to be poor; 0.4 and 0.59 to be fair; 0.6 and 0.75 good and greater than 0.75 excellent. Ten studies were included in the final review. Meta-analysis was not appropriate because of differences between studies. The intersession reliability of the CPM effect was investigated in 8 studies and reported as good (ICC = 0.6-0.75) in 3 studies and excellent (ICC > 0.75) in subgroups in 2 of those 3. The assessment of risk of bias demonstrated that reporting is not comprehensive for the description of sample demographics, recruitment strategy, and study attrition. The absence of blinding, a lack of control for confounding factors, and lack of standardisation in statistical analysis are common. Conditioned pain modulation is a reliable measure; however, the degree of reliability is heavily dependent on stimulation parameters and study methodology and this warrants consideration for investigators. The validation of CPM as a robust prognostic factor in experimental and clinical pain studies may be facilitated by improvements in the reporting of CPM reliability studies.

A systematic review and meta-analysis of the prevalence of chronic widespread pain in the general population.

Abstract: Chronic widespread pain (CWP) is common and associated with poor general health. There has been no attempt to derive a robust prevalence estimate of CWP or assess how this is influenced by sociodemographic factors. This study therefore aimed to determine, through a systematic review and meta-analysis, the prevalence of CWP in the adult general population and explore variation in prevalence by age, sex, geographical location, and criteria used to define CWP. MEDLINE, Embase, CINAHL, and AMED were searched using a search strategy combining key words and related database-specific subject terms to identify relevant cohort or cross-sectional studies published since 1990. Included articles were assessed for risk of bias. Prevalence figures for CWP (American College of Rheumatology criteria) were stratified according to geographical location, age, and sex. Potential sources of variation were investigated using subgroup analyses and meta-regression. Twenty-five articles met the eligibility criteria. Estimates for CWP prevalence ranged from 0% to 24%, with most estimates between 10% and 15%. The random-effects pooled prevalence was 10.6% (95% confidence intervals: 8.6-12.9). When only studies at low risk of bias were considered pooled, prevalence increased to 11.8% (95% confidence intervals: 10.3-13.3), with reduced but still high heterogeneity. Prevalence was higher in women and in those aged more than 40 years. There was some limited evidence of geographic variation and cultural differences. One in 10 adults in the general population report chronic widespread pain with possible sociocultural variation. The possibility of cultural differences in pain reporting should be considered in future research and the clinical assessment of painful conditions.

Patient phenotyping in clinical trials of chronic pain treatments: IMMPACT recommendations.

Abstract: There is tremendous interpatient variability in the response to analgesic therapy (even for efficacious treatments), which can be the source of great frustration in clinical practice This has led to calls for "precision medicine" or personalized pain therapeutics (ie, empirically based algorithms that determine the optimal treatments, or treatment combinations, for individual patients) that would presumably improve both the clinical care of patients with pain and the success rates for putative analgesic drugs in phase 2 and 3 clinical trials However, before implementing this approach, the characteristics of individual patients or subgroups of patients that increase or decrease the response to a specific treatment need to be identified The challenge is to identify the measurable phenotypic characteristics of patients that are most predictive of individual variation in analgesic treatment outcomes, and the measurement tools that are best suited to evaluate these characteristics In this article, we present evidence on the most promising of these phenotypic characteristics for use in future research, including psychosocial factors, symptom characteristics, sleep patterns, responses to noxious stimulation, endogenous pain-modulatory processes, and response to pharmacologic challenge We provide evidence-based recommendations for core phenotyping domains and recommend measures of each domain

The Pain in Neuropathy Study (PiNS): a cross-sectional observational study determining the somatosensory phenotype of painful and painless diabetic neuropathy.

Abstract: Disabling neuropathic pain (NeuP) is a common sequel of diabetic peripheral neuropathy (DPN). We aimed to characterise the sensory phenotype of patients with and without NeuP, assess screening tools for NeuP, and relate DPN severity to NeuP. The Pain in Neuropathy Study (PiNS) is an observational cross-sectional multicentre study. A total of 191 patients with DPN underwent neurological examination, quantitative sensory testing, nerve conduction studies, and skin biopsy for intraepidermal nerve fibre density assessment. A set of questionnaires assessed the presence of pain, pain intensity, pain distribution, and the psychological and functional impact of pain. Patients were divided according to the presence of DPN, and thereafter according to the presence and severity of NeuP. The DN4 questionnaire demonstrated excellent sensitivity (88%) and specificity (93%) in screening for NeuP. There was a positive correlation between greater neuropathy severity (r = 0.39, P < 0.01), higher HbA1c (r = 0.21, P < 0.01), and the presence (and severity) of NeuP. Diabetic peripheral neuropathy sensory phenotype is characterised by hyposensitivity to applied stimuli that was more marked in the moderate/severe NeuP group than in the mild NeuP or no NeuP groups. Brush-evoked allodynia was present in only those with NeuP (15%); the paradoxical heat sensation did not discriminate between those with (40%) and without (41.3%) NeuP. The "irritable nociceptor" subgroup could only be applied to a minority of patients (6.3%) with NeuP. This study provides a firm basis to rationalise further phenotyping of painful DPN, for instance, stratification of patients with DPN for analgesic drug trials.

Mindfulness-based stress reduction and cognitive behavioral therapy for chronic low back pain: similar effects on mindfulness, catastrophizing, self-efficacy, and acceptance in a randomized controlled trial

Abstract: Cognitive behavioral therapy (CBT) is believed to improve chronic pain problems by decreasing patient catastrophizing and increasing patient self-efficacy for managing pain. Mindfulness-based stress reduction (MBSR) is believed to benefit patients with chronic pain by increasing mindfulness and pain acceptance. However, little is known about how these therapeutic mechanism variables relate to each other or whether they are differentially impacted by MBSR vs CBT. In a randomized controlled trial comparing MBSR, CBT, and usual care (UC) for adults aged 20 to 70 years with chronic low back pain (N = 342), we examined (1) baseline relationships among measures of catastrophizing, self-efficacy, acceptance, and mindfulness and (2) changes on these measures in the 3 treatment groups. At baseline, catastrophizing was associated negatively with self-efficacy, acceptance, and 3 aspects of mindfulness (nonreactivity, nonjudging, and acting with awareness; all P values <0.01). Acceptance was associated positively with self-efficacy (P < 0.01) and mindfulness (P values <0.05) measures. Catastrophizing decreased slightly more posttreatment with MBSR than with CBT or UC (omnibus P = 0.002). Both treatments were effective compared with UC in decreasing catastrophizing at 52 weeks (omnibus P = 0.001). In both the entire randomized sample and the subsample of participants who attended ≥6 of the 8 MBSR or CBT sessions, differences between MBSR and CBT at up to 52 weeks were few, small in size, and of questionable clinical meaningfulness. The results indicate overlap across measures of catastrophizing, self-efficacy, acceptance, and mindfulness and similar effects of MBSR and CBT on these measures among individuals with chronic low back pain.

Understanding stigma and chronic pain: a-state-of-the-art review.

Abstract: Chronic nonmalignant pain makes individuals prone to stigmatizing reactions of others. Stigmatizing responses are devaluing and discrediting responses of observers toward individuals who possess a particular characteristic that deviates from societal norms. In the context of chronic nonmalignant pain, an absence of clear tissue damage deviates from the widely held biomedical model, which presumes that clear physiological pathology underlies the pain experience. As well, most people understand pain through acute pain experience, which resolves relatively rapidly over time, leading to uncertainty about pain that does not diminish. These and other processes must be understood to explain the substantial evidence that individuals with chronic pain commonly experience stigmatization by others. The stigma associated with chronic pain is not well understood, with research lacking accounts of determinants, including underlying mechanisms in stigmatizing persons and details concerning vulnerabilities and the impact on stigmatized persons. Furthermore, prevention strategies for teaching how to deal with others’ stigmatizing reactions and programs aimed at minimizing stigmatizing behaviors of observers are scarce. This topical review briefly describes the current understanding of stigma attached to chronic pain and has the intent to provide some thought-provoking ideas and highlight future directions that will inspire both researchers and clinicians.

A systematic review and meta-analysis of risk factors for postherpetic neuralgia

Abstract: Patients with herpes zoster can develop persistent pain after rash healing, a complication known as postherpetic neuralgia. By preventing zoster through vaccination, the risk of this common complication is reduced. We searched MEDLINE and Embase for studies assessing risk factors for postherpetic neuralgia, with a view to informing vaccination policy. Nineteen prospective studies were identified. Meta-analysis showed significant increases in the risk of postherpetic neuralgia with clinical features of acute zoster including prodromal pain (summary rate ratio 2.29, 95% confidence interval: 1.42-3.69), severe acute pain (2.23, 1.71-2.92), severe rash (2.63, 1.89-3.66), and ophthalmic involvement (2.51, 1.29-4.86). Older age was significantly associated with postherpetic neuralgia; for individual studies, relative risk estimates per 10-year increase ranged from 1.22 to 3.11. Evidence for differences by gender was conflicting, with considerable between-study heterogeneity. A proportion of studies reported an increased risk of postherpetic neuralgia with severe immunosuppression (studies, n = 3/5) and diabetes mellitus (n = 1/4). Systemic lupus erythematosus, recent trauma, and personality disorder symptoms were associated with postherpetic neuralgia in single studies. No evidence of higher postherpetic neuralgia risk was found with depression (n = 4) or cancer (n = 5). Our review confirms a number of clinical features of acute zoster are risk factors for postherpetic neuralgia. It has also identified a range of possible vaccine-targetable risk factors for postherpetic neuralgia; yet aside from age-associated risks, evidence regarding risk factors to inform zoster vaccination policy is currently limited.

Meta-analytic evidence for decreased heart rate variability in chronic pain implicating parasympathetic nervous system dysregulation.

Abstract: Both sympathetic and parasympathetic nervous systems are involved in regulating pain states. The activity of these systems seems to become disturbed in states of chronic pain. This disruption in autonomic balance can be measured through the assessment of heart rate variability (HRV), that is, the variability of the interval between consecutive heart beats. However, there is yet to be a systematic evaluation of the body of literature concerning HRV across several chronic pain conditions. Moreover, modern meta-analytical techniques have never been used to validate and consolidate the extent to which HRV may be decreased in chronic pain. Following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement guidelines, this study systematically evaluated and critically appraised the literature concerning HRV in people living with chronic pain. After screening 17,350 sources, 51 studies evaluating HRV in a chronic pain group met the inclusion criteria. Twenty-six moderate-high quality studies were included in quantitative meta-analyses. On average, the quality of studies was moderate. There were 6 frequency-domain and time-domain measures of HRV across a broad range of chronic pain conditions. High heterogeneity aside, pooled results from the meta-analyses reflected a consistent, moderate-to-large effect of decreased high-frequency HRV in chronic pain, implicating a decrease in parasympathetic activation. These effects were heavily influenced by fibromyalgia studies. Future research would benefit from wider use of standardised definitions of measurement, and also investigating the synergistic changes in pain state and HRV throughout the development and implementation of mechanism-based treatments for chronic pain.

Internet-delivered cognitive-behavioral treatment for adolescents with chronic pain and their parents: a randomized controlled multicenter trial.

Abstract: Internet-delivered interventions are emerging as a strategy to address barriers to care for individuals with chronic pain. This is the first large multicenter randomized controlled trial of Internet-delivered cognitive-behavioral therapy (CBT) for pediatric chronic pain. Participants included were 273 adolescents (205 females and 68 males), aged 11 to 17 years with mixed chronic pain conditions and their parents, who were randomly assigned in a parallel-group design to Internet-delivered CBT (n = 138) or Internet-delivered Education (n = 135). Assessments were completed before treatment, immediately after treatment, and at 6-month follow-up. All data collection and procedures took place online. The primary analysis used linear growth models. Results demonstrated significantly greater reduction on the primary outcome of activity limitations from baseline to 6-month follow-up for Internet CBT compared with Internet education (b = -1.13, P = 0.03). On secondary outcomes, significant beneficial effects of Internet CBT were found on sleep quality (b = 0.14, P = 0.04), on reducing parent miscarried helping (b = -2.66, P = 0.007) and protective behaviors (b = -0.19, P = 0.001), and on treatment satisfaction (P values < 0.05). On exploratory outcomes, benefits of Internet CBT were found for parent-perceived impact (ie, reductions in depression, anxiety, self-blame about their adolescent's pain, and improvement in parent behavioral responses to pain). In conclusion, our Internet-delivered CBT intervention produced a number of beneficial effects on adolescent and parent outcomes, and could ultimately lead to wide dissemination of evidence-based psychological pain treatment for youth and their families.

A randomized, phase 2 study investigating TRV130, a biased ligand of the μ-opioid receptor, for the intravenous treatment of acute pain.

Abstract: Efficacy of conventional opioids can be limited by adverse events (AEs). TRV130 is a structurally novel biased ligand of the μ-opioid receptor that activates G protein signaling with little β-arrestin recruitment. In this phase 2, randomized, placebo- and active-controlled study, we investigated the efficacy and tolerability of TRV130 in acute pain after bunionectomy. We used an adaptive study design in which 144 patients experiencing moderate-to-severe acute pain after bunionectomy were randomized to receive double-blind TRV130, placebo, or morphine in a pilot phase. After pilot phase analysis, 195 patients were randomized to receive double-dummy TRV130 0.5, 1, 2, or 3 mg every 3 hours (q3h); placebo; or morphine 4 mg q4h intravenously. The primary end point was the time-weighted average change in numeric rating scale pain intensity over the 48-hour treatment period. Secondary end points included stopwatch and categorical assessments of pain relief. Safety and tolerability were also assessed. TRV130 2 and 3 mg q3h, and morphine 4 mg q4h produced statistically greater mean reductions in pain intensity than placebo over 48 hours (P < 0.005). TRV130 at 2 and 3 mg produced significantly greater categorical pain relief than morphine (P < 0.005) after the first dose, with meaningful pain relief occurring in under 5 minutes. TRV130 produced no serious AEs, with tolerability similar to morphine. These results demonstrate that TRV130 rapidly produces profound analgesia in moderate-to-severe acute pain, suggesting that G-protein-biased μ-opioid receptor activation is a promising target for development of novel analgesics.

Relieving patients' pain with expectation interventions: a meta-analysis.

Abstract: Patients' expectations are important predictors of the outcome of analgesic treatments, as demonstrated predominantly in research on placebo effects. Three commonly investigated interventions that have been found to induce expectations (verbal suggestion, conditioning, and mental imagery) entail promising, brief, and easy-to-implement adjunctive procedures for optimizing the effectiveness of analgesic treatments. However, evidence for their efficacy stems mostly from research on experimentally evoked pain in healthy samples, and these findings might not be directly transferable to clinical populations. The current meta-analysis investigated the effects of these expectation inductions on patients' pain relief. Five bibliographic databases were systematically searched for studies that assessed the effects of brief verbal suggestion, conditioning, or imagery interventions on pain in clinical populations, with patients experiencing experimental, acute procedural, or chronic pain, compared with no treatment or control treatment. Of the 15,955 studies retrieved, 30 met the inclusion criteria, of which 27 provided sufficient data for quantitative analyses. Overall, a medium-sized effect of the interventions on patients' pain relief was observed (Hedges g = 0.61, I = 73%), with varying effects of verbal suggestion (k = 18, g = 0.75), conditioning (always paired with verbal suggestion, k = 3, g = 0.65), and imagery (k = 6, g = 0.27). Subset analyses indicated medium to large effects on experimental and acute procedural pain and small effects on chronic pain. In conclusion, patients' pain can be relieved with expectation interventions; particularly, verbal suggestion for acute procedural pain was found to be effective.

Depression in patients with chronic pain attending a specialised pain treatment centre: prevalence and impact on health care costs.

Abstract: This cross-sectional study aimed to determine the prevalence and impact of depression on health care costs in patients with complex chronic pain. The sample included 1204 patients attending a tertiary pain management service for people with chronic disabling pain, unresponsive to medical treatment. As part of routine care, patients completed a web-based questionnaire assessing mental and physical health, functioning, and service use in the preceding 3 months. Depression was assessed using the 9-item Patient Health Questionnaire. Self-report health care utilisation was measured across 4 domains: general practitioner contacts, contacts with secondary/tertiary care doctors, accident and emergency department visits, and days hospitalised. The participation rate was 89%. Seven hundred and thirty-two patients (60.8%; 95% CI 58.0-63.6) met criteria for probable depression, and 407 (33.8%) met the threshold for severe depression. Patients with depression were more likely to be unable to work because of ill health and reported greater work absence, greater pain-related interference with functioning, lower pain acceptance, and more generalised pain. Mean total health care costs per 3-month period were £731 (95% CI £646-£817) for patients with depression, compared with £448 (95% CI £366-£530) for patients without depression. A positive association between severe depression and total health care costs persisted after controlling for key demographic, functional, and clinical covariates using multiple linear regression models. These findings reveal the extent, severity, and impact of depression in patients with chronic pain and make evident a need for action. Effective treatment of depression may improve patient health and functioning and reduce the burden of chronic pain on health care services.

Mesolimbic dopamine signaling in acute and chronic pain: implications for motivation, analgesia, and addiction

Abstract: The mesolimbic dopamine system comprises neurons in the ventral tegmental area (VTA) and substantia nigra (SN), projecting to the ventral striatum. This system was originally described to mediate pleasure and goal-directed movement associated with rewarding stimuli.70 However, it is now clear that dopamine, although crucial for reward processing, drives not the hedonic experience of reward (“liking”) but rather the instrumental behavior of reward-driven actions (“wanting”).6 Phasic dopamine acts as an incentive salience signal underlying reinforcement learning.57,59 Moreover, aversive stimuli, such as pain, also stimulate dopamine, further diminishing the idea of dopamine as a “reward” signal.9,10 Recent studies suggest that dopamine neurons in the VTA and SN form a heterogeneous population tuned to either (or both) aversive or rewarding stimuli.3,8,30,39 This review will summarize our current understanding of the role of the mesolimbic dopamine system in acute pain and the changes that occur in chronic pain.

Sex differences in pain: a tale of two immune cells.

Abstract: Substantial evidence has implicated microglia in neuropathic pain. After peripheral nerve injury, microglia in the spinal cord proliferate and increase cell-surface expression of the purinergic receptor P2X4. Activation of P2X4 receptors results in release of brain-derived neurotrophic factor, which acts on neurons to produce disinhibition of dorsal horn neurons which transmit nociceptive information to the brain. Disinhibition of these neurons produces pain hypersensitivity, a hallmark symptom of neuropathic pain. However, elucidating this microglia-neuronal signalling pathway was based on studies using only male rodents. Recent evidence has shown that the role of microglia in pain is sexually dimorphic. Despite similar microglia proliferation in the dorsal horn in both sexes, females do not upregulate P2X4Rs and use a microglia-independent pathway to mediate pain hypersensitivity. Instead, adaptive immune cells, possibly T cells, may mediate pain hypersensitivity in female mice. This profound sex difference highlights the importance of including subjects of both sexes in preclinical pain research.

Assessment of physical function and participation in chronic pain clinical trials: IMMPACT/OMERACT recommendations

Abstract: Although pain reduction is commonly the primary outcome in chronic pain clinical trials, physical functioning is also important. A challenge in designing chronic pain trials to determine efficacy and effectiveness of therapies is obtaining appropriate information about the impact of an intervention on physical function. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) and Outcome Measures in Rheumatology (OMERACT) convened a meeting to consider assessment of physical functioning and participation in research on chronic pain. The primary purpose of this article is to synthesize evidence on the scope of physical functioning to inform work on refining physical function outcome measurement. We address issues in assessing this broad construct and provide examples of frequently used measures of relevant concepts. Investigators can assess physical functioning using patient-reported outcome (PRO), performance-based, and objective measures of activity. This article aims to provide support for the use of these measures, covering broad aspects of functioning, including work participation, social participation, and caregiver burden, which researchers should consider when designing chronic pain clinical trials. Investigators should consider the inclusion of both PROs and performance-based measures as they provide different but also important complementary information. The development and use of reliable and valid PROs and performance-based measures of physical functioning may expedite development of treatments, and standardization of these measures has the potential to facilitate comparison across studies. We provide recommendations regarding important domains to stimulate research to develop tools that are more robust, address consistency and standardization, and engage patients early in tool development.

Must we reduce pain intensity to treat chronic pain

Abstract: The idea that physicians have a duty to relieve human suffering dates back to antiquity. However, the notion that suffering can be quantified and monitored as a pain level is a much more recent development. A corollary to this quantitative approach to pain assessment is the notion that pain treatment should be “titrated to effect” on a measured pain intensity level. The titrate to effect principle was developed for treating acute and cancer pain, but was then extended to outpatient treatment of chronic noncancer pain. Because opioids have no strict ceiling dose and may produce rapid and marked reductions in pain intensity, they are uniquely suitable for titrating to effect. The idea that opioids should be used at whatever dose produces a satisfactory reduction in pain intensity, and especially the extension of this principle to chronic pain treatment, has led to dramatic increases in opioid prescribing in many developed countries. Unfortunately, this increased use has been accompanied by increases in opioid abuse, overdose, and death without any significant easing of the population burden of chronic pain. In this article, we will argue that focusing on pain intensity for the assessment and care of patients with chronic pain (1) establishes the wrong goal for care, (2) results in the selection of the wrong patients for the strongest analgesics, and (3) retards our understanding of chronic pain. Let us consider our duty toward the following patient: Mr. Harris is a 41-year-old man who has had axial low back pain for 1 year. He has just moved into town and comes for his first appointment with you, his new primary care physician. A previous lumbar magnetic resonance imaging showed a disk bulge at L5–S1 and some degenerative changes at the other levels, but there is no evidence on physical examination for nerve root irritation. He rates his average pain intensity as 10/10. He takes oxycodone sustained-release 20 mg b.i.d, which used to provide him significant relief, but no longer does. He wants his opioids increased until they relieve his pain. He explains that this was the treatment goal that he agreed onwith his previous physician, who had called it the titrate to effect principle.When you express doubt as to whether an opioid dose increase is the right treatment, he responds, “Don’t you believe I am in pain? Don’t you believe that I deserve relief? Do you just want me to suffer?” You are confused. You do believe Mr. Harris is in pain and deserves relief, but you doubt that escalating his opioid dosewill provide him a lasting and overall benefit. 1. Establishing the right to pain relief

Chronic pain in adolescence and internalizing mental health disorders: a nationally representative study.

Abstract: Chronic pain in childhood and adolescence has been shown to heighten the risk for depressive and anxiety disorders in specific samples in adulthood; however, little is known about the association between a wider variety of chronic pains and internalizing mental health disorders. Using nationally representative data, the objectives of this study were to establish prevalence rates of internalizing mental health disorders (anxiety and depressive disorders) among cohorts with or without adolescent chronic pain, and to examine whether chronic pain in adolescence is associated with lifetime history of internalizing mental health disorders reported in adulthood. Data from the National Longitudinal Study of Adolescent to Adult Health (Add Health) was used (N = 14,790). Individuals who had chronic pain in adolescence subsequently reported higher rates of lifetime anxiety disorders (21.1% vs 12.4%) and depressive disorders (24.5% vs 14.1%) in adulthood as compared with individuals without a history of adolescent chronic pain. Multivariate logistic regression confirmed that chronic pain in adolescence was associated with an increased likelihood of lifetime history of anxiety disorders (odds ratio: 1.33; 95% confidence interval: 1.09-1.63, P = 0.005) and depressive disorders (odds ratio: 1.38; confidence interval: 1.16-1.64, P < 0.001) reported in adulthood. Future research is needed to examine neurobiological and psychological mechanisms underlying these comorbidities.

Expectations predict chronic pain treatment outcomes.

Abstract: Accumulating evidence suggests an association between patient pretreatment expectations and numerous health outcomes. However, it remains unclear if and how expectations relate to outcomes after treatments in multidisciplinary pain programs. The present study aims at investigating the predictive association between expectations and clinical outcomes in a large database of chronic pain patients. In this observational cohort study, participants were 2272 patients treated in one of 3 university-affiliated multidisciplinary pain treatment centers. All patients received personalized care, including medical, psychological, and/or physical interventions. Patient expectations regarding pain relief and improvements in quality of life and functioning were measured before the first visit to the pain centers and served as predictor variables. Changes in pain intensity, depressive symptoms, pain interference, and tendency to catastrophize, as well as satisfaction with pain treatment and global impressions of change at 6-month follow-up, were considered as treatment outcomes. Structural equation modeling analyses showed significant positive relationships between expectations and most clinical outcomes, and this association was largely mediated by patients' global impressions of change. Similar patterns of relationships between variables were also observed in various subgroups of patients based on sex, age, pain duration, and pain classification. Such results emphasize the relevance of patient expectations as a determinant of outcomes in multimodal pain treatment programs. Furthermore, the results suggest that superior clinical outcomes are observed in individuals who expect high positive outcomes as a result of treatment.

Preoperative pain mechanisms assessed by cuff algometry are associated with chronic postoperative pain relief after total knee replacement

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

Vagus nerve stimulation inhibits cortical spreading depression.

Abstract: Vagus nerve stimulation has recently been reported to improve symptoms of migraine. Cortical spreading depression is the electrophysiological event underlying migraine aura and is a trigger for headache. We tested whether vagus nerve stimulation inhibits cortical spreading depression to explain its antimigraine effect. Unilateral vagus nerve stimulation was delivered either noninvasively through the skin or directly by electrodes placed around the nerve. Systemic physiology was monitored throughout the study. Both noninvasive transcutaneous and invasive direct vagus nerve stimulations significantly suppressed spreading depression susceptibility in the occipital cortex in rats. The electrical stimulation threshold to evoke a spreading depression was elevated by more than 2-fold, the frequency of spreading depressions during continuous topical 1 M KCl was reduced by ∼40%, and propagation speed of spreading depression was reduced by ∼15%. This effect developed within 30 minutes after vagus nerve stimulation and persisted for more than 3 hours. Noninvasive transcutaneous vagus nerve stimulation was as efficacious as direct invasive vagus nerve stimulation, and the efficacy did not differ between the ipsilateral and contralateral hemispheres. Our findings provide a potential mechanism by which vagus nerve stimulation may be efficacious in migraine and suggest that susceptibility to spreading depression is a suitable platform to optimize its efficacy.

The epidemiology of chronic pain.

Abstract: Epidemiological studies have demonstrated that, within the past month, around half us will have experienced an episode of pain which has lasted at least 1 day, with the most common sites reported, in a United Kingdom population study, being the low back (30%), hip (25%), neck and shoulder (25%) and knee (24%).9 Using a more stringent defi nition (suffered pain for 6 months, experienced pain in the last month and several times during the last week), a pan-European study reported a prevalence of 19%.1 Prevalence of chronic pain increases through adult life, reaching a peak around the seventh decade (eg, Ref. 5). Pain at some regional sites, particularly in the lower limb, increase in prevalence across the age range (eg, Ref. 12), whereas some such as low back pain decrease at older ages.3 Such a decrease has been hypothesised to be related to changes in pain perception, expectation of pain at older ages and comorbidities. Chronic pain may be related to premature mortality; a review of studies showed a relationship with cancer and cardiovascular death11 which may partly be related to lifestyle factors such as low levels of physical activity and poor quality diet.14

Endogenous opioidergic dysregulation of pain in fibromyalgia: a PET and fMRI study.

Abstract: Endogenous opioid system dysfunction potentially contributes to chronic pain in fibromyalgia (FM), but it is unknown if this dysfunction is related to established neurobiological markers of hyperalgesia. We previously reported that µ-opioid receptor (MOR) availability was reduced in patients with FM as compared with healthy controls in several pain-processing brain regions. In the present study, we compared pain-evoked functional magnetic resonance imaging with endogenous MOR binding and clinical pain ratings in female opioid-naive patients with FM (n = 18) using whole-brain analyses and regions of interest from our previous research. Within antinociceptive brain regions, including the dorsolateral prefrontal cortex (r = 0.81, P 0.67; all P < 0.02), reduced MOR availability was associated with decreased pain-evoked neural activity. Additionally, reduced MOR availability was associated with lower brain activation in the nucleus accumbens (r = 0.47, P = 0.050). In many of these regions, pain-evoked activity and MOR binding potential were also associated with lower clinical affective pain ratings. These findings are the first to link endogenous opioid system tone to regional pain-evoked brain activity in a clinical pain population. Our data suggest that dysregulation of the endogenous opioid system in FM could lead to less excitation in antinociceptive brain regions by incoming noxious stimulation, resulting in the hyperalgesia and allodynia commonly observed in this population. We propose a conceptual model of affective pain dysregulation in FM.

Expose or protect? A randomized controlled trial of exposure in vivo vs pain-contingent treatment as usual in patients with complex regional pain syndrome type 1

Abstract: Complex regional pain syndrome type I (CRPS-I) highly affects patients' ability to perform daily life activities. Pain-related fear might be a key target to reduce disability in chronic pain. Current treatments aiming at reducing pain show little improvements on pain and disability, whereas novel exposure-based treatments targeting pain-related fears have shown to be promising. We conducted a randomized controlled trial (N = 46) comparing exposure in vivo (EXP) with pain-contingent treatment as usual (TAU), for CRPS-I patients with at least moderate levels of pain-related fear. Primary outcome is self-reported disability, for upper and lower extremity, respectively. Secondary outcomes are self-reported pain-intensity, pain-catastrophizing, perceived harmfulness of physical activity, and health-related quality of life. Pretreatment to posttreatment and pretreatment to 6-month follow-up change scores were tested using randomization-based inference. EXP was superior to TAU in reducing upper extremity disability from pretreatment to posttreatment (between-group difference, 1.082; 95% confidence interval [CI], 0.563-1.601; P < 0.001) and from pretreatment to 6-month follow-up (1.303; 95% CI, 0.917-1.690; P < 0.001). EXP was superior in reducing lower extremity disability from pretreatment to 6-month follow-up (3.624; 95% CI, 0.467-6.781; P = 0.02), but not from pretreatment to posttreatment (3.055; 95% CI, -0.018 to 6.128; P = 0.054). All secondary outcomes significantly favored EXP pretreatment to posttreatment, as well as pretreatment to 6-month follow-up. Exposure to daily activities shows to be more effective than a protective pain-contingent TAU in reducing self-reported disability in daily life of CRPS-I patients with at least moderate levels of pain-related fear.