Chronic Pain Syndromes: Fibromyalgia.

Fibromyalgia is a chronic pain syndrome that is considered a pain processing disorder; its pathophysiology is not completely understood. The estimated prevalence in the general population varies from 0.5% to 12%, depending on the population studied and diagnostic criteria used. It is more common in females than males. There is no diagnostic laboratory test. The two currently used diagnostic methods are scoring criteria from the American College of Rheumatology (ACR) and the Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks (ACTTION)-American Pain Society (APS). These diagnostic criteria include chronic widespread pain of at least 3 months' duration plus poor sleep and/or fatigue and other somatic symptoms. Other pain syndromes also should be considered in the differential diagnosis. A multimodal, targeted symptom management approach that emphasizes self-management is recommended. Nonpharmacotherapies include patient education, exercise, and cognitive behavior therapy. Pharmacotherapy should be based on predominant symptoms. Amitriptyline and pregabalin are effective for management of pain, fatigue, and sleep issues. Milnacipran (Savella) is effective for pain and fatigue. Duloxetine is effective for management of pain and depression. There is no evidence of benefit of analgesics. Common comorbidities, such as regional pain conditions and mental disorders, should be addressed.

Effect of milnacipran on brain­derived neurotrophic factor and oxidative stress biomarkers in patients of major depressive disorder.

Emerging hypotheses in the pathophysiology of major depressive disorder (MDD) suggest important role of neurotrophic factors and oxidative stress. This study assessed the effect of milnacipran (a dual serotonin­noradrenaline reuptake inhibitor) on brain­derived neurotrophic factor (BDNF) and oxidative stress biomarkers i.e., malondialdehyde (MDA), glutathione­s­ transferase (GST) and glutathione reductase (GR) in patients of MDD. Thirty patients (aged 18 to 60 years) with MDD diagnosed by DSM­IV criteria, with Hamilton Depression Rating scale (HAM­D) score ≥ 14 were included in the study. Patients were given milnacipran in the doses of 50­100 mg once daily. Patients were followed up for 12 weeks. HAM­D score at the start of treatment was 17.8±1.7 which significantly reduced to 8.9±3.1 at 12 weeks of treatment. In responders, the plasma BDNF levels increased significantly at 12 weeks post treatment. There was no significant change in the pre­ and post­treatment values of oxidative stress parameters (MDA, GST and GR) after 12 week treatment. Milnacipran is effective and well tolerated in MDD patients, and its therapeutic response is associated with an increase in plasma BDNF levels. However, milnacipran did not affect oxidative stress biomarkers.

Comparison of Amitriptyline and US Food and Drug Administration-Approved Treatments for Fibromyalgia: A Systematic Review and Network Meta-analysis.

Importance: Amitriptyline is an established medication used off-label for the treatment of fibromyalgia, but pregabalin, duloxetine, and milnacipran are the only pharmacological agents approved by the US Food and Drug Administration (FDA) to treat fibromyalgia. Objective: To investigate the comparative effectiveness and acceptability associated with pharmacological treatment options for fibromyalgia. Data Sources: Searches of PubMed/MEDLINE, Cochrane Library, Embase, and Clinicaltrials.gov were conducted on November 20, 2018, and updated on July 29, 2020. Study Selection: Randomized clinical trials (RCTs) comparing amitriptyline or any FDA-approved doses of investigated drugs. Data Extraction and Synthesis: This study follows the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline. Four independent reviewers extracted data using a standardized data extraction sheet and assessed quality of RCTs. A random-effects bayesian network meta-analysis (NMA) was conducted. Data were analyzed from August 2020 to January 2021. Main Outcomes and Measures: Comparative effectiveness and acceptability (defined as discontinuation of treatment owing to adverse drug reactions) associated with amitriptyline (off-label), pregabalin, duloxetine, and milnacipran (on-label) in reducing fibromyalgia symptoms. The following doses were compared: 60-mg and 120-mg duloxetine; 150-mg, 300-mg, 450-mg, and 600-mg pregabalin; 100-mg and 200-mg milnacipran; and amitriptyline. Effect sizes are reported as standardized mean differences (SMDs) for continuous outcomes and odds ratios (ORs) for dichotomous outcomes with 95% credible intervals (95% CrIs). Findings were considered statistically significant when the 95% CrI did not include the null value (0 for SMD and 1 for OR). Relative treatment ranking using the surface under the cumulative ranking curve (SUCRA) was also evaluated. Results: A total of 36 studies (11 930 patients) were included. The mean (SD) age of patients was 48.4 (10.4) years, and 11 261 patients (94.4%) were women. Compared with placebo, amitriptyline was associated with reduced sleep disturbances (SMD, -0.97; 95% CrI, -1.10 to -0.83), fatigue (SMD, -0.64; 95% CrI, -0.75 to -0.53), and improved quality of life (SMD, -0.80; 95% CrI, -0.94 to -0.65). Duloxetine 120 mg was associated with the highest improvement in pain (SMD, -0.33; 95% CrI, -0.36 to -0.30) and depression (SMD, -0.25; 95% CrI, -0.32 to -0.17) vs placebo. All treatments were associated with inferior acceptability (higher dropout rate) than placebo, except amitriptyline (OR, 0.78; 95% CrI, 0.31 to 1.66). According to the SUCRA-based relative ranking of treatments, duloxetine 120 mg was associated with higher efficacy for treating pain and depression, while amitriptyline was associated with higher efficacy for improving sleep, fatigue, and overall quality of life. Conclusions and Relevance: These findings suggest that clinicians should consider how treatments could be tailored to individual symptoms, weighing the benefits and acceptability, when prescribing medications to patients with fibromyalgia.

Evidence Needed for Efficacy of Antidepressant Medications Among Patients With Rheumatoid Arthritis.

Patients with rheumatoid arthritis (RA) experience pain from inflammation, joint destruction, and neuropathy. Antidepressants may play a role among patients with RA and depression, fibromyalgia, or neuropathy to achieve desired outcomes. This commentary evaluated evidence for medications individually and identified important variables for future research. While we await the results of well-designed studies, a trial of duloxetine or milnacipran may be considered for patients with remnant pain and RA remission. Research is needed to evaluate the efficacy and safety of serotonin-norepinephrine reuptake inhibitors and tricyclic antidepressants in patients with RA and associated comorbid conditions.

Prediction of Differential Pharmacologic Response in Chronic Pain Using Functional Neuroimaging Biomarkers and a Support Vector Machine Algorithm: An Exploratory Study.

OBJECTIVE: There is increasing demand for prediction of chronic pain treatment outcomes using machine-learning models, in order to improve suboptimal pain management. In this exploratory study, we used baseline brain functional connectivity patterns from chronic pain patients with fibromyalgia (FM) to predict whether a patient would respond differentially to either milnacipran or pregabalin, 2 drugs approved by the US Food and Drug Administration for the treatment of FM. METHODS: FM patients participated in 2 separate double-blind, placebo-controlled crossover studies, one evaluating milnacipran (n = 15) and one evaluating pregabalin (n = 13). Functional magnetic resonance imaging during rest was performed before treatment to measure intrinsic functional brain connectivity in several brain regions involved in pain processing. A support vector machine algorithm was used to classify FM patients as responders, defined as those with a ≥20% improvement in clinical pain, to either milnacipran or pregabalin. RESULTS: Connectivity patterns involving the posterior cingulate cortex (PCC) and dorsolateral prefrontal cortex (DLPFC) individually classified pregabalin responders versus milnacipran responders with 77% accuracy. Performance of this classification improved when both PCC and DLPFC connectivity patterns were combined, resulting in a 92% classification accuracy. These results were not related to confounding factors, including head motion, scanner sequence, or hardware status. Connectivity patterns failed to differentiate drug nonresponders across the 2 studies. CONCLUSION: Our findings indicate that brain functional connectivity patterns used in a machine-learning framework differentially predict clinical response to pregabalin and milnacipran in patients with chronic pain. These findings highlight the promise of machine learning in pain prognosis and treatment prediction.

Efficacy of pregabalin as a monotherapy versus combined pregabalin and milnacipran in the management of fibromyalgia.

AIM: To compare the efficacy and tolerability of combined pregabalin (PGB) and milnacipran (MLN) in female patients with fibromyalgia (FM) versus PGB as a monotherapy. METHODS: The present randomized open study included 58 female patients diagnosed with FM (registered on 4/2/19: NCT03905486). Patients were randomly divided into 2 groups (2:2); group 1 included 29 patients who received PGB monotherapy (150 mg twice daily) and group 2 included 29 patients who received combined PGB (150 mg twice daily) and MLN (50 mg twice daily) for 3 months. At the initial visit, patients were subjected to demographic data collection and assessed by the visual analog scale (VAS) for pain and the FM impact questionnaire (FIQ). Outcome measures after 3 months: FIQ, VAS and Leeds Sleep Evaluation Questionnaire. RESULTS: The median disease duration was 2 years in group 1 (6 months to 5 years) and 2 years in group 2 (6 months to 12 years). The dropout rate was 20.7% in group 1 (n = 6) and 10.3% in group 2 (n = 3). At the follow-up evaluation, a statistically significant improvement was observed in VAS and FIQ scores in both groups (P < 0.001). Although the percentage of patients demonstrating significant improvement in pain, disease impact and sleep pattern were higher in group 2, this did not reach statistical significance. CONCLUSION: Although PGB as a monotherapy and in combination with MLN have both shown adequate efficacy in the treatment of patients with FM, the combined therapy did not demonstrate superiority over the monotherapy.

Non-specific analgesia during a clinical trial in fibromyalgia.

BACKGROUND: When patients suffering from fibromyalgia undergo a therapeutic trial, a non-negligible part of analgesia is not explained by the drug itself. The mechanisms of this non-specific effect need to be understood. MATERIALS AND METHODS: We undertook secondary analyses of a double-blind randomized trial in fibromyalgia patients in which 100 mg/day milnacipran was not found superior to placebo. Data from 49 patients belonging to both groups were pooled. Both before treatment and one month after treatment, all patients underwent a CaNTAB® neuropsychological test (related to spatial planning, reaction time, decision-making and risk-taking, and ability to name objects), and measurements of sensation and pain thresholds to heat and cold, supraliminal heat pain threshold, punctuate mechanical pain threshold and temporal summation, mechanical allodynia to skin brushing, and response to conditioned pain modulation. We studied the baseline predictors of analgesia and the indicators of change associated to analgesia separately. A stepwise approach was used to select the factors to enter into the final ANCOVAs, in which age, body mass index, treatment group and pain at baseline were covariates. RESULTS: No baseline predictor of non-specific analgesia other than pain at baseline was found to be predictive. Conversely, several neuropsychological (higher performance) or psychophysical (lower sensitivity) changes correlated with analgesia in unadjusted analyses. Multivariable analyses identified increases in warm/heat thermal thresholds and an increased ability to name objects, as factors associated with analgesia. CONCLUSIONS: The changes observed concomitantly to non-specific pain analgesia might be related to mild changes in brain functioning, based on convergent literature data.

Pharmacotherapy in relieving the symptoms of burning mouth syndrome: A 1-year follow-up study.

OBJECTIVE: Burning mouth syndrome (BMS) is a chronic intraoral burning sensation with no identifiable causes. In this study, we aim to demonstrate the effectiveness of treatment strategy using ethyl loflazepate monotherapy or in combination with milnacipran or amitriptyline. METHOD: A hospital-based, retrospective study was conducted in 86 patients. The patients were divided into remission group and non-remission group. The remission group comprised patients who were satisfied with their pain relief within a year of treatment initiation and did not require any follow-up treatment. The treatment was considered effective if the patient got remission within 1 year or was able to reduce the visual analogue scale (VAS) score to <20, in the absence of remission. RESULTS: The treatment strategy was effective in 76.7% of the patients. Significant reductions (p < .05) in VAS scores from 73.5 ± 14.2 at first visit to 14.7 ± 8.7 at last visit in the remission group, and from 79.7 ± 14.3 at first visit to 33.4 ± 23.7 after 1 year of treatment in the non-remission group were noted. CONCLUSION: The treatment strategy using ethyl loflazepate monotherapy or in combination with milnacipran or amitriptyline can be very effective in reducing pain in BMS patients.

Managing fibromyalgia syndrome in pregnancy no bridges between USA and EU.

The first aim of this article is to analyze the risk/benefit ratio of using psychotropic drugs approved in some countries for treating fibromyalgia syndrome (FMS) during pregnancy. Assessing the effectiveness of non-pharmacological interventions is the second scope of this article, in order to help clinicians to manage FMS in pregnancy in those countries were no drugs are approved for treating the disease. Following the PRISMA guidelines for systematic reviews, a literature search was conducted on PubMed and Google Scholar. Separate literature searches were performed for the three psychotropic drugs approved in the USA for treating FMS, psychotherapy, and transcranial magnetic stimulation (TMS). Perinatal duloxetine exposure is associated with increased risk of gestational and perinatal complications. With regards pregabalin, available information suggests that the drug is not devoid of structural teratogenicity potential. No data are available for milnacipran. Duloxetine and pregabalin should be only given to pregnant women diagnosed with severe forms of FMS after carefully weighing the benefits and risks for the mother-fetus dyad. On the other hand, we have to consider that the proportion of women who discontinue psychotropic drugs during pregnancy is as high as 85.4%. This figure raises further questions about adequate alternative treatment of FMS during the perinatal period. Moreover, neither duloxetine nor milnacipran or pregabalin have been approved by the EMEA for the treatment of FMS. Unfortunately, psychological treatment of FMS in perinatal women are not yet tested and data on TMS are conflicting.

Milnacipran poorly modulates pain in patients suffering from fibromyalgia: a randomized double-blind controlled study.

INTRODUCTION: Fibromyalgia is characterized by widespread and chronic pain, and its prevalence is increasing worldwide. Milnacipran, an antidepressant, is often prescribed for fibromyalgia with a possible beneficial effect on central pain modulation. The aim of this study was to evaluate if milnacipran could modify the status of conditioned pain modulation (CPM) in patients suffering from fibromyalgia. DESIGN AND SETTING: Randomized, double-blind controlled trial. SUBJECTS AND METHODS: Women with fibromyalgia received milnacipran 100 mg or placebo. The primary end point was the evolution of CPM with treatments after a 30-second painful stimulus. Secondary outcomes included the predictability of milnacipran efficacy from CPM performance, evolution of global pain, mechanical sensitivity, thermal pain threshold, mechanical allodynia, cognitive function, and tolerance. RESULTS: Fifty-four women with fibromyalgia (46.7±10.6 years) were included and randomized, and 24 patients were analyzed in each group. At inclusion, CPM was dysfunctional (CPM30=-0.5±1.9), and global pain was 6.5±1.8. After treatment, there was a nonsignificant CPM difference between milnacipran and placebo (CPM30=-0.46±1.22 vs -0.69±1.43, respectively, p=0.55) and 18.8% vs 6.3% (p=0.085) patients did reactivate CPM after milnacipran vs placebo. Initial CPM was not a predictor of milnacipran efficacy. Global pain, mechanical and thermal thresholds, allodynia, cognition, and tolerance were not significantly different between both groups. CONCLUSION: Milnacipran did not display a significant analgesic effect after 1-month treatment, but the tendency of milnacipran to reactivate CPM in a number of patients must be explored with longer treatment duration in future studies and pleads for possible subtypes of fibromyalgia patients.