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.

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.

Influenza vaccination is safe and effective in patients suffering from fibromyalgia syndrome.

The fibromyalgia syndrome (FMS) is considered to result from the exposure of a genetically susceptible individual to various triggers, such as physical trauma, stress, viral infections etc. A possible role of vaccination in FMS etiology has been suspected. Our objective was to evaluate the efficacy and safety of influenza vaccination in FMS patients. Nineteen FMS patients underwent physical and dolorimetric examinations and answered the fibromyalgia impact questionnaire (FIQ), the widespread pain index (WPI) checklist and the symptoms severity scale (SSS), which are part of the 2010 diagnostic criteria. Thirty-eight healthy subjects were recruited as controls. All participants were vaccinated with the inactivated split virion influenza vaccine. Serum was collected for antibody titration. Six weeks after vaccination, sera were tested by hemagglutination (HI) against A/California (H1N1), A/Perth (H3N2) and B/Brisbane. Humoral response was defined as either a fourfold or greater increase in titer, or an increase from a non-protective baseline level of <1/40 to a level of 1/40. No severe vaccination reactions were observed. No significant change was observed between WPI, SSS and FIQ values before and after vaccination, indicating no worsening of FMS symptoms. Vaccine immunogenicity: Six weeks after vaccination, FMS patients showed a significant increase in geometric mean titers of HI antibody. The rates of sero-protection increased from 22.9% for H1N1 to 89.5% post-vaccination. A significant increase in HI antibody titers was also demonstrated among healthy controls. Influenza vaccination was both safe and effective in FMS patients. In view of these results, FMS patients should be encouraged to undergo influenza vaccination according to the standard WHO recommendations.

Predicting fibromyalgia, a narrative review: are we better than fools and children?

Fibromyalgia syndrome (FMS) is a common and intriguing condition, manifest by chronic pain and fatigue. Although the pathogenesis of FMS is not yet completely understood, predicting the future development of FMS and chronic pain is a major challenge with great potential advantages, both from an individual as well as an epidemiological standpoint. Current knowledge indicates a genetic underpinning for FMS, and as increasing data are accumulated regarding the genetics involved, the prospect of utilizing these data for prediction becomes ever more attractive. The co-existence of FMS with multiple other functional disorders indicates that the clinical identification of such symptom constellations in a patient can alert the physician to the future development of FMS. Hypermobility syndrome is another clinical (as well as genetic) phenotype that has emerged as a risk factor for the development of FMS. Stressful events, including early life trauma, are also harbingers of the future development of FMS. Functional neuroimaging may help to elucidate the neural processes involved in central sensitization, and may ultimately also evolve into markers of predictive value. Last but not least, obesity and disturbed sleep are clinical (inter-related) features relevant for this spectrum. Future efforts will aim at integrating genetic, clinical and physiological data in the prediction of FMS and chronic pain.

Pediatric fibromyalgia.

Fibromyalgia (FM) is currently defined as chronic widespread pain (CWP) with allodynia or hyperalgesia to pressure pain. It is classified as one of the large group of soft-tissue pain syndromes. Pain is the cardinal symptom of FM; however, most patients also experience additional symptoms such as debilitating fatigue, disrupted or non-restorative sleep, functional bowel disturbances, and a variety of neuropsychiatric problems, including cognitive dysfunction, anxiety and depressive symptoms. Its pathogenesis is not entirely understood, although it is currently believed to be the result of a central nervous system (CNS) malfunction that increases pain transmission and perception. FMS usually involves females, and in these patients it often makes its first appearance during menopause. But it is often diagnosed both in young as well as elderly individuals. Pediatric FMS is a frustrating condition affecting children and adolescents at a crucial stage of their physical and emotional development. Pediatric FMS is an important differential diagnosis to be considered in the evaluation of children suffering from widespread musculoskeletal pain, and must be differentiated from a spectrum of inflammatory joint disorders such as juvenile idiopathic arthritis (JIA), juvenile ankylosing spondylitis, etc. The management of pediatric FMS is centered on the issues of education, behavioral and cognitive change (with a strong emphasis on physical exercise), and a relatively minor role for pharmacological treatment with medications such as muscle relaxants, analgesics and tricyclic agents.

Sexual dysfunction is correlated with tenderness in female fibromyalgia patients.

OBJECTIVES: The purpose of the current study was to evaluate sexual dysfunction among female fibromyalgia syndrome (FMS) patients. METHODS: Fifty female subjects were recruited and were asked to complete a questionnaire regarding sexual functioning. The control group included fifty-five healthy age-matched volunteers. The participants underwent a physical examination and tender point assessment was performed using manual palpation. All participants filled out the Arizona Sexual Experience Scale, which evaluates five areas of sexual functioning: sexual drive, sexual arousal, vaginal wetting, orgasm and sexual satisfaction. RESULTS: FMS patients had significantly lower scores on all five aspects of sexual function assessed. A positive correlation was observed between the sexual drive score, signifying a decrease in sexual drive, and the number of tender points documented on examination. Similarly, a positive correlation was observed between the sexual satisfaction scale (indicating decreasing levels of sexual satisfaction) and the number of tender points documented. A positive correlation was demonstrated between the sexual arousal and orgasmatic scales and between the tender point counts, indicating a decrease in sexual arousal and in orgasmatic function in correlation with an increasing number of tender points. CONCLUSIONS: The results of the current study indicate a multi-factorial sexual dysfunction among female FMS patients. All stages of sexual functioning, evaluated were significantly disturbed in comparison with the healthy controls. Physicians treating FMS patients should be aware of, and actively inquire about, sexual dysfunction as part of a multi-disciplinary evaluation of such patients.

Holocaust survivors: the pain behind the agony. Increased prevalence of fibromyalgia among Holocaust survivors.

OBJECTIVES: To assess the frequency of fibromyalgia among a population of Holocaust survivors in Israel as well as the occurrence of post-traumatic stress disorder (PTSD) and concurrent psychiatric symptoms, including depression and anxiety among survivors. METHODS: Eighty-three survivors of the Nazi Holocaust and 65 age-matched individuals not exposed to Nazi occupation were recruited. Physical examination and manual tender point assessment was performed for the establishment of the diagnosis of fibromyalgia and information was collected regarding quality of life (SF-36), physical function and health (FIQ), psychiatric symptoms (SCL-90) and PTSD symptoms (CAPS). RESULTS: Significantly increased rates of fibromyalgia were identified among Holocaust survivors compared with controls (23.81% vs. 10.94, p<0.05). Significantly increased rates of posttraumatic symptoms and measures of mental distress were also identified among survivors. CONCLUSIONS: The results indicate a significantly increased prevalence of fibromyalgia among Holocaust survivors six decades after the end of the Second World War. This finding furthers our knowledge regarding the long-term effect of stress on the development of fibromyalgia.

A tale of two cities - the effect of low intensity conflict on prevalence and characteristics of musculoskeletal pain and somatic symptoms associated with chronic stress.

UNLABELLED: Although both acute and chronic stress leads to pain, the precise characteristics of this association have not been well defined. Sderot is an Israeli town exposed to repeated missile attacks. Ofakim, a town of similar demographic and socioeconomic characteristics, had not been targeted, as of the period of our study. We examined the occurrence and characteristics of pain and related somatic symptoms in Sderot and Ofakim. METHODS: One thousand and twenty-four individuals in Sderot and 1006 in Ofakim were interviewed regarding pain, somatic symptoms, mood, trauma-exposure, and general health status. RESULTS: Significantly higher levels of trauma-related symptoms and somatic symptoms were noted in Sderot compared with Ofakim (p<0.001). Chronic widespread pain (CWP) was more common in Sderot (11.1%) than Ofakim (8.3%; OR 1.37, p=0.038). Women were more likely (13.9% vs. 9.3%; OR 1.45, p=0.06) than men (8.9% vs. 7.3%, OR 1.24, p=0.37) to experience CWP in Sderot vs. Ofakim. Amongst males, chronic regional pain (CRP) was more common in Sderot (19.2%) than in Ofakim (14.2%; p=0.036). Pain severity in Sderot was significantly higher than in Ofakim (p<0.001). CONCLUSIONS: Similar to previous studies that have suggested that chronic stress is associated with chronic pain, this study demonstrates significantly increased rates of somatic complaints, including pain, fatigue and IBS-like symptoms, among individuals in Sderot compared with Ofakim, as well as significantly higher rates of trauma-related symptoms. Thus, a fibromyalgia-like symptoms cluster was more likely to be found in Sderot compared with Ofakim. Widespread pain was reported as being significantly more frequent by inhabitants of Sderot compared with Ofakim. These results have relevance to both the general population and for populations enduring chronic stress.

Decreased levels of CCR3 in CD4+ lymphocytes of rheumatoid arthritis patients.

OBJECTIVES: To evaluate the expression of CCR3 receptors as well as CCR3 agonists, including eotaxin-2 and RANTES, among patients suffering from rheumatoid arthritis and healthy controls, as a possible pathogenetic mechanism in inflammatory joint disease. METHODS: Twenty-two patients and 13 healthy controls were recruited and clinically evaluated. CCR3 expression on CD4+ lymphocytes and mononuclear cells was evaluated by FACS analysis after staining with human CD4 APC (bioscience) and human CCR3 (CD193)PE. Levels of eotaxin-2 and RANTES were analysed by ELISA. RESULTS: A significant decrease was observed in the level of CD4+ cells expressing the CCR3 receptor in serum of RA patients (0.96+/-0.5) as compared with healthy controls (1.48+/-0.6) (p<0.05). A significant decrease in serum eotaxin-2 levels was evident among RA patients suffering from active disease, defined by a DAS-28 score above 5.5, compared with RA patients with lower activity scores (2.1+/-1.6 vs. 7.0+/-5.1; p=0.01). A significant decrease was evident in the number of CCR3 expressing Monocytes among RA patients treated with steroids and anti TNF-a medications as compared with RA patients not receiving such treatment. CONCLUSIONS: CCR3 is differentially expressed on inflammatory cells in RA, while eotaxin-2, a potent CCR3 agonist, is differentially expressed in active disease. Anti-inflammatory medications may down-regulate CCR3 expression in RA. The CCR3-CCR3 agonist pathway may thus have a pathogenic role in RA and may be a future target for novel treatment modalities.

Protective effect of eotaxin-2 inhibition in adjuvant-induced arthritis.

Eotaxin-2 is a potent chemoattractant for eosinophils, basophils and T helper type 2 (Th2) lymphocytes. The eotaxin-2/CCL24 receptor CCR3 is expressed in human brain, skin, endothelium and macrophages. The aim of the current study was to evaluate the protective effect of a monoclonal anti-eotaxin-2 antibody on the development of adjuvant-induced arthritis in rats (AIA). Adjuvant arthritis was induced in Lewis rats by intradermal injection of incomplete Freund's adjuvant +Mycobacterium tuberculosis. Rats were treated by intraperitoneal (i.p.) injection with three monoclonal antibodies against eotaxin-2 (G7, G8, D8) three times per week. Controls were treated with total mouse immunoglobulin G (IgG), methotrexate (MTX) or phosphate-buffered saline (PBS). Arthritis severity was evaluated by measuring ankle swelling, arthritic score, whole animal mobility and body weight. Sample joints were obtained for pathological evaluation and postmortem X-ray of ankle joints was performed to document erosions. Significant inhibition of arthritis was observed in rats treated with anti-eotaxin-2 antibodies compared to those treated with immunoglobulin or PBS. Inhibition was manifest in ankle diameter, arthritic score and mobility score. The antibody marked D8 showed the greatest efficacy. The effect was observed both in animals treated before the appearance of arthritis and in those where treatment was begun after development of joint inflammation. Combined treatment with D8 and MTX caused additional protection. Significant reduction of inflammation in D8-treated animals was also demonstrated in pathological and X-ray examinations. Inhibition of eotaxin-2 by monoclonal antibodies has a significant protective effect in adjuvant arthritis. These results may introduce a novel therapeutic target in rheumatoid arthritis and additional inflammatory joint disorders.

Candidate-gene approach in fibromyalgia syndrome: association analysis of the genes encoding substance P receptor, dopamine transporter and alpha1-antitrypsin.

BACKGROUND: Substance P receptor modulates stress, depression, anxiety and pain. Substance P is increased in CSF of fibromyalgia (FMS) patients. We examined the frequency of the substance P receptor (TACR1) 1354 G>C polymorphism in FMS.The dopamine transporter (DAT) SLC6A3 3' variable number tandem repeat (VNTR) polymorphism is associated with post traumatic stress disorder (PTSD), a condition with clinical and epidemiological overlap with FMS. We have evaluated the allele frequency of this polymorphism in FMS.Alpha1-antitrypsin (AAT) deficiency is an autosomal recessive metabolic disease. The PI ZZ phenotype, encoded by the E342K mutation, is associated with emphysema and liver disease, and has been linked with FMS. We have examined the frequency of this mutation in FMS. METHODS: Eighty-seven Jewish FMS patients participated; 45 of Ashkenazi origin, 32 of non-Ashkenazi origin and 10 of unknown or mixed Jewish origin. Controls consisted of 200 healthy Jewish individuals. Genotyping of the 1354G >C allele in the 3' UTR of TACR1 gene was performed by DdeI restriction analysis, genotyping the SCL6A3 DAT 3' VNTR polymorphism was performed by PCR combined with GeneScan analysis, and the AAT E342K mutation was identified by TaqI restriction analysis. RESULTS: No significant association was found between FMS and the three genetic markers studied here. CONCLUSIONS: The current candidate-gene approach study failed to identify significant associations between FMS and three genetic markers with hypothesis-driven clinical relevance. We suggest that a genome-wide association study would be a more fruitful approach for further investigation of the genetic basis of FMS.

A painful train of events: increased prevalence of fibromyalgia in survivors of a major train crash.

OBJECTIVES: To evaluate the prevalence of fibromyalgia in survivors of a major train crash in southern Israel, three years after the event. METHODS: Survivors were contacted by mail and telephone. Individuals consenting to participate in the study underwent physical examination, including a tender point count and dolorimetry, as well as extensive evaluation of parameters relating to quality of life, presence of widespread pain, fatigue, physical and social function, posttraumatic symptoms and symptoms related to anxiety, dissociation, depression, somatisation, etc. RESULTS: Fifteen percent of survivors participating in the study met ACR criteria for the classification of fibromyalgia. Significantly lower rates of physical and emotional functioning were found among survivors with fibromyalgia compared with those not meeting the classification criteria. Survivors with fibromyalgia rated significantly higher on scales of somatisation, obsessive-compulsive ideation, interpersonal sensitivity, depression, anger and hostility, phobic and general anxiety, paranoid ideation and psychoticism. Survivors with fibromyalgia also rated significantly higher on scales of posttraumatic symptoms including intrusion, avoidance and arousal. These individuals also rated significantly higher on the Peritraumatic Dissociative Experiences Questionnaire (PDE-Q) and the Dissociative Experiences Scale (Hebrew version) (DES-H). CONCLUSION: Fibromyalgia was found to be highly prevalent, three years after a major train crash, among individuals exposed to the combination of physical injury and extreme stress. This finding is in accordance with previous data regarding the association of fibromyalgia with both physical and emotional trauma and calls attention to studying the underlying susceptibility factors which may partake in this association.

Vaccination against influenza in patients with rheumatoid arthritis: the effect of rituximab on the humoral response.

OBJECTIVE: To assess the effect of rituximab on the efficacy and safety of influenza virus vaccine in patients with rheumatoid arthritis (RA). METHODS: The study group comprised patients with RA treated with conventional disease-modifying drugs with or without rituximab. Split-virion inactivated vaccine containing 15 microg haemagglutinin/dose of B/Shanghai/361/02 (SHAN), A/New Caledonian/20/99 (NC) (H1N1) and A/California/7/04 (CAL) (H3N2) was used. Disease activity was assessed by the number of tender and swollen joints, duration of morning stiffness and evaluation of pain on the day of vaccination and 4 weeks later. CD19-positive cell levels were assessed in rituximab-treated patients. Haemagglutination inhibition (HI) antibodies were tested and response was defined as a greater than fourfold rise 4 weeks after vaccination or seroconversion in patients with a non-protective baseline level of antibodies (<1/40). Geometric mean titres (GMT) were calculated in all subjects. RESULTS: The participants were divided into three groups: RA (n = 29, aged 64 (12) years), rituximab-treated RA (n = 14, aged 53 (15) years) and healthy controls (n = 21, aged 58 (15) years). All baseline protective levels of HI antibodies and GMT were similar. Four weeks after vaccination, there was a significant increase in GMT for NC and CAL antigens in all subjects, but not for the SHAN antigen in the rituximab group. In rituximab-treated patients, the percentage of responders was low for all three antigens tested, achieving statistical significance for the CAL antigen. Measures of disease activity remained unchanged. CONCLUSION: Influenza virus vaccine generated a humoral response in all study patients with RA and controls. Although the response was significantly lower among rituximab-treated patients, treatment with rituximab does not preclude administration of vaccination against influenza.

Quinidine and procainamide inhibit murine macrophage uptake of apoptotic and necrotic cells: a novel contributing mechanism of drug-induced-lupus.

UNLABELLED: A number of mechanisms have been proposed to explain the etiology of drug-induced lupus (DIL) but the effect of apoptotic and necrotic cell handling has not been previously examined. OBJECTIVE: To evaluate the effect of quinidine and procainamide at therapeutic range concentrations, on the uptake of apoptotic and necrotic thymocytes by murine peritoneal macrophages and on macrophage survival, as a novel mechanism for DIL. METHODS: Thymocytes were stained and induced to undergo apoptosis by serum withdrawal. Apoptosis was evaluated using annexin V and propidum iodide (PI) and PI staining. Necrosis was induced by heating. Peritoneal macrophages were treated with quinidine or procainamide at a range of therapeutic concentrations and incubated with stained apoptotic and necrotic thymocytes. Apoptotic and necrotic cell uptake was evaluated by flow cytometry using double staining of thymocytes and macrophages and by confocal microscopy. Green fluorescent latex beads were used as controls for phagocytosis. RESULTS: Significantly decreased uptake of apoptotic and necrotic cells was seen in the presence of quinidine and procainamide. The documented effect was mainly on the number of apoptotic/necrotic cells per macrophage. Uptake of fluorescent latex beads offered to resident macrophages was not significantly affected by quinidine or procainamide. No pro-apoptotic effect of quinidine or procainamide on macrophages was seen. CONCLUSION: Quinidine and procainamide at therapeutic range concentrations specifically inhibit clearance of apoptotic and necrotic cells by peritoneal macrophages. Altered handling of apoptotic and necrotic cells may represent a contributing mechanism for DIL.

Deferiprone, an oral iron chelator, ameliorates experimental colitis and gastric ulceration in rats.

Iron is pivotal is producing tissue-damaging reactive oxygen metabolites. Our aim is to determine the antiinflammatory activity of deferiprone, an oral iron chelator, in experimental colitis and gastritis. Colitis was induced by intraceccal administration of 2 ml 5% acetic acid or by intracolonic administration of 0.1 ml 3% iodoacetamide, with or without cotreatment with deferiprone. Gastritis was induced by intragastric administration of ethanol or hydrochloric acid (HCl) and by subcutaneous injection of indomethacin, with and without deferiprone. Rats were killed 24 hours after acetic acid and iodoacetamide, 30 minutes after ethanol, one hour after HCl, and three hours after indomethacin administration. The colon or stomach was isolated, macroscopic damage was measured, and mucosal samples were obtained for determination of eicosanoid generation, myeloperoxidase (MPO), and nitric oxide synthase (NOS) activities. Deferiprone decreased iodoacetamide and acetic acid-induced macroscopic colonic damage by 67% and 69%, respectively, and macroscopic gastric damage by 91%, 68%, and 46% induced by ethanol, HCl, and indomethacin, respectively. The effect of deferiprone was accompanied by significant decrease in colonic and gastric, MPO and NOS activities, and colonic prostaglandin E2 (PGE2) generation, in acetic acid, ethanol, and indomethacin models, whereas in the iodoacetamide and HCl models attenuation of the decrease in PGE2 generation was seen. Deferiprone is protective in experimental colitis and gastritis, probably due to decreased production of iron-dependent oxygen-free radicals. Oral iron chelators may constitute a novel approach to ameliorate gastrointestinal inflammatory disorders.

Brucellosis and the gastrointestinal tract. The odd couple.

Though pathogenetically qualifying as an enteric fever, the gastroenterological manifestations of Brucella in humans are relatively uncommon. We present a typical case of Brucellosis with gastrointestinal symptoms and review these by organ involvement, ranging from the mild nonspecific, such as diarrhea and abdominal pain, to the pathologically distinct hepatic lesions, and to the rare colonic, pancreatic, and peritoneal involvement. The limited indications for diagnostic procedures, such as endoscopy and liver biopsy are discussed.