Synergistic combination of carvedilol, amlodipine, amitriptyline, and antibiotics as an alternative treatment approach for the susceptible and multidrug-resistant A. baumannii infections via drug repurposing.

We evaluated in vitro activity of 13 drugs used in the treatment of some non-communicable diseases via repurposing to determine their potential use in the treatment of Acinetobacter baumannii infections caused by susceptible and multidrug-resistant strains. A. baumannii is a multidrug-resistant Gram-negative bacteria causing nosocomial infections, especially in intensive care units. It has been identified in the WHO critical pathogen list and this emphasises urgent need for new treatment options. As the development of new therapeutics is expensive and time consuming, finding new uses of existing drugs via drug repositioning has been favoured. Antimicrobial susceptibility tests were conducted on all 13 drugs according to CLSI. Drugs with MIC values below 128 µg/mL and control antibiotics were further subjected to synergetic effect and bacterial time-kill analysis. Carvedilol-gentamicin (FICI 0.2813) and carvedilol-amlodipine (FICI 0.5625) were determined to have synergetic and additive effect, respectively, on the susceptible A. baumannii strain, and amlodipine-tetracycline (FICI 0.75) and amitriptyline-tetracycline (FICI 0.75) to have additive effect on the multidrug-resistant A. baumannii strain. Most remarkably, both amlodipine and amitriptyline reduced the MIC of multidrug-resistant, including some carbapenems, A. baumannii reference antibiotic tetracycline from 2 to 0.5 µg/mL, for 4-folds. All these results were further supported by bacterial time-kill assay and all combinations showed bactericidal activity, at certain hours, at 4XMIC. Combinations proposed in this study may provide treatment options for both susceptible and multidrug-resistant A. baumannii infections but requires further pharmacokinetics and pharmacodynamics analyses and in vivo re-evaluations using appropriate models.

Does the addition of electrical stimulation or kinesiotherapy improve outcomes of amitriptyline treatment for women with vulvodynia? A randomized clinical trial.

INTRODUCTION AND HYPOTHESIS: Women diagnosed with provoked vulvodynia frequently report a great deal of frustration in achieving symptomatic relief. Physical therapy and drug treatment are among the interventions most indicated by guidelines; however, whether those modalities are effective when combined remains unclear. The objective was to evaluate the effectiveness of adding a physical therapy modality compared with amitriptyline alone for the treatment of vulvodynia. METHODS: Eighty-six women with vulvodynia were randomized to (G1) 25 mg amitriptyline, once a day (n=27), (G2) amitriptyline + electrical stimulation therapy (n=29) or (G3) amitriptyline + kinesiotherapy (n=30). All treatment modalities were administered for 8 weeks. The primary endpoint was the reduction in vestibular pain. Secondary measurements focused on sexual pain, frequency of vaginal intercourse, Friedrich score, and overall sexual function. Data were analyzed using intention-to-treat. RESULTS: All treatment modalities resulted in a significant decrease in vestibular pain (p<0.001), sexual pain (p<0.05), Friedrich score (p<0.001), and an increase in the frequency of sexual intercourse (p<0.05). G3 was more effective than G1 at reducing sexual pain (G1: 5.3±3.3 vs G3: 3.2±2.7; p=0.01) and at improving sexual function (G1: 18.8±9.8 vs G3: 23.9±7.8; p=0.04). CONCLUSION: Kinesiotherapy and electrotherapy additions to amitriptyline administration as well as amitriptyline alone, were effective at improving vestibular pain in women with vulvodynia. Women receiving physical therapy had the greatest improvement in sexual function and frequency of intercourse at post-treatment and follow-up.

Efficacy and safety of different antidepressants and anticonvulsants in central poststroke pain: A network meta-analysis and systematic review.

OBJECTIVE: To evaluate the efficacy and safety of different antidepressants and anticonvulsants in the treatment of central poststroke pain (CPSP) by network meta-analysis and provide an evidence-based foundation for clinical practice. METHODS: PubMed, Cochrane Library, EMBASE, CNKI, APA PsycINFO, Wanfang, VIP and other databases were searched by computer to find clinical randomized controlled studies (RCTs) on drug treatment of CPSP. The retrieval time limit was from the establishment of each database to July 2022. The quality of the included RCTs was evaluated using the bias risk assessment tool recommended by Cochrane. Stata 14.0 was used for network meta-analysis. RESULTS: A total of 13 RCTs, 1040 patients and 9 drugs were finally included. The results of the network meta-analysis showed that the effectiveness ranking as rated by the visual analog scale (VAS) was gabapentin > pregabalin > fluoxetine > lamotrigine > duloxetine > serqulin > amitriptyline > carbamazepine > vitamin B. Ranking according to the numerical rating scale (NRS) was pregabalin > gabapentin > carbamazepine. Ranking derived from the Hamilton depression scale (HAMD) was pregabalin > duloxetine > gabapentin > amitriptyline. CONCLUSION: All nine drugs can relieve the pain of CPSP patients to different degrees; among them pregabalin and gabapentin have the most significant effect, and gabapentin and pregabalin also have the most adverse reactions. In the future, more multicenter, large sample, double-blind clinical randomized controlled trials need to be carried out to supplement and demonstrate the results of this study.

Survey of Child Neurologists on Management of Pediatric Post-traumatic Headache.

Traumatic brain injury causes significant morbidity in youth, and headache is the most common postconcussive symptom. No established guidelines exist for pediatric post-traumatic headache management. We aimed to characterize common clinical practices of child neurologists. Of 95 practitioners who completed our survey, most evaluate <50 pediatric concussion patients per year, and 38.9% of practitioners consistently use International Classification of Headache Disorders criteria to diagnose post-traumatic headache. Most recommend nonsteroidal anti-inflammatory drugs as abortive therapy, though timing after injury and frequency of use varies, as does the time when providers begin prophylactic medications. Amitriptyline, topiramate, and vitamins/supplements are most commonly used for prophylaxis. Approach to rest and return to activities varies; one-third recommend rest for 1 to 3 days and then progressive return, consistent with current best practice. With no established guidelines for pediatric post-traumatic headache management, it is not surprising that practices vary considerably. Further studies are needed to define the best, evidence-based management for pediatric post-traumatic headache.

Headache: Tension-Type Headache.

Tension-type headache (TTH) is the most common primary headache disorder, with a worldwide lifetime prevalence of 46% to 78%. TTH causes greater disability and accounts for more missed work days than migraine. The etiology of TTH is thought to be multifactorial, involving genetic and environmental factors. The three subtypes of TTH are infrequent episodic, frequent episodic, and chronic. Patients typically describe headache pain as pressing, dull, and with the sensation of a tight band around the head. Nonprescription analgesics are indicated for management of episodic TTH. Prophylaxis should be considered for patients with chronic TTH, with very frequent episodic TTH, at risk of medication overuse headache, and who are unable to tolerate effective doses of first-line drugs. Amitriptyline is recommended as a first-line drug for prophylaxis. (This is an off-label use of amitriptyline.) Physical and integrative therapies for TTH management include electromyography biofeedback, cognitive behavioral therapy, exercise, massage, and trigger point injection.

An evaluation of the pharmacotherapy for interstitial cystitis.

INTRODUCTION: Interstitial cystitis (IC) and bladder pain syndrome (BPS) are chronic conditions that can be debilitating for patients. There is no consensus as to their etiology, and there are many proposed treatment algorithms. Oftentimes multimodal therapy, such as combining behavioral modification and physical therapy alongside pharmacotherapies, will be utilized. With the various treatment options available to patients and providers, there is an ever-growing need to implement evidence-based therapies. AREAS COVERED: The authors explore the different pharmacotherapies as commonly recommended in the American Urological Association (AUA) and European Association of Urology (EAU) multitiered guidelines for IC/BPS treatment as well as other investigational therapies. Pharmacotherapies targeting bladder, pelvic, and/or systemic factors in the overall treatment of IC/BPS are discussed with a particular focus on evidence-based guideline therapies. This article also looks at emerging therapies of interest. EXPERT OPINION: IC/BPS is a syndrome that requires a multimodal approach, including clinical phenotyping and directed therapy based on the patient's symptoms. The AUA and EAU provide guidelines for practitioners to follow, but adequate treatment requires the therapy to be targeted toward the patient's phenotypic domain.

A double- blind, randomized, and placebo-controlled clinical trial with omega-3 polyunsaturated fatty acids (OPFA É·-3) for the prevention of migraine in chronic migraine patients using amitriptyline.

OBJECTIVE: To determine the prophylactic effect of OPFAϖ-3 in migraine. SUBJECTS AND METHODS: This was a prospective, experimental, controlled, double-blind, and with comparison groups study. Sixty patients diagnosed with chronic migraine, according to the criteria of the International Classification of Headache Disorders, Third Edition (beta version) (ICHD-3ß), were prophylactically treated with amitriptyline. They were divided into two equal groups: in group 1, prophylaxis was associated with OPFAϖ-3 and in group 2 with placebo. After 60 days, both groups were assessed by a second researcher. RESULTS: Of the 60 patients with chronic migraine, only 51 patients (15 men and 36 women) completed the treatment. The group that received OPFAϖ-3 consisted of 27 (52.9%) patients (six men and 21 women), while the control group was equal to 24 (47.1%) patients (nine men and 15 women). These differences were not significant (χ2 = 1.428; P = 0.375). In 66.7% (18/27) of the patients who used OPFAϖ-3, there was a reduction of more than 80.0% per month in the number of days of headache, while in the control group, the same improvement occurred in 33.3% (8/24) of patients. This difference was significant (χ2 = 5.649; P = 0.036). CONCLUSIONS: Polyunsaturated omega 3 fatty acids (OPFAϖ-3) are useful for prophylaxis of migraine attacks.

Alpha Lipoic Acid Plus Omega-3 Fatty Acids for Vestibulodynia Associated With Painful Bladder Syndrome.

OBJECTIVE: This study assessed the effectiveness of alpha lipoic acid (ALA) plus omega-3 polyunsaturated fatty acids (n-3 PUFAs) in combination with amitriptyline therapy in patients with vestibulodynia/painful bladder syndrome (VBD/PBS). METHODS: Women with VBD/PBS were randomly assigned to receive amitriptyline or amitriptyline plus a commercially available preparation (ALAnerv Age; Alfa Wassermann, Bologna, Italy) containing, in 2 capsules, ALA 600 mg plus docosahexaenoic acid 250 mg and eicosapentaenoic acid 16.67 mg. Symptoms of burning and pain were assessed using a 10-cm visual analog scale and the short form of the McGill-Melzack Pain Questionnaire. RESULTS: Among 84 women who were randomized, the mean ± standard deviation dose of amitriptyline was 21.7 ± 6.6 mg/day, without statistical difference between the two groups. Pain, as assessed using both the pain rating index of the visual analog scale and the short-form McGill Pain Questionnaire, decreased significantly in both trial groups, with a greater effect seen with the addition of ALA and n-3 PUFAs. The addition of ALA/n-3 PUFAs to amitriptyline treatment was also associated with improvements in dyspareunia and pelvic floor muscle tone. The overall incidence of adverse events was low, and none led to treatment discontinuation. CONCLUSIONS: The addition of ALA/n-3 PUFAs to amitriptyline treatment in patients with VBD/PBS appears to improve outcomes and may allow for a lower dosage of amitriptyline, which may lead to fewer adverse effects.

Single-blind, randomized, pilot study combining shiatsu and amitriptyline in refractory primary headaches.

Complementary alternative medicine, such as shiatsu, can represent a suitable treatment for primary headaches. However, evidence-based data about the effect of combining shiatsu and pharmacological treatments are still not available. Therefore, we tested the efficacy and safety of combining shiatsu and amitriptyline to treat refractory primary headaches in a single-blind, randomized, pilot study. Subjects with a diagnosis of primary headache and who experienced lack of response to ≥2 different prophylactic drugs were randomized in a 1:1:1 ratio to receive shiatsu plus amitriptyline, shiatsu alone, or amitriptyline alone for 3 months. Primary endpoint was the proportion of patients experiencing ≥50%-reduction in headache days. Secondary endpoints were days with headache per month, visual analogue scale, and number of pain killers taken per month. After randomization, 37 subjects were allocated to shiatsu plus amitriptyline (n = 11), shiatsu alone (n = 13), and amitriptyline alone (n = 13). Randomization ensured well-balanced demographic and clinical characteristics at baseline. Although all the three groups improved in terms of headache frequency, visual analogue scale score, and number of pain killers (p < 0.05), there was no between-group difference in primary endpoint (p = ns). Shiatsu (alone or in combination) was superior to amitriptyline in reducing the number of pain killers taken per month (p < 0.05). Seven (19%) subjects reported adverse events, all attributable to amitriptyline, while no side effects were related with shiatsu treatment. Shiatsu is a safe and potentially useful alternative approach for refractory headache. However, there is no evidence of an additive or synergistic effect of combining shiatsu and amitriptyline. These findings are only preliminary and should be interpreted cautiously due to the small sample size of the population included in our study. Trial registration 81/2010 (Ethical Committee, S. Andrea Hospital, Sapienza University, Rome, Italy).

EULAR revised recommendations for the management of fibromyalgia.

OBJECTIVE: The original European League Against Rheumatism recommendations for managing fibromyalgia assessed evidence up to 2005. The paucity of studies meant that most recommendations were 'expert opinion'. METHODS: A multidisciplinary group from 12 countries assessed evidence with a focus on systematic reviews and meta-analyses concerned with pharmacological/non-pharmacological management for fibromyalgia. A review, in May 2015, identified eligible publications and key outcomes assessed were pain, fatigue, sleep and daily functioning. The Grading of Recommendations Assessment, Development and Evaluation system was used for making recommendations. RESULTS: 2979 titles were identified: from these 275 full papers were selected for review and 107 reviews (and/or meta-analyses) evaluated as eligible. Based on meta-analyses, the only 'strong for' therapy-based recommendation in the guidelines was exercise. Based on expert opinion, a graduated approach, the following four main stages are suggested underpinned by shared decision-making with patients. Initial management should involve patient education and focus on non-pharmacological therapies. In case of non-response, further therapies (all of which were evaluated as 'weak for' based on meta-analyses) should be tailored to the specific needs of the individual and may involve psychological therapies (for mood disorders and unhelpful coping strategies), pharmacotherapy (for severe pain or sleep disturbance) and/or a multimodal rehabilitation programme (for severe disability). CONCLUSIONS: These recommendations are underpinned by high-quality reviews and meta-analyses. The size of effect for most treatments is relatively modest. We propose research priorities clarifying who will benefit from specific interventions, their effect in combination and organisation of healthcare systems to optimise outcome.

Treating Painful Diabetic Peripheral Neuropathy: An Update.

Painful diabetic peripheral neuropathy occurs in approximately 25% of patients with diabetes mellitus who are treated in the office setting and significantly affects quality of life. It typically causes burning pain, paresthesias, and numbness in a stocking-glove pattern that progresses proximally from the feet and hands. Clinicians should carefully consider the patient's goals and functional status and potential adverse effects of medication when choosing a treatment for painful diabetic peripheral neuropathy. Pregabalin and duloxetine are the only medications approved by the U.S. Food and Drug Administration for treating this disorder. Based on current practice guidelines, these medications, with gabapentin and amitriptyline, should be considered for the initial treatment. Second-line therapy includes opioid-like medications (tramadol and tapentadol), venlafaxine, desvenlafaxine, and topical agents (lidocaine patches and capsaicin cream). Isosorbide dinitrate spray and transcutaneous electrical nerve stimulation may provide relief in some patients and can be considered at any point during therapy. Opioids and selective serotonin reuptake inhibitors are optional third-line medications. Acupuncture, traditional Chinese medicine, alpha lipoic acid, acetyl-l-carnitine, primrose oil, and electromagnetic field application lack high-quality evidence to support their use.

Cannabinoids for fibromyalgia.

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

Mancha hiperpigmentada muy pruriginosa en la espalda / Highly pigmented stain on the back

No disponible

Síndrome doloroso regional complejo tipo i. Análisis de una casuística infantil / Complex regional pain syndrome type i. An analysis of 7 cases in children

Introducción: El síndrome doloroso regional complejo (SDRC) se caracteriza por la presencia de dolor acompañado de síntomas sensoriales, autonómicos y motores. Es precedido habitualmente por una lesión o inmovilización. Su curso clínico es desproporcionado con respecto a la lesión inicial tanto en su intensidad como en su duración. Su distribución es regional, predominando en las extremidades. Se clasifica en tipo I y tipo II según ausencia o presencia de lesión nerviosa. Casos clínicos: Se presentan 7 casos clínicos, 6 niñas y un varón con SDRC tipo I, con edades comprendidas entre 7-15 años. Tres tenían antecedente de traumatismo previo. En 5 casos los síntomas se localizaron en miembros inferiores. La demora diagnóstica fue entre 4-90 días. Tres pacientes presentaron elementos de ansiedad y depresión. En todos se realizaron pruebas complementarias de imagen e inmunológicas para descartar diagnósticos diferenciales. Se realizó tratamiento interdisciplinario no farmacológico (fisioterapia y psicoterapia) y farmacológico con analgésicos mayores, gabapentina o pregabalina. Todos presentaron buena evolución, sin recidivas en el seguimiento que fue entre 4 meses y 2,5 años. Conclusiones: El poco reconocimiento de este síndrome en niños, la ansiedad familiar que genera y los costos en paraclínica innecesaria, resaltan la importancia de su difusión entre pediatras y neuropediatras para favorecer su reconocimiento, evitar estudios innecesarios y múltiples consultas a especialistas que retrasan el diagnóstico y el inicio de un tratamiento efectivo

Introduction: Complex regional pain syndrome (CRPS) is characterised by the presence of pain accompanied by sensory, autonomic and motor symptoms, usually preceded by a lesion or immobilisation. The clinical course is disproportionate to the initial injury in intensity and in duration. Its distribution is regional, predominantly in limbs. It is classified as type I and type II according to the absence or presence of nerve injury. Cases: We present the cases of seven children, 6 girls and 1 boy, aged 7 to 15 years. Three had a history of previous trauma. In 5 cases, the symptoms were located in the lower limbs. Time to diagnosis was between 4 and 90 days. Three patients had clinical features of anxiety and depression. Imaging and immunological studies were performed to rule out differential diagnoses in all the children. Interdisciplinary treatment was performed with physiotherapy, psychotherapy, and gabapentin or pregabalin. All patients had a good clinical outcome, with no relapses in the follow-up period (between 4 and 30 months). Conclusions: CRPS is frequently unrecognised in children, leading to family anxiety and unnecessary para-clinical costs. Paediatricians and paediatric neurologists should be aware of this syndrome in order to avoid delay in diagnosis, unnecessary studies, and multiple visits to specialists, with a view to providing effective treatment

Topical treatment in pain medicine: from ancient remedies to modern usage.

Over several millennia, substances have been applied to the skin for treatment of pain. Some ingredients are in current use; others have been discontinued. Mechanisms of action include interactions with nociceptive neural networks and inflammatory processes. Substances must penetrate the stratum corneum barrier and vehicles that enhance penetration have been developed. Topical drugs with links to the past include menthol, capsaicin, some opioids, local anesthetic agents and NSAIDs. Mandragora is also described as an example of a herbal remedy that has been discontinued due to its toxicity. The future for topical drugs is promising, with the advent of new drugs tailored for specific pain mechanisms and the development of both penetration enhancers and sterile preparation methods.

Establishment and characterization of an optimized mouse model of multiple sclerosis-induced neuropathic pain using behavioral, pharmacologic, histologic and immunohistochemical methods.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that causes debilitating central neuropathic pain in many patients. Although mouse models of experimental autoimmune encephalomyelitis (EAE) have provided insight on the pathobiology of MS-induced neuropathic pain, concurrent severe motor impairments confound quantitative assessment of pain behaviors over the disease course. To address this issue, we have established and characterized an optimized EAE-mouse model of MS-induced neuropathic pain. Briefly, C57BL/6 mice were immunized with MOG35-55 (200µg) and adjuvants comprising Quil A (45µg) and pertussis toxin (2×250ng). The traditionally used Freund's Complete Adjuvant (FCA) was replaced with Quil A, as FCA itself induces CNS neuroinflammation. Herein, EAE-mice exhibited a mild relapsing-remitting clinical disease course with temporal development of mechanical allodynia in the bilateral hindpaws. Mechanical allodynia was fully developed by 28-30days post-immunization (p.i.) and was maintained until study completion (52-60days p.i.), in the absence of confounding motor deficits. Single bolus doses of amitriptyline (1-7mg/kg), gabapentin (10-50mg/kg) and morphine (0.1-2mg/kg) evoked dose-dependent analgesia in the bilateral hindpaws of EAE-mice; the corresponding ED50s were 1.5, 20 and 1mg/kg respectively. At day 39 p.i. in EAE-mice exhibiting mechanical allodynia in the hindpaws, there was marked demyelination and gliosis in the brain and lumbar spinal cord, mirroring these pathobiologic hallmark features of MS in humans. Our optimized EAE-mouse model of MS-associated neuropathic pain will be invaluable for future investigation of the pathobiology of MS-induced neuropathic pain and for efficacy profiling of novel molecules as potential new analgesics for improved relief of this condition.

More ubiquitous effects from non-pharmacologic than from pharmacologic treatments for fibromyalgia syndrome: a meta-analysis examining six core symptoms.

This study aimed to characterize and compare the efficacy profile on six fibromyalgia syndrome (FM) core symptoms associated with pharmacologic and non-pharmacologic treatments. We screened PubMed, Embase and the Cochrane Library for FM articles from 1990 to September 2012 to analyse randomized controlled trials comparing pharmacologic or non-pharmacologic treatments to placebo or sham. Papers including assessments of at least 2 of the 6 main FM symptom domains - pain, sleep disturbance, fatigue, affective symptoms (depression/anxiety), functional deficit and cognitive impairment - were selected for analysis. Studies exploring pharmacologic approaches (n = 21) were mainly dedicated to treating a small number of dimensions, mostly pain. They were of good quality but were not prospectively designed to simultaneously document efficacy for the management of multiple core FM symptom domains. Only amitriptyline demonstrated a significant effect on as many as three core FM symptoms, but it exhibited many adverse effects and was subject to early tachyphylaxis. Studies involving non-pharmacologic approaches (n = 64) were typically of poorer quality but were more often dedicated to multidimensional targets. Pool therapy demonstrated significant effects on five symptom domains, repetitive transcranial magnetic stimulation on four domains, balneotherapy on three domains and exercise, cognitive behaviour therapy and massage on two domains each. Differences between pharmacologic and non-pharmacologic approaches may be related to different modes of action, tolerability profiles and study designs. Very few drugs in well-designed clinical trials have demonstrated significant relief for multiple FM symptom domains, whereas non-pharmacologic treatments with weaker study designs have demonstrated multidimensional effects. Future therapeutic trials for FM should prospectively examine each of the core domains and should attempt to combine pharmacologic and non-pharmacologic therapies in well-designed clinical trials.