The IASP Satellite Symposium on Fibromyalgia (FM) took place from October 1 to 2 in Nagasaki, Japan. The conference was co-hosted by Dr. Hiroshi Ueda of Nagaskai University and Dr. Daniel Clauw from the University of Michigan. The conference began with opening remarks from Dr. Ueda and then the Keynote address was delivered by Dr. Clauw. Dr. Clauw stated his opinion that the pathophysiology of FM is fairly well understood and is primarily due to central nervous system (CNS) dysfunction that leads to multifocal pain, as well as fatigue accompanied by sleep, memory, and mood difficulties. Dr. Clauw made the case that the CNS theory of FM is the only one that has moved past simply showing an association between findings and the presence of FM to showing that specific CNS abnormality  targeted by drugs with specific mechanisms of action leading to improvement in the subset of individuals with FM who display that particular pathophysiological abnormality. The following talk was by Dr. Winfried Hauser, who emphasized the importance of psychosocial stressors in the development and worsening of individuals with FM. Dr. Kathleen Sluka presented both preclinical and clinical data, suggesting that FM was characterized by diffuse hyperalgesia/allodynia and that both the periphery and CNS may be contributing to symptoms such as fatigue. Dr. Jon Levine presented mainly preclinical studies, suggesting that both CNS and peripheral factors could potentially be playing a role in FM. Dr. Hiroshi Ueda then presented a series of preclinical studies using an intermittent cold stress model in mice that leads to the development of diffuse hyperalgesia and pain behaviors, reminiscent of those seen in FM, and responds to the same types of CNS-acting drugs that work in patients. Dr. Lars Arendt-Nielsen presented a series of studies performed by his group and others showing that the cardinal features of diffuse hyperalgesia/allodynia can be identified in subsets of virtually every chronic pain condition. Dr. Hiroshi Oka introduced the current status of FM treatment in Japan. The first day ended with 2 speakers in oral presentation. Dr. Chie Usui gave a talk about positron emission tomography study in FM, and Dr. Deepak Sharan gave a talk about the 5-year follow-up of individuals in a multidisciplinary FM treatment center in India.The following day began with Dr. Claudia Sommer's presentation of her group's and others data showing that patients with FM have reduced intraepidermal nerve fiber density and postulated that this is playing a role in the pathogenesis of FM. Dr. Manuel Martinez-Lavin then presented his theory that FM is a sympathetically mediated pain syndrome. Dr. Roland Staud suggested that some of the CNS hyperalgesia in FM is reduced when individuals are infused with lidocaine, such that peripheral nociceptive input might be partly responsible for driving the central sensitization seen in FM. Dr. Eva Kosek then followed by presenting neuroimaging and quantitative sensory testing data, suggesting that the CNS hyperactivity in FM can be modulated by both pharmacological and nonpharmacological therapies. Dr. Richard Harris followed by showing evidence that the endogenous opioid system may be partly responsible for the CNS hyperactivity and symptoms seen in FM and suggested that this may explain why opioid therapy is often either ineffective in FM or sometimes actually leads to worsening of symptoms. The following oral presentation was by Dr. Kenji Miki who showed a phase IIa trial of mirtazapine which showed some evidence of efficacy in FM, and then Dr. Kenichi Osada presented a new device for detection of small fiber neuropathy. Abstracts of all presentations whose authors expressed an interest in participating in this report are presented below.In summary, this internationally recognized set of speakers highlighted the fact that much is now known regarding the potential pathogenic mechanisms in FM. Nearly all agree that CNS factors play a predominant role in FM, but there are emerging data suggesting that peripheral factors may also play a role in some individuals and that these individuals might benefit from a different treatment plan than those with pure CNS disease.Daniel J. ClauwThe University of Michigan, Ann Arbor MI, USAThe thinking regarding fibromyalgia (FM) has changed tremendously over the past 2 decades. Originally thought to be a discrete disorder, it is now clear that it might be better considered the end of a continuum, where the key clinical features are multifocal pain accompanied by somatic syndromes such as fatigue, sleep, and memory difficulties. Many but not all individuals with FM also have elevated levels of psychological distress—but both clinical and mechanistic studies clearly demonstrate that the key elements of fibromyalgia and psychological distress are independent of each other (but often co-occur). This independence of FM from psychological factors is especially true in individuals who have elevated high levels of “fibromyalgianess”  but do not meet criteria for fibromyalgia. In these individuals with “sub-threshold FM,” there is a linear relationship between FMness and important clinical features , and this linear relationship only disappears when studies focus only on individuals at the end of this continuum .The neurobiology of FM and centralized pain is becoming increasingly well understood, with abnormalities in levels of central nervous system (CNS) neurotransmitters, increases in pain and sensory responsiveness, and neuroimaging evidence of changes in functional connectivity as well as the size and shape of key brain structures. Nearly all of the treatments that are effective for subsets of patients with FM are directed toward these CNS abnormalities.Fibromyalgia is now considered in the broader pain field to be the model for centralized pain, wherein pain and other symptoms are originating more so from the CNS than the periphery. Individuals with centralized pain are less responsive to classic and commonly used analgesic regimens . They respond better to CNS-acting analgesics and aggressive use of nonpharmacological therapies aimed at the CNS. In summary, FM and centralized pain is “a different type of pain that requires an entirely different type of treatment.”Winfried HäuserDepartment of Psychosomatic Medicine and Psychotherapy, Technische Universität München, GermanyA model of interacting biological and psychosocial variables in the predisposition, triggering, and development of the chronicity of fibromyalgia syndrome (FMS) has been suggested. One prospective longitudinal population-based study demonstrated the association of lifestyle factors  and the development of FMS. Workplace bullying and depression predicted the onset of FMS in one longitudinal cohort study each. A systematic review of case–control studies demonstrated an association of retrospective reports of childhood physical and sexual abuse and diagnosis of FMS in adulthood. Traumatic and major life events and long-term daily hassles might contribute—in genetically predisposed individuals—to central sensitivity and impaired descending pain inhibition.The lifetime prevalence of mental disorders  is up to 80% in patients with FMS. A systematic review of case series demonstrated that depression has a negative impact on FMS outcome (severity of symptoms and disability) and the success of multicomponent treatment. Two case series demonstrated that posttraumatic stress disorder has a negative impact on FMS outcome and working status.A network meta-analysis demonstrated that drugs and cognitive behavioral therapies (CBTs) did not significantly differ in their efficacy at the end of treatment. However, the positive effects of drugs disappear after discontinuation within 2 weeks. In contrast, CBTs have a sustained reduction of pain, disability, and depression at 6-months follow-up . Finally, acceptance-based CBT was superior to the best available drug therapy  in improvement of quality of life at the end of treatment and at 6 months in a randomized controlled trial. Management of moderate and severe forms of FMS which are mainly due to mental comorbidities should include a mental health care specialist.Kathleen A. SlukaThe University of Iowa, Iowa, USAThe underling mechanisms involved in the transition from acute to chronic pain are critically important for preventing and treating chronic pain. Multiple stressors in a critical window may alter central neuron excitability and local immune responses. Neuronal plasticity in the nervous system and alterations in the local immune system by these stressors may underlie the development of chronic widespread pain. Dr. Sluka will present ongoing research examining the neurobiological mechanisms underlying the development of chronic widespread pain. She will show data examining sex differences and the protective role of testosterone, altered immune system activation in the muscle, and alterations in descending facilitation in animal models of chronic widespread pain.Jon D. LevineDepartment of Medicine and Division of Neuroscience, University of California, San Francisco, USAFibromyalgia is a chronic widespread pain syndrome that currently has no pathognomonic feature or biomarker that allows diagnostic certainty and may present as a manifestation of another condition . Thus, development of preclinical models provides a special opportunity to dissect underlying mechanisms. Given the importance of stress in fibromyalgia syndrome, we have focused on models of stress-induced pain. The results of these studies will be presented and the role of the neuroendocrine stress axis presented.Hiroshi UedaDepartment of Pharmacology and Therapeutic Innovation, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japanpm to 10:00 am), followed by ICS with alternating environmental temperatures between 24 and 4°C every 30 min from 10:00 am to 4:30 pm. These procedures were repeated twice. On day 3 (P1), the mice were returned to and adapted to a room temperature of 24°C for 1 hour before the nociception tests. In the ICS-induced generalized chronic pain model in mice, morphine had no significant analgesic effects when given in a systemic or intracerebroventricular (i.c.v.) route. Significant morphine analgesia was observed when NMDA receptor subunit, NR2A-deficient mice, or an NR2A antagonist (i.c.v.) was treated. The repeated co-administration of pregabalin with valspodar, an inhibitor of P-glycoprotein (p-gp), showed complete relief of pain at least for another week after the cessation of treatments. However, there was no morphine analgesia even after the complete recovery from chronic pain. The co-administration with the p-gp inhibitor also showed a potent potentiation of antihyperalgesia by duloxetine . In contrast, mirtazapine, another type of antidepressant (NaSSA) showed potent antihyperalgesic effects without the p-gp inhibitor, and repeated treatments showed complete relief from pain memory. After the repeated treatments with mirtazapine, morphine analgesic effects were recovered. Repeated treatments with donepezil also showed a complete relief from the chronic pain, but morphine analgesia was not recovered. I will discuss about brain mechanisms of all these pharmacotherapeutic effects.We have established a novel mouse model of generalized chronic pain model similar to fibromyalgia, using intermittent cold stress (ICS) exposure. This model was found to show long-lasting mechanical allodynia, thermal hyperalgesia, and other hypersensitivities to chemical and electrical stimuli. Female-predominant gender difference was observed only after the gonadectomy. In this talk, I will introduce a series of pharmacological studies and discuss underlying brain mechanisms and better pharmacotherapy. For the ICS exposure, mice were placed in a cold room at 4°C overnight  and musculoskeletal pain conditions in general. Many similarities exist between different chronic musculoskeletal pain conditions. Musculoskeletal pain may transit from a localized pain problem through a regional representation to a widespread pain condition such as FM. As the pain condition transit from one to the other, more and more sensory abnormalities occur with many sensory abnormalities in FM. There is evidence that as well the intensity of ongoing pain as the duration of pain determine the degree of generalized hyperalgesia. This is important to realize as it underpins the importance of the ongoing nociception for the chronification process in conditions  where the peripheral nociceptive drivers are known, whereas it is more complicated in, eg, FM where the drivers are less obvious.It is generally accepted that pain diagnosis and therapy should be mechanism based, and hence, pain assessment tools (pain biomarkers) should be sufficiently sensitive and advanced to provide such mechanistic information. Translating clinical observations to mechanisms and vice versa are not trivial, and tools to assess quantitatively the different phenomena are mandatory.Such techniques for assessing the peripheral–central pain sensitization mechanisms in patients with FM and other patients with musculoskeletal pain have been developed and provide the opportunity to quantify pain mechanisms such as temporal summation, descending inhibition, spreading sensitization, and additional modality-specific hyperalgesic reactions. Such tools can help to phenotype patients with FM based on the role of the various pain sensitization mechanisms involved and have recently been used as tools to predict pain outcomes after pharmacological or surgical interventions in various groups of musculoskeletal pain conditions.Relating clinical benefit of a given therapy with quantitative assessment of the pain sensitization mechanisms involved provides new opportunities for better diagnostics and hence for tailored and individualized management regimes.Although assessed differently in specific tissues for various musculoskeletal pain conditions, the underlying mechanisms share common underlying features. This mechanistic understanding is of importance for developing better diagnostics and for implementing tailored pain management programs. The understanding that FM and other musculoskeletal conditions share common fundamental features has positioned FM as the one extreme end as opposed to, eg, a myofascial pain problem at the other end. This has provided some new insight into the development of the sensitization processes from one extreme to the other.Hiroshi OkaTokyo Rheumatism Pain Clinic, Tokyo, JapanWe have 3 double-blind multicenter placebo-controlled clinical trials for fibromyalgia (FM) in Japan. The first clinical trial was pregabalin (P-3). This trial demonstrated that pregabalin, at doses of up to 450 mg/d, was effective for the symptomatic relief of pain in Japanese patients with FM. Pregabalin also improved measures of sleep and functioning and was well tolerated. These data indicate that pregabalin is an effective treatment option for the relief of pain and sleep problems in Japanese patients with FM.The second clinical trial was duloxetine (P-3). Duloxetine treatment was associated with improved outcomes in secondary and post-hoc analyses of the mean change in the BPI average pain score and most of the secondary outcomes, including analgesia and QOL. Duloxetine treatment was safe and well tolerated. These results suggest that duloxetine treatment could be associated with improvements in pain relief and QOL in Japanese patients with FM.The third clinical trial was mirtazapine (P-2). Compared with placebo, mirtazapine produced a significantly greater analgesic effect and significantly greater improvements in QOL in terms of job ability, anxiety, and role or social functioning. Of note, mirtazapine was found to be effective in controlling FM pain even in patients without coexisting depression; other treatments are neurotropin, tramadol, and tramset in Japan.Claudia SommerDepartment of Neurology, University of Würzburg, GermanyIn recent years, data have accumulated showing pathoanatomical and functional abnormalities of peripheral nociceptors in patients with fibromyalgia syndrome (FMS). Taking together the cumulative data by several groups of researchers, this may be true for approximately 50% of the patients classified as the fibromyalgia group and may indicate an important subtype. In particular, quantitative sensory testing has shown deficits in thermal and tactile sensation in patients with FMS, indicating loss of function in A-delta and C-fibers or their afferent tracts. These data from the psychophysical testing are supported by findings from studies using evoked potentials like laser-evoked potentials and so-called pain-related evoked potentials, which show reduced amplitudes in patients with FMS. While these techniques do not allow a differentiation between a lesion in peripheral or central parts of the somatosensory system, skin biopsy and microneurography findings have clarified this issue. Confirmed by data from several laboratories, a subgroup of patients with FMS has a reduced intraepidermal nerve fiber density, indicating a peripheral pathology. This is supported by microneurography findings, where patients with FMS, like those with painful small fiber neuropathy, have increased spontaneous activity in nociceptors. Furthermore, patients with FMS have abnormal activity-induced slowing, which further differentiates them from patients with classical small fiber neuropathy. A possible explanation for this phenomenon is the finding that dermal C-fibers in patients with FMS are thinner than those of controls. A first potential explanation for the small fiber pathology of FMS has come from research on micro RNAs. We recently showed that miR-let-7d and its downstream target insulin-like growth factor-1 (IGF-1R) are aberrantly expressed in skin of patients with FMS with small nerve fiber impairment. Further research is needed to evaluate the significance of these findings for the pathophysiology of FMS.Manuel Martinez-LavinDepartment of Rheumatology, National Institute of Cardiology, MexicoOur group has proposed that fibromyalgia is a neuropathic pain syndrome based on the following 3 arguments: (1) fibromyalgia is a stimulus-independent pain state; (2) the presence of allodynia as an essential feature of fibromyalgia; and (3) the presence of paresthesias as a distinctive feature of fibromyalgia. Among neuropathic syndromes, we propose that fibromyalgia pain is sympathetically maintained based on the following issues: the high frequency of physical, infectious, or psychological stressors as a triggering event; diverse heart rate variability studies showing that patients with fibromyalgia have changes consistent with ongoing sympathetic hyperactivity; a double-blind study demonstrating that norepinephrine injections rekindle fibromyalgia pain; the associated variations of the COMT gene and the adrenergic receptor gene, and finally, studies using the Composite Autonomic Symptom Score (COMPASS) questionnaire showing that fibromyalgia patients have prominent dysautonomia symptoms.The recent finding of small fiber neuropathy in most patients with fibromyalgia reinforces the notion of fibromyalgia as a sympathetically maintained neuropathic pain syndrome. Corneal confocal microscopy has corroborated the presence of small nerve fiber pathology in fibromyalgia.v1.7) genetic variations provide an additional link between fibromyalgia and small fiber neuropathy. Severe fibromyalgia is associated with the Nav1.7 rs6754031 GG genotype. However, gain-of-function mutations in sodium channel Nav1.7 are present in 28% of patients with small fiber neuropathy.The SCN9A-encoded dorsal root ganglia sodium channels'  complain of chronic pain from deep tissues including muscles as well as often disabling fatigue. Previous research suggests the relevance of impulse input from deep tissues for clinical FM pain. Similarly, activated metaboreceptors of muscles seem to contribute to chronic fatigue.We enrolled 62 female patients with FM and 58 patients with chronic fatigue into 2 double-blind controlled studies to receive 200 mg lidocaine or saline injections into the trapezius and gluteal muscles. In addition to pain and fatigue, study variables included pressure and heat hyperalgesia. Furthermore, all patients were asked to indicate by forced choice after the injections whether they had received the active study drug or normal saline.P < 0.05). Similar results were obtained for secondary heat hyperalgesia at the arms (P < 0.05). After muscle injections, clinical FM pain and chronic fatigue significantly declined by 38% and 35%, respectively. According to postinjection questionnaires, subjects could not reliably distinguish whether they had received lidocaine or saline injections.Primary mechanical hyperalgesia at the shoulders and buttocks of FM and chronic fatigue syndrome subjects decreased significantly more after lidocaine than saline injections  is associated with a generalized hypersensitivity to painful stimuli, and behaviour data indicate a dysfunction of descending pain inhibitory pathways. Therefore, central sensitization has been proposed to be an important pathophysiological mechanism in FM. The latter is supported by studies using functional magnetic resonance imaging demonstrating augmented nociceptive processing and reduced pain-related activation of rostral anterior cingulate cortex and thalamus, ie, cerebral regions implicated in pain modulation. These abnormalities were not associated with the degree of rated depression or anxiety, suggesting separate processing of negative affect and nociceptive input. In addition, patients with FM had less pain-related functional connectivity within the brain's pain inhibitory network and structural changes such as decreased cortical thickness and reduced brain volumes. There was an overlap between these functional and structural abnormalities, and both were more pronounced in patients with a longer duration of FM, suggesting a time-dependent progress of cerebral pathology in FM.Furthermore, a short duration of FM predicted a better outcome after a 12-week treatment with the serotonin–noradrenalin reuptake inhibitor milnacipran. The degree of improvement and reductions in pain sensitivity after the milnacipran treatment corresponded to increased pain-related activation of precuneus, a cerebral area associated with pain modulation, and the default-mode network. In contrast, 12 weeks of cognitive behaviour therapy did not affect clinical pain or pain sensitivity but increased activations of cerebral regions implicated in executive cognitive control during painful stimulation and thus likely affected reappraisal of painful stimuli. Finally, a newly developed protocol of individually graded physical exercise for 15 weeks reduced symptoms and pain sensitivity. The elevated interstitial glutamate and pyruvate concentrations in the quadriceps muscle of patients with FM normalized after the exercise intervention. Pain-related cerebral activation was not affected, indicating that peripheral muscular mechanisms were involved in pain relief. However, a partial normalization of cerebral resting-state activity and improved cognitive functioning was seen in patients with FM after the exercise intervention. In conclusion, we demonstrated that at least some of the cerebral abnormalities in patients with FM are reversible. The fact that different treatment modalities affected specific cerebral mechanisms would support the rational for combination therapies in FM.Richard E. HarrisDepartment of Anesthesiology, University of Michigan, Ann Arbor MI, USAPain can be elicited throughout all mammalian sensory pathways, yet cross-modal sensory integration, and its relationship to pain in clinical conditions, has largely been unexplored. Fibromyalgia is the prototypical centralized chronic pain condition that is characterized by symptoms of multimodal sensory hypersensitivity, wherein individuals have aversive responses to touch/thermal stimuli, loud sounds, and even bright lights. As such, it is thought that this condition involves a large-scale amplification of sensory processes that cut across multiple modalities. Previous work suggests that the locus for this sensory integration may lie within the insular cortex as this structure has consistently displayed altered neurochemical imbalances as well as aberrant functional connectivity that have both been associated with the magnitude of clinical pain in this population. Here, I will present data demonstrating cross-modal sensory hypersensitivity to visual as well as pressure stimuli in patients with fibromyalgia and also investigate how changes in this activity can be modulated with pregabalin, a compound showing efficacy in this population. We will explore how functional magnetic resonance imaging has revealed that insular activity evoked by simple visual stimulation is intimately associated with chronic pain in fibromyalgia. Moreover, attenuation of this insular activity by the analgesic pregabalin is accompanied by concomitant reductions in clinical pain. These dynamic processes during pregabalin treatment occur in concert with reductions in insular glutamate (the brain's major excitatory neurotransmitter), gray matter volume, and functional connectivity between the default mode network . Finally, I will also present data from multivariate classification methods using support vector machines applied to visual-evoked brain activity that can distinguish patients with fibromyalgia from healthy controls with significant accuracy. Interestingly, a separate support vector machine classification of treatment effects on visual-evoked activity can also identify patients administered with pregabalin as compared with placebo: importantly regions differentiating patients from controls and pregabalin from placebo treatment share overlapping insular topology. These data strongly suggest that abnormal integration of multisensory pathways within the insula may represent a pathophysiological mechanism in centralized chronic pain. Furthermore, insular response to aversive visual stimulation may also have utility as a marker for analgesic drug development beyond pregabalin, in particular for compounds that target the central nervous system.This work is supported by grants from Pfizer Inc, the Dana Foundation, Department of Defense (Army Grant: DAMD-W81XWH-07-2-0050), and National Institutes of Health .Chie UsuiDepartment of Psychiatry, Juntendo University Nerima Hospital, JapanPurpose: The aim of this study was to determine the brain regions with altered metabolism in patients with treatment-naive fibromyalgia (FM).Methods: We studied a total of 18 drug-naive patients with FM and 18 healthy controls without suffering from pain and who were matched for age and sex. [18F] fluoro-d-glucose positron emission tomography was tested in both patients with FM and controls. A voxel-by-voxel group analysis was performed using SPM8.Results: No significant voxel (peak)-level result was detected in this study; however, some regions were detected as significant-size clusters. There was no significant difference in brain metabolism between patients with FM and controls. However, the right thalamus and left lentiform nucleus were hypermetabolic areas in patients with FM with poor prognosis compared with the healthy controls. In contrast, the left insula and left lentiform nucleus were hypometabolic areas in patients with FM with good prognosis compared with the healthy controls. Compared with patients with FM with good prognosis, FM patients with poor prognosis showed significant hypermetabolism in the left thalamus, bilateral lentiform nucleus, and right parahippocampal gyrus.Conclusion: These findings suggest an association between the metabolism in the thalamus, lentiform nucleus, and parahippocampal gyrus and a prognosis in patients with FM. Further study with larger number of patients is required to confirm this finding.This research is supported by the chronic pain research project from the Japan Agency for Medical Research and development, AMED.Deepak SharanRECOUP Neuromusculoskeletal Rehabilitation Centre, Bangalore, Indiat test showed a significant difference (P > 0.05) between Fibromyalgia Impact Questionnaire and Short Form-36 scores of the first visit, 1-year, and 5-year follow-ups. Significant improvement (P > 0.05) in pain reduction, sleep, and fatigue was noticed after the 5-year follow-up. The subjects were not taking any specific treatment for FMS other than home-based exercises at the time of the last follow-up. This study emphasizes the need for a comprehensive sequenced multidisciplinary approach for effective treatment of FMS. There was a significant improvement in pain, sleep, fatigue, depression, and general quality of life, and the effects were maintained at a follow-up of 5 years.A study was conducted in 2009 to assess the outcome of a sequenced multidisciplinary rehabilitation for fibromyalgia syndrome (FMS) in 30 subjects  at a follow-up of 1 year. A 5-year follow-up study was performed in the same individuals. All the subjects were diagnosed by an experienced orthopedic and rehabilitation physician and were treated with a sequenced multidisciplinary rehabilitation protocol. The outcomes measured included pain and sleep with visual analog scale, fatigue using Borg CR 10 scale, and depression with help of Beck Depression Inventory, Fibromyalgia Impact Questionnaire, and Short Form-36. Of the samples, 26 were software professionals, 3 were house wives, and 1 was a teacher. Nineteen subjects  participated in the 5-year follow-up study. Eleven subjects had changed their contact details and could not be contacted. Mean scores during the first visit, at 1-year, and 5-year follow-ups were 6.56, 2.1, and 1.2 for pain, 5.36, 1.53, and 1 for fatigue, 5.7, 1.56, and 1 for sleeplessness, and 10.6, 4.7, and 2.64 for Beck Depression Inventory, respectively. Results of paired a, Masato Murakamib, Hiroshi Okac, Kaname Onozawad, Sadahiro Yoshidad, Kenichi OsadaeKenji MikiaDepartment of Pain Medicine, Osaka University Graduate School of Medicine, Center for pain management, Hayaishi HospitalbSanno Hospital, International University of Health and WelfarecDepartment of Rheumatology, Hachioji Medical Center, Tokyo Medical UniversitydClinical Research Planning Department, Meiji Seika Pharma Co, LtdeDepartment of Neuropsychiatry, St. Marianna University School of Medicine, JapanP = 0.0018). The reduction by mirtazapine remained greater compared with placebo from week 6 onward. Mirtazapine also improved pain-related quality of life assessed by the Japanese version of the Fibromyalgia Impact Questionnaire and the Short Form-36 questionnaire. Adverse events were more common with mirtazapine than placebo (68.8% vs 56.7%), including somnolence (32.1% vs 7.4%), weight gain (17.7% vs 0.9%), and increased appetite (11.6% vs 3.3%). In conclusion, mirtazapine was an effective and safe treatment for Japanese patients with FM.To evaluate the efficacy and safety of mirtazapine in Japanese patients with fibromyalgia (FM), a parallel-group randomized double-blind placebo-controlled phase IIa study was conducted at 57 sites. Patients aged 20 to 64 years who met the American College of Rheumatology 1990 diagnostic FM criteria and had stably high pain scores during a placebo run-in period were randomly assigned to receive mirtazapine (15 mg/d for 1 week and then 30 mg/d) or matching placebo for 12 weeks. The primary endpoint was change in mean numerical rating scale pain score from baseline to endpoint (week 12 or early discontinuation). Of 430 patients randomized (n = 215 each group), 422 (n = 211 each group) were analyzed for the primary endpoint. At the endpoint, mirtazapine caused a significantly greater reduction of mean numerical rating scale pain score compared with placebo . We investigate the offset analgesia responses for the 119 patients with fibromyalgia by the pain detected with medical instrument X .This study was a prospective cohort study in multi-institutional joint research. Offset analgesia responses were measured by medical instrument X .P < 0.001; r = 0.343). The peak value to the pain of the patients with depression (n = 5) was decreased compared with that of the controls (n = 17).Offset analgesia was diapered to patients with fibromyalgia, as the same as the patients with neuropathic pain. After offset, the pain of fibromyalgia was correlated with the total J-FIQ score  patients had lower urinary tract complaints, of which there were 16 (65%) bladder pain syndrome or interstitial bladder cases, 8 (27%) nonneurogenic overactive bladder cases, 2 (7%) neurogenic overactive bladder cases.The efficacy rate of treatment with and without lower urinary tract complaints was 83% and 62%, respectively. The patients with fibromyalgia with lower urinary tract complaints were relieved of pain easier than those without lower urinary tract complaints, but their lower urinary tract complaints got worse alternatively after pain relief.Conclusion: Patients with fibromyalgia with lower urinary tract complaints could get pain control easier than those without lower urinary tract complaints, but their lower urinary tract complaints remain after pain relief.a, Richard Kwiatekb, R. Burnetc, P. Del Fanted, D. R. Stainesa, S. M. Marshall-Gradisnika, L. R. BarndenaZ. Y. ShanaNational Centre for Neuroimmunology and Emerging Diseases, Griffith University, Southport, QLDbModbury Hospital, Adelaide, SAcRoyal Adelaide Hospital, Adelaide, SAdHealthfirst Network, Adelaide, SA, AustraliaPFWE = 0.03, MNI co-ordinates −45, −20, −20). Cross-sectional between-group VBM of T2 plus T3 (40 CFS vs 14 HC) revealed significantly reduced regional WM volume in the left inferior fronto-occipital fasciculus in CFS . For the first time, in any functional somatic syndrome, in any organ system, we have demonstrated progressive structural pathology, confirmed by a larger cross-sectional study. At the very least, these data indicate that patients with CFS experience a chronic organic brain syndrome. Notably, there exist no published reports of temporal lobe WM volume loss in depression, anxiety, or stress.Acceptance of fibromyalgia as a debilitating multidimensional medical disorder has been hampered by limited longitudinal research and lack of evidence of structural pathology. The chronic fatigue syndrome (CFS) is a disorder with considerable overlap of clinical features with fibromyalgia . The aim of this study was to uniquely assess for progressive regional and total brain volume changes in CFS. Twenty-five Canadian Consensus Criteria defined patients with CFS, and 25 matched healthy controls (HCs) had 3D gradient-echo brain magnetic resonance imaging scans performed (T1). Six years later, 15 CFS and 10 HCs of original study had repeat scans (T2). Twenty-five new CFS and 4 new HCs were recruited for an independent cross-sectional study (T3). Magnetic resonance imaging scans were interrogated using optimised , whole-brain, SPM12 voxel-based morphometry (VBM). Cross-sectional between-group grey matter and white matter (WM) VBM analysis of T1, T2, and T3 revealed no significant differences. Voxel-based morphometry comparison of rates of change in WM volume between T2 and T1 for the 15 CFS and 10 HCs in T2 revealed a significant regional 4.5% reduction over 6 years in the posterior left inferior fronto-occipital fasciculus , followed by ICS with alternating environmental temperatures between 24 and 4°C every 30 min from 10:00 am to 4:30 pm. These procedures were repeated twice. On day 3 (P1), the mice were returned to and adapted to a room temperature of 24°C for 1 hour before the nociception tests. Duloxetine and milnacipran showed potent antihyperalgesic effects when given intrathecally (i.t.) but not systemically (i.p.) or i.c.v. at P5. Mirtazapine, a nonclassical receptor antagonist-type antidepressant showed potent antihyperalgesic effects by i.p. injection. Its potent antihyperalgesic effects were also observed by i.c.v. injection but not i.t. injection. Repeated i.p. injections of mirtazapine from P5 to P11 caused the complete relief of abnormal pain even at P19, 7 days after the cessation of treatments. In addition, these treatments also recovered the morphine analgesic effects. All these findings suggest that repeated mirtazapine treatments cure the abnormal pain disease or pain memory in a FM-like animal model.We have established a novel mouse model of generalized chronic pain model similar to fibromyalgia (FM), using intermittent cold stress (ICS) exposure. This model was found to show long-lasting mechanical allodynia, thermal hyperalgesia, and other hypersensitivities to chemical and electrical stimuli. Female-predominant gender difference was observed only after the gonadectomy. In a series of studies, we obtained the therapeutic effects of gabapentinoids and classical antidepressants, but not morphine in the ICS model. All these findings suggest the consistency to the clinical evidence for FM. In this study, we focus the beneficial effects of various types of antidepressants in terms of the site of action and therapeutic potentials. For the ICS exposure, mice were placed in a cold room at 4°C overnight , followed by ICS with alternating environmental temperatures between 24 and 4°C every 30 min from 10:00 am to 4:30 pm. These procedures were repeated twice. On day 3 (P1), the mice were returned to and adapted to a room temperature of 24°C for 1 hour before the nociception tests. In this study, we focused the beneficial potentials of P-glycoprotein (P-gp) inhibitors for the antihyperalgesic effects of pregabalin and duloxetine. Pregabalin (i.p.) showed potent antihyperalgesic effects in the ICS model. The combined treatment with valspodar, a P-gp inhibitor, decreased effective doses and prolonged the duration of pregabalin (i.p.)-induced antihyperalgesic effects. The repeated combined daily treatments of pregabalin and valspodar from P5 to P11 completely cured the basal hyperalgesic threshold 7 days after the cessation of drug treatments. Duloxetine showed potent antihyperalgesic effects when given i.t. but not i.p. The combination of duloxetine (i.p.) with tariquidal, another type of P-gp inhibitor, showed potent antihyperalgesic effects, and repeated treatments also cured the basal hyperalgesic threshold 7 days after the cessation of drug treatments. We are pursuing the mechanistic clarification of the P-gp–induced potentiation in terms of neurochemical and pharmacokinetic aspects.We are looking for better pharmacotherapeutic treatments for generalized chronic pain disease by use of our established intermittent cold stress (ICS) model in mice. In a series of studies, we have demonstrated that the ICS model has many features similar to fibromyalgia in terms of pathophysiological  and pharmacotherapeutic aspects (sensitive to gabapentinoids and antidepressants but not morphine). In the ICS exposure, mice were placed in a cold room at 4°C overnight , followed by ICS with alternating environmental temperatures between 24 and 4°C every 30 minute from 10:00 am to 4:30 pm. These procedures were repeated twice. On day 3 (P1), the mice were returned to and adapted to a room temperature of 24°C for 1 hour before the nociception tests . For the acidic saline model, it was as reported previously by Sluka et al. . Intermittent cold stress model showed abnormal pain behaviors in thermal hyperalgesia, mechanical allodynia, and hypersensitivities to electrical, chemical , and muscle pain stimulation, respectively. Acidic saline model showed mechanical allodynia but not thermal hyperalgesia. To compare the pharmacological effects in both ICS and acidic saline models, mechanical paw withdrawal tests were performed at P5 when they were given i.p. or subcutaneously, respectively. Donepezil showed potent antiallodynic effects in the mechanical paw withdrawal tests in a dose range of 0.001 to 0.01 mg/kg (i.p.) at P5 in the ICS model. When donepezil was treated at P5, P7, and P9, the hyperalgesia was completely gone at P12 and P18. In the acidic saline model, however, donepezil shows much weaker effect with the median effective dose (ED50) ∼1 mg/kg (i.p.) at P5. On the contrary, morphine  did not show any antiallodynic effect in the ICS model, whereas it showed significant beneficial effects with 1 mg/kg s.c., 0.1 nmol i.c.v., and 1 nmol i.t., respectively in the acidic saline model. Pregabalin (i.p.) showed significant allodynic effects in both models. These results suggest that ICS model has more generalized pain symptoms and closer pharmacotherapeutic features to the clinical evidence in terms of lack of morphine analgesia than acidic saline model. To propose that donepezil is a new candidate for the treatment of FM, further basic and clinical information should be obtained.We have established a novel mouse model of generalized chronic pain model similar to fibromyalgia (FM), using intermittent cold stress (ICS) exposure. This model was found to show long-lasting mechanical allodynia, thermal hyperalgesia, and other hypersensitivities to chemical and electrical stimuli. Female-predominant gender difference was observed only after the gonadectomy. In this presentation, we compared the pharmacological features in ICS model and intramuscular acidic saline model. Particularly in this presentation, we focus the therapeutic effects of donepezil and morphine. For the ICS exposure, mice were placed in a cold room at 4°C overnight (from 4:30


Non-specific neck pain represents a quarter of all chiropractic patient visits in Denmark. Evidence informed practice can help ensure providers use best available treatment, speed up patient recovery rate and reduce healthcare utilization. It is generally believed that Danish chiropractors treat according to best practice, but we do not know if this is true for management of neck-pain. The objective of this study was to investigate how Danish chiropractors treat patients with acute and chronic non-specific neck pain and determine if management is compliant with recent Canadian guideline recommendations.An online survey was sent to 554 members of the Danish chiropractic association. A three-part questionnaire was administered asking participants to: 1) rank the frequency of use of a list of treatment modalities; 2) rank treatment modalities they normally use for acute and chronic non-specific neck pain cases; and 3) provide demographic data. Treatment modalities ranked as “used often” were considered in further analysis and compared to the Canadian Guideline recommendations for neck pain. Chi-squared test was used to investigate differences between treatment and guideline compliance for chronic and acute patients.A 65% (362/544) response rate was achieved. The sample demographics were representative of a recent Danish study of the entire chiropractic profession. Danish chiropractors use a wide range of treatment modalities, including spinal manipulation, manual therapy, exercises and information/patient education on most of their acute neck pain patients. The use of other treatment modalities and especially exercises was more commonly used with chronic cases. Guideline compliance was 10% for recommendations for acute patients and 43% for chronic patients.Danish chiropractors use a wide range of treatment options for managing adult patients with acute and chronic non-specific neck-pain. However, there were important differences in treatments chiropractors offered for acute and chronic patients, particularly for the use of exercise therapy, which was mainly reserved for chronic patients. Danish chiropractors’ compliance with guidelines for neck-pain patients was low, but is neither worse nor better than what is seen for other complaints or health disciplines. Our findings suggest a need for active knowledge translation strategies and robust implementation research.The online version of this article (doi:10.1186/s12998-017-0148-9) contains supplementary material, which is available to authorized users. The estimated annual prevalence of non-specific neck pain is around 35% in Denmark and Scandinavia , 2. In tNeck pain is considered an episodic condition  and peopRelease of new CPGs often involves the need for clinicians to change current practice. However, many barriers hinder the uptake of the new knowledge . This unWhich treatment modalities do Danish chiropractors use to manage patients with non-specific neck-pain?To what extent does the use of treatment modalities by chiropractors differ for patients with acute or chronic neck-pain?To what extent is the utilization of treatment modalities used by Danish chiropractors compliant with available guideline recommendations?The objective of the current study was to investigate if Danish chiropractors’ management of patients with acute and chronic non-specific neck pain complies with recent Canadian guideline recommendations for the treatment of adults with non-specific neck pain. More specifically, we sought to answer the following research questions:A cross-sectional online survey was administered between October 30, 2014 and December 20, 2014. All 554 members of the Danish Chiropractic Association (DCA) with a valid email address known by DCA were invited to complete the survey.A PubMed and online search for relevant CPG’s within the past 5 years was carried out and references from each search result were manually reviewed for other relevant guidelines. This revealed only one clinical practice guideline for the chiropractic treatment of adults with non-specific neck pain . The recThe questionnaire was developed solely for the purpose of this study and was not previously validated. The survey consisted of three parts. The first part included a list of treatment modalities Danish chiropractors commonly use. The list of treatments modalities was informed by an international study investigating treatment preferences of physiotherapists and chiropractors . The lisThe second part of the questionnaire presented two clinical vignettes, representing a patient with acute neck pain and a patient with chronic neck-pain. For each vignette, chiropractors were asked how they would manage these patients by indicating which treatment group/s they would use and by stating how often they would use each group, using the same response options as above. The two vignettes where developed by the authors based on clinical experience to reflect a ‘typical’ patient presenting with a non-specific neck pain complaint, with no red flags (or serious pathology) and normal cervical spine x-rays.The last part of the questionnaire included demographics questions  adapted from a recent study of the Danish chiropractic profession .The questionnaire was pilot-tested for face and content validity among 8 chiropractors with a range of clinical and research expertise. Written feedback was collected on the comprehensiveness of treatment modalities and the overall understanding of the vignettes and related questions. The questionnaire was modified based on feedback received. An English version of the final questionnaire is available  and the University of Southern Denmark (SDU) both located in Odense, Denmark, using the licensed SurveyXact software . An invitation to participate and a unique questionnaire link was sent out to all Danish chiropractors using e-mail contact information from the DCA. Non-respondents and respondents who had only filled out parts of the questionnaire were sent up to two email reminders after 2 and 3 weeks respectively. Clinicians who indicated they did not wish to participate were not sent reminders.Descriptive statistics was used to analyze the demographic characteristics of respondents presented as proportions. The results were compared to a recent study of the Danish Chiropractic profession . In the The different treatment modalities used by Danish chiropractors were described as count data . A given treatment modality was considered to be used if the respondent selected “Often”. A group of modalities as a whole was considered being used by the chiropractor when at least one of the modalities within this group were used “Often”.Respondents could write additional treatment modalities in plain text if desired. Answers were manually reviewed, and if a similar treatment modality was already stated in the questionnaire, the pre-defined treatment modality was checked accordingly. Any additional treatment options not stated in any of the original questions were coded into new suitable categories for presentation.p < 0.05 level.The utilization frequency for each modality group used to manage patients with acute and chronic neck-pain was coded as numbers and percentages. Only modality groups stated to be used “Often” were included in further analyses. Differences between the treatment of acute and chronic neck-pain patients were explored using Pearson’s chi-square test and considered significant at the p < 0.05 level.The Canadian CPG for managing acute and chronic neck-pain recommends that clinicians use multimodal care . This isThe statistical analyses were carried out using STATA 14 .Approvals from The Danish Health Research Ethics Committee System and Danish Data Protection Agency were not required, as no sensitive information were collected regarding racial or ethnic background, political, religious or philosophical conviction, trade union membership information, information about health, sexual or criminal matters, information about significant social problems, or other similar information related to one’s private life and all data were collected anonymously. This is according to Danish legislation stipulated in Act on Research Ethics Review of Health Research Projects, section 14, subsection 1–2 and the Danish Data Protection Act .Of the 554 DCA members invited to participate, 362 returned their questionnaire (65% response rate) of which 344 completed questionnaires were eligible for analyses (62%). A flowchart of the study, as well as reasons for exclusion in the final analyses can be found in Fig. The demographics of 344 respondents are summarized in Table The different treatment modalities commonly used by Danish chiropractors to manage non-specific neck-pain are shown in Table Other manual therapies used by 88% included trigger-point therapy, massage, stretching and traction. Other treatment modalities were used by 62% of chiropractors, consisting primarily of Cold application and Dry Needling. Most chiropractors prescribed exercise as part of their treatment (88%) with general physical activity being recommended by 3 out of 4 respondents and stretching exercises for the neck recommended by over half of clinicians. Also strengthening of the neck musculature (48%) and stability exercises (39%) were commonly prescribed. Only 18% recommended the use of orthoses or supportive devices, with pillows (11%) and tape (3%) being most popular.Of the 59 participants stating that they used treatment modalities not previously listed, 18 were coded within pre-defined categories, leaving 41 new treatment options. These were grouped into the following 14 categories: Non-manipulative neurological stimulation , fascia release/Active Release Technique (ART), advice on over the counter painkillers, breathing drills, NeuroImpulse Protocol (NIP), stress management and mindfulness, articulation/mobilization, reflex locomotion/Dynamic Neuromuscular Stabilization (DNS), treatment of the temporomandibular joint or skull, reflexology, Posture Pumps/Dakota traction, Applied Kinesiology (AK), referral to hypnosis or psychologist, Primal Reflex Release Technique (PRRT) and the Mensendieck system.p = 0.004). Only 19% reported they would recommend exercise therapy for acute cases compared with 63% for chronic neck-pain patients (p < 0.001). Very few chiropractors indicated that they would use orthoses or other supportive devices for when treating neck-pain patients, regardless of symptom duration. The detailed usage of each modality groups for both acute and chronic patients can be found in Table Almost every Danish chiropractor indicated they would use manipulation therapy and information/patient education as part of their treatment approach for both acute and chronic neck-pain patients (over 90% in both cases), whereas 2/3 would also use other types of manual therapy. No statistically significant difference was found between the management of acute and chronic patients for both manipulation, information/patient education and manual therapies. There was a significant difference in treatment offered between acute and chronic neck pain patients, with around 1/3 of respondents saying they would use “other treatment modalities” for acute neck-pain patients, whereas 46% would use these for chronic neck-pain patients (p < 0.001) and compliance to multimodal care (p < 0.001), as compared to acute neck-pain.The guideline compliance for both the acute and chronic recommendations are shown in Table To the best of our knowledge this is the first study to investigate how Danish chiropractors treat patients with acute and chronic non-specific neck-pain and to determine chiropractors’ compliance with recent published guidelines. All chiropractors reported that they inform their patients about the clinical diagnosis and monitored patients’ symptoms as part of their usual management. Most would advise their patients undertake or keep an active lifestyle or said they delivered advice on rest/offloading. Our results suggest that Danish chiropractors use a wide range of treatment modalities including, but not limited to, spinal manipulation, trigger point therapy, massage, passive stretching, cold application, dry needling and various exercises. Orthoses or other supportive devices were rarely used.The chiropractors use of manipulation, other manual therapies or information/patient education did not differ between acute and chronic non-specific neck-pain. However the use of other treatment modalities including orthoses and especially exercise was far more common for chronic neck pain patients. The compliance with guideline recommendations was very low for the treatment of acute neck pain , which was significantly lower than compliance with the recommendations for chronic patients (97% and 43% respectively).HVLA-manipulation techniques appears to be utilized by almost every Danish chiropractor. This is not surprising as these techniques are seen as core treatments of the profession . The higThe Diversified technique was the most commonly used  type of manipulation technique. This finding is supported by other studies showing ‘Diversified’ technique in general being utilized by up to 93% of chiropractors in Belgium  and for The use of soft tissue techniques seems to be higher in our study compared to other studies related to treatment of neck-pain , but simHalf of the Danish chiropractors reported that they would use cold application and less than 10% would use heat therapy. These findings contrast with other studies, indicating thermal agents (ice or heat) are used by up to 75% of chiropractors and physiotherapists , 18, butAlmost 90% indicated that they routinely prescribed exercise therapy as part of their management for neck-pain patients. This is consistent with other studies showing that 81–98% chiropractors commonly recommend exercise therapy , 18, 23.Our finding indicates that almost every respondent use information/patient education as part of their management of neck pain patients, chronic and acute. Therefore this can be considered one of the core services provided by Danish chiropractors. The high utilization of information/patient education is in line with what is reported for chiropractors in North America by Coulter et al. . A largeWe found the use of other treatment modalities such as orthoses/supportive devices and exercise to be significantly higher with chronic patients than for acute patients. This is consistent with findings by Carlesso et al. , who fouEven though 88% of respondents stated that they often use exercises as part of their management of neck-pain patients, exercise therapy appears to be primarily reserved for chronic patients. We do not know the reason for this distinct difference, but one speculation could be, that chronic patients might have tried simpler approaches without the expected results, and therefore invite to, or even demand, the use of more modalities, including exercise therapy. Another reason could be, that acute patients might experience satisfying outcomes without the use of exercises, and neither the chiropractor nor patient might feel the need to incorporate this into the management, even though it might provide quicker or better results. The apparent low use of exercise with acute patients could also be because some chiropractors might not consider certain management strategies as exercise, such as MDT or stretching.Evidence Informed Practice (EIP) consists of three sources of knowledge: 1) research evidence; 2) clinical expertise/clinical reasoning, and 3) patient’s preferences and values . When thWhile few studies have investigated guideline adherence for the management of neck pain, the majority of studies investigating guidelines in general and for low back pain specifically have shown low to moderate adherence across health care professions –30. WhenDespite the satisfying response rate and representativeness of our sample with the Danish chiropractic profession, this survey has a number of limitations. First, our study was cross-sectional design, and therefore only presents a here and now perspective of management trends. Second, we found only a single clinical practice guideline published at the time of the survey, and with Danish chiropractors not being the main audience, this of course limits our results, as we are dependent of the quality of recommendations in this guideline. The rigid fashion of the recommendations and our resulting strict definition of compliance made it harder for our respondents to be guideline compliant. This is especially true for acute neck-pain where only 2 out of 3 recommendations was considered multimodal, both requiring a combinations of 3 or 4 modalities to meet compliance. Had the recommendations been less rigid, our compliance rate would have been much higher. Third, the survey was carried out after the publication of the clinical practice guidelines. To truly uncover an evidence-practice gap the study should have been executed before publication of the guideline. It could be argued, however, that publication alone is not an effective implementation strategy , and thaClosed-end checklists may result in a cueing effect, for respondents, to select additional actions. The different responses to the two identical closed-ended checklists for chronic and acute patients respectively, however indicate that this might not have been as big an issue, or at least that our respondents actually are aware that they treat chronic and acute patients differently.Danish chiropractors wishing to be considered experts in the field of musculoskeletal care should aim to incorporate clinical guidelines into the routine management and keep up to date with the newest research. Even though the Canadian Guidelines were not actively disseminated to Danish Chiropractors prior to this survey, this study shows low utilization of exercise therapy, especially with acute patients, which again results in low adherence to guideline recommendations for acute neck-pain patients in particular, but also for chronic neck-pain. More recent context specific Danish Guidelines  advocateOur findings indicate that Danish chiropractors use a wide range of treatment options for managing adult patients with acute and chronic non-specific neck-pain. However, there were differences in treatments offered to acute and chronic patients, especially in regards to the use of exercise therapy, which were mainly reserved for chronic patients. Guideline compliance for acute and chronic neck-pain patients was low to moderate respectively, primarily because of underutilization of multimodal management. The low use of exercise therapy with acute patients contributed to this.


Pain in opioid-dependent patients is common but data measuring the course of pain (and its correlates) using validated scales in patients initiating methadone treatment are sparse. We aimed to assess pain and its interference in daily life, associated correlates, and undertreatment before and during methadone treatment.This is a secondary analysis using longitudinal data of a randomized trial comparing two methadone initiation models. We assessed the effect of methadone initiation and other correlates on pain intensity and interference (using the Brief Pain Inventory) at months 0, 6 and 12 using a mixed multinomial logistic regression model.The study group comprised 168 patients who had data for either pain intensity or interference for at least one visit. Moderate to severe pain was reported in 12.9% of patients at M0, 5.4% at M6 and 7.3% at M12. Substantial interference with daily functioning was reported in 36.0% at M0, 14.5% at M6 and 17.1% at M12. Of the 98 visits where patients reported moderate to severe pain or substantial interference, 55.1% reported no treatment for pain relief, non-opioid analgesics were reported by 34.7%, opioid analgesics by 3.1% and both opioid and non-opioid analgesics by 7.1%. Methadone was associated with decreased pain intensity at 6 months  and 12 months  of follow-up and tended to be associated with substantial pain interference. Suicide risk was associated with both pain intensity and pain interference.Methadone in opioid-dependent patients can reduce pain. However, undertreatment of pain in methadone patients remains a major clinical concern. Patients with pain are at higher risk of suicide. Adequate screening and management of pain in this population is a priority and needs to be integrated into routine comprehensive care. Methadone is a long-acting opioid agonist prescribed to treat opioid dependence and pain as a second-line treatment or in opioid rotation ,2. PrevaAmong MMT patients, pain is associated with older age ,7, a higAlthough one would expect methadone to reduce pain among opioid-dependent patients, given that it is a powerful analgesic, to our knowledge, no study has assessed the course of pain (and its correlates) before and during MMT using a validated scale .Clinicians treating opioid-dependent patients are often faced with the complex challenge of treating pain in patients with a history of opioid-dependence ,17. A reWe used data from the ANRS Methaville trial to 1) assess the impact of MMT initiation and other correlates on two dimensions of pain—intensity and interference—using the BPI  in opioiThe ANRS Methaville study is a pragmatic multi-site, open-label, randomized and controlled, non-inferiority trial, which compares methadone induction in France in specialized centers (hereafter “standard care”) with methadone induction by primary care physicians. Two previous articles describe the complete protocol  and the From January 2009 to January 2010, 195 men and women were recruited in 10 sites and followed up for 12 months. Inclusion criteria were as follows: over 18 and under 70 years old, opioid-dependent in accordance with the DSM-IV criteria, and having an indication for methadone treatment (i.e. being methadone naive or not having had methadone treatment during the previous 30 days or switching from buprenorphine treatment). Exclusion criteria were as follows: having a triple  dependence and not being reachable by phone for interview. All patients who agreed to participate in the study provided written informed consent. Subjects were identified only by number.Each participant was followed up for 12 months during which he/she had 4 programmed medical visits: at enrolment and at months 3, 6 and 12 . At each visit, a medical questionnaire and a short self-administered questionnaire were completed. A phone interview (Computer-Assisted Telephone Interview: CATI) was conducted after each visit.We assessed pain intensity and interference (i.e. the repercussions of pain on daily functioning) using the self-administered BPI-Short Form  at enrolPain intensity was measured using an 11-point visual analogue scale from 0 (no pain) to 10 (worst possible pain). Patients used this scale to record pain ‘‘right now,” average pain in the previous 24 hours, and their highest and lowest pain levels during the previous 24 hours. A pain intensity score was calculated when patients completed all four related questionnaire items. It equaled the average of the four different scores. We used cut-off points employed by Serlin et al., 1995 . A pain Seven additional questions on a 10-point visual scale  evaluated pain interference in the previous 24 hours with the following seven items: general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life. An interference score was obtained by averaging the scores of the interference items when at least four of the seven items were completed, as suggested by Cleeland, 1994 . We usedThe BPI-short Form included a question about treatments taken against pain. Analgesics were classified as follows: non-opioid analgesics, opioid analgesics and combination of non-opioid and opioid analgesics.At enrolment, information on socio-demographic characteristics including gender, age, educational level, employment status, having child(ren) or not, and housing situation  was collected. At the M12 visit, employment status and housing situation were reassessed.After each follow-up visit, drug use in the previous month was assessed using a section of the Opiate Treatment Index (OTI) questionnaire focusing on drug use . IndividAt each follow-up visit, patients who reported drug injection at least once during the previous month were defined as active injectors. Patients reporting drug injection at least once during their lifetime were defined as having a history of drug injection.We recorded anxiolytic/hypnotic agent use as positive when at least one of the following data sources indicated their use: medical questionnaire, self-report and urine test.Alcohol consumption was assessed at M0 and M12 during the CATI using the AUDIT questionnaire, with a cut-off point higher than 13 identifying alcohol dependence . Binge dDaily prescribed methadone doses were recorded at M6 and M12.During each medical visit, physicians collected data on withdrawal symptoms using the Objective Opioid Withdrawal Scale (OOWS) which comprises a list of 13 withdrawal symptoms .The self-administered questionnaire at M0, M6 and M12 included 2 screening tools. The first was the Adult ADHD (Attention Deficit Hyperactivity Disorder) Self-Report Scale-Version 1.1 (ASRS-V1.1). The scoring algorithm used was the summed score obtained after adding the scores (0–4) of the first 6 items of the adult ADHD scale . We defiDuring CATI, depressive symptoms were assessed at M0, M6 and M12 using the Center for Epidemiologic Studies Depression (CES-D) scale. The validated French cut-off points of 17 for men and 23 for women was employed .We used a mixed multinomial logistic regression model to test the following factors for association with pain intensity , and interference with daily functioning  at M0, M6 and M12: 1) Follow-up characteristics: follow-up time (i.e. time on methadone: M6 versus M0 and M12 versus M0), methadone initiation ; 2) Socio-demographic characteristics: gender, age, educational level (< high school certificate versus ≥ high school certificate), having child(ren), employment status, stable housing , receiving food assistance; 3) Addictive practices and medication use: methadone dose, anxiolytic/hypnotic agents, cocaine, non-prescribed opioids, and cannabis consumption, current drug injection, alcohol dependence, binge drinking, nicotine dependence; 4) History of drug use: switching from buprenorphine to methadone, history of drug overdose, history of drug injection, time since first regular drug use; 5) Health conditions: number of withdrawal symptoms, ADHD, current major depressive episode and suicide risk.Variables associated with pain intensity and pain interference severity with a p-value lower than 0.20 in the univariable analysis for at least one category of the outcome were considered eligible to enter multivariable models. A stepwise procedure was used to identify the best model by removing variables one at a time based on a p-value of >0.05 for at least one of the outcome’s categories. When coefficient estimates for different categories of pain and interference were similar in the multivariable analysis, the categories were collapsed together to obtain a single estimate.All analyses were performed using Intercooled Stata 12  software packages. The GLAMM Stata procedure was used to create a multinomial distribution.The study group included 168 individuals with a score for pain intensity or interference at least once over the follow-up visits . No statistical difference was found between included (n = 168) and excluded (n = 27) patients regarding the following sociodemographic variables: age, gender, employment, housing, having children and educational level.Among the 168 patients of the study group, 14% were female, aged 33.2 years on average  and 31% had high school certificates. At M0, 52% were employed, 32% had unstable housing and 39% had a child(ren). Use of anxiolytic/hypnotic agents was reported by 24% of patients, cocaine by 29%, non-prescribed opioids by 72% and daily cannabis by 83%. Thirty percent had injected drugs in the previous month while 14% were alcohol dependent. Half the study group was switching from buprenorphine maintenance at trial inclusion, and 47% had a history of injection.At M0, M6 and M12, respectively, 21.6%, 36.9% and 31.3% patients reported no pain. Moderate to severe pain was reported by 12.9% of patients at M0, 5.4% at M6 and 7.3% at M12. Average score of pain intensity varied from 2.4 (SD = 2.0) at M0 to 1.3 (SD = 1.5) at M6 and 1.5 (SD = 1.8) at M12.In univariable analysis, mild and moderate to severe pain (versus no pain) were negatively associated with MMT at 6 and 12 months .Results of the multivariable multinomial regression for mild pain and moderate to severe pain (versus no pain) were similar. For this reason, the multivariate analysis of the dependent variable pain versus no pain is presented in At M0, 24.5% of the study group reported no pain interference. This increased to 32.1% at M6 and 36.9% at M12. At M0, 36.0% of the patients reported substantial interference, 14.5% at M6 and 17.1% at M12. The average score of interference varied from 3.0 (SD = 2.6) at M0 to 1.7 (SD = 2.0) at M6 and 1.7 (SD = 2.0) at M12.The results of the univariable analysis are presented in After adjusting for potential confounding factors , being at suicide risk  was positively associated with substantial interference . MMT at At M0, among the 55 patients reporting moderate to severe pain with substantial interference, 30 declared receiving no analgesic treatment, 13 opioid analgesics and 12 non-opioid analgesics. At M6, 20 patients reported moderate to severe pain with substantial interference, among them 11 declared receiving no analgesic treatment and 9 non-opioid analgesics. At M12, 23 patients reported moderate to severe pain with substantial interference, among them 11 declared receiving no analgesic treatment and 12 non-opioid analgesics.There are 3 main results of this study: 1) pain decreases with methadone treatment; 2) pain is considerably undertreated in MMT patients; 3) suicide risk is a major correlate of pain intensity and pain interference with daily functioning.At M0, 30 out of 55 patients reporting moderate to severe pain with substantial interference declared receiving no pain treatment, 11 out of 20 at M6 and 11 out of 23 at M12. This suggests that pain was inadequately treated, which is in line with other studies where pain of MMT patients was undertreated ,32. One As shown by our results, methadone can reduce pain among opioid-dependent patients. However, its standard once-a-day administration for the treatment of opioid addiction often fails to provide sustained pain relief . AccordiSuicide risk was significantly and independently associated with both pain intensity and interference in our study. Many factors may lead to suicide in pain patients. First, many experience concomitant depression . MoreoveWhether methadone can reduce suicide risk through pain relief is still unknown. A previous study using data from the Methaville trial showed that methadone and suicide risk were associated in univariable analysis but no longer associated after multiple adjustment. This is probably because of collinearity between suicide risk and the number of health problems, which are significantly reduced during methadone treatment . Our resADHD was associated in univariable analyses with pain intensity and interference. A recent study showed that patients with ADHD are more likely to experience pain, and that while common mental disorder influences this association, it does not fully explain the reason for this .The challenge of treatment decisions by physicians regarding pain in opioid-dependent populations is compounded by the conflicting literature on the association between pain and addiction. Although some previous surveys demonstrated a link between pain and drug use behaviors ,13,50–52Our study has strengths and limitations. The main strengths are that as a pragmatic trial, the study population is representative of people seeking care for opioid dependence in France. Second, the assessment of pain is based on a validated scale, the BPI-short Form. In terms of limitations, the study is based on self-reports to measure medication and drug use. However, the reliability of self-reports in people who use drugs has already been widely demonstrated .Methadone in opioid-dependent patients can reduce pain. However, undertreatment of pain in MMT patients remains a major clinical concern. Patients presenting pain and reporting interference with their daily life are at higher risk of suicide. Adequate screening and management of pain in this population is a priority and needs to be incorporated in routine comprehensive care.


One of the currently used surgical techniques in isolated type II SLAP lesions is arthroscopic SLAP repair. Postoperatively, patients tend to suffer from a prolonged period of pain and are restricted in their sports activities for at least 6 months. The aim of this study was to prospectively evaluate the clinical outcome as well as the postoperative course of pain after arthroscopic type II SLAP repair.indiv), the American Shoulder and Elbow Surgeons (ASES) Score, the Visual Analogue Scale (VAS), and the Short Form 36 (SF-36). Data were collected preoperatively, as well as at 3, 6, 12 and >24 months postoperatively.Outcome measures were assessed using the Individual Relative Constant Score (CSindiv (p = 0.004), the ASES Score (p = 0.006), and the SF-36 subscale “physical functioning” (p = 0.014) and a statistically significant decrease of pain according to the VAS (p = 0.007) and the SF-36 subscale “bodily pain” (p = 0.022) compared to preoperative levels.Eleven patients with an average age of 31.8 years (range: 22.8-49.8 years) underwent arthroscopic repair of isolated type II SLAP lesions. Mean follow-up time was 41.9 months (range: 36.1–48.4 months). 6 months after surgery, there was a statistically significant improvement of function according to the CSArthroscopic repair of isolated type II SLAP lesions with suture anchors leads to a satisfactory functional outcome and return to pre-injury sports levels, with delayed, but significant pain relief observed 6 months after surgery. Thus, a return to sports should not be allowed earlier than 6 months after surgery, when patients have reached pain-free function and recovered strength.Researchregistry1761 (UIN). Lesions to the long head of the biceps tendon were first described in baseball players by James Andrews in 1985  – which According to the Snyder classification, 4 types of SLAP lesions are described – type II lesions being the most common, with an incidence of 55%. In an analysis of 140 injuries, Snyder observed that an isolated type II SLAP lesion was found in one third of patients , though In the literature, various techniques have been developed to stabilize type II lesions. Altchek et al.  reportedindiv) [Currently, only a few prospective studies are available which present data concerning functional outcome and return to sports following repair of isolated type II SLAP lesions at a final follow-up of at least 24 months –14. The indiv)  it is noTherefore, the purpose of this study was to evaluate the progression of function and pain relief after arthroscopic isolated type II SLAP repair in active patients. We hypothesized that there would be a significant improvement in function and reduction of pain over a postoperative observation period of two years, and that the ability to return to pre-injury sports activities is in the first line determined by regaining a pain-free condition, a full range of motion (ROM) and adequate strength. We furthermore hypothesized that the achievement of all these factors indicates the appropriate time point for a return to sports, which we expect to be - in most cases - not earlier than 6 months after surgery.From June 2010 to June 2011, a total of 84 patients were treated at our outpatient clinic for an injury to the tendon of the long head of the biceps. In this prospective study, only patients who fulfilled the following criteria were included for analysis: (a) Patients presenting with an isolated type II SLAP lesion which was (b) verified by magnetic resonance arthrography (MRA), (c) who would be available for at least 24 months of follow-up after surgery and (d) for whom a complete data set was also available. Exclusion criteria were as follows: (a) The presence of any concomitant lesions, including a partial- or full-thickness rotator cuff tear, symptomatic acromioclavicular joint arthrosis, or a labral tear requiring a repair outside the SLAP region , (b) additional repairs being performed at the time of surgery , (c) a follow-up time of less than 24 months or being lost to follow-up, and (d) possession of an incomplete data set.For the SLAP diagnosis 4 different evaluation criteria were used . First, n = 3; 2 SLAP I lesions and 1 SLAP III lesion with a partial rotator-cuff tear) or other intraoperatively addressed pathologies . One patient was lost to follow-up, leaving 11 patients who were ultimately included in this study. All of these patients had a history of overhead activities . Five patients  performed their sports at competitive and 6 patients  on recreational levels. The institutional review board (EK-No: 2010/355) approved this study and informed consent was obtained from all patients prior to the investigation.Preoperatively, 17 patients (20%) with an isolated type II SLAP lesion were included. Following arthroscopy, 5 patients were excluded due to either intraoperative findings (indiv) [Functional assessments were performed preoperatively, and at 3, 6, 12 and >24 months postoperatively, using the following metrics: The Individual Relative Constant Score (CSindiv) , The Ameindiv) , The Visindiv) .For evaluation of the ability to return to pre-injury sports activities at final follow-up patients were preoperatively asked for their sports as well as their sports level, either competitive or recreational.All patients were examined by two independent, blinded observers (senior orthopedic and trauma surgeons) who were not involved in the primary treatment. The examination was based upon the aforementioned tests. Range of motion (ROM) measurements were performed using a handheld goniometer graded in single degrees, and assessment of isometric muscular strength was achieved using a dynamometer  in abduction in the scapular plane – as suggested for the Constant Score .Two shoulder-fellowship-trained surgeons performed all arthroscopically assisted SLAP repairs. All surgeries were performed in beach chair position, starting with an arthroscopic diagnostic confirmation of the MRA findings Fig. . If therAll patients underwent a standardized postoperative rehabilitation protocol administered by this department. During the first two weeks, the shoulder was immobilized with an abduction sling, and patients were allowed to only remove their arm for hygiene and to perform daily pendulum exercises. Patients began physical therapy with 1 visit per week and started a home exercise program.After removal of the abduction sling physical therapy was increased to 2 visits per week. Isometric exercises and passive ROM exercises for the elbow and hand, as well as hand-gripping exercises, were also allowed. Throughout week 3 and 4, ROM exercises were performed passively in the scapular plane, to approximately 45 degrees of internal rotation and to 60 degrees of elevation. Passive and active range of flexion was increased to 60, then 90, and ultimately >90 degrees, in 2 week intervals. Following the standard protocol at our institution, no external rotation or resisted biceps activity (both elbow flexion and forearm supination) was allowed for 8 weeks.After regaining full ROM that is usually reached between week 8 and 12 under physical therapy, isometric strengthening and stretching exercises in all planes were started. Additionally, patients were advised to continue their home exercises including rotator cuff strengthening using therabands. According to the patients’ preference the strengthening training between month 4 and 6 after surgery was performed under physiotherapeutic guidance or by self-organized exercises. However, a return to sports typically occurred at approximately 6 months following surgery, after regaining pain-free function and strength.p-values of less than 0.05 were regarded as statistically significant.The free software environment R version 3.0.2, as well as the lme4 package, were used for statistical analysis. Time courses were analyzed with linear mixed effects models, where random effects were defined by subject IDs and fixed effects by the second degree polynomial of approximate time in months. False discovery rate (FDR) corrected In post-hoc analysis, the Wilcoxon signed-rank test for paired data was used for comparison of measurements at specific time points. Confidence intervals for the figures were estimated using 1000 bootstrap samples for each figure.Since this study was designed as a case series, no formal power calculation was done a priori. Nevertheless, we empirically estimated power to detect a difference in scores between 6 months and a baseline visit, as well as between 3 months and a baseline visit, using 1000 bootstrap samples.n = 4; 36.4%) described a traumatic event to their shoulder as being the cause of the SLAP lesion. The remainder  could not identify an isolated traumatic event as the cause of their shoulder injury. Patients’ main complaints at time of first presentation were pain and recurrent instability. 9 patients (81%) presented with an injury to the dominant extremity. In 7 patients 1 metal screw anchor was placed posterior to the biceps tendon anchor and in 4 patients 2 metal screw anchors, 1 anterior and 1 posterior to the biceps tendon anchor, were used for SLAP repair according to the size of the lesion (mean: 1.3 anchors). Patient demographics are presented in detail in Table A total of 11 patients (92%) completed the study at a mean follow-up of 41.9 months (range: 36.1–48.4 months). There were 8 males and 3 females, with a mean age of 31.8 years (range: 22.8–49.8 years). About one third (indiv (p < 0.001), the ASES Score (p < 0.001), and the SF-36 “physical functioning” subscale (p < 0.001)  Fig. .Fig. 4ASp < 0.001) and the SF-36 “bodily pain” subscale (p = 0.039)  Fig. . In the indiv (p = 0.004), the ASES Score (p = 0.006), and the SF-36 “physical functioning” subscale (p = 0.014) at 6 months postoperatively (Tables p = 0.021), and at 12 months postoperatively in the SF-36 “bodily pain” subscale (p = 0.022)  6 months after surgery. The return to pre-injury sports level was determined by asking the patient for his sports activity and level at final follow-up. If the patient practiced the same sport at the same level  compared to the time before injury, a return to pre-injury sports level was assumed which has to be considered critically due to some recall bias .There were no surgically related postoperative complications in this series. However, one patient presented with a thrombosis of the upper extremity shortly before his 6-month follow-up, after he had slept on the affected arm. The thrombosis was verified by ultrasound, and the patient immediately received an anti-thrombotic therapy. In the end, functional outcome and measurements were not influenced by this episode.Two patients presented with pain at follow-up investigations. In one patient, persistent pain remained after surgery. As dictated by the symptoms, an MRA was performed to rule out a re-rupture. The SLAP repair appeared intact, as did the other structures. We therefore suspected the presence of a persisting acromio-humeral impingement, and offered the patient an arthroscopic treatment. The patient refused to undergo another arthroscopy and began intensive physical therapy. At the last follow-up, the patient presented with a reduction in pain and was satisfied with the overall result.One patient at final follow-up reported experiencing pain after taking part in intensive sports activity . Due to the persistence of pain, an MRA was performed, which showed the healed type II SLAP lesion with the suture anchor in correct position – as well as a supraspinatus tendinopathy Fig. . ApparenBoth patients were able to return to their preoperative sports activities.The most important finding of this study was that the arthroscopic repair of isolated type II SLAP lesions with metal screw suture anchors provides for satisfactory functional outcomes and a return to pre-injury sports levels at long-term follow-up. Although these rather satisfying results were not reached immediately after surgery, there was a significant increase of function and decrease in pain seen at 6 months postoperatively – a condition which thereafter remained stable, at least up through the last follow-up. To the best of our knowledge, this is the first study investigating the chronology of pain relief and return-of-function after anatomical SLAP repair using suture anchors. Our results indicate that a return to sports should not be allowed earlier than 6 months after surgery.The largest study addressing the repair of isolated type II SLAP lesions was performed by Provencher et al.  who, usiProvencher et al.  reportedn = 36) as well as metal anchors (n = 11) for SLAP repair, representing a significant increase of evaluated scores with respect to time. Although the ASES score was satisfying, with 93 points at final follow-up, only 74% of patients were capable of fully returning to their previous competitive level. The authors showed that patients presenting with a distinct traumatic aetiology had a greater likelihood of a successful return to sports [Brockmeier et al.  reviewedo sports . In our o sports .Three authors prospectively reviewed patients older than 45 years , 13, 14 In the present literature, the focus lies on clinical outcome measurement at a final follow-up of at least 2 years or greater –14. All Recommendations as to the right time point for a return to sports vary in the literature, ranging from 5 to 12 months after SLAP repair , 25–28. indiv, the ASES and the SF-36 “physical functioning” subscale at 6 months postoperatively – and remaining stable thereafter. We also separately investigated the progression of pain and found that in this sample pain decreased significantly at 6 months postoperatively according to the VAS and, at 12 months postoperatively according to the SF-36 “bodily pain” subscale. However, the VAS scores at 3 months were already trending towards significance and an increased sample size would probably show an earlier significant pain relief. Furthermore, it has to be considered, that this significant improvement from VAS 3 to VAS 1 out of 10 with average and median VAS scores of approximately 3 out of 10 represent mild to moderate levels of pain thus being uncomfortable but not clinically concerning.In the present study, we took a closer look at the progression of function after isolated arthroscopic type II SLAP repair. We were able to show significant improvement according to the CSAlthough biceps tenodesis or tenotomy , 7 lead The major strengths are the prospective study design, a mean follow-up time of 3.5 years, and the assessment of patients’ outcomes with multiple validated outcome scores and physical examinations at fixed time points. The major limitations are the small study group limiting the generalizability of the results as well as the lack of a comparison group. Furthermore, our study group is very heterogeneous in means of performed sports activities both on competitive or recreational levels. The wide range of ages limits interpretability as the results may differ in a more homogeneous study group regarding sports activity, level, and age. Another point that has to be kept in mind is that pain itself is difficult to measure as there are many different factors influencing a person’s pain. Not only the extent of trauma or performed surgery exert an influence on the subjective sensation of pain but also central sensitization or psychological constructs.Arthroscopic repair of isolated type II SLAP lesions with suture anchors leads to a satisfactory functional outcome and a return to pre-injury sports levels with delayed but significant pain relief seen at 6 months after surgery. This indicates that a return to sports should not be allowed earlier than 6 months postoperatively, when the patient has regained pain-free function and recovered strength.