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The Cochrane Database of Systematic... Apr 2005Primary biliary cirrhosis is a chronic progressive cholestatic liver disease of presumed autoimmune etiology, characterised by the destruction of small intrahepatic bile... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Primary biliary cirrhosis is a chronic progressive cholestatic liver disease of presumed autoimmune etiology, characterised by the destruction of small intrahepatic bile ducts and the eventual development of cirrhosis and liver failure. Its progression may be influenced by immunosuppression. Glucocorticosteroids are potent immunosuppressive agents, but they are associated with significant adverse effects, including osteoporosis.
OBJECTIVES
To systematically evaluate the beneficial and harmful effects of glucocorticosteroids versus placebo or no intervention for patients with primary biliary cirrhosis.
SEARCH STRATEGY
The Cochrane Hepato-Biliary Controlled Trials Register,The Cochrane Library, MEDLINE, EMBASE, and the full text of the identified studies were searched until June 2004. The search strategy included terms for primary biliary cirrhosis and glucocorticosteroids (including the names of frequently used preparations). Previous research groups and manufacturers were contacted for additional references. No language restrictions were applied.
SELECTION CRITERIA
Double-blind, single-blind, or unblinded randomised clinical trials evaluating any preparation of glucocorticosteroids versus placebo or no intervention in patients with primary biliary cirrhosis diagnosed by abnormal liver function tests and either anti-mitochondrial antibodies or histology were included. Additional agents were allowed if they were administered to both groups equally.
DATA COLLECTION AND ANALYSIS
The quality of the randomised clinical trials was evaluated by methodology components (generation of allocation sequence; allocation concealment; blinding; follow up). Analyses were performed according to the intention-to-treat method with missing data being accounted for by imputation.
MAIN RESULTS
Only two underpowered trials (reporting 36 and 40 patients) were identified. These differed markedly in their inclusion criteria and treatment protocols. Both stated that they used placebo. However, allocation concealment was unclear. Only one trial reported any patient deaths. No significant improvement in mortality was identified (odds ratio (OR) 0.42, 95% confidence interval (CI) 0.10 to 1.76). Improvements in serum markers of liver inflammation and liver histology were identified. Potentially prognostically linked markers such as bilirubin and albumin were incompletely reported. Bone mineral density (weighted mean difference -2.84%, 95% CI -4.16 to -1.53) and the number of patients with any adverse event (OR 8.99, 95% CI 2.15 to 37.58) were significantly increased in the glucocorticosteroid group.
AUTHORS' CONCLUSIONS
There is insufficient data to support or reject the use of glucocorticosteroids for patients with primary biliary cirrhosis. It may be appropriate to consider a large prospective randomised clinical trial on this topic.
Topics: Budesonide; Glucocorticoids; Humans; Liver Cirrhosis, Biliary; Prednisolone; Randomized Controlled Trials as Topic
PubMed: 15846681
DOI: 10.1002/14651858.CD003778.pub2 -
Pharmacological Research Feb 2021Conducting randomised clinical trials (RCTs) in idiosyncratic drug-induced liver injury (DILI) is challenging. This systematic review aims to summarise the design and... (Meta-Analysis)
Meta-Analysis
Conducting randomised clinical trials (RCTs) in idiosyncratic drug-induced liver injury (DILI) is challenging. This systematic review aims to summarise the design and findings of RCTs in the prevention and management of idiosyncratic DILI. A systematic literature search up to January 31, 2020 was performed. Recognised scales were used to assess methodological bias and quality of the studies. Quantitative and qualitative analyses were performed. Heterogeneity was assessed with I statistic. Overall, 22 RCTs were included: 12 on prevention (n = 2,471 patients) and 10 in management (n = 797) of DILI/non-acetaminophen DILI-related acute liver failure (ALF). Silymarin (eight studies), bicyclol (four), magnesium isoglycyrrhizinate (three), N-acetylcysteine (three), tiopronin (one), L-carnitine (one), and traditional Chinese medicines (two) were tested in the intervention arm, while control arm mostly received standard supportive care or placebo. Main efficacy criteria in the prevention RCTs was DILI incidence or peak of liver enzymes value. In management RCTs, the efficacy parameter was usually 50 % decrease or normalisation of liver enzymes, or survival rate in DILI-related ALF patients. Overall, 15 trials described the randomisation method, eight were double-blind (n = 672) and nine had sample size estimation (n = 880). Four RCTs involving 377 patients used an intention-to-treat analysis. Based on the scarce number of trials available, tested agents showed limited efficacy in DILI prevention and management and a favourable safety profile. In conclusion, heterogeneity among studies in DILI case qualification and methodologic quality was evident, and the RCTs performed demonstrated limited efficacy of specific interventions. International research networks are needed to establish a framework on RCTs design and therapeutic endpoints.
Topics: Chemical and Drug Induced Liver Injury; Humans; Protective Agents; Randomized Controlled Trials as Topic
PubMed: 33359912
DOI: 10.1016/j.phrs.2020.105404 -
The Cochrane Database of Systematic... May 2017Neuropathic pain, which is caused by a lesion or disease affecting the somatosensory system, may be central or peripheral in origin. Neuropathic pain often includes... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Neuropathic pain, which is caused by a lesion or disease affecting the somatosensory system, may be central or peripheral in origin. Neuropathic pain often includes symptoms such as burning or shooting sensations, abnormal sensitivity to normally painless stimuli, or an increased sensitivity to normally painful stimuli. Neuropathic pain is a common symptom in many diseases of the nervous system. Opioid drugs, including morphine, are commonly used to treat neuropathic pain. Most reviews have examined all opioids together. This review sought evidence specifically for morphine; other opioids are considered in separate reviews.
OBJECTIVES
To assess the analgesic efficacy and adverse events of morphine for chronic neuropathic pain in adults.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase for randomised controlled trials from inception to February 2017. We also searched the reference lists of retrieved studies and reviews, and online clinical trial registries.
SELECTION CRITERIA
We included randomised, double-blind trials of two weeks' duration or longer, comparing morphine (any route of administration) with placebo or another active treatment for neuropathic pain, with participant-reported pain assessment.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data and assessed trial quality and potential bias. Primary outcomes were participants with substantial pain relief (at least 50% pain relief over baseline or very much improved on Patient Global Impression of Change scale (PGIC)), or moderate pain relief (at least 30% pain relief over baseline or much or very much improved on PGIC). Where pooled analysis was possible, we used dichotomous data to calculate risk ratio (RR) and number needed to treat for an additional beneficial outcome (NNT) or harmful outcome (NNH). We assessed the quality of the evidence using GRADE and created 'Summary of findings' tables.
MAIN RESULTS
We identified five randomised, double-blind, cross-over studies with treatment periods of four to seven weeks, involving 236 participants in suitably characterised neuropathic pain; 152 (64%) participants completed all treatment periods. Oral morphine was titrated to maximum daily doses of 90 mg to 180 mg or the maximum tolerated dose, and then maintained for the remainder of the study. Participants had experienced moderate or severe neuropathic pain for at least three months. Included studies involved people with painful diabetic neuropathy, chemotherapy-induced peripheral neuropathy, postherpetic neuralgia criteria, phantom limb or postamputation pain, and lumbar radiculopathy. Exclusions were typically people with other significant comorbidity or pain from other causes.Overall, we judged the studies to be at low risk of bias, but there were concerns over small study size and the imputation method used for participants who withdrew from the studies, both of which could lead to overestimation of treatment benefits and underestimation of harm.There was insufficient or no evidence for the primary outcomes of interest for efficacy or harm. Four studies reported an approximation of moderate pain improvement (any pain-related outcome indicating some improvement) comparing morphine with placebo in different types of neuropathic pain. We pooled these data in an exploratory analysis. Moderate improvement was experienced by 63% (87/138) of participants with morphine and 36% (45/125) with placebo; the risk difference (RD) was 0.27 (95% confidence interval (CI) 0.16 to 0.38, fixed-effects analysis) and the NNT 3.7 (2.6 to 6.5). We assessed the quality of the evidence as very low because of the small number of events; available information did not provide a reliable indication of the likely effect, and the likelihood that the effect will be substantially different was very high. A similar exploratory analysis for substantial pain relief on three studies (177 participants) showed no difference between morphine and placebo.All-cause withdrawals in four studies occurred in 16% (24/152) of participants with morphine and 12% (16/137) with placebo. The RD was 0.04 (-0.04 to 0.12, random-effects analysis). Adverse events were inconsistently reported, more common with morphine than with placebo, and typical of opioids. There were two serious adverse events, one with morphine, and one with a combination of morphine and nortriptyline. No deaths were reported. These outcomes were assessed as very low quality because of the limited number of participants and events.
AUTHORS' CONCLUSIONS
There was insufficient evidence to support or refute the suggestion that morphine has any efficacy in any neuropathic pain condition.
Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Chronic Pain; Humans; Middle Aged; Morphine; Neuralgia; Numbers Needed To Treat; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 28530786
DOI: 10.1002/14651858.CD011669.pub2 -
The Cochrane Database of Systematic... May 2011Benign prostatic hyperplasia (BPH), nonmalignant enlargement of the prostate, can lead to obstructive and irritative lower urinary tract symptoms (LUTS). The... (Review)
Review
BACKGROUND
Benign prostatic hyperplasia (BPH), nonmalignant enlargement of the prostate, can lead to obstructive and irritative lower urinary tract symptoms (LUTS). The pharmacologic use of plants and herbs (phytotherapy) for the treatment of LUTS associated with BPH has been growing steadily. Cernilton, prepared from the rye-grass pollen Secale cereale, is one of the several phytotherapeutic agents available for the treatment of BPH.
OBJECTIVES
This systematic review aims to assess the effects of Cernilton on urinary symptoms and flow measures in men with benign prostatic hyperplasia (BPH).
SEARCH STRATEGY
Trials were searched in computerized general and specialized databases (MEDLINE, EMBASE, Cochrane Library, Phytodok), by checking bibliographies, and by contacting manufacturers and researchers.
SELECTION CRITERIA
Trials were eligible if they were: (1) randomized controlled trials or controlled clinical trials comparing Cernilton with placebo or other BPH medications in men with BPH; and (2) included clinical outcomes such as urologic symptom scales, symptoms, or urodynamic measurements.
DATA COLLECTION AND ANALYSIS
Information on patients, interventions, and outcomes was extracted by at least two independent reviewers using a standard form. Main outcome measure for comparing the effects of Cernilton with placebo and standard BPH medications were the change in urologic symptoms scales. Secondary outcomes included changes in nocturia as well as urodynamic measures (peak and mean urine flow, residual volume, prostate size). Main outcome measure for side effects was the number of men reporting side effects.
MAIN RESULTS
Four hundred forty-four men were enrolled in two placebo-controlled and two comparative trials lasting from 12 to 24 weeks. Three studies used a double-blind method although treatment allocation concealment was unclear in all. Cernilton improved "self rated urinary symptoms" (percent reporting satisfactory or improving symptoms) versus placebo and Tadenan. The weighted risk ratio (RR) for self-rated improvement versus placebo was 2.40 (95% CI = 1.21 to 4.75), and the weighted RR versus Tadenan was 1.42 (95% CI = 1.21 to 4.75). Cernilton reduced nocturia compared with placebo and Paraprost. Versus placebo, the weighted RR was 2.05 (95% CI = 1.41 to 3.00), and versus Paraprost, the WMD was -0.40 times per evening (95% CI = -0.73 to -0.07). Cernilton was not more effective than placebo or the comparative study agents in improving urinary flow rates, residual volume or prostate size. Adverse events were rare and mild. The withdrawal rate for Cernilton was 4.8% compared to 2.7% for placebo and 5.2% for Paraprost.
AUTHORS' CONCLUSIONS
The Cernilton trials analyzed were limited by short duration, limited number of enrollees, gaps in reported outcomes, and unknown quality of the preparations utilized. The comparative trials lacked a proven active control. The available evidence suggests Cernilton is well tolerated and modestly improves overall urologic symptoms including nocturia. Additional randomized placebo and active-controlled trials are needed to evaluate the long-term clinical effectiveness and safety of Cernilton.
Topics: Humans; Male; Phytotherapy; Plant Extracts; Prostatic Hyperplasia; Secale
PubMed: 21563128
DOI: 10.1002/14651858.CD001042.pub2 -
Nature and Science of Sleep 2021Obstructive sleep apnea (OSA) is a highly prevalent disease with substantial public health burden. In most of the cases, there is a genetic predisposition to OSA.... (Review)
Review
Polymorphism of the Serotonin Transporter Gene and the Peripheral 5-Hydroxytryptamine in Obstructive Sleep Apnea: What Do We Know and What are We Looking for? A Systematic Review of the Literature.
BACKGROUND
Obstructive sleep apnea (OSA) is a highly prevalent disease with substantial public health burden. In most of the cases, there is a genetic predisposition to OSA. Serotonin/T-HydroxyTriptamine (5-HT) plays a key role in ventilatory stimulation, while the polymorphism of the serotonin transporter gene (STG) leads to alterations in serotonin level, making it important in OSA.
OBJECTIVE
To examine whether the 5-HydroxyTriptamine and the genetic predisposition influence the incidence and evolution of OSA, we reviewed randomized, controlled trials and observational studies on the selected topic. The secondary objective was to determine the metabolic effects of the circulating serotonin in other tissues (liver, pancreas, gut, brown adipose tissue, and white adipose tissue) and its role in the development of obesity.
DATA SOURCES
A systematic review of English articles was performed based on PubMed and the Cochrane Library databases. Search filters included randomized controlled trial, controlled clinical trial, random allocation, double-blind method, and case-control studies and used the following keywords: Brain Serotonin OR Serotonin Transporter Gene Polymorphism OR Peripheral 5-HydroxyTryptamine AND Obstructive Sleep Apnea OR Sleep Disorder Breathing OR brain serotonin AND OSA OR serotonin transporter gene OR Peripheral 5-Hydroxytryptamine AND Sleep.
STUDY ELIGIBILITY CRITERIA
The inclusion criteria for the current review were previous diagnosis of OSA, age above 18 years, and articles including quantitative data about serotonin transporter gene or peripheral serotonin. Language and time criteria were added - English articles published in the last 15 years. Studies that were not included were reviews and case reports.
STUDY APPRAISAL AND SYNTHESIS METHODS
In order to study the serotonin function, a literature research was conducted in the databases Pubmed and Cochrane Library. The following search terms were used: serotonin, 5-hydroxytryptamine, serotonin transporter gene. A critical appraisal of the included studies was performed with the Newcastle-Ottawa scale (NOS) and Delphi list.
RESULTS
The search yielded 1210 articles, from which 43 were included. The included studies suggest that the two polymorphisms of serotonin transporter gene (5HTT) - variable number of tandem repeats (VNTR) and linked polymorphic region (LPR) - are strong candidates in the pathogenesis of OSA. The allele 10 of 5HTTVNTR and the long/long (L/L) allele genotype were associated with a higher prevalence of OSA and the L allele with a higher apnea-hypopnea index and a longer time during sleep with oxygen desaturation.
LIMITATIONS
The main limitation of the present study consists of heterogeneity of the information. Being a less studied subject, randomized trials are not widely available and most data were obtained from case-control trials. Moreover, the included material indirectly approached the subject by demonstrating the effects of serotoninergic system over the metabolism, the connection between serotonin and obesity, factors which are implied in the pathogenesis of OSA.
CONCLUSION AND IMPLICATIONS OF KEY FINDINGS
The two polymorphisms of serotonin gene can be considered important factors in the diagnosis and management of OSA.
PubMed: 33603523
DOI: 10.2147/NSS.S278170 -
The British Journal of General Practice... Jun 2003Impetigo is a common clinical problem seen in general practice. Uncertainty exists as to the most effective treatment, or indeed if treatment is necessary. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Impetigo is a common clinical problem seen in general practice. Uncertainty exists as to the most effective treatment, or indeed if treatment is necessary.
AIM
To determine the most effective treatment for impetigo in a systemically well patient.
DESIGN OF STUDY
Systematic review and meta-analysis.
METHOD
Databases were searched for relevant studies. The Cochrane highly sensitive randomised controlled trial (RCT) search string was employed and combined with the word 'impetigo' as the MeSH term and keyword. The bibliographies of relevant articles were searched for additional references. RCTs that were either double- or observer-blind, and involved systemically well patients of any age in either primary or secondary care settings, were included. Studies that selected patients on the basis of skin swab results were excluded, as were studies that were not in English. Cure or improvement of impetigo reported at seven to 14 days from start of treatment was the primary outcome measure. Meta-analysis was performed on homogeneous studies.
RESULTS
Three hundred and fifty-nine studies were identified, of which 16 met the inclusion criteria. Meta-analysis demonstrated that topical antibiotics are more effective than placebo (odds ratio [OR] = 2.69, 95% confidence interval [CI] = 1.49 to 4.86). There is weak evidence for the superiority of topical antibiotics over some oral antibiotics, such as erythromycin (OR = 0.48, 95% CI = 0.23 to 1.00). There is no significant difference between the effects of mupirocin and fusidic acid (OR = 1.76, 95% CI = 0.77 to 4.03).
CONCLUSION
This review found limited high-quality evidence to inform the treatment of impetigo. From that which is available, we would recommend the use of a topical antibiotic for a period of seven days in a systemically well patient with limited disease. Further research is needed on the role of flucloxacillin and non-antibiotic treatments for impetigo.
Topics: Administration, Topical; Adolescent; Algorithms; Child; Child, Preschool; Double-Blind Method; Drug Therapy, Combination; Erythromycin; Family Practice; Fusidic Acid; Humans; Impetigo; Infant; Infant, Newborn; Mupirocin; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 12939895
DOI: No ID Found -
Journal of the Royal Society of Medicine Oct 2016To quantify the risk of suicidality and violence when selective serotonin and serotonin-norepinephrine reuptake inhibitors are given to adult healthy volunteers with no... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To quantify the risk of suicidality and violence when selective serotonin and serotonin-norepinephrine reuptake inhibitors are given to adult healthy volunteers with no signs of a mental disorder.
DESIGN
Systematic review and meta-analysis.
MAIN OUTCOME MEASURE
Harms related to suicidality, hostility, activation events, psychotic events and mood disturbances.
SETTING
Published trials identified by searching PubMed and Embase and clinical study reports obtained from the European and UK drug regulators.
PARTICIPANTS
Double-blind, placebo-controlled trials in adult healthy volunteers that reported on suicidality or violence or precursor events to suicidality or violence.
RESULTS
A total of 5787 publications were screened and 130 trials fulfilled our inclusion criteria. The trials were generally uninformative; 97 trials did not report the randomisation method, 75 trials did not report any discontinuations and 63 trials did not report any adverse events or lack thereof. Eleven of the 130 published trials and two of 29 clinical study reports we received from the regulatory agencies presented data for our meta-analysis. Treatment of adult healthy volunteers with antidepressants doubled their risk of harms related to suicidality and violence, odds ratio 1.85 (95% confidence interval 1.11 to 3.08, p = 0.02, I= 18%). The number needed to treat to harm one healthy person was 16 (95% confidence interval 8 to 100; Mantel-Haenszel risk difference 0.06). There can be little doubt that we underestimated the harms of antidepressants, as we only had access to the published articles for 11 of our 13 trials.
CONCLUSIONS
Antidepressants double the occurrence of events in adult healthy volunteers that can lead to suicide and violence.
Topics: Adult; Antidepressive Agents; Female; Healthy Volunteers; Humans; Male; Risk; Selective Serotonin Reuptake Inhibitors; Serotonin and Noradrenaline Reuptake Inhibitors; Suicide; Violence
PubMed: 27729596
DOI: 10.1177/0141076816666805 -
Developmental Medicine and Child... Dec 2017To evaluate the actual evidence of efficacy of oral pharmacological treatments in the management of dyskinetic cerebral palsy (CP). (Review)
Review
AIM
To evaluate the actual evidence of efficacy of oral pharmacological treatments in the management of dyskinetic cerebral palsy (CP).
METHOD
A systematic review was performed according to the American Academy for Cerebral Palsy and Developmental Medicine (AACPDM) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology. Articles were searched for in PubMed/MEDLINE, Scopus, Web of Science, Cochrane Library, Database of Reviews of Effectiveness, OTSeeker, Physiotherapy Evidence Database, REHABDATA, and ClinicalTrials.gov.
RESULTS
Sixteen articles met the eligibility criteria. Eight studies on trihexyphenidyl and two on levodopa showed contradictory results. Low efficacy was reported for diazepam, dantrolene sodium, perphenazine, and etybenzatropine. Tetrabenazine, gabapentin and levetiracetam should be studied in more detail. The updated available evidence does not support any therapeutic algorithm for the management of dyskinetic CP.
INTERPRETATION
This lack of evidence is partially owing to the inconsistency of classifications of patients and of outcome measures used in the reviewed studies. Further randomized, double-blind, placebo-controlled pharmacological trials, optimized for different age groups, based on valid, reliable, and disease-specific rating scales are strongly needed. Outcome measures should be selected within the framework of the International Classification of Functioning, Disability and Health.
WHAT THIS PAPER ADDS
Evidence to prove (or disprove) the efficacy of oral drugs in dyskinetic cerebral palsy is low. The most investigated drugs, trihexyphenidyl and levodopa, show contradictory results. Tetrabenazine, levetiracetam, and gabapentin efficacy should be studied in more detail. Lack of evidence is partially due to the inconsistency of classifications and outcome measures used. Outcome measures should be selected within the framework of the International Classification of Functioning, Disability and Health in next clinical trials.
Topics: Anticonvulsants; Cerebral Palsy; Dyskinesias; Humans; Neurotransmitter Agents; Outcome Assessment, Health Care
PubMed: 28872668
DOI: 10.1111/dmcn.13532 -
Nutrients Jan 2021Recent systematic reviews and meta-analyses of randomized, double-blind, placebo-controlled trials (double-blind, placebo-controlled RCTs) have reported controversial... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Recent systematic reviews and meta-analyses of randomized, double-blind, placebo-controlled trials (double-blind, placebo-controlled RCTs) have reported controversial findings regarding the associations between calcium supplements on the risk of cardiovascular disease (CVD). This meta-analysis aimed to investigate the association between them.
METHODS
We searched PubMed, EMBASE, the Cochrane Library, and the bibliographies of relevant articles for double-blind, placebo-controlled RCTs in November, 2020. Relative risks (RRs) with 95% confidence intervals (CIs) for the risk of cardiovascular disease were calculated using a random effects model. The main outcomes were CVD, coronary heart disease (CHD), and cerebrovascular disease.
RESULTS
A total of 13 double-blind, placebo-controlled RCTs ( = 28,935 participants in an intervention group and 14,243 in a control group)) were included in the final analysis. Calcium supplements significantly increased the risk of CVD (RR 1.15, 95% CI 1.06-1.25], I2 = 0.0%, = 14) and CHD (RR 1.16, 95% CI 1.05-1.28], I2 = 0.0%, = 9) in double-blind, placebo-controlled RCTs, specifically in healthy postmenopausal women. In the subgroup meta-analysis, dietary calcium intake of 700-1000 mg per day or supplementary calcium intake of 1000 mg per day significantly increased the risk of CVD and CHD.
CONCLUSIONS
The current meta-analysis found that calcium supplements increased a risk of CVD by about 15% in healthy postmenopausal women.
Topics: Calcium; Calcium, Dietary; Cardiovascular Diseases; Clinical Trials as Topic; Coronary Disease; Databases, Factual; Dietary Supplements; Double-Blind Method; Eating; Female; Humans; Randomized Controlled Trials as Topic
PubMed: 33530332
DOI: 10.3390/nu13020368 -
The Cochrane Database of Systematic... Oct 2015This is an updated version of the original Cochrane review published in Issue 3, 2012. That review considered both fibromyalgia and neuropathic pain, but the efficacy of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This is an updated version of the original Cochrane review published in Issue 3, 2012. That review considered both fibromyalgia and neuropathic pain, but the efficacy of milnacipran for neuropathic pain is now dealt with in a separate review.Milnacipran is a serotonin-norepinephrine (noradrenaline) reuptake inhibitor (SNRI) that is licensed for the treatment of fibromyalgia in some countries, including Canada, Russia, and the United States.
OBJECTIVES
To assess the analgesic efficacy of milnacipran for pain in fibromyalgia in adults and the adverse events associated with its use in clinical trials.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE to 18 May 2015, together with reference lists of retrieved papers and reviews, and two clinical trial registries. For the earlier review, we also contacted the manufacturer.
SELECTION CRITERIA
We included randomised, double-blind studies of eight weeks' duration or longer, comparing milnacipran with placebo or another active treatment in fibromyalgia in adults.
DATA COLLECTION AND ANALYSIS
We extracted efficacy and adverse event data, and two review authors examined issues of study quality independently.
MAIN RESULTS
We identified one new study with 100 participants for the pooled analysis. We identified two additional reports of a study using an enriched enrolment randomised withdrawal (EERW) design that included participants from earlier randomised controlled trials and an open-label study. Because this study used the same participants already included in our main analysis, and a different design, we dealt with it separately.The main analysis included six studies (five from the earlier review; 4238 participants in total), all of which were placebo-controlled, and used titration to a target dose of milnacipran 100 or 200 mg, with assessment after 8 to 24 weeks of stable treatment. There were no studies with active comparators. Study quality was generally good, although the imputation method used in analyses of the primary outcomes could overestimate treatment effect.Both doses of milnacipran provided moderate levels of pain relief (at least 30% pain intensity reduction) to about 40% of participants treated, compared to 30% with placebo, giving a number needed to treat for an additional beneficial outcome (NNT) of 6 to 10 (high quality evidence). Using a stricter definition for responder and a more conservative method of analysis gave lower levels of response (while maintaining a 10% difference between milnacipran and placebo) and increased the NNT to 11 (high quality evidence). One EERW study was broadly supportive.Adverse events were common in both milnacipran (86%) and placebo (78%) groups (high quality evidence), but serious adverse events did not differ between groups (less than 2%) (low quality evidence). Nausea, constipation, and headache were the most common events showing the greatest difference between groups (number needed to treat for an additional harmful outcome (NNH) of 5.7 for nausea, 13 for constipation, and 29 for headache) (moderate quality evidence).Withdrawals for any reason were more common with milnacipran than placebo, and more common with 200 mg (NNH 9) than 100 mg (NNH 23), compared with placebo. This was largely driven by adverse event withdrawals, where the NNH compared with placebo was 14 for 100 mg and 7.0 for 200 mg (high quality evidence). Withdrawals due to lack of efficacy were less common with milnacipran than placebo but did not differ between doses (number needed to treat to prevent an additional unwanted outcome (NNTp) of 41) (moderate quality evidence).
AUTHORS' CONCLUSIONS
The evidence available indicates that milnacipran 100 mg or 200 mg is effective for a minority in the treatment of pain due to fibromyalgia, providing moderate levels of pain relief (at least 30%) to about 40% of participants, compared with about 30% with placebo. There were insufficient data to assess substantial levels of pain relief (at least 50%), and the use of last observation carried forward imputation may overestimate drug efficacy. Using stricter criteria for 'responder' and a more conservative method of analysis gave lower response rates (about 26% with milnacipran versus 17% with placebo). Milnacipran was associated with increased adverse events and adverse event withdrawals, which were significantly greater for the higher dose.
Topics: Adult; Analgesics; Chronic Disease; Cyclopropanes; Fibromyalgia; Humans; Milnacipran; Neuralgia; Selective Serotonin Reuptake Inhibitors
PubMed: 26482422
DOI: 10.1002/14651858.CD008244.pub3