Safety and Efficacy of Levomilnacipran Extended Release in Pediatric Patients Aged 7-17 Years with Major Depressive Disorder: Results of Two Phase 3, Randomized, Double-Blind Studies.

Objective: Major depressive disorder (MDD) presents a significant psychosocial burden, and there is an unmet need for additional treatment options in pediatric patients. Here, we report the results of two phase 3 multicenter, randomized, double-blind, placebo- and active-controlled, parallel-group studies evaluating the efficacy and safety of levomilnacipran extended release in children and adolescents with MDD. Methods: In the first study, LVM-MD-11, patients aged 12-17 years received daily doses of levomilnacipran 40 mg (n = 134), levomilnacipran 80 mg (n = 138), fluoxetine 20 mg (n = 134), or placebo (n = 141). In the second study, LVM-MD-14, patients aged 7-17 years received levomilnacipran 40 to 80 mg (n = 166), fluoxetine 20 mg (n = 166), or placebo (n = 160) daily. Primary and secondary efficacy endpoints were changes in Children's Depression Rating Scale-Revised (CDRS-R) total score and Clinical Global Impressions-Severity (CGI-S) score, respectively. Results: In LVM-MD-11, there were no significant differences in change in CDRS-R total score between patients treated daily with placebo (least squares mean [LSM] change in CDRS-R total score -22.9) versus levomilnacipran 40 mg (-23.3; p = 0.8035) or 80 mg (-22.6; p = 0.8681). Similarly, in LVM-MD-14, there were no significant differences in LSM change in CDRS-R total score with placebo (-21.3) versus levomilnacipran 40 to 80 mg daily (-23.0; p = 0.2215). There were also no significant differences between the fluoxetine and placebo groups in either study for changes in CDRS-R total score. Changes in CGI-S score were not significant between placebo and levomilnacipran 40 to 80 mg daily or between placebo and fluoxetine. Levomilnacipran was generally well tolerated. Conclusions: The high placebo response in this study prevented the detection of an effect of levomilnacipran in children and adolescents. Clinical Trial Registration numbers: NCT02431806 and NCT03569475.

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.

Differential Contribution of 5-HT4, 5-HT5, and 5-HT6 Receptors to Acute Pruriceptive Processing Induced by Chloroquine and Histamine in Mice.

The involvement of serotonin (5-HT) and/or noradrenaline in acute pruriceptive processing in the central nervous system (CNS) has been reported using antidepressants, such as milnacipran, a serotonin and noradrenaline reuptake inhibitor, and mirtazapine, a noradrenergic and specific serotonergic antidepressant; however, the roles of 5-HT receptor family in acute pruriceptive processing have not been fully elucidated in the CNS. In the present study, scratching behavior induced by chloroquine (CQ) was ameliorated by milnacipran or mirtazapine, and these effects were reversed by SB207266, a 5-HT4 antagonist, or SB258585, a 5-HT6 antagonist, but not by SB258585, a 5-HT5 antagonist. Moreover, CQ-induced scratches were mitigated by intrathecal injection of 5-HT4 agonists, such as BIMU8 and ML10302, and the 5-HT6 agonist, WAY208466. Conversely, histamine-induced scratches were not affected by the 5-HT4 agonists or a 5-HT6 agonist. Similarly, the amelioration of histamine-induced scratches by these antidepressants was not reversed by the 5-HT4, 5-HT5, or 5-HT6 receptor antagonist. Therefore, 5-HT is involved in the amelioration of CQ-induced scratches by milnacipran and mirtazapine, and 5-HT4, 5-HT5, and 5-HT6 receptors play differential roles in acute pruriceptive processing after administration of CQ or histamine.

Antidepressants for pain management in adults with chronic pain: a network meta-analysis.

BACKGROUND: Chronic pain is common in adults, and often has a detrimental impact upon physical ability, well-being, and quality of life. Previous reviews have shown that certain antidepressants may be effective in reducing pain with some benefit in improving patients' global impression of change for certain chronic pain conditions. However, there has not been a network meta-analysis (NMA) examining all antidepressants across all chronic pain conditions. OBJECTIVES: To assess the comparative efficacy and safety of antidepressants for adults with chronic pain (except headache). SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, LILACS, AMED and PsycINFO databases, and clinical trials registries, for randomised controlled trials (RCTs) of antidepressants for chronic pain conditions in January 2022. SELECTION CRITERIA: We included RCTs that examined antidepressants for chronic pain against any comparator. If the comparator was placebo, another medication, another antidepressant, or the same antidepressant at different doses, then we required the study to be double-blind. We included RCTs with active comparators that were unable to be double-blinded (e.g. psychotherapy) but rated them as high risk of bias. We excluded RCTs where the follow-up was less than two weeks and those with fewer than 10 participants in each arm.  DATA COLLECTION AND ANALYSIS: Two review authors separately screened, data extracted, and judged risk of bias. We synthesised the data using Bayesian NMA and pairwise meta-analyses for each outcome and ranked the antidepressants in terms of their effectiveness using the surface under the cumulative ranking curve (SUCRA). We primarily used Confidence in Meta-Analysis (CINeMA) and Risk of Bias due to Missing Evidence in Network meta-analysis (ROB-MEN) to assess the certainty of the evidence. Where it was not possible to use CINeMA and ROB-MEN due to the complexity of the networks, we used GRADE to assess the certainty of the evidence. Our primary outcomes were substantial (50%) pain relief, pain intensity, mood, and adverse events. Our secondary outcomes were moderate pain relief (30%), physical function, sleep, quality of life, Patient Global Impression of Change (PGIC), serious adverse events, and withdrawal. MAIN RESULTS: This review and NMA included 176 studies with a total of 28,664 participants. The majority of studies were placebo-controlled (83), and parallel-armed (141). The most common pain conditions examined were fibromyalgia (59 studies); neuropathic pain (49 studies) and musculoskeletal pain (40 studies). The average length of RCTs was 10 weeks. Seven studies provided no useable data and were omitted from the NMA. The majority of studies measured short-term outcomes only and excluded people with low mood and other mental health conditions. Across efficacy outcomes, duloxetine was consistently the highest-ranked antidepressant with moderate- to high-certainty evidence. In duloxetine studies, standard dose was equally efficacious as high dose for the majority of outcomes. Milnacipran was often ranked as the next most efficacious antidepressant, although the certainty of evidence was lower than that of duloxetine. There was insufficient evidence to draw robust conclusions for the efficacy and safety of any other antidepressant for chronic pain.  Primary efficacy outcomes Duloxetine standard dose (60 mg) showed a small to moderate effect for substantial pain relief (odds ratio (OR) 1.91, 95% confidence interval (CI) 1.69 to 2.17; 16 studies, 4490 participants; moderate-certainty evidence) and continuous pain intensity (standardised mean difference (SMD) -0.31, 95% CI -0.39 to -0.24; 18 studies, 4959 participants; moderate-certainty evidence). For pain intensity, milnacipran standard dose (100 mg) also showed a small effect (SMD -0.22, 95% CI -0.39 to 0.06; 4 studies, 1866 participants; moderate-certainty evidence). Mirtazapine (30 mg) had a moderate effect on mood (SMD -0.5, 95% CI -0.78 to -0.22; 1 study, 406 participants; low-certainty evidence), while duloxetine showed a small effect (SMD -0.16, 95% CI -0.22 to -0.1; 26 studies, 7952 participants; moderate-certainty evidence); however it is important to note that most studies excluded participants with mental health conditions, and so average anxiety and depression scores tended to be in the 'normal' or 'subclinical' ranges at baseline already. Secondary efficacy outcomes Across all secondary efficacy outcomes (moderate pain relief, physical function, sleep, quality of life, and PGIC), duloxetine and milnacipran were the highest-ranked antidepressants with moderate-certainty evidence, although effects were small. For both duloxetine and milnacipran, standard doses were as efficacious as high doses. Safety There was very low-certainty evidence for all safety outcomes (adverse events, serious adverse events, and withdrawal) across all antidepressants. We cannot draw any reliable conclusions from the NMAs for these outcomes. AUTHORS' CONCLUSIONS: Our review and NMAs show that despite studies investigating 25 different antidepressants, the only antidepressant we are certain about for the treatment of chronic pain is duloxetine. Duloxetine was moderately efficacious across all outcomes at standard dose. There is also promising evidence for milnacipran, although further high-quality research is needed to be confident in these conclusions. Evidence for all other antidepressants was low certainty. As RCTs excluded people with low mood, we were unable to establish the effects of antidepressants for people with chronic pain and depression. There is currently no reliable evidence for the long-term efficacy of any antidepressant, and no reliable evidence for the safety of antidepressants for chronic pain at any time point.

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.

Milnacipran Ameliorates Executive Function Impairments following Frontal Lobe Traumatic Brain Injury in Male Rats: A Multimodal Behavioral Assessment.

Traumatic brain injuries (TBIs) affect more than 10 million patients annually worldwide, causing long-term cognitive and psychosocial impairments. Frontal lobe TBIs commonly impair executive function, but laboratory models typically focus primarily on spatial learning and declarative memory. We implemented a multi-modal approach for clinically relevant cognitive-behavioral assessments of frontal lobe function in rats with TBI and assessed treatment benefits of the serotonin-norepinephrine reuptake inhibitor, milnacipran (MLN). Two attentional set-shifting tasks (AST) evaluated cognitive flexibility via the rats' ability to locate food-based rewards by learning, unlearning, and relearning sequential rule sets with shifting salient cues. Adult male rats reached stable pre-injury operant AST (oAST) performance in 3-4 weeks, then were isoflurane-anesthetized, subjected to a unilateral frontal lobe controlled cortical impact (2.4 mm depth, 4 m/sec velocity) or Sham injury, and randomized to treatment conditions. Milnacipran (30 mg/kg/day) or vehicle (VEH; 10% ethanol in saline) was administered intraperitoneally via implanted osmotic minipumps (continuous infusions post-surgery, 60 µL/h). Rats had a 10-day recovery post-TBI/Sham before performing light/location-based oAST for 10 days and, subsequently, odor/media-based digging AST (dAST) on the last test day (26-27 days post-injury) before sacrifice. Both AST tests revealed significant deficits in TBI+VEH rats, seen as elevated total trials and errors (p < 0.05), which generally normalized in MLN-treated rats (p < 0.05). This first simultaneous dual AST assessment demonstrates oAST and dAST are sufficiently sensitive and robust to detect subtle attentional and cognitive flexibility executive impairments after frontal lobe TBI in rats. Chronic MLN administration shows promise for attenuation of post-TBI executive function deficits, thus meriting further investigation.

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.

Identifying Antidepressants Less Likely to Cause Hyponatremia: Triangulation of Retrospective Cohort, Disproportionality, and Pharmacodynamic Studies.

Antidepressants are known to cause hyponatremia, but conflicting evidence exists regarding specific antidepressants. To identify antidepressants less likely to cause hyponatremia, we conducted a triangulation study integrating retrospective cohort, disproportionality, and pharmacodynamic studies. In the retrospective cohort study of patients (≥ 60 years) in Nihon University School of Medicine's Clinical Data Warehouse (2004-2020), a significant decrease in serum sodium levels was observed within 30 days after initiation of a selective serotonin reuptake inhibitor (SSRI; mean change -1.00 ± 0.23 mmol/L, P < 0.001) or serotonin-noradrenaline reuptake inhibitor (SNRI; -1.01 ± 0.31 mmol/L, P = 0.0013), whereas no decrease was found for a noradrenergic and specific serotonergic antidepressant (mirtazapine; +0.55 ± 0.47 mmol/L, P = 0.24). Within-class comparison revealed no decrease in serum sodium levels for fluvoxamine (+0.74 ± 0.75 mmol/L, P = 0.33) among SSRIs and milnacipran (+0.08 ± 0.87 mmol/L, P = 0.93) among SNRIs. In the disproportionality analysis of patients (≥ 60 years) in the Japanese Adverse Drug Event Report database (2004-2020), a significant increase in hyponatremia reports was observed for SSRIs (reporting odds ratio 4.41, 95% confidence interval 3.58-5.45) and SNRIs (5.66, 4.38-7.31), but not for mirtazapine (1.08, 0.74-1.58), fluvoxamine (1.48, 0.94-2.32), and milnacipran (0.85, 0.45-1.62). Finally, pharmacoepidemiological-pharmacodynamic analysis revealed a significant correlation between the decrease in serum sodium levels and binding affinity for serotonin transporter (SERT; r = -0.84, P = 0.02), suggesting that lower binding affinity of mirtazapine, fluvoxamine, and milnacipran against SERT is responsible for the above difference. Although further research is needed, our data suggest that mirtazapine, fluvoxamine, and milnacipran are less likely to cause hyponatremia.

A feasible fluorimetric approach anchored in diaryl pyrrolone derivative for the facile analysis of milnacipran in tablets; evaluation of the method greenness.

In the present work a new, feasible, and green approach was employed for the analysis of milnacipran. A drug is used in the management of depression in addition to fibromyalgia. It inhibits of the reuptake of two essential neurotransmitters serotonin and nor-adrenaline. In slightly alkaline buffer (pH 8.5) the primary amino group of milnacipran reacted with fluorescamine to give a substituted pyrrolone derivative which exhibited high fluorescence activity. The fluorescence of produced derivative was measured at (λex 385 nm, λem 477 nm), and the experimental factors were cautiously optimized. The measured intensity of fluorescence was plotted versus the respective concentration of milnacipran to setup the calibration plot which has a linear concentration range of 50-300 ng/mL. The ICH guidelines were utilized to totally validate the presented approach. In addition the method could be efficiently incorporated in the analysis of commercial milnacipram tablets with no considerable effect on the results of the assay for milnacipran. The developed approach is characterized by its high simplicity and greenness of the procedure which make it suitable for routine analysis.

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.

Preventive effect of a Kampo medicine, kososan, on recurrent depression in a mouse model of repeated social defeat stress.

Depression is deemed a mood disorder characterized by a high rate of relapse. Therefore, overcoming of the recurrent depression is globally expecting. Kososan, a traditional Japanese herbal medicine, has been clinically used for mild depressive mood, and our previous studies have shown some evidence for its antidepressive-like efficacy in experimental animal models of depression. However, it remains unclear whether kososan has beneficial effects on recurrent depression. Here, we examined its effect using a mouse model of modified repeated social defeat stress (SDS) paradigm. Male BALB/c mice were exposed to a 5-min SDS from unfamiliar aggressive CD-1 mice for 5 days. Kososan extract (1.0 kg/kg/day) or an antidepressant milnacipran (60 mg/kg/day) was administered orally for 26 days (days 7-32) to depression-like mice with social avoidant behaviors on day 6. Single 5 min of SDS was subjected to mice recovered from the social avoidance on day 31, and then the recurrence of depression-like behaviors was evaluated on day 32. Hippocampal gene expression patterns were also assayed by DNA microarray analysis. Water- or milnacipran-administered mice resulted in a recurrence of depression-like behaviors by re-exposure of single SDS, whereas kososan-administered mice did not recur depression-like behaviors. Distinct gene expression patterns were also found for treating kososan and milnacipran. Collectively, this finding suggests that kososan exerts a preventive effect on recurrent depression-like behaviors in mice. Pretreatment of kososan is more useful for recurrent depression than that of milnacipran.

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.

Use of Hantzsch reaction for quantitation of milnacipran as a magic treatment for fibromyalgia syndrome in human plasma and urine.

A new fluorimetric procedure is described for analysis of milnacipran in its bulk, tablet dosage forms, as well as in biological human samples such as plasma and urine. The suggested method relies on the construction of a derivative with strong fluorescence called dihydropyridine derivative. This derivative resulted from the interaction of the primary amino group in the studied drug and acetylacetone/formaldehyde in McIlvaine buffer (pH 5). The fluorescent dihydropyridine derivative was measured at 470 nm. Influences of experimental variables namely pH, reagent concentration and temperature were examined and optimized. The calibration curve showed linearity over the range of 0.15-1.25 µg ml-1 of milnacipran with an R2 value of 0.9998. The detection limit was 0.02 µg ml-1 and the determination limit was 0.07 µg ml-1 . The developed procedure was successfully used in the assay of the studied drug in Avermilan® tablets with excellent selectivity. In addition, the reaction was applied to estimate the drug in spiked human plasma and urine with mean percentage recoveries of 100.04 ± 1.61 and 99.78 ± 0.81% for urine and plasma, respectively.

III. Detecting Treatment Effects in Clinical Trials With Different Indices of Pain Intensity Derived From Ecological Momentary Assessment.

Pain intensity represents the primary outcome in most pain clinical trials. Identifying methods to measure aspects of pain that are most sensitive to treatment may facilitate discovery of effective interventions. In this third of 3 articles examining alternative indices of pain intensity derived from ecological momentary assessments (EMA), we compare treatment effects based on Average Pain, Maximum Pain, Minimum Pain, Pain Variability, Time in High Pain, Time in Low Pain, and Pain After Wake-Up. We also examine which indices contribute to Patient Global Impressions of Change (PGIC). Data came from 2 randomized, double-blind, placebo-controlled trials examining the efficacy of milnacipran for fibromyalgia treatment; 2,084 patients provided >1 million EMA pain intensity ratings over 24 (Study 1) or 26 (Study 2) treatment weeks. Pain Variability and Time in High Pain produced significantly smaller treatment effects than Average Pain; other pain indices showed effects that were numerically smaller, but not significantly different from Average Pain. Changes in all pain indices were significantly associated with PGIC, with improvements in Maximum Pain and in Pain Variability offering small incremental contributions to understanding PGIC over Average Pain. Results suggest that different pain indices could be used to detect treatment effects in pain clinical trials. PERSPECTIVE: Alternative summary measures of pain intensity derived from EMA may broaden the scope of outcomes useful in pain clinical trials. In this analysis of a pharmacological treatment for fibromyalgia, most pain summary measures indicated similar effects; improvements in Maximum Pain and Pain Variability contributed to understanding PGIC over Average Pain.

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.

Anti-inflammatory and anti-hyperalgesic effects of milnacipran in inflamed rats: involvement of myeloperoxidase activity, cytokines and oxidative/nitrosative stress.

BACKGROUND: Many injuries cause pain and inflammation, which are one of the major challenges for physicians. In this study, the analgesic and the anti-inflammatory effects of milnacipran were investigated on carrageenan-induced nociception and inflammation in male rats. METHODS: Pain and inflammation were induced by injection of λ-carrageenan (1% v/v) into the hind paw. Indomethacin (10 mg/kg: ip) or milnacipran (10, 20 and 40 mg/kg: ip) were administered 30 min before carrageenan. Analgesia and inflammation were measured by hot plate and plethysmometer. Finally, lipid peroxidation, tumor necrosis factor alpha (TNF-α), Interleukin 1 beta (IL-1ß), Interleukin 6 (IL-6), myeloperoxidase (MPO) activity, nitric oxide (NO) and total antioxidant capacity (TAC) status evaluated in the hind paw tissue. RESULTS: The results showed that carrageenan caused hyperalgesia and inflammation in the hind paw tissue. Milnacipran (20 and 40 mg/kg) significantly and dose-dependently attenuated (65 ± 3.2%; p ≤0.01 and 42 ± 6.2%; p ≤ 0.001, respectively) carrageenan-induced inflammation and significantly increased (p ≤ 0.001) nociception threshold. Also, milnacipran (20 and 40 mg/kg) significantly suppressed levels of malondialdehyde (MDA), NO (p ≤ 0.05), MPO activity, TNF-α, IL-1ß and IL-6 (p ≤ 0.001) following carrageenan injection. Additionally, milnacipran (10, 20 and 40 mg/kg) significantly augmented (p ≤ 0.05) TAC status following carrageenan in the hind paw tissue. CONCLUSION: In the present study, milnacipran showed anti-nociceptive and anti-inflammatory effects on carrageenan-induced hyperalgesia and inflammation in a dose-dependent manner. Milnacipran reduced inflammatory edema and increased the paw withdrawal threshold probably through suppression of MDA, NO, TNF-α, IL-1ß, IL-6 and MPO activity, and increase of TAC status in the hind paw tissue. Therefore, milnacipran holds important potential as an anti-inflammatory and anti-nociceptive drug. Although, further clinical trials to confirm this issue, is required.

Life-Threatening Serotonin Syndrome Precipitated by Discontinuation of Serotonin-Dopamine Antagonist in the Presence of Serotonergic Agents: A Case Report.

INTRODUCTION: Serotonin syndrome is caused by excessive activation of serotonin (5-hydroxytryptamine [5-HT]) neurotransmission. Although the discontinuation of antipsychotics with 5-HT2 receptor antagonistic characteristics could theoretically result in serotonin syndrome, there have been very few reports on the syndrome thus far. CASE PRESENTATION: A 75-year-old woman with somatoform disorder was transferred to our emergency room because of pyrexia, unconsciousness, and myoclonus with hyperreflexia. She had been taking milnacipran and perospirone for 10 years and had started taking duloxetine 2 months before the event. Thereafter, she suffered diaphoresis, gait disturbance, and tremor. Her psychiatrist advised her to stop taking perospirone, because of suspicion of extrapyramidal symptoms, a day before admission. The clinical diagnosis of serotonin syndrome was made based on her symptoms while using serotonergic agents. Her symptoms were so severe that she was transferred to the intensive care unit, where supportive care was successful. CONCLUSIONS: Discontinuation of antipsychotics that are 5-HT2 receptor antagonists may lead to serotonin syndrome in patients who take serotonergic agents. As extrapyramidal symptoms and serotonin toxicity share some clinical features, detailed drug history and physical examination are necessary for successful treatment.

In Vivo Evaluation of a Novel Chitosan-Polycaprolactone Based Mucoadhesive Gastro-Retentive Sustained Release Drug Delivery System for Milnacipran HCl.

The study was aimed to develop a gastro-retentive mucoadhesive sustained release matrix formulation for milnacipran HCl (MCN) by using the design of experiment (DoE). The gastro-retentive swellable mucoadhesive matrix tablets were prepared by modified solvent-based wet granulation through mixing milnacipran (MCN), chitosan low molecular weight (CH-LM), chitosan medium molecular weight (CH-MM), and polycaprolactone (PCL). Optimization of the formulation was carried out via DoE. Formulations were characterized by DSC, FTIR, and in vitro drug release testing. In vitro mucoadhesive studies were performed on rabbit's intestinal mucosa. In vivo drug release studies were performed on dogs. Optimized matrix formulations showed no significant interaction among the polymers and MCN, confirmed by DSC and FTIR, and were characterized as swellable controlled release matrix systems. The optimized formulations MOPT3 and MOPT4 showed significantly improved adhesion time of 12 h on the gastric mucosa. Based on the in vivo analysis, the elimination half-life of MCN was increased that proved the matrix formulation to be sustained release DDS. The Tmax was extended from 2 to 12 ± 1.63 h for MOPT4. Cmax of matrix was reduced to 121.60 ± 9.496 ng/ml as compared to 149.22 ± 9.942 ng/ml of solution. The bioavailability of the matrix formulation was significantly improved as compared to the MCN solution by 272.20 ± 48.11%. The controlled drug release and strong mucoadhesive properties of the gastro-retentive matrix formulations suggested the potential application of the formulations for the extended oral delivery of MCN.