Efficacy, tolerability and safety of cannabinoids in chronic pain associated with rheumatic diseases (fibromyalgia syndrome, back pain, osteoarthritis, rheumatoid arthritis): A systematic review of randomized controlled trials.

BACKGROUND: In the absence of an ideal treatment for chronic pain associated with rheumatic diseases, there is interest in the potential effects of cannabinoid molecules, particularly in the context of global interest in the legalization of herbal cannabis for medicinal use. METHODS: A systematic search until April 2015 was conducted in Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, www.cannabis-med.org and clinicaltrials.gov for randomized controlled trials with a study duration of at least 2 weeks and at least ten patients per treatment arm with herbal cannabis or pharmaceutical cannabinoid products in fibromyalgia syndrome (FMS), osteoarthritis (OA), chronic spinal pain, and rheumatoid arthritis (RA) pain. Outcomes were reduction of pain, sleep problems, fatigue and limitations of quality of life for efficacy, dropout rates due to adverse events for tolerability, and serious adverse events for safety. The methodology quality of the randomized controlled trials (RCTs) was evaluated by the Cochrane Risk of Bias Tool. RESULTS: Two RCTs of 2 and 4 weeks duration respectively with nabilone, including 71 FMS patients, one 4-week trial with nabilone, including 30 spinal pain patients, and one 5-week study with tetrahydrocannbinol/cannabidiol, including 58 RA patients were included. One inclusion criterion was pain refractory to conventional treatment in three studies. No RCT with OA patients was found. The risk of bias was high for three studies. The findings of a superiority of cannabinoids over controls (placebo, amitriptyline) were not consistent. Cannabinoids were generally well tolerated despite some troublesome side effects and safe during the study duration. CONCLUSIONS: Currently, there is insufficient evidence for recommendation for any cannabinoid preparations for symptom management in patients with chronic pain associated with rheumatic diseases.

Medical use of cannabis products: Lessons to be learned from Israel and Canada.

INTRODUCTION: The German government intends to reduce the barriers for the medical use of cannabis products. A discussion on the indications and contraindications of the medical use of cannabis and on the changes of the regulatory framework has already begun in Germany. It is useful to draw from the experiences of other countries with a more liberal medical use of cannabis. METHODS: The Israeli and Canadian experience is outlined by physicians who have been charged with expertise on the medical use of cannabis by their jurisdiction. RESULTS: In Israel, only the plant-based cannabinoid nabiximol (mixture of tetrahydrocannabinol/cannabidiol) can be prescribed for spasticity/chronic pain in multiple sclerosis and for cancer pain. The costs of nabiximole are reimbursed by some, but not by all health maintenance organizations. The medical use of marijuana is permitted; however, it is strictly regulated by the government. Selected companies are allowed to produce marijuana for medical use, and only certain physicians are licensed to prescribe marijuana as a therapeutic drug for specific indications such as chronic neuropathic, and cancer pain, inflammatory bowel diseases, or posttraumatic stress disorder if conventional treatments have failed. The costs of marijuana are not reimbursed by health insurance companies. In Canada, synthetic cannabinoids and the plant-based (nabiximol) are licensed for neuropathic and cancer pain, HIV-related anorexia and chemotherapy-associate nausea. The costs of these synthetic cannabinoids are covered by health insurance companies. The medical use of marijuana as a treatment option is allowed for individual patients suffering from any medical condition when authorized by a medical practitioner or nurse. Licensed producers are the only source for patients to newly access medical cannabis, although those with previous permission to grow may continue cultivation at the present time. The costs of marijuana are not reimbursed by health insurance companies. There are multiple contraindications for the medical use of cannabis products in both countries. CONCLUSIONS: The use of standardized, synthetic, and plant-based cannabis products should be allowed in Germany for defined medical conditions when high-level evidence of efficacy and safety exists. The costs should be reimbursed by the health insurance companies. Contraindications for the medical use of cannabis should be defined. Growing marijuana by patients for their medical use should not be allowed.

Medical cannabis: A forward vision for the clinician.

Medical cannabis has entered mainstream medicine and is here to stay. Propelled by public advocacy, the media and mostly anecdote rather than sound scientific study, patients worldwide are exploring marijuana use for a vast array of medical conditions including management of chronic pain. Contrary to the usual path of drug approval, medical cannabis has bypassed traditional evidence-based study and has been legalized as a therapeutic product by legislative bodies in various countries. While there is a wealth of basic science and preclinical studies demonstrating effects of cannabinoids in neurobiological systems, especially those pertaining to pain and inflammation, clinical study remains limited. Cannabinoids may hold promise for relief of symptoms in a vast array of conditions, but with many questions as yet unanswered. Rigorous study is needed to examine the true evidence for benefits and risks for various conditions and in various patient populations, the specific molecular effects, ideal methods of administration, and interaction with other medications and substances. In the context of prevalent use, there is an urgency to gather pertinent clinical information about the therapeutic effects as well as risks. Even with considerable uncertainties, the health care community must adhere to the guiding principle of clinical care 'primum non nocere' and continue to provide empathetic patient care while exercising prudence and caution. The health care community must strongly advocate for sound scientific evidence regarding cannabis as a therapy. SIGNIFICANCE: Legalization of medical cannabis has bypassed usual drug regulatory procedures in jurisdictions worldwide. Pending sound evidence for effect in many conditions, physicians must continue to provide competent empathetic care with attention to harm reduction. A vision to navigate the current challenges of medical cannabis is outlined.

Efficacy, tolerability and safety of cannabis-based medicines for chronic pain management - An overview of systematic reviews.

Medicinal cannabis has already entered mainstream medicine in some countries. This systematic review (SR) aimed at evaluating the efficacy, acceptability and safety of cannabis-based medicines for chronic pain management. Qualitative systematic review of SRs of randomized controlled trials with cannabis-based medicines for chronic pain management. The Cochrane databases of SRs, Database of Abstracts of Reviews of Effects and PubMed were searched for SR published in the period January 2009 to January 2017. Assessment of the methodological quality of SR was performed by the AMSTAR checklist. Out of 748 papers identified, 10 SRs met the inclusion criteria. The methodological quality was high in four and moderate in six SRs. There were inconsistent findings of four SRs on the efficacy of cannabis-based medicines in neuropathic pain and of one SR for painful spasms in multiple sclerosis. There were consistent results that there was insufficient evidence of any cannabis-based medicine for pain management in patients with rheumatic diseases (three SRs) and in cancer pain (two SRs). Cannabis-based medicines undoubtedly enrich the possibilities of drug treatment of chronic pain conditions. It remains the responsibility of the health care community to continue to pursue rigorous study of cannabis-based medicines to provide evidence that meets the standard of 21st century clinical care. SIGNIFICANCE: We provide an overview of systematic reviews on the efficacy, tolerability and safety of cannabis-based medicines for chronic pain management. There are inconsistent findings of the efficacy of cannabinoids in neuropathic pain and painful spasms in multiple sclerosis. There are inconsistent results on tolerability and safety of cannabis-based medicines for any chronic pain.

Comorbid fibromyalgia: A qualitative review of prevalence and importance.

Fibromyalgia (FM) may be an unrecognized cause of suffering for persons with an array of medical conditions. This is especially true for illness that is characterized by pain of any nature. Once believed to be a unique diagnosis, FM is recently reported to occur concomitantly with various rheumatic diseases, and importantly adversely impacts global health status. However, there is increasing report of FM associated with other diseases that are not defined by chronic pain. This qualitative review examines the evidence for comorbid FM in illness, and where available the effect of FM on the primary disease. Other than for musculoskeletal disorders, the published literature reporting an association of FM with illness is limited with scanty reports for some neurological, gastrointestinal, mental health and other overlapping pain conditions. Comorbid FM adversely affects both health status and outcome for rheumatic diseases, but with limited study in other diseases. When unrecognized, comorbid FM may be mistaken as poor control of the primary disease, leading to incorrect treatment decisions. FM may be a neglected condition that pervades many conditions and may contribute to the burden of illness. Physicians should be alert to the possibility of comorbid FM, and symptoms of FM should be specifically addressed. SIGNIFICANCE: Comorbid fibromyalgia (FM) in other medical conditions is largely unrecognized. When reported as accompanying rheumatic diseases, FM adversely affects global health status. With limited reports of comorbid FM with other conditions, neglect to diagnose comorbid FM may misdirect treatments.

A controlled study of diffuse idiopathic skeletal hyperostosis. Clinical features and functional status.

Diffuse idiopathic skeletal hyperostosis (DISH) is a common but little-studied disorder in the elderly that is infrequently recognized by physicians. Its prevalence in adults over 40 years of age is estimated at 3.8% for men and 2.6% for women. The present case-control study evaluated the history of pain and stiffness, radicular pain and enthesitis, physical findings on the musculoskeletal examination, and level of physical and psychologic disability in 130 persons: 56 patients with DISH, 43 control patients with spondylosis of the lumbar spine, and 31 healthy control patients. DISH patients were more likely to report a past history of upper extremity pain, medial epicondylitis of the elbow, enthesitis of the patella or heel, or dysphagia than spondylosis patients. They had more extremity and spinal stiffness and pain than healthy controls. DISH patients weighed more at a young age and their body mass index was greater at the time of the clinical evaluation than either spondylosis or healthy control patients. On musculoskeletal examination, DISH patients had a greater reduction in neck rotation and thoracic movements than either spondylosis patients or healthy controls, and had a greater reduction in lumbar movement than healthy controls. DISH patients had similar levels of spinal disability and physical disability overall, as measured by standardized indices, as spondylosis patients. No differences were found among the 3 groups of patients for the laboratory tests evaluated. DISH is clearly a distinct disorder with signs and symptoms that distinguish it from other causes of spinal complaint and from healthy individuals. It has the potential to cause major disability. Future studies need to address the natural history of DISH, pursue pathogenic mechanisms, and evaluate treatment modalities.

The assessment of cartilage degradation in vivo: development of an immunoassay for the measurement in body fluids of type II collagen cleaved by collagenases.

A monoclonal antibody has been developed which recognizes a neoepitope in type II collagen which is generated by the intrahelical cleavage of collagenases. Antibody reactivity is directed at the carboxyl-terminus of the TCA or 3/4 piece of the degraded alpha1(II) chain. Reactivity is dependent upon hydroxylation of proline. Evidence is provided suggesting that epitope binding involves the recognition of a conformational neoepitope. Using an ELISA, we show that this neoepitope can be detected in the urines and sera of nonarthritic persons and patients with rheumatoid arthritis (RA). An increased content is observed in the sera and urines of patients. The assay may be of value in studying cartilage type II degradation both in vitro and in vivo such as in those with arthritis.

The overdiagnosis of fibromyalgia syndrome.

PURPOSE: As fibromyalgia syndrome (FM) has gained greater acceptance and awareness in both the medical and the lay community, the possibility of overdiagnosis exists. Diffuse body pain in a woman is likely to suggest this diagnosis. We report the diagnosis of FM in 11 female patients whose primary cause for musculoskeletal symptoms was spondyloarthritis rather than only FM. PATIENTS AND METHODS: Of a total of 321 new rheumatology referrals in a 1-year period, 35 (11%) were diagnosed with FM. A further 11 (3%) were referred with either a previous diagnosis of FM or a presumed diagnosis of FM in whom the musculoskeletal syndrome could be attributed to previously unrecognized spondyloarthropathy. RESULTS: The 11 female patients had mostly experienced musculoskeletal symptoms for prolonged periods of time ranging from 1 to 40 years. Symptoms included prominent spinal pain involving at least 2 locations in the spine (n = 10), night pain that disturbed sleep (n = 10), and prolonged morning stiffness (n = 9). A previous history of enthesopathy, or history in the patient or first-degree relative of one of the seronegative associated diseases, such as psoriasis or ulcerative colitis, occurred in nine patients. Most patients had already undergone extensive investigations by various specialists in musculoskeletal medicine, but spondyloarthritis had only infrequently been considered a diagnostic possibility. CONCLUSION: Spondyloarthropathy in women may present subtly and have considerable overlap in symptomalogy with FM. A diagnosis of spondyloarthropathy should be considered in women with an ill-defined pain syndrome with prominent spinal pain and associated enthesopathy, or history or family history of seronegative-associated disease. It is possible that a primary diagnosis of FM is being made too freely, without consideration of other diagnoses, in the setting of ill-defined musculoskeletal pain.

Alternative medicine use in fibromyalgia syndrome.

OBJECTIVE: To record the prevalence, extent, cost, and satisfaction with use of alternative medicine practices by patients with fibromyalgia syndrome (FMS), compared to control rheumatology patients. METHODS: An interviewer-based questionnaire was administered to 221 consecutive rheumatology patients and 80 FMS patients. RESULTS: Alternative medicine interventions were currently being used extensively by rheumatology patients overall, and by FMS patients in particular. All categories of alternative practices were used more often by FMS patients, compared to controls, including overall use 91% versus 63% (P = 0.0001), over-the-counter products 70% versus 54% (NS), spiritual practices 48% versus 37% (NS), and alternative practitioners 26% versus 12% (P = 0.003), respectively. Two-thirds of patients using alternative medicine practices were concurrently using multiple interventions. Patient satisfaction ratings were highest for spiritual interventions. CONCLUSIONS: Alternative medicine practices were currently being used by almost all FMS patients. This observation might indicate that traditional medical therapies are inadequate in providing symptomatic relief to FMS patients.

The needs of patients with arthritis: the patient's perspective.

OBJECTIVE: To identify concerns and learning interests of patients with arthritis. METHODS: A questionnaire was developed, pilot tested, and then used to evaluate 197 patients with arthritis, including osteoarthritis (OA) (n = 41), rheumatoid arthritis (RA) (n = 57), back disease (n = 55), systemic lupus erythematosus (n = 27), and systemic sclerosis (SSc) (n = 17). Twenty concerns and 12 learning interests were rated. Questionnaires were also administered to assess physical disability (Health Assessment Questionnaire), psychological disability (Arthritis Impact Measurement Scales 2), and pain (visual analog scale). Participants addressed accessibility of health services, satisfaction with their physician, psychosocial needs, use of self-help groups, and behavioral strategies used to assist coping. Patients with RA, OA, and back disease, at both a community and a hospital center, were tested to assess whether concerns and learning interests differed based on site of treatment. Analytic methods included analysis of variance, factor analysis, and multiple linear regression. RESULTS: There were no differences in concerns or learning interests based on treatment site. Between diagnostic groups, patients with SSc were more interested in learning about self-help groups. The most frequently reported concern was worsening of the illness. The majority of respondents were interested in learning more about topics that were illness specific. The physician was chosen as the preferred source of information, and the preferred format was in writing. On factor analysis, the 20 concerns were reduced to 5 factors: psychological, coping, medication, social, and financial. Three factors were identified for learning interests: the illness, traditional health management topics, and nontraditional health management topics. Stepwise multiple linear regression revealed predictors for the 5 concern and 3 learning interest factors. The concerns were best predicted by self-reported disease severity, physical disability, and psychological distress, while learning interests were best predicted by self-reported disease severity, pain, and self-help group membership. CONCLUSION: Concerns and learning interests of persons with arthritis did not differ based on the center of treatment or the diagnosis, but can be predicted by the level of pain and simple measures of disability. Better understanding of the relationship between health status and patient-perceived needs will result in improved patient-centered care.

The clinimetric properties of the World Health Organization Disability Assessment Schedule II in early inflammatory arthritis.

OBJECTIVE: To assess the clinimetric properties of a new health-related quality of life (HRQOL) instrument, the World Health Organization Disability Assessment Schedule II (WHODAS II), in patients with early inflammatory arthritis. METHODS: Internal consistency as well as criterion, construct, and discriminative validity of the WHODAS II were assessed in 172 patients with early inflammatory arthritis who completed the WHODAS II, the Medical Outcomes Study Short Form 36 (SF-36), and other measures of disease severity, functioning, pain, depression, and resource use. Test-retest reliability of the WHODAS II was assessed by having a subset of 20 patients complete the WHODAS II a second time, 1 week after the first assessment. RESULTS: The WHODAS II had high internal consistency (Cronbach's alpha = 0.96 for patients working or in school and 0.93 for patients not working or in school). Test-retest intraclass correlation coefficients of the WHODAS II total score and subscales ranged from 0.82-0.96. The WHODAS II total score was strongly correlated with the SF-36 physical component score (Kendall's tau-b 0.51, P < 0.001) and moderately correlated with the SF-36 mental component score (tau-b 0.43, P < 0.001). WHODAS II correlations with disease outcomes ranged from Kendall's tau-b 0.15-0.55. The WHODAS II significantly differentiated between every aspect of disease severity assessed with the exception of measures of health resource use. CONCLUSION: The WHODAS II is a valid and reliable measure of HRQOL in cross-sectional studies of patients with early inflammatory arthritis. Research is still required to investigate potential item redundancy and determine its usefulness in longitudinal studies.

A randomized clinical trial of an individualized home-based exercise programme for women with fibromyalgia.

OBJECTIVE: To determine the efficacy of a 12-week individualized home-based exercise programme on physical functioning, pain severity and psychological distress for women with fibromyalgia (FM). METHODS: Seventy-nine women with a primary diagnosis of FM were randomized to a 12-week individualized home-based moderate-intensity exercise programme or to a usual care control group. Outcomes were functional capacity (Fibromyalgia Impact Questionnaire), pain severity and psychological distress. Outcomes were measured at study entry, at the end of the 12-week intervention, and at 3 and 9 months following completion of the intervention. RESULTS: On the basis of intention-to-treat analyses, a significant improvement in functional capacity at 3 and 9 months following treatment for participants in the exercise group who were more functionally disabled at study entry was observed. At both 3 and 9 months post-treatment, the mean estimated benefit of the intervention was more than 10 points [-12.3 (95% CI, -21.9 to -2.8); -10.8 (95% CI, -21.5 to -0.2)]. Compared with the control group, statistically significant improvements in upper body pain were evident in the exercise group at post-treatment. These between-group differences in upper body pain were maintained at 3 and 9 months post-treatment. No statistically significant group differences on lower body pain and psychological distress were found. CONCLUSIONS: Home-based exercise, a relatively low-cost treatment modality, has the potential to improve important health outcomes in FM.

Is fibromyalgia a distinct clinical entity? The approving rheumatologist's evidence.

Fibromyalgia is a challenge to the modern day physician. Today's practice of medicine is evidence-based, but fibromyalgia shifts this paradigm. There is even still debate as to whether this diffuse musculoskeletal pain syndrome, with a reduced pain threshold, and tender points on examination constitutes a definitive entity or disease process. We do not have the luxury of measurable abnormal findings on clinical examination or laboratory testing. The diagnosis of this condition is not aided by the use of any modern-day technology, and is simply a clinical syndrome. No treatment which we prescribe for fibromyalgia is universally successful in managing symptoms. Our skills as physicians are constantly challenged by treatment options offered to patients by non-conventional medicine. Even so, as physicians, our role should be to support our patients and continue to pursue scientific study in order to better understand this enigma.

Inaccuracy in the diagnosis of fibromyalgia syndrome: analysis of referrals.

OBJECTIVE: To examine prospectively the accuracy of an initial diagnosis for fibromyalgia (FM). METHODS: All patients newly referred for rheumatology consultation in a 6-month period were evaluated prospectively for either a preceding, current or subsequent diagnosis of FM. Clinical characteristics, previous and subsequent management and health care utilization were assessed. The final diagnosis at 6 months was verified and accuracy regarding the diagnosis of FM was assessed. RESULTS: Seventy six (12%) of all new patients were either referred with a question of FM or finally diagnosed with FM. At the final evaluation the accuracy of the diagnosis regarding FM by either the referring physician or by the rheumatologist at the time of the initial visit was correct in 34% of patients. The FM group in comparison with those with some other rheumatological diagnosis had more tender points (12.5 vs 4) and were more fatigued. In contrast, prolonged early morning stiffness and limitation of lumbar spinal mobility in more than one plane was more common in the non-FM group. CONCLUSION: There is a disturbing inaccuracy, mostly observed to be overdiagnosis, in the diagnosis of FM by referring physicians. This finding may help explain the current high reported rates of FM and caution physicians to consider other diagnostic possibilities when addressing diffuse musculoskeletal pain.

Atypical presentations of polymyalgia rheumatica.

Seventy patients with polymyalgia rheumatica (PMR) were seen at a suburban rheumatology practice from July 1983 to December 1987. Six of these patients presented without the typical limb girdle features associated with PMR. Presenting symptoms included peripheral synovitis or unilateral shoulder pain (3 patients), lower leg pain (3 patients), carpal tunnel syndrome (1 patient), and abdominal pain (1 patient). The disease evolved into the recognizable syndrome of PMR over a period of 2-12 months. We suggest that PMR may present in a variety of guises, or have a "stuttering evolution" to the full syndrome. The presenting manifestations of these atypical cases result from peripheral synovitis and thus represent a variant of the more common subclinical proximal synovitis seen in PMR. Increased clinical awareness of atypical presentations may assist earlier diagnosis and effective treatment.

Carpal tunnel syndrome complicated by reflex sympathetic dystrophy syndrome.

This report describes three patients with reflex sympathetic dystrophy complicating carpal tunnel syndrome. Pain disproportionate and more diffuse than that commonly associated with carpal tunnel syndrome suggested the associated diagnosis in each patient and facilitated prompt management.

Goodpasture's syndrome: case report of a survivor.

A patient with Goodpasture's syndrome who presented with severe pulmonary haemorrhage and minimal renal involvement is described. The diagnosis was substantiated by immunofluorescence studies on a renal biopsy specimen and by the detection of circulating antiglomerular basement membrane antibody. The patient was treated with corticosteroids and cyclophosphamide. He remains in good health 20 months after diagnosis, although there is a persisting abnormality in single-breath gas transfer for carbon monoxide. Recovery from Goodpasture's syndrome is reviewed in the light of recent advances.

Alternative medicine use by rheumatology patients in a universal health care setting.

OBJECTIVE: To assess the prevalence, extent of use, and cost of alternative medicine by patients attending a rheumatology clinic. METHODS: Two hundred and thirty-five unselected consecutive patients attending a rheumatology clinic were evaluated by questionnaire to record their current use of alternative medicine practices. RESULTS: Sixty-six percent of patients had used alternative medicine interventions in the preceding 12 months; 54% used over the counter products, 39% spiritual aids (including prayer, relaxation, meditation), and 13% each had visited alternative practitioners or used dietary interventions. Patients in the upper middle income group and French speaking patients used more bought products, but no other differences were observed when the groups were analyzed according to level of education, income or cultural background. The current annual cost for the patients of alternative medical therapies was $100. CONCLUSION: Our results demonstrate a moderate use of alternative medicine by rheumatology patients, mostly inexpensive products and no cost spiritual aids. Universal health care may have a negative impact on the extent of use of more costly practices.

Nonphysician practitioner treatments and fibromyalgia syndrome.

OBJECTIVE: Patients with fibromyalgia syndrome (FM) are high consumers of alternative medical interventions and frequently consult nonphysician practitioners. Although individuals may express satisfaction with alternative treatment methods, their effect upon symptoms and outcome of FM is not known. We compare symptom reporting and functional status in patients with FM being treated or not being treated by nonphysician practitioners. METHODS: 82 patients with FM enrolled in a cross sectional study were divided into current users (n = 33) and nonusers (n = 49) of nonphysician practitioner treatment over the preceding 6 months. Included were treatments by physiotherapists and psychologists, as well as all categories of alternative practitioners. The measurements studied were a patient global assessment of disease severity on a 100 mm visual analog scale (VAS), a physician global assessment on a 100 mm VAS, the Health Assessment Questionnaire (HAQ), and the Fibromyalgia Impact Questionnaire (FIQ). RESULTS: There were no differences for the FIQ, HAQ, or patient or physician global severity scores for users and nonusers of nonphysician practitioner treatments. The total number of health care professional visits in the preceding 6 months was higher for users than nonusers (27.0 vs 9.3; p < 0.001), although physician visits did not differ (9.0 vs 9.3). CONCLUSION: Patients with FM who had been treated by nonphysician practitioners during the preceding 6 months reported similar pain and functional impairment to those not receiving treatments.