Eva Kosek

EULAR evidence-based recommendations for the management of fibromyalgia syndrome

Objective: To develop evidence-based recommendations for the management of fibromyalgia syndrome. Methods: A multidisciplinary task force was formed representing 11 European countries. The design of the study, including search strategy, participants, interventions, outcome measures, data collection and analytical method, was defined at the outset. A systematic review was undertaken with the keywords “fibromyalgia”, “treatment or management” and “trial”. Studies were excluded if they did not utilise the American College of Rheumatology classification criteria, were not clinical trials, or included patients with chronic fatigue syndrome or myalgic encephalomyelitis. Primary outcome measures were change in pain assessed by visual analogue scale and fibromyalgia impact questionnaire. The quality of the studies was categorised based on randomisation, blinding and allocation concealment. Only the highest quality studies were used to base recommendations on. When there was insufficient evidence from the literature, a Delphi process was used to provide basis for recommendation. Results: 146 studies were eligible for the review. 39 pharmacological intervention studies and 59 non-pharmacological were included in the final recommendation summary tables once those of a lower quality or with insufficient data were separated. The categories of treatment identified were antidepressants, analgesics, and “other pharmacological” and exercise, cognitive behavioural therapy, education, dietary interventions and “other non-pharmacological”. In many studies sample size was small and the quality of the study was insufficient for strong recommendations to be made. Conclusions: Nine recommendations for the management of fibromyalgia syndrome were developed using a systematic review and expert consensus.

Modulatory influence on somatosensory perception from vibration and heterotopic noxious conditioning stimulation (HNCS) in fibromyalgia patients and healthy subjects

Abstract In order to assess the function of endogenous mechanisms modulating somatosensory input in fibromyalgia (FM), the effect of vibratory stimulation (VS) and heterotopic noxious conditioning stimulation (HNCS) on perception of various somatosensory modalities was assessed. Ten female FM patients and 10 healthy, age‐matched, females participated. VS (100 Hz) was applied to the left forearm for 45 min and quantitative sensory testing (QST) was performed within the vibrated area and in the right thigh before, during and 45 min following vibration. Pressure pain thresholds (PPTs) were assessed by pressure algometry. Perception thresholds to non‐painful cold (CT) and warmth (WT), heat pain thresholds (HPTs), cold pain thresholds (CPTs) and stimulus‐response curves of pain intensity as a function of graded nociceptive heat stimulation were assessed using a Peltier element based thermal stimulator. The effects of HNCS were tested using the upper extremity submaximal effort tourniquet test. Subjects rated tourniquet induced pain intensity on a visual analogue scale (VAS). QST was performed in the right thigh before, during and 60 min following the tourniquet. FM patients did not differ from controls in the response to VS. There was a local increase of PPTs during vibration (P<0.001) and of WTs following vibration (P<0.001). HPTs increased in the forearm and in the thigh (P<0.009) during vibration. CTs and sensitivity to suprathreshold heat pain were not influenced by VS. The intensity of pain induced by the tourniquet did not differ between groups. PPTs increased during the tourniquet in controls (P<0.001) but not in FM patients (difference between groups P<0.001). Decreased sensitivity to non‐painful cold (P<0.001) and non‐painful warmth (P<0.001) was seen during and following (P<0.01; P<0.05, respectively) the tourniquet in both groups alike. HPTs and perception of suprathreshold heat pain remained unaffected in both groups. In conclusion, FM patients did not differ from healthy controls in their response to vibration, but no modulation of pressure pain was induced by HNCS, as opposed to controls, suggesting a dysfunction in systems subserving ‘diffuse noxious inhibitory controls’ (DNIC).

Lack of pressure pain modulation by heterotopic noxious conditioning stimulation in patients with painful osteoarthritis before, but not following, surgical pain relief

&NA; To investigate the influence of chronic nociceptive pain on endogenous pain modulation, the effect of heterotopic noxious conditioning stimulation (HNCS) on perception of various somatosensory modalities was assessed in 15 patients with painful osteoarthritis of the hip. Thirteen patients were re‐assessed when pain‐free 6–14 months following surgery. Sex‐ and age matched healthy subjects assessed at similar time intervals served as controls. The effects of HNCS were tested using the upper extremity submaximal effort tourniquet test. Subjects rated tourniquet‐induced pain intensity on a visual analogue scale (VAS). Quantitative sensory testing (QST) was performed contralaterally to the maximally painful area in 13 patients and contralaterally to the second most painful area in two patients (i.e. lateral thigh n=12, frontal thigh n=1, lateral calf n=2). Sensibility was assessed before, during and 45 min following the tourniquet test. Perception thresholds to light touch were assessed using von Frey filaments and pressure pain thresholds by pressure algometry. Perception thresholds to non‐painful and painful warmth and cold were determined using a Thermotest. In both sessions, patients rated the tourniquet‐induced pain higher than controls at the start (P<0.003 and P<0.006, respectively), but not at the end of the tourniquet test. Decreased sensitivity to light touch (P<0.001) and innocuous cold (P<0.002) was seen during the tourniquet in patients and controls alike, on both occasions, while perception thresholds to innocuous warmth and heat pain remained unaffected. In the first session, pressure pain thresholds increased during the tourniquet test in controls (P<0.002), but not in patients. In the second session, pressure pain thresholds increased during the tourniquet test in controls (P<0.001) and in patients (P<0.02). In conclusion, no pressure pain modulation was induced by HNCS in patients before surgery, as opposed to controls, suggesting a dysfunction in systems subserving ‘diffuse noxious inhibitory controls’ (DNIC). Normal pressure pain modulation induced by HNCS was seen when patients were re‐assessed in a pain‐free state following surgery, indicating that the dysfunction of DNIC had been maintained by chronic nociceptive pain.

Sensory dysfunction in fibromyalgia patients with implications for pathogenic mechanisms.

&NA; This study, addressing etiologic and pathogenic aspects of fibromyalgia (FM), aimed at examining whether sensory abnormalities in FM patients are generalized or confined to areas with spontaneous pain. Ten female FM patients and 10 healthy, age‐matched females participated. The patients were asked to rate the intensity of ongoing pain using a visual analogue scale (VAS) at the site of maximal pain, the homologous contralateral site and two homologous sites with no or minimal pain. Quantitative sensory testing was performed for assessment of perception thresholds in these four sites. Von Frey filaments were used to test low‐threshold mechanoreceptive function. Pressure pain sensitivity was assessed with a pressure algometer and thermal sensitivity with a Thermotest®. In addition the stimulus‐response curve of pain intensity as a function of graded nociceptive heat stimulation was studied at the site of maximal pain and at the homologous contralateral site. FM patients had increased sensitivity to non‐painful warmth (P < 0.01) over painful sites and a tendency to increased sensitivity to non‐painful cold (P < 0.06) at all sites compared to controls, but there was no difference between groups regarding tactile perception thresholds. Compared to controls, patients demonstrated increased sensitivity to pressure pain (P < 0.001), cold pain (P < 0.001) and heat pain (P < 0.02) over all tested sites. The stimulus‐response curve was parallely shifted to the left of the curve obtained from controls (P < 0.003). Intragroup comparisons showed that patients had increased sensitivity to pressure pain (P < 0.01) and light touch (P < 0.05) in the site of maximal pain compared to the homologous contralateral site. These findings could be explained in terms of sensitization of primary afferent pathways or as a dysfunction of endogenous systems modulating afferent activity. However, the generalized increase in sensitivity found in FM patients was unrelated to spontaneous pain and thus most likely due to a central nervous system (CNS) dysfunction. The additional hyperphenomena related to spontaneous pain are probably dependent on disinhibition/facilitation of nociceptive afferent input from normal (or ischemic) muscles.

A classification of chronic pain for ICD-11

Chronic pain has been recognized as pain that persists past normal healing time5 and hence lacks the acute warning function of physiological nociception.35 Usually pain is regarded as chronic when it lasts or recurs for more than 3 to 6 months.29 Chronic pain is a frequent condition, affecting an estimated 20% of people worldwide6,13,14,18 and accounting for 15% to 20% of physician visits.25,28 Chronic pain should receive greater attention as a global health priority because adequate pain treatment is a human right, and it is the duty of any health care system to provide it.4,13 The current version of the International Classification of Diseases (ICD) of the World Health Organization (WHO) includes some diagnostic codes for chronic pain conditions, but these diagnoses do not reflect the actual epidemiology of chronic pain, nor are they categorized in a systematic manner. The ICD is the preeminent tool for coding diagnoses and documenting investigations or therapeutic measures within the health care systems of many countries. In addition, ICD codes are commonly used to report target diseases and comorbidities of participants in clinical research. Consequently, the current lack of adequate coding in the ICD makes the acquisition of accurate epidemiological data related to chronic pain difficult, prevents adequate billing for health care expenses related to pain treatment, and hinders the development and implementation of new therapies.10,11,16,23,27,31,37 Responding to these shortcomings, the International Association for the Study of Pain (IASP) contacted the WHO and established a Task Force for the Classification of Chronic Pain. The IASP Task Force, which comprises pain experts from across the globe,19 has developed a new and pragmatic classification of chronic pain for the upcoming 11th revision of the ICD. The goal is to create a classification system that is applicable in primary care and in clinical settings for specialized pain management. A major challenge in this process was finding a rational principle of classification that suits the different types of chronic pain and fits into the general ICD-11 framework. Pain categories are variably defined based on the perceived location (headache), etiology (cancer pain), or the primarily affected anatomical system (neuropathic pain). Some diagnoses of pain defy these classification principles (fibromyalgia). This problem is not unique to the classification of pain, but exists throughout the ICD. The IASP Task Force decided to give first priority to pain etiology, followed by underlying pathophysiological mechanisms, and finally the body site. Developing this multilayered classification was greatly facilitated by a novel principle of assigning diagnostic codes in ICD-11, termed “multiple parenting.” Multiple parenting allows the same diagnosis to be subsumed under more than 1 category (for a glossary of ICD terms refer to Table ​Table1).1). Each diagnosis retains 1 category as primary parent, but is cross-referenced to other categories that function as secondary parents. Table 1 Glossary of ICD-11 terms. The new ICD category for “Chronic Pain” comprises the most common clinically relevant disorders. These disorders were divided into 7 groups (Fig. ​(Fig.1):1): (1) chronic primary pain, (2) chronic cancer pain, (3) chronic posttraumatic and postsurgical pain, (4) chronic neuropathic pain, (5) chronic headache and orofacial pain, (6) chronic visceral pain, and (7) chronic musculoskeletal pain. Experts assigned to each group are responsible for the definition of diagnostic criteria and the selection of the diagnoses to be included under these subcategories of chronic pain. Thanks to Bedirhan Ustun and Robert Jakob of the WHO, these pain diagnoses are now integrated in the beta version of ICD-11 (http://id.who.int/icd/entity/1581976053). The Task Force is generating content models for single entities to describe their clinical characteristics. After peer review overseen by the WHO Steering Committee,39 the classification of chronic pain will be voted into action by the World Health Assembly in 2017. Figure 1 Organizational chart of Task Force, IASP, and WHO interactions. The IASP Task Force was created by the IASP council and its scope defined in direct consultation of the chairs (R.D.T. and W.R.) with WHO representatives in 2012. The Task Force reports to ... 2. Classification of chronic pain Chronic pain was defined as persistent or recurrent pain lasting longer than 3 months. This definition according to pain duration has the advantage that it is clear and operationalized. Optional specifiers for each diagnosis record evidence of psychosocial factors and the severity of the pain. Pain severity can be graded based on pain intensity, pain-related distress, and functional impairment. 2.1. Chronic primary pain Chronic primary pain is pain in 1 or more anatomic regions that persists or recurs for longer than 3 months and is associated with significant emotional distress or significant functional disability (interference with activities of daily life and participation in social roles) and that cannot be better explained by another chronic pain condition. This is a new phenomenological definition, created because the etiology is unknown for many forms of chronic pain. Common conditions such as, eg, back pain that is neither identified as musculoskeletal or neuropathic pain, chronic widespread pain, fibromyalgia, and irritable bowel syndrome will be found in this section and biological findings contributing to the pain problem may or may not be present. The term “primary pain” was chosen in close liaison with the ICD-11 revision committee, who felt this was the most widely acceptable term, in particular, from a nonspecialist perspective.

Modulation of pressure pain thresholds during and following isometric contraction in patients with fibromyalgia and in healthy controls

&NA; This study aimed at evaluating the influence of submaximal isometric contraction on pressure pain thresholds (PPTs) in 14 fibromyalgia (FM) patients and 14 healthy volunteers, before and after skin hypoesthesia. PPTs were determined with pressure algometry over m. quadriceps femoris before, during and following an isometric contraction. Maximum voluntary contraction (MVC) was assessed using a computerized dynamometer. A contraction of 22% MVC on average was held until exhaustion (max. 5 min) and PPTs were assessed every 30 sec. A local anesthetic cream and a control cream were applied following a double‐blind design and PPTs were reassessed. In healthy volunteers,PPTs increased during contraction (P < 0.001), then decreased after the end of contraction (P < 0.001) but remained above precontraction values during the 5 min of post‐contraction assessments (P < 0.001). In FM patients PPTs decreased in the middle of the contraction period (P < 0.05) and remained below precontraction levels during the rest of the contraction period (P < 0.05) and during the 5 min of post‐contraction assessment (immediately post‐contraction NS; 2.5 min post‐contraction P < 0.01; 5 min post‐contraction P < 0.05). The normalized PPTs were significantly lower in patients than in controls during contraction (start P < 0.01; middle P < 0.001; end P < 0.001.) and at all times during post‐contraction assessments (P < 0.001). Anesthetic cream raised PPTs at rest in controls (P < 0.01) but not in FM patients, and did not influence contraction or post‐contraction PPTs in either group. Therefore, the increased pressure pain sensibility in FM patients is more pronounced deep to the skin. The observed decrease of PPTs during isometric contraction in FM patients could be due to sensitization of mechanonociceptors caused by muscle ischemia and/or dysfunction in pain modulation during muscle contraction.

Somatosensory perception and function of diffuse noxious inhibitory controls (DNIC) in patients suffering from rheumatoid arthritis.

The purpose was to investigate the influence of ongoing pain from an inflammatory nociceptive pain with two different disease durations on somatosensory functions and the effect of heterotopic noxious conditioning stimulation (HNCS) on ‘diffuse noxious inhibitory controls’ (DNIC) related mechanisms. Eleven patients with rheumatoid arthritis of a short duration (< 1 year) (RAI), and 10 patients with rheumatoid arthritis of longer duration (>5 years) (RA5) as well as 21 age‐and sex‐matched healthy controls participated. Pressure pain sensitivity, low threshold mechanoreceptive function and thermal sensitivity, including thermal pain, were assessed over a painful and inflamed joint as well as in a pain‐free area, i.e. the right thigh before HNCS (cold‐pressor test) and repeated at the thigh only during and following HNCS. In RAI and RA5 allodynia to pressure was seen over the joint (p < 0.02 and p < 0.001 respectively) in conjunction with hypoaesthesia to light touch (p < 0.02) and hyperaesthesia to innocuous cold (p < 0.05) in RA5. At the thigh, allodynia to pressure was found in RA5 (p < 0.002). During HNCS, the sensitivity to pressure pain decreased in patients and controls alike (p < 0.001). In conclusion, over an inflamed joint allodynia to pressure was found in both RA groups, with additional sensory abnormalities in RA5. In a non‐painful area, allodynia to pressure was found in RA5, suggesting altered central processing of somatosensory functions in RA5 patients. The response to HNCS was similar in both RA groups and controls, indicating preserved function of DNIC‐related mechanisms.

Decreased muscle blood flow in fibromyalgia patients during standardised muscle exercise: a contrast media enhanced colour Doppler study.

The aim of the study was to investigate if contrast enhanced ultrasound (US) imaging of muscular blood flow during and following exercise could detect alterations in vascularity in fibromyalgia (FM) patients. Ten FM patients and 10 matched controls were examined with US during standardised static and directly following static and dynamic muscular contractions of the infraspinatus muscle. Doppler ultrasound evaluation was performed before and after the administration of ultrasound contrast media. The FM patients had lower magnitude of muscle vascularity following dynamic (p < 0.001) and during (p < 0.002) static exercise compared to controls. The immediate flow response to muscular activity was not only of a lower magnitude, but also of a shorter duration in FM patients following dynamic exercise (p < 0.001) and during static exercise (p < 0.01). There were no statistically significant group differences in blood flow intensity or duration following static contraction. In conclusion, contrast enhanced US was found useful to study real‐time muscle blood flow changes during and following standardised, low‐intensity exercise in FM patients and healthy controls. Our results support the suggestion that muscle ischemia can contribute to pain in FM, possibly by maintaining the central nervous changes such as central sensitisation/disinhibition. US with contrast can be a new valuable approach to assess muscle perfusion in pain patients during standardised exercise.

Patients with fibromyalgia display less functional connectivity in the brain's pain inhibitory network

BackgroundThere is evidence for augmented processing of pain and impaired endogenous pain inhibition in Fibromyalgia syndrome (FM). In order to fully understand the mechanisms involved in FM pathology, there is a need for closer investigation of endogenous pain modulation. In the present study, we compared the functional connectivity of the descending pain inhibitory network in age-matched FM patients and healthy controls (HC).We performed functional magnetic resonance imaging (fMRI) in 42 subjects; 14 healthy and 28 age-matched FM patients (2 patients per HC), during randomly presented, subjectively calibrated pressure pain stimuli. A seed-based functional connectivity analysis of brain activity was performed. The seed coordinates were based on the findings from our previous study, comparing the fMRI signal during calibrated pressure pain in FM and HC: the rostral anterior cingulate cortex (rACC) and thalamus.ResultsFM patients required significantly less pressure (kPa) to reach calibrated pain at 50 mm on a 0–100 visual analogue scale (p < .001, two-tailed). During fMRI scanning, the rACC displayed significantly higher connectivity to the amygdala, hippocampus, and brainstem in healthy controls, compared to FM patients. There were no regions where FM patients showed higher rACC connectivity. Thalamus showed significantly higher connectivity to the orbitofrontal cortex in healthy controls but no regions showed higher thalamic connectivity in FM patients.ConclusionPatients with FM displayed less connectivity within the brain’s pain inhibitory network during calibrated pressure pain, compared to healthy controls. The present study provides brain-imaging evidence on how brain regions involved in homeostatic control of pain are less connected in FM patients. It is possible that the dysfunction of the descending pain modulatory network plays an important role in maintenance of FM pain and our results may translate into clinical implications by using the functional connectivity of the pain modulatory network as an objective measure of pain dysregulation.

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

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