Nociplastic pain: towards an understanding of prevalent pain conditions.

Nociplastic pain is the semantic term suggested by the international community of pain researchers to describe a third category of pain that is mechanistically distinct from nociceptive pain, which is caused by ongoing inflammation and damage of tissues, and neuropathic pain, which is caused by nerve damage. The mechanisms that underlie this type of pain are not entirely understood, but it is thought that augmented CNS pain and sensory processing and altered pain modulation play prominent roles. The symptoms observed in nociplastic pain include multifocal pain that is more widespread or intense, or both, than would be expected given the amount of identifiable tissue or nerve damage, as well as other CNS-derived symptoms, such as fatigue, sleep, memory, and mood problems. This type of pain can occur in isolation, as often occurs in conditions such as fibromyalgia or tension-type headache, or as part of a mixed-pain state in combination with ongoing nociceptive or neuropathic pain, as might occur in chronic low back pain. It is important to recognise this type of pain, since it will respond to different therapies than nociceptive pain, with a decreased responsiveness to peripherally directed therapies such as anti-inflammatory drugs and opioids, surgery, or injections.

Cannabidiol (CBD) in Rheumatic Diseases (Musculoskeletal Pain).

PURPOSE OF REVIEW: This review will address the many uncertainties surrounding the medical use of cannabidiol (CBD). We will begin with an overview of the legal and commercial environment, examine recent preclinical and clinical evidence on CBD, explore questions concerning CBD raised by healthcare professionals and patients, investigate dosing regimens and methods of administration, and address current challenges in the accumulation of sound evidence. RECENT FINDINGS: CBD has potential for relief of symptoms of pain, sleep, and mood disturbance in rheumatology patients, but sound clinical evidence is lacking. CBD is safe when accessed from a regulated source, whereas wellness products are less reliable regarding content and contaminants. Dosing for symptom relief has not yet been established. As many rheumatology patients are trying CBD as a self-management strategy, the healthcare community must urgently accrue sound evidence for effect.

"It feels like an endless fight": a qualitative study exploring healthcare utilization of persons with rheumatic conditions waiting for pain clinic admission.

BACKGROUND: Individuals living with a rheumatic pain condition can face delays in accessing pain clinics, which prevents them from receiving timely treatment. Little is known regarding their specific healthcare utilization in order to alleviate pain while waiting to obtain services in pain clinics. Hence, the aim of this study was to explore the perceptions and experiences of persons living with rheumatic conditions regarding healthcare utilization while waiting to access a pain clinic. METHODS: In this qualitative descriptive study, semi-structured interviews were conducted with adults living with a painful rheumatic condition that reported either being waiting for admission in a pain clinic, having been referred but then denied pain clinic services, or having received services during the previous six months, in the province of Quebec, Canada. The interviews were transcribed verbatim, and an inductive thematic analysis was performed. RESULTS: Twenty-six individuals were interviewed (22 women and 4 men; mean age 54 ± 10 years). Three themes were identified: 1) lacking guidance in identifying solutions to their complex and multidimensional needs, 2) struggling to obtain and maintain services due to systemic access barriers, and 3) displaying resilience through a search for accessible and sustainable self-management strategies. CONCLUSIONS: The current approaches and structures of health services fail to adequately answer the service needs of individuals experiencing painful rheumatic conditions. Important shifts are required in pain education, in increasing access to multidisciplinary approaches at the primary care level and in breaking down barriers individuals with chronic pain face to receive appropriate and timely care.

Use of medical cannabis by patients with fibromyalgia in Canada after cannabis legalisation: a cross-sectional study.

OBJECTIVES: Medications have only small to moderate effects on symptoms in fibromyalgia (FM). Cannabinoids, including medical cannabis (MC) may have potential to fill this gap. Since recreational legalisation of cannabis in Canada, patients have easier access and may be self-medicating with cannabis. We have examined the prevalence and characteristics of MC use in FM patients. METHODS: During a two-month period (June-August 2019), consecutive attending rheumatology patients participated in an onsite survey comprising 2 questionnaires: 1) demographic and disease information completed by the rheumatologist, 2) patient anonymous questionnaire of health status, cannabis use (recreational and/or medicinal) and characteristics of use. RESULTS: In a cohort of 1000 rheumatology attendees, 117 (11.7%) were diagnosed with FM. Ever use of MC was reported by 28 (23.9%; 95%CI: 16.5%-32.7%) FM patients compared to 98 (11.1%; 95%CI: 9.1%-13.4%) non-FM patients. Among FM ever users, 17 (61%) patients continued use of MC. FM ever users vs. FM nonusers tended to be younger, 53 vs. 58 years (p=0.072), were more likely unemployed or disabled 39% vs. 17% (p=0.019) and used more medication types (p=0.013) but did not differ in symptom severity parameters. Cigarette smoking and recreational cannabis were more common in ever users. Global symptom relief on a VAS (1-10) was 7.0±2.3. CONCLUSIONS: FM patients have commonly used MC, with more than half continuing use. Reported symptom relief was substantial. Cigarette smoking and recreational cannabis use may play a facilitatory role in MC use in FM. Adjunctive MC may be a treatment consideration for some FM patients.

The burden of waiting to access pain clinic services: perceptions and experiences of patients with rheumatic conditions.

BACKGROUND: Extensive waiting times before receiving services is a major barrier to adequate pain management. Waiting times may have a detrimental impact on patients' conditions and quality of life. However, there remains a lack of knowledge on the actual experiences of patients waiting to receive services, especially for those with rheumatic conditions. The present study aimed to gain an in-depth understanding of perceptions and experiences of patients with rheumatic conditions regarding access to pain clinic services. The secondary objective was to identify possible solutions to improve this access according to patients' perspectives. METHODS: This qualitative study based on semi-structured interviews was conducted with adults with rheumatic conditions waiting to access pain clinics in the province of Quebec, Canada. Interviews were transcribed verbatim and analyzed using thematic content analysis. RESULTS: Twenty-six participants were interviewed (22 women and 4 men; mean age 54 ± 10 years). Four main themes were identified: 1) the perception that waiting time is unacceptably long; 2) how the lack of information affects patients' experiences of waiting; 3) patients' various expectations towards the pain clinic, from high hopes to disillusionment and 4) carrying an emotional, physical and financial burden resulting from the wait. Participants reported several solutions to improve the experience of waiting, including providing information to patients, increasing resources, improving prioritization processes and care coordination, and providing alternative interventions to patients during the wait. CONCLUSIONS: For patients with rheumatic conditions, access to pain clinic services is challenging due to extensive waiting times. The burden it imposes on them adds to the existing challenge of living with a chronic rheumatic condition. The solutions identified by participants could serve as building blocks to develop and implement measures to improve patients' experience of accessing pain-related services.

All-cause mortality in patients with long-term opioid therapy compared with non-opioid analgesics for chronic non-cancer pain: a database study.

BACKGROUND: Hitherto only studies with selected populations have found an increased all-cause mortality of some selected opioids compared to selected non-opioids for chronic non-cancer pain (CNCP). We have examined the all-cause mortality for CNCP associated with all established opioids compared to non-opioid analgesic therapy (anticonvulsants, antidepressants, dipyrone, non-steroidal agents). METHODS: The study used the InGef (Institute for Applied Health Research Berlin) database which is an anonymized healthcare claims database including 4,711,668 insured persons who were covered by 61 German statutory health insurances between 2013 and 2017.The health insurance companies are the owners of the database. All-cause mortality was determined from death certificates. Adjusted hazard ratios (HRs) including age, gender, comorbidity index, and propensity score as covariates and risk differences (RD) in incidence of death between patients with long-term opioid therapy (LTOT) and control-drug therapy were calculated. RESULTS: The mean age of participants was 66 years; 55% were women. There were 554 deaths during 10,435 person-years for the LTOT patients, whereas there were 340 deaths during 11,342 person-years in the control group. The HR for all-cause mortality was 1.59 (95% CI, 1.38-1.82) with a risk difference of 148 excess deaths (95% CI 99-198) per 10,000 person-years. The elevated risk of death for LTOT was confined to the out-of-hospital deaths: LTOT patients had 288 out-of-hospital deaths during 10,435 person-years (276 per 10,000 person-years) whereas there were 110 deaths during 11,342 person-years (97 per 10,000 person-years) in the control group. HR was 2.29 (95% CI 1.86, 2.83). Although our propensity score matching model indicated a good classification, residual confounding cannot be fully excluded. The opioid group had a higher prevalence of heart failure and a higher use of anti-thrombotic and antiplatelet agents and of psycholeptics. CONCLUSIONS: LTOT for CNCP compared to non-opioid analgesics was associated with an increased risk for all-cause mortality. When considering treatment options for patients with CNCP, the relevant risk of increased all-cause mortality with opioids should be discussed. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03778450, Registered on 7 December 2018.

Gut microbiome: pertinence in fibromyalgia.

The human gut microbiome constitutes a diverse and dynamic community of microorganisms that inhabit the digestive tract. In recent years, there is growing appreciation for the role of the gut microbiome in host health and disease. Gut bacteria are involved in the pathogenesis of numerous medical conditions in a variety of medical fields including gastroenterology, metabolic, rheumatologic, neurologic and psychiatric disorders. Recently, evidence is mounting that gut bacteria could also play a role in chronic pain and specifically fibromyalgia (FM). The composition of the gut bacterial community is altered in individuals with FM, with an altered abundance of a small subset of bacterial species. Some of these species, either with increased or decreased abundance in patients, have established metabolic activity which could have pertinence in the expression of FM symptoms. The putative mechanisms which could allow these bacterial species to affect pain, fatigue, mood and other symptoms include the entry of short-chain-fatty-acids, bile acids, neurotransmitters and bacterial antigens into the host circulation. While these are merely the first steps in understanding the role of the gut microbiome in chronic pain and specifically FM, one might envision exciting future perspectives for better mechanistic understanding of FM, for the development of objective diagnostic aids and potentially for new therapeutic modalities.

Fibromyalgia syndrome: under-, over- and misdiagnosis.

Fibromyalgia syndrome (FM) is an enigma. During the past three decades, with the gradual acceptance of the validity of FM, it is variously under-, over and misdiagnosed. Evidence-based interdisciplinary guidelines have suggested a comprehensive clinical assessment to avoid this diagnostic conundrum. Every patient with chronic pain should be screened for chronic widespread pain (pain in four of five body regions) (CWP). Those with CWP should be screened for presence of additional major symptoms of FM: unrefreshed sleep and fatigue. A complete medical (including drug) history and complete physical examination is mandatory in the evaluation of a patient with CWP in order to consolidate the diagnosis of FM or identify features that may point to some other condition that may have a presentation similar to FM. Limited simple laboratory testing is recommended to screen for possible other diseases. The 2016 criteria may be used to further confirm the clinical diagnosis of FM. In consideration of the differential diagnosis of FM, attention should be paid to the presence of other chronic overlapping pain conditions and of mental disorders. FM as a stand alone diagnosis is however rare, as most patients with FM meet criteria for other chronic overlapping pain conditions or mental disorders. The severity of FM should be assessed in order to direct treatment approaches and help inform the likely outcome for an individual patient.

Efficacy, tolerability and safety of cannabis-based medicines for cancer pain : A systematic review with meta-analysis of randomised controlled trials.

BACKGROUND: The importance of medical cannabis and cannabis-based medicines for cancer pain management needs to be determined. METHODS: A systematic literature search until December 2018 included CENTRAL, PubMed, SCOPUS and trial registers. Randomised controlled trials (RCTs) investigating medical cannabis and/or pharmaceutical cannabinoids for pain control in cancer patients with a study duration of at least 2 weeks and a sample size of at least 20 participants per study arm were included. Clinical outcomes comprised efficacy (pain intensity, patient impression of improvement, combined responder, sleep problems, psychological distress, opioid maintenance and breakthrough dosage), tolerability (dropout rate due to adverse events) and safety (nervous system, psychiatric and gastrointestinal side effects; serious adverse events). The quality of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: Five RCTs with oromucosal nabiximols or tetrahydrocannabinol (THC) including 1534 participants with moderate and severe pain despite opioid therapy were identified. Double blind period of the RCTs ranged between 2 and 5 weeks. Four studies with a parallel design and 1333 patients were available for meta-analysis. The quality of evidence was very low for all comparisons. Oromucosal nabiximols and THC did not differ from placebo in reducing pain, sleep problems, opioid dosages and in the frequency of combined responder, serious adverse events and psychiatric disorders side effects. The number of patients who reported to be much or very much improved was higher with oromucosal nabiximols and THC than with placebo (number needed to treat for an additional benefit 16; 95% confidence interval [CI] 8 to infinite). The dropout rates due to adverse events (number needed to treat for an additional harm [NNTH]: 20; 95% CI 11-100), the frequency of nervous system (NNTH: 10; 95% CI 7-25) and of gastrointestinal side effects (NNTH: 11; 95% CI 7-33) was higher with oromucosal nabiximols and THC than with placebo. CONCLUSIONS: Very low quality evidence suggests that oromucosal nabiximols and THC have no effect on pain, sleep problems and opioid consumption in patients with cancer pain with insufficient pain relief from opioids. The complete manuscript is written in English.

Histological Underpinnings of Grey Matter Changes in Fibromyalgia Investigated Using Multimodal Brain Imaging.

Chronic pain patients present with cortical gray matter alterations, observed with anatomical magnetic resonance (MR) imaging. Reduced regional gray matter volumes are often interpreted to reflect neurodegeneration, but studies investigating the cellular origin of gray matter changes are lacking. We used multimodal imaging to compare 26 postmenopausal women with fibromyalgia with 25 healthy controls (age range: 50-75 years) to test whether regional gray matter volume decreases in chronic pain are associated with compromised neuronal integrity. Regional gray matter decreases were largely explained by T1 relaxation times in gray matter, a surrogate measure of water content, and not to any substantial degree by GABAA receptor concentration, an indirect marker of neuronal integrity measured with [18F] flumazenil PET. In addition, the MR spectroscopy marker of neuronal viability, N-acetylaspartate, did not differ between patients and controls. These findings suggest that decreased gray matter volumes are not explained by compromised neuronal integrity. Alternatively, a decrease in neuronal matter could be compensated for by an upregulation of GABAA receptors. The relation between regional gray matter and T1 relaxation times suggests decreased tissue water content underlying regional gray matter decreases. In contrast, regional gray matter increases were explained by GABAA receptor concentration in addition to T1 relaxation times, indicating perhaps increased neuronal matter or GABAA receptor upregulation and inflammatory edema. By providing information on the histological origins of cerebral gray matter alterations in fibromyalgia, this study advances the understanding of the neurobiology of chronic widespread pain. SIGNIFICANCE STATEMENT: Regional gray matter alterations in chronic pain, as detected with voxel-based morphometry of anatomical magnetic resonance images, are commonly interpreted to reflect neurodegeneration, but this assumption has not been tested. We found decreased gray matter in fibromyalgia to be associated with T1 relaxation times, a surrogate marker of water content, but not with GABAA receptor concentration, a surrogate of neuronal integrity. In contrast, regional gray matter increases were partly explained by GABAA receptor concentration, indicating some form of neuronal plasticity. The study emphasizes that voxel-based morphometry is an exploratory measure, demonstrating the need to investigate the histological origin of gray matter alterations for every distinct clinical entity, and advances the understanding of the neurobiology of chronic (widespread) pain.

Attitudes Toward and Management of Fibromyalgia: A National Survey of Canadian Rheumatologists and Critical Appraisal of Guidelines.

BACKGROUND: Canadian rheumatologists' attitudes toward and management of fibromyalgia remain uncertain. OBJECTIVE: The aim of this study was to explore management strategies and attitudes of Canadian rheumatologists toward fibromyalgia and concordance with guideline recommendations. METHODS: We administered a 17-item cross-sectional survey to Canadian rheumatologists and explored the concordance between respondents' management practices with the 2012 Canadian Guidelines for the diagnosis and management of fibromyalgia. RESULTS: Among 331 Canadian rheumatologists who were approached, 140 returned the survey for a 42% response rate. The majority felt that fibromyalgia was a useful clinical diagnosis (110/138 [80%]) but was divided as to whether fibromyalgia was objectively defined (75/138 [54%]) or a psychosocial condition (42/138 [30%]) or could result in an inability to work (37/138 [27%]). Contrary to guideline recommendations, most (82/134 [61%]) endorsed that tender points were useful for diagnosis. Half endorsed potentially refusing consultations with fibromyalgia patients, and only 42% (59/139) agreed that there were effective therapies for this syndrome. Consistent with the guideline, most respondents managed fibromyalgia with education, exercise therapy, antidepressants, and nonnarcotic analgesics (≥89% for all); however, fewer than half agreed that any of these modalities were effective (endorsement ranged from 9% to 47%). Assessment of the 2012 guideline revealed a number of important limitations. CONCLUSIONS: Canadian rheumatologists largely do not provide primary care for fibromyalgia. Most adhere to guideline recommendations for management of fibromyalgia, but few endorse these interventions as effective. Further research, including updating of the 2012 Canadian Guidelines for the diagnosis and management of fibromyalgia, is required to inform this disconnect.

Is a Responsive Default Mode Network Required for Successful Working Memory Task Performance?

In studies of cognitive processing using tasks with externally directed attention, regions showing increased (external-task-positive) and decreased or "negative" [default-mode network (DMN)] fMRI responses during task performance are dynamically responsive to increasing task difficulty. Responsiveness (modulation of fMRI signal by increasing load) has been linked directly to successful cognitive task performance in external-task-positive regions but not in DMN regions. To investigate whether a responsive DMN is required for successful cognitive performance, we compared healthy human subjects (n = 23) with individuals shown to have decreased DMN engagement (chronic pain patients, n = 28). Subjects performed a multilevel working-memory task (N-back) during fMRI. If a responsive DMN is required for successful performance, patients having reduced DMN responsiveness should show worsened performance; if performance is not reduced, their brains should show compensatory activation in external-task-positive regions or elsewhere. All subjects showed decreased accuracy and increased reaction times with increasing task level, with no significant group differences on either measure at any level. Patients had significantly reduced negative fMRI response (deactivation) of DMN regions (posterior cingulate/precuneus, medial prefrontal cortex). Controls showed expected modulation of DMN deactivation with increasing task difficulty. Patients showed significantly reduced modulation of DMN deactivation by task difficulty, despite their successful task performance. We found no evidence of compensatory neural recruitment in external-task-positive regions or elsewhere. Individual responsiveness of the external-task-positive ventrolateral prefrontal cortex, but not of DMN regions, correlated with task accuracy. These findings suggest that a responsive DMN may not be required for successful cognitive performance; a responsive external-task-positive network may be sufficient. SIGNIFICANCE STATEMENT: We studied the relationship between responsiveness of the brain to increasing task demand and successful cognitive performance, using chronic pain patients as a probe. fMRI working memory studies show that two main cognitive networks ["external-task positive" and "default-mode network" (DMN)] are responsive to increasing task difficulty. The responsiveness of both of these brain networks is suggested to be required for successful task performance. The responsiveness of external-task-positive regions has been linked directly to successful cognitive task performance, as we also show here. However, pain patients show decreased engagement and responsiveness of the DMN but can perform a working memory task as well as healthy subjects, without demonstrable compensatory neural recruitment. Therefore, a responsive DMN might not be needed for successful cognitive performance.

Cannabinoids in the Management of Musculoskeletal or Rheumatic Diseases.

The endocannabinoid system impacts pain and inflammation with potential for therapeutic effect on patients with rheumatic diseases. The current treatment options include the herbal product derived from the plant Cannabis sativa, as well as pharmaceutical preparations. The legalization of medicinal cannabis (marijuana) in many jurisdictions and widespread public advocacy has propelled an interest in use either by prescription or self-medication. In this review, we examine current evidence for efficacy and adverse effects of any cannabinoid product in rheumatic conditions. The evidence to date is scant and precludes making recommendations for the use of cannabinoid preparations in rheumatology patients. In particular, the risks of herbal cannabis in patients are not well defined. Anecdote and advocacy cannot supersede sound evidence.

Cannabinoids for fibromyalgia.

BACKGROUND: This review is one of a series on drugs used to treat fibromyalgia. Fibromyalgia is a clinically well-defined chronic condition of unknown aetiology characterised by chronic widespread pain that often co-exists with sleep problems and fatigue affecting approximately 2% of the general population. People often report high disability levels and poor health-related quality of life (HRQoL). Drug therapy focuses on reducing key symptoms and disability, and improving HRQoL. Cannabis has been used for millennia to reduce pain and other somatic and psychological symptoms. OBJECTIVES: To assess the efficacy, tolerability and safety of cannabinoids for fibromyalgia symptoms in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE to April 2016, together with reference lists of retrieved papers and reviews, three clinical trial registries, and contact with trial authors. SELECTION CRITERIA: We selected randomised controlled trials of at least four weeks' duration of any formulation of cannabis products used for the treatment of adults with fibromyalgia. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted the data of all included studies and assessed risk of bias. We resolved discrepancies by discussion. We performed analysis using three tiers of evidence. First tier evidence was derived from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction, intention-to-treat analysis without imputation for drop-outs; at least 200 participants in the comparison, eight to 12 weeks' duration, parallel design), second tier evidence from data that did not meet one or more of these criteria and were considered at some risk of bias but with adequate numbers (i.e. data from at least 200 participants) in the comparison, and third tier evidence from data involving small numbers of participants that were considered very likely to be biased or used outcomes of limited clinical utility, or both. We assessed the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation). MAIN RESULTS: We included two studies with 72 participants. Overall, the two studies were at moderate risk of bias. The evidence was derived from group mean data and completer analysis (very low quality evidence overall). We rated the quality of all outcomes according to GRADE as very low due to indirectness, imprecision and potential reporting bias.The primary outcomes in our review were participant-reported pain relief of 50% or greater, Patient Global Impression of Change (PGIC) much or very much improved, withdrawal due to adverse events (tolerability) and serious adverse events (safety). Nabilone was compared to placebo and to amitriptyline in one study each. Study sizes were 32 and 40 participants. One study used a cross-over design and one used a parallel group design; study duration was four or six weeks. Both studies used nabilone, a synthetic cannabinoid, with a bedtime dosage of 1 mg/day. No study reported the proportion of participants experiencing at least 30% or 50% pain relief or who were very much improved. No study provided first or second tier (high to moderate quality) evidence for an outcome of efficacy, tolerability and safety. Third tier (very low quality) evidence indicated greater reduction of pain and limitations of HRQoL compared to placebo in one study. There were no significant differences to placebo noted for fatigue and depression (very low quality evidence). Third tier evidence indicated better effects of nabilone on sleep than amitriptyline (very low quality evidence). There were no significant differences between the two drugs noted for pain, mood and HRQoL (very low quality evidence). More participants dropped out due to adverse events in the nabilone groups (4/52 participants) than in the control groups (1/20 in placebo and 0/32 in amitriptyline group). The most frequent adverse events were dizziness, nausea, dry mouth and drowsiness (six participants with nabilone). Neither study reported serious adverse events during the period of both studies. We planned to create a GRADE 'Summary of findings' table, but due to the scarcity of data we were unable to do this. We found no relevant study with herbal cannabis, plant-based cannabinoids or synthetic cannabinoids other than nabilone in fibromyalgia. AUTHORS' CONCLUSIONS: We found no convincing, unbiased, high quality evidence suggesting that nabilone is of value in treating people with fibromyalgia. The tolerability of nabilone was low in people with fibromyalgia.