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Psychotherapy and Psychosomatics 2018Serotonin-noradrenaline reuptake inhibitors (SNRI) are widely used in medical practice. Their discontinuation has been associated with a wide range of symptoms. The aim... (Review)
Review
BACKGROUND
Serotonin-noradrenaline reuptake inhibitors (SNRI) are widely used in medical practice. Their discontinuation has been associated with a wide range of symptoms. The aim of this paper is to identify the occurrence, frequency, and features of withdrawal symptoms after SNRI discontinuation.
METHODS
PRISMA guidelines were followed to conduct a systematic review. Electronic databases included PubMed, the Cochrane Library, Web of Science, and MEDLINE from the inception of each database to June 2017. Titles, abstracts, and topics were searched using a combination of the following terms: "duloxetine" OR "venlafaxine" OR "desvenlafaxine" OR "milnacipran" OR "levomilnacipran" OR "SNRI" OR "second generation antidepressant" OR "serotonin norepinephrine reuptake inhibitor" AND "discontinuation" OR "withdrawal" OR "rebound." Only published trials in the English language were included.
RESULTS
Sixty-one reports met the criteria for inclusion. There were 22 double-blind randomized controlled trials, 6 studies where patients were treated in an open fashion and then randomized to a double-blind controlled phase, 8 open trials, 1 prospective naturalistic study, 1 retrospective study, and 23 case reports. Withdrawal symptoms occurred after discontinuation of any type of SNRI. The prevalence of withdrawal symptoms varied across reports and appeared to be higher with venlafaxine. Symptoms typically ensued within a few days from discontinuation and lasted a few weeks, also with gradual tapering. Late onset and/or a longer persistence of disturbances occurred as well.
CONCLUSIONS
Clinicians need to add SNRI to the list of drugs potentially inducing withdrawal symptoms upon discontinuation, together with other types of psychotropic drugs. The results of this study challenge the use of SNRI as first-line treatment for mood and anxiety disorders.
Topics: Adrenergic Uptake Inhibitors; Desvenlafaxine Succinate; Duloxetine Hydrochloride; Humans; Mood Disorders; Randomized Controlled Trials as Topic; Substance Withdrawal Syndrome; Venlafaxine Hydrochloride
PubMed: 30016772
DOI: 10.1159/000491524 -
The Cochrane Database of Systematic... Feb 2018Fibromyalgia is a clinically defined chronic condition of unknown etiology characterized by chronic widespread pain that often co-exists with sleep disturbances,... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Fibromyalgia is a clinically defined chronic condition of unknown etiology characterized by chronic widespread pain that often co-exists with sleep disturbances, cognitive dysfunction and fatigue. People with fibromyalgia often report high disability levels and poor quality of life. Drug therapy, for example, with serotonin and noradrenaline reuptake inhibitors (SNRIs), focuses on reducing key symptoms and improving quality of life. This review updates and extends the 2013 version of this systematic review.
OBJECTIVES
To assess the efficacy, tolerability and safety of serotonin and noradrenaline reuptake inhibitors (SNRIs) compared with placebo or other active drug(s) in the treatment of fibromyalgia in adults.
SEARCH METHODS
For this update we searched CENTRAL, MEDLINE, Embase, the US National Institutes of Health and the World Health Organization (WHO) International Clinical Trials Registry Platform for published and ongoing trials and examined the reference lists of reviewed articles, to 8 August 2017.
SELECTION CRITERIA
We selected randomized, controlled trials of any formulation of SNRIs against placebo or any other active treatment of fibromyalgia in adults.
DATA COLLECTION AND ANALYSIS
Three review authors independently extracted data, examined study quality, and assessed risk of bias. For efficacy, we calculated the number needed to treat for an additional beneficial outcome (NNTB) for pain relief of 50% or greater and of 30% or greater, patient's global impression to be much or very much improved, dropout rates due to lack of efficacy, and the standardized mean differences (SMD) for fatigue, sleep problems, health-related quality of life, mean pain intensity, depression, anxiety, disability, sexual function, cognitive disturbances and tenderness. For tolerability we calculated number needed to treat for an additional harmful outcome (NNTH) for withdrawals due to adverse events and for nausea, insomnia and somnolence as specific adverse events. For safety we calculated NNTH for serious adverse events. We undertook meta-analysis using a random-effects model. We assessed the evidence using GRADE and created a 'Summary of findings' table.
MAIN RESULTS
We added eight new studies with 1979 participants for a total of 18 included studies with 7903 participants. Seven studies investigated duloxetine and nine studies investigated milnacipran against placebo. One study compared desvenlafaxine with placebo and pregabalin. One study compared duloxetine with L-carnitine. The majority of studies were at unclear or high risk of bias in three to five domains.The quality of evidence of all comparisons of desvenlafaxine, duloxetine and milnacipran versus placebo in studies with a parallel design was low due to concerns about publication bias and indirectness, and very low for serious adverse events due to concerns about publication bias, imprecision and indirectness. The quality of evidence of all comparisons of duloxetine and desvenlafaxine with other active drugs was very low due to concerns about publication bias, imprecision and indirectness.Duloxetine and milnacipran had no clinically relevant benefit over placebo for pain relief of 50% or greater: 1274 of 4104 (31%) on duloxetine and milnacipran reported pain relief of 50% or greater compared to 591 of 2814 (21%) participants on placebo (risk difference (RD) 0.09, 95% confidence interval (CI) 0.07 to 0.11; NNTB 11, 95% CI 9 to 14). Duloxetine and milnacipran had a clinically relevant benefit over placebo in patient's global impression to be much or very much improved: 888 of 1710 (52%) on duloxetine and milnacipran (RD 0.19, 95% CI 0.12 to 0.26; NNTB 5, 95% CI 4 to 8) reported to be much or very much improved compared to 354 of 1208 (29%) of participants on placebo. Duloxetine and milnacipran had a clinically relevant benefit compared to placebo for pain relief of 30% or greater. RD was 0.10; 95% CI 0.08 to 0.12; NNTB 10, 95% CI 8 to 12. Duloxetine and milnacipran had no clinically relevant benefit for fatigue (SMD -0.13, 95% CI -0.18 to -0.08; NNTB 18, 95% CI 12 to 29), compared to placebo. There were no differences between either duloxetine or milnacipran and placebo in reducing sleep problems (SMD -0.07; 95 % CI -0.15 to 0.01). Duloxetine and milnacipran had no clinically relevant benefit compared to placebo in improving health-related quality of life (SMD -0.20, 95% CI -0.25 to -0.15; NNTB 11, 95% CI 8 to 14).There were 794 of 4166 (19%) participants on SNRIs who dropped out due to adverse events compared to 292 of 2863 (10%) of participants on placebo (RD 0.07, 95% CI 0.04 to 0.10; NNTH 14, 95% CI 10 to 25). There was no difference in serious adverse events between either duloxetine, milnacipran or desvenlafaxine and placebo (RD -0.00, 95% CI -0.01 to 0.00).There was no difference between desvenlafaxine and placebo in efficacy, tolerability and safety in one small trial.There was no difference between duloxetine and desvenlafaxine in efficacy, tolerability and safety in two trials with active comparators (L-carnitine, pregabalin).
AUTHORS' CONCLUSIONS
The update did not change the major findings of the previous review. Based on low- to very low-quality evidence, the SNRIs duloxetine and milnacipran provided no clinically relevant benefit over placebo in the frequency of pain relief of 50% or greater, but for patient's global impression to be much or very much improved and in the frequency of pain relief of 30% or greater there was a clinically relevant benefit. The SNRIs duloxetine and milnacipran provided no clinically relevant benefit over placebo in improving health-related quality of life and in reducing fatigue. Duloxetine and milnacipran did not significantly differ from placebo in reducing sleep problems. The dropout rates due to adverse events were higher for duloxetine and milnacipran than for placebo. On average, the potential benefits of duloxetine and milnacipran in fibromyalgia were outweighed by their potential harms. However, a minority of people with fibromyalgia might experience substantial symptom relief without clinically relevant adverse events with duloxetine or milnacipran.We did not find placebo-controlled studies with other SNRIs than desvenlafaxine, duloxetine and milnacipran.
Topics: Adrenergic Uptake Inhibitors; Adult; Carnitine; Cyclopropanes; Desvenlafaxine Succinate; Duloxetine Hydrochloride; Fibromyalgia; Humans; Milnacipran; Norepinephrine; Pregabalin; Quality of Life; Selective Serotonin Reuptake Inhibitors; Syndrome
PubMed: 29489029
DOI: 10.1002/14651858.CD010292.pub2 -
The Cochrane Database of Systematic... Feb 2018Fibromyalgia is a chronic widespread pain condition affecting millions of people worldwide. Current pharmacotherapies are often ineffective and poorly tolerated.... (Review)
Review
BACKGROUND
Fibromyalgia is a chronic widespread pain condition affecting millions of people worldwide. Current pharmacotherapies are often ineffective and poorly tolerated. Combining different agents could provide superior pain relief and possibly also fewer side effects.
OBJECTIVES
To assess the efficacy, safety, and tolerability of combination pharmacotherapy compared to monotherapy or placebo, or both, for the treatment of fibromyalgia pain in adults.
SEARCH METHODS
We searched CENTRAL, MEDLINE, and Embase to September 2017. We also searched reference lists of other reviews and trials registries.
SELECTION CRITERIA
Double-blind, randomised controlled trials comparing combinations of two or more drugs to placebo or other comparators, or both, for the treatment of fibromyalgia pain.
DATA COLLECTION AND ANALYSIS
From all studies, we extracted data on: participant-reported pain relief of 30% or 50% or greater; patient global impression of clinical change (PGIC) much or very much improved or very much improved; any other pain-related outcome of improvement; withdrawals (lack of efficacy, adverse events), participants experiencing any adverse event, serious adverse events, and specific adverse events (e.g. somnolence and dizziness). The primary comparison was between combination and one or all single-agent comparators. We also assessed the evidence using GRADE and created a 'Summary of findings' table.
MAIN RESULTS
We identified 16 studies with 1474 participants. Three studies combined a non-steroidal anti-inflammatory drug (NSAID) with a benzodiazepine (306 participants); two combined amitriptyline with fluoxetine (89 participants); two combined amitriptyline with a different agent (92 participants); two combined melatonin with an antidepressant (164 participants); one combined carisoprodol, paracetamol (acetaminophen), and caffeine (58 participants); one combined tramadol and paracetamol (acetaminophen) (315 participants); one combined malic acid and magnesium (24 participants); one combined a monoamine oxidase inhibitor with 5-hydroxytryptophan (200 participants); and one combined pregabalin with duloxetine (41 participants). Six studies compared the combination of multiple agents with each component alone and with inactive placebo; three studies compared combination pharmacotherapy with each individual component but did not include an inactive placebo group; two studies compared the combination of two agents with only one of the agents alone; and three studies compared the combination of two or more agents only with inactive placebo.Heterogeneity among studies in terms of class of agents evaluated, specific combinations used, outcomes reported, and doses given prevented any meta-analysis. None of the combinations of drugs found provided sufficient data for analysis compared with placebo or other comparators for our preferred outcomes. We therefore provide a narrative description of results. There was no or inadequate evidence in any comparison for primary and secondary outcomes. Two studies only reported any primary outcomes of interest (patient-reported pain relief of 30%, or 50%, or greater). For each 'Risk of bias' item, only half or fewer of studies had unequivocal low risk of bias. Small size and selective reporting were common as high risk of bias.Our GRADE assessment was therefore very low for primary outcomes of pain relief of 30% or 50% or greater, PGIC much or very much improved or very much improved, any pain-related outcome, participants experiencing any adverse event, any serious adverse event, or withdrawing because of an adverse event.Three studies found some evidence that combination pharmacotherapy reduced pain compared to monotherapy; these trials tested three different combinations: melatonin and amitriptyline, fluoxetine and amitriptyline, and pregabalin and duloxetine. Adverse events experienced by participants were not serious, and where they were reported (in 12 out of 16 studies), all participants experienced them, regardless of treatment. Common adverse events were nausea, dizziness, somnolence, and headache.
AUTHORS' CONCLUSIONS
There are few, large, high-quality trials comparing combination pharmacotherapy with monotherapy for fibromyalgia, consequently limiting evidence to support or refute the use of combination pharmacotherapy for fibromyalgia.
Topics: 5-Hydroxytryptophan; Acetaminophen; Adult; Amitriptyline; Anti-Inflammatory Agents, Non-Steroidal; Antidepressive Agents; Benzodiazepines; Carisoprodol; Drug Therapy, Combination; Duloxetine Hydrochloride; Fibromyalgia; Fluoxetine; Humans; Magnesium; Malates; Melatonin; Monoamine Oxidase Inhibitors; Muscle Relaxants, Central; Pregabalin; Randomized Controlled Trials as Topic
PubMed: 29457627
DOI: 10.1002/14651858.CD010585.pub2 -
The Cochrane Database of Systematic... Jul 2017Major depressive disorder is a common mental disorder affecting a person's mind, behaviour and body. It is expressed as a variety of symptoms and is associated with... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Major depressive disorder is a common mental disorder affecting a person's mind, behaviour and body. It is expressed as a variety of symptoms and is associated with substantial impairment. Despite a range of pharmacological and non-pharmacological treatment options, there is still room for improvement of the pharmacological treatment of depression in terms of efficacy and tolerability. The latest available antidepressant is vortioxetine. It is assumed that vortioxetine's antidepressant action is related to a direct modulation of serotonergic receptor activity and inhibition of the serotonin transporter. The mechanism of action is not fully understood, but it is claimed to be novel. Vortioxetine was placed in the category of "Other" antidepressants and may therefore provide an alternative to existing antidepressant drugs.
OBJECTIVES
To assess the efficacy and acceptability of vortioxetine compared with placebo and other antidepressant drugs in the treatment of acute depression in adults.
SEARCH METHODS
We searched Cochrane's Depression, Anxiety and Neurosis Review Group's Specialised Register to May 2016 without applying any restrictions to date, language or publication status. We checked reference lists of relevant studies and reviews, regulatory agency reports and trial databases.
SELECTION CRITERIA
We included randomised controlled trials comparing the efficacy, tolerability, or both of vortioxetine versus placebo or any other antidepressant agent in the treatment of acute depression in adults.
DATA COLLECTION AND ANALYSIS
Two review authors independently selected the studies and extracted data. We extracted data on study characteristics, participant characteristics, intervention details and outcome measures in terms of efficacy, acceptability and tolerability. We analysed intention-to-treat (ITT) data only and used risk ratios (RR) as effect sizes for dichotomous data and mean differences (MD) for continuous data with 95% confidence intervals (CI). Meta-analyses used random-effects models.
MAIN RESULTS
We included 15 studies (7746 participants) in this review. Seven studies were placebo controlled; eight studies compared vortioxetine to serotonin-norepinephrine reuptake inhibitors (SNRIs). We were unable to identify any study that compared vortioxetine to antidepressant drugs from other classes, such as selective serotonin reuptake inhibitors (SSRIs).Vortioxetine may be more effective than placebo across the three efficacy outcomes: response (Mantel-Haenszel RR 1.35, 95% CI 1.22 to 1.49; 14 studies, 6220 participants), remission (RR 1.32, 95% CI 1.15 to 1.53; 14 studies, 6220 participants) and depressive symptoms measured using the Montgomery-Åsberg Depression Scale (MADRS) (score range: 0 to 34; higher score means worse outcome: MD -2.94, 95% CI -4.07 to -1.80; 14 studies, 5566 participants). The quality of the evidence was low for response and remission and very low for depressive symptoms. We found no evidence of a difference in total dropout rates (RR 1.05, 95% CI 0.93 to 1.19; 14 studies, 6220 participants). More participants discontinued vortioxetine than placebo because of adverse effects (RR 1.41, 95% CI 1.09 to 1.81; 14 studies, 6220 participants) but fewer discontinued due to inefficacy (RR 0.56, 95% CI 0.34 to 0.90, P = 0.02; 14 studies, 6220 participants). The quality of the evidence for dropouts was moderate.The subgroup and sensitivity analyses did not reveal factors that significantly influenced the results.In comparison with other antidepressants, very low-quality evidence from eight studies showed no clinically significant difference between vortioxetine and SNRIs as a class for response (RR 0.91, 95% CI 0.82 to 1.00; 3159 participants) or remission (RR 0.89, 95% CI 0.77 to 1.03; 3155 participants). There was a small difference favouring SNRIs for depressive symptom scores on the MADRS (MD 1.52, 95% CI 0.50 to 2.53; 8 studies, 2807 participants). Very low quality evidence from eight studies (3159 participants) showed no significant differences between vortioxetine and the SNRIs as a class for total dropout rates (RR 0.89, 95% CI 0.73 to 1.08), dropouts due to adverse events (RR 0.74, 95% CI 0.51 to 1.08) and dropouts due to inefficacy (RR 1.52, 95% CI 0.70 to 3.30).Against individual antidepressants, analyses suggested that vortioxetine may be less effective than duloxetine in terms of response rates (RR 0.86, 95% CI 0.79 to 0.94; 6 studies, 2392 participants) and depressive symptoms scores on the MADRS scale (MD 1.99, 95% CI 1.15 to 2.83; 6 studies; 2106 participants). Against venlafaxine, meta-analysis of two studies found no statistically significant differences (response: RR 1.03, 95% CI 0.85 to 1.25; 767 participants; depressive symptom scores: MD 0.02, 95% CI -2.49 to 2.54; 701 participants). In terms of number of participants reporting at least one adverse effect (tolerability), vortioxetine was better than the SNRIs as a class (RR 0.90, 95% CI 0.86 to 0.94; 8 studies, 3134 participants) and duloxetine (RR 0.89, 95% CI 0.84 to 0.95; 6 studies; 2376 participants). However, the sensitivity analysis casts some doubts on this result, as only two studies used comparable dosing.We judged none of the studies to have a high risk of bias for any domain, but we rated all studies to have an unclear risk of bias of selective reporting and other biases.
AUTHORS' CONCLUSIONS
The place of vortioxetine in the treatment of acute depression is unclear. Our analyses showed vortioxetine may be more effective than placebo in terms of response, remission and depressive symptoms, but the clinical relevance of these effects is uncertain. Furthermore, the quality of evidence to support these findings was generally low. In comparison to SNRIs, we found no advantage for vortioxetine. Vortioxetine was less effective than duloxetine, but fewer people reported adverse effects when treated with vortioxetine compared to duloxetine. However, these findings are uncertain and not well supported by evidence. A major limitation of the current evidence is the lack of comparisons with the SSRIs, which are usually recommended as first-line treatments for acute depression. Studies with direct comparisons to SSRIs are needed to address this gap and may be supplemented by network meta-analyses to define the role of vortioxetine in the treatment of depression.
Topics: Adult; Antidepressive Agents; Depressive Disorder, Major; Duloxetine Hydrochloride; Humans; Patient Dropouts; Piperazines; Placebos; Randomized Controlled Trials as Topic; Remission Induction; Serotonin and Noradrenaline Reuptake Inhibitors; Sulfides; Venlafaxine Hydrochloride; Vortioxetine
PubMed: 28677828
DOI: 10.1002/14651858.CD011520.pub2 -
Basic & Clinical Pharmacology &... Jan 2016Major depressive disorder is common among women in child-bearing age, and medical treatment is subject to substantial discussions and controversies. For Selective... (Review)
Review
Major depressive disorder is common among women in child-bearing age, and medical treatment is subject to substantial discussions and controversies. For Selective Serotonin reuptake inhibitors, SSRIs, a vast amount of data are available. For the newer antidepressant group of serotonin and noradrenaline reuptake inhibitors, SNRIs, significantly less data are available. Following the PRISMA guideline for systematic reviews, we performed a systematic search on the risk of major congenital malformations after first trimester in utero exposure to venlafaxine or duloxetine. We identified eight cohort studies reporting on the outcome upon in utero exposure to venlafaxine or duloxetine during the first trimester. The cumulated data for venlafaxine were 3186 exposed infants and 107 major malformations, resulting in a relative risk estimate and 95% confidence interval of 1.12 (0.92-1.35). The corresponding data for duloxetine were 668 infants and 16 major malformations, resulting in a relative risk estimate and 95% confidence interval of 0.80 (0.46-1.29). First-trimester in utero exposure to venlafaxine is not associated with an increased risk of major congenital malformations. The amount of data for duloxetine are significantly smaller but does not suggest a clinically important increased risk.
Topics: Abnormalities, Drug-Induced; Cohort Studies; Depressive Disorder, Major; Duloxetine Hydrochloride; Female; Humans; Pregnancy; Pregnancy Trimester, First; Prenatal Exposure Delayed Effects; Serotonin and Noradrenaline Reuptake Inhibitors; Venlafaxine Hydrochloride
PubMed: 26435496
DOI: 10.1111/bcpt.12497