Inhibidores de la recaptación de serotonina y noradrenalina (IRSN) para la fibromialgia
Información
- DOI:
- https://doi.org/10.1002/14651858.CD010292.pub2Copiar DOI
- Base de datos:
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- Cochrane Database of Systematic Reviews
- Versión publicada:
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- 28 febrero 2018see what's new
- Tipo:
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- Intervention
- Etapa:
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- Review
- Grupo Editorial Cochrane:
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Grupo Cochrane de Dolor y cuidados paliativos
- Copyright:
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- Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cifras del artículo
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Citado por:
Autores
Contributions of authors
WH and PK developed and ran the search. BW and WH selected which studies to include. BW, NÜ, PW and WH extracted data from studies. WH entered data into Review Manager 5 and carried out the analysis. Data entry was checked by BW, NÜ and PW. All authors interpreted the analysis. WH drafted the final review update.
Sources of support
Internal sources
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Technische Universität München, Germany
General institutional support
External sources
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New Source of support, Other
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The National Institute for Health Research (NIHR), UK
NIHR Cochrane Programme Grant: 13/89/29 ‐ Addressing the unmet need of chronic pain: providing the evidence for treatments of pain
Declarations of interest
PW: none known. PW is a specialist pain physician and manages patients with fibromyalgia.
NÜ is a neurologist and pain physician who treats patients with fibromyalgia. She is member of the German guideline group on fibromyalgia. She received travel grants, research support and speaker honoraria from Genzyme (2015, 2016). She received speaker honoraria from Baxalta (2016). She received research grants from Genzyme (2015) and Shire (2017). She received travel grants from Grunenthal (2017).
PK: none known
BW: none known; BW is a specialist pain physician and manages patients with fibromyalgia.
WH is a specialist in general internal medicine, psychosomatic medicine and pain medicine, who treats patients with fibromyalgia and chronic neuropathic pain. He is a member of the medical board of the German Fibromyalgia Association. He is the head of the steering committee of the German guideline on fibromyalgia and a member of the steering committee of the European League Against Rheumatism (EULAR) update recommendations on the management of fibromyalgia. He received speaking fees for one educational lecture from Grünenthal (2015) on pain management.
Acknowledgements
We thank Gerard Urrútia and Sera Tort for their contributions to the first version of the review (Häuser 2013 b).
This review was initially managed by Cochrane Musculoskeletal; in June 2016 it was transferred to Cochrane Pain, Palliative and Supportive Care (PaPaS), which primarily manages reviews on fibromyalgia.
Cochrane Review Group funding acknowledgement: this project was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to Cochrane Pain, Palliative and Supportive Care(PaPaS). The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health.
This research was supported (in part) by the Intramural Research Program of the NIH, National Institute of Nursing Research.
Version history
| Published | Title | Stage | Authors | Version |
| 2018 Feb 28 | Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia | Review | Patrick Welsch, Nurcan Üçeyler, Petra Klose, Brian Walitt, Winfried Häuser | |
| 2013 Jan 31 | Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome | Review | Winfried Häuser, Gerard Urrútia, Sera Tort, Nurcan Üçeyler, Brian Walitt | |
Differences between protocol and review
For the earlier review, the protocol 'Antidepressants and centrally active agents for fibromyalgia syndrome' was split into several systematic reviews (Nishishinya 2006). We added an additional comparison, namely cognitive disturbances. We used a random‐effects model for all analysis irrespective of the amount of heterogeneity. We used the GRADE approach for the grading of the quality of the body of evidence.
For this update in 2017, we made the following minor changes:
Background
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We considered recent literature.
Methods/Criteria for considering studies for this review
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We excluded mirtazapine from searches and analysis, because mirtazapine has been classified to another class of antidepressants from serotonin and noradrenaline reuptake inhibitors (SNRIs), namely noradrenergic and specific serotonergic antidepressants (NaSSAs).
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We defined more precisely the criteria of including and excluding studies.
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We included studies with an active drug as comparator.
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We substituted 'pain intensity' with 'patient global impression much or very much improved' as a primary outcome. We reduced the number of primary outcomes from seven to four. Self‐reported sleep problems, self‐reported health‐related quality of life and self‐reported fatigue were changed from primary to secondary outcomes. We added number of participants dropping out due to lack of efficacy, and specific adverse events frequently associated with the use of SNRIs (nausea, somnolence, insomnia), as secondary outcomes with regard to the Cochrane Pain, Palliative and Supportive Care template for reviews in fibromyalgia.
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We defined outcomes for studies with an enriched enrolment randomized withdrawal design.
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We included the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) in our search.
Methods/Measures of treatment effect
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We changed from risk ratio to risk difference for categorical variables, because this type of effect size is more meaningful for clinicians.
Methods/Assessment of risk of bias in included studies
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We deleted 'external validity' as a risk of bias and included this item in GRADE assessment within 'indirectness of evidence'.
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We changed the criteria of 'blinding of the outcome assessment' from blinding of the statistician to blinding of the participants for participant‐reported outcomes and to blinding of the outcome assessor for outcomes of safety.
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We extended the 'Risk of bias' assessment by two items (selection and sample size bias).
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We changed the methods of screening for publication bias.
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We predefined the criteria for downgrading the quality of evidence for each GRADE item.
Analyses
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We deleted the calculation of intra‐group effect sizes (baseline and final treatment) of true drug and placebo on pain and health‐related quality of life.
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We added a comparison of SNRIs versus placebo in studies with a randomized withdrawal design.
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We added a comparison of SNRIs versus other active drugs.
Discussion
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We rearranged the sections according to MECIR standards.
Characteristics of included studies
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We added details of the declaration of conflicts of interest and funding.
Notes
The protocol 'Antidepressants and centrally active agents for fibromyalgia syndrome' published in 2006 (Nishishinya 2006) has been split into several systematic reviews that will be/have been published as:
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Anticonvulsants for fibromyalgia syndrome (Üceyler 2017 b);
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Monoamine oxidase inhibitors (MAOIs) for fibromyalgia syndrome (Tort 2012);
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Non‐steroidal anti‐inflammatory drugs (NSAIDs) for fibromyalgia (Derry 2017);
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Analgesics and opioid agents for fibromyalgia syndrome;
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Sedatives and hypnotic agents for fibromyalgia syndrome;
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Selective serotonin reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Walitt 2015);
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Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Häuser 2013 a)
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Tricyclic agents for fibromyalgia syndrome.
Assessed for updating in 2020
A restricted search in January 2020 did not identify any potentially relevant studies likely to change the conclusions. Therefore, this review has now been stabilised following discussion with the authors and editors. The review will be re‐assessed for updating in three years. If appropriate, we will update the review before this date if new evidence likely to change the conclusions is published, or if standards change substantially which necessitate major revisions.
Keywords
MeSH
Medical Subject Headings (MeSH) Keywords
- Adrenergic Uptake Inhibitors [*therapeutic use];
- Carnitine [therapeutic use];
- Cyclopropanes [*therapeutic use];
- Desvenlafaxine Succinate [*therapeutic use];
- Duloxetine Hydrochloride [*therapeutic use];
- Fibromyalgia [*drug therapy];
- Milnacipran;
- Norepinephrine [*metabolism];
- Pregabalin [therapeutic use];
- Quality of Life;
- Selective Serotonin Reuptake Inhibitors [*therapeutic use];
- Syndrome;
Medical Subject Headings Check Words
Adult; Humans;
PICO
Study flow diagram
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 1: Self‐reported pain relief of 50% or greater
Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 2: PGIC much or very much improved
Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 3: Withdrawal due to adverse events
Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 4: Serious adverse events
Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 5: Self‐reported fatigue
Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 6: Self‐reported sleep problems
Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 7: Self‐reported health‐related quality of life
Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 8: Self‐reported pain relief of 30% or greater
Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 9: Self‐reported mean pain intensity
Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 10: Self‐reported depression
Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 11: Self‐reported anxiety
Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 12: Self‐reported disability
Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 13: Self‐reported cognitive disturbances
Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 14: Tenderness
Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 15: Withdrawal due to lack of efficacy
Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 16: Nausea
Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 17: Somnolence
Comparison 1: SNRIs versus placebo in parallel and cross‐over design trials, Outcome 18: Insomnia
| Serotonin noradrenaline reuptake inhibitors compared with placebo for fibromyalgia ‐ studies with parallel design | ||||||
| Patient or population: people with fibromyalgia Settings: study centers in North, Central and South America, Asia and Europe Intervention: serotonin noradrenaline reuptake inhibitors (duloxetine, milnacipran) Comparison: placebo | ||||||
| Outcomes | Probable outcome with intervention (95% CI) | Probable outcome with placebo | Relative effect SMD or risk difference | No of participants | Quality of the evidence | Comments |
|---|---|---|---|---|---|---|
| Self‐reported pain relief of 50% or greater | 309 per 1000 (282 to 344) | 210 per 1000 | RD 0.09 (0.07 to 0.11) | 6918 (15 studies) | ⊕⊕⊝⊝ | NNTB 11 (95% CI 9 to 14) |
| Patient Global Impression to be much or very much improved (PGIC) | 519 per 1000 (459 to 573) | 293 per 1000 | RD 0.19 (0.12 to 0.26) | 2918 (6 studies) | ⊕⊕⊝⊝ | NNTB 5 (95% CI 4 to 8) |
| Self‐reported fatigue (20‐100 scale) Higher scores indicate higher fatigue problem levels | Mean fatigue | Baseline mean score 69.4 (SD 12.3)3 | SMD ‐0.13 (‐0.18 to ‐0.08) | 6168 (12 studies) | ⊕⊕⊝⊝ | NNTB 18 (95% CI 12 to 29) |
| Self‐reported sleep problems (0‐100 scale) Higher scores indicate higher sleep problem levels | Mean sleep problems | Baseline mean score 68.0 (23.8)4 | SMD ‐0.07 (‐0.15 to 0.01) | 4547 (8 studies) | ⊕⊕⊝⊝ | NNTB not calculated due to lack of statistically significant difference |
| Self‐reported health‐related quality of life (0‐100 scale) Higher scores indicate higher burden of disease (lower quality of life) | Mean health‐related quality of life problems score was 3.9 points lower (2.3 to | Baseline mean score 57.9 (SD | SMD ‐0.20 (‐0.25 to ‐0.15) | 6861 (14 studies) | ⊕⊕⊝⊝ | NNTB 11 (95% CI 8 to 14) |
| Tolerability (withdrawal due to adverse events) | 191 per 1000 (172 to 210) | 102 per 1000 | RD 0.07 (0.04 to 0.10) | 7029 (15 studies) | ⊕⊕⊝⊝ | NNTH 14 (95% CI 10 to 25) |
| Safety (serious adverse events) | 18 per 1000 (16 to 20) | 21 per 1000 | RD ‐0.00 (‐0.01 to 0.00) | 6732 (13 studies) | ⊕⊝⊝⊝ | NNTH not calculated due to lack of statistically significant difference |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; FIQ: Fibromyalgia Impact Questionnaire; MFI: Multidimensional Fatigue Inventory; MOS‐Sleep problem index: Medical Outcome Study ‐ sleep problem index; NNTB: number needed to treat for an additional beneficial outcome; NNTH: number needed to treat for an additional harm; NRS: numerical rating scale; RD: risk difference; SMD: standardized mean difference; VAS: visual analog scale | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded once: indirectness: participants with major medical diseases and mental disorders except major depression excluded in > 50% of studies | ||||||
| Outcome | Number of participants (studies) | Effect size RD (95% CI) | Test for overall effect P value | Heterogeneity I² (%)
| Test of interaction: effect estimate and P value |
| Self‐reported pain relief 50% or greater |
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|
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| Z = 0.78; P = 0.43 |
| Only North American participants | 3935 (8) | 0.10 (0.08 to 0.13) | < 0.001 | 0 | |
| Only European participants | 960 (2) | 0.06 (0.01 to 0.12) | 0.02 | 0 |
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| Withdrawal due to adverse events |
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|
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| Z = 1.14; P = 0.25 |
| Only North American participants | 3935 (8) | 0.08 (0.04 to 0.13) | < 0.0002 | 71 | |
| Only European participants | 960 (2) | 0.12 (0.08 to 0.17) | < 0.0001 | 0 |
|
| CI: confidence interval; RD: risk difference; SNRIs: serotonin and noradrenaline reuptake inhibitors | |||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Self‐reported pain relief of 50% or greater Show forest plot | 15 | 6918 | Risk Difference (IV, Random, 95% CI) | 0.09 [0.07, 0.11] |
| 1.1.1 Duloxetine | 7 | 2582 | Risk Difference (IV, Random, 95% CI) | 0.10 [0.06, 0.14] |
| 1.1.2 Milnacipran | 8 | 4336 | Risk Difference (IV, Random, 95% CI) | 0.09 [0.06, 0.11] |
| 1.2 PGIC much or very much improved Show forest plot | 6 | 2918 | Risk Difference (M‐H, Random, 95% CI) | 0.19 [0.12, 0.26] |
| 1.2.1 Duloxetine | 1 | 530 | Risk Difference (M‐H, Random, 95% CI) | 0.35 [0.27, 0.42] |
| 1.2.2 Milnacipran | 5 | 2388 | Risk Difference (M‐H, Random, 95% CI) | 0.15 [0.11, 0.19] |
| 1.3 Withdrawal due to adverse events Show forest plot | 15 | 7029 | Risk Difference (IV, Random, 95% CI) | 0.07 [0.04, 0.10] |
| 1.3.1 Desvenlafaxine | 1 | 82 | Risk Difference (IV, Random, 95% CI) | ‐0.03 [‐0.09, 0.04] |
| 1.3.2 Duloxetine | 7 | 2642 | Risk Difference (IV, Random, 95% CI) | 0.05 [0.02, 0.07] |
| 1.3.3 Milnacipran | 7 | 4305 | Risk Difference (IV, Random, 95% CI) | 0.11 [0.07, 0.14] |
| 1.4 Serious adverse events Show forest plot | 13 | 6732 | Risk Difference (IV, Random, 95% CI) | ‐0.00 [‐0.01, 0.00] |
| 1.4.1 Desvenlafaxine | 1 | 82 | Risk Difference (IV, Random, 95% CI) | 0.00 [‐0.05, 0.05] |
| 1.4.2 Duloxetine | 6 | 2432 | Risk Difference (IV, Random, 95% CI) | ‐0.00 [‐0.01, 0.01] |
| 1.4.3 Milnacipran | 6 | 4218 | Risk Difference (IV, Random, 95% CI) | ‐0.00 [‐0.01, 0.01] |
| 1.5 Self‐reported fatigue Show forest plot | 12 | 6168 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.13 [‐0.18, ‐0.08] |
| 1.5.1 Duloxetine | 5 | 1954 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.12 [‐0.21, ‐0.03] |
| 1.5.2 Milnacpran | 7 | 4214 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.14 [‐0.21, ‐0.07] |
| 1.6 Self‐reported sleep problems Show forest plot | 8 | 4547 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.07 [‐0.15, 0.01] |
| 1.6.1 Duloxetine | 3 | 1382 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.20 [‐0.31, ‐0.10] |
| 1.6.2 Milnacipran | 5 | 3165 | Std. Mean Difference (IV, Random, 95% CI) | 0.02 [‐0.05, 0.10] |
| 1.7 Self‐reported health‐related quality of life Show forest plot | 14 | 6861 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.20 [‐0.25, ‐0.15] |
| 1.7.1 Duloxetine | 7 | 2604 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.22 [‐0.30, ‐0.13] |
| 1.7.2 Milnacipran | 7 | 4257 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.19 [‐0.25, ‐0.12] |
| 1.8 Self‐reported pain relief of 30% or greater Show forest plot | 15 | 6924 | Risk Difference (IV, Random, 95% CI) | 0.10 [0.08, 0.12] |
| 1.8.1 Duloxetine | 7 | 2588 | Risk Difference (IV, Random, 95% CI) | 0.11 [0.07, 0.15] |
| 1.8.2 Milnacipran | 8 | 4336 | Risk Difference (IV, Random, 95% CI) | 0.10 [0.07, 0.13] |
| 1.9 Self‐reported mean pain intensity Show forest plot | 16 | 7014 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.22 [‐0.27, ‐0.17] |
| 1.9.1 Desvenlafaxine | 1 | 82 | Std. Mean Difference (IV, Random, 95% CI) | 0.16 [‐0.27, 0.59] |
| 1.9.2 Duloxetine | 7 | 2619 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.26 [‐0.35, ‐0.18] |
| 1.9.3 Milncipran | 8 | 4313 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.20 [‐0.26, ‐0.13] |
| 1.10 Self‐reported depression Show forest plot | 14 | 6478 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.16 [‐0.21, ‐0.11] |
| 1.10.1 Duloxetine | 7 | 2264 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.25 [‐0.34, ‐0.17] |
| 1.10.2 Milnacipran | 7 | 4214 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.11 [‐0.17, ‐0.05] |
| 1.11 Self‐reported anxiety Show forest plot | 9 | 3533 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.08 [‐0.21, 0.05] |
| 1.11.1 Duloxetine | 4 | 1403 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.07 [‐0.17, 0.04] |
| 1.11.2 Milnacipran | 5 | 2130 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.11 [‐0.36, 0.13] |
| 1.12 Self‐reported disability Show forest plot | 13 | 6789 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.21 [‐0.26, ‐0.16] |
| 1.12.1 Duloxetine | 7 | 2602 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.29 [‐0.37, ‐0.21] |
| 1.12.2 Milnacipran | 6 | 4187 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.16 [‐0.22, ‐0.10] |
| 1.13 Self‐reported cognitive disturbances Show forest plot | 8 | 5444 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.16 [‐0.21, ‐0.10] |
| 1.13.1 Duloxetine | 3 | 1360 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.27 [‐0.38, ‐0.16] |
| 1.13.2 Milnacipran | 5 | 4084 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.12 [‐0.18, ‐0.05] |
| 1.14 Tenderness Show forest plot | 5 | 1444 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.21 [‐0.33, ‐0.09] |
| 1.14.1 Duloxetine | 4 | 1364 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.23 [‐0.35, ‐0.12] |
| 1.14.2 Milnacipran | 1 | 80 | Std. Mean Difference (IV, Random, 95% CI) | 0.12 [‐0.31, 0.56] |
| 1.15 Withdrawal due to lack of efficacy Show forest plot | 14 | 6924 | Risk Difference (IV, Random, 95% CI) | ‐0.03 [‐0.04, ‐0.02] |
| 1.15.1 Desvenlafaxine | 1 | 82 | Risk Difference (IV, Random, 95% CI) | 0.07 [‐0.02, 0.16] |
| 1.15.2 Duloxetine | 7 | 2642 | Risk Difference (IV, Random, 95% CI) | ‐0.04 [‐0.06, ‐0.02] |
| 1.15.3 Milnacipran | 6 | 4200 | Risk Difference (IV, Random, 95% CI) | ‐0.02 [‐0.04, ‐0.01] |
| 1.16 Nausea Show forest plot | 12 | 6606 | Risk Difference (IV, Random, 95% CI) | 0.16 [0.14, 0.19] |
| 1.16.1 Desvenlafaxine | 1 | 82 | Risk Difference (IV, Random, 95% CI) | 0.04 [‐0.10, 0.18] |
| 1.16.2 Duloxetine | 6 | 2432 | Risk Difference (IV, Random, 95% CI) | 0.19 [0.15, 0.22] |
| 1.16.3 Milnacipran | 5 | 4092 | Risk Difference (IV, Random, 95% CI) | 0.15 [0.12, 0.18] |
| 1.17 Somnolence Show forest plot | 7 | 2514 | Risk Difference (IV, Random, 95% CI) | 0.05 [0.02, 0.08] |
| 1.17.1 Desvenlafaxine | 1 | 82 | Risk Difference (IV, Random, 95% CI) | ‐0.05 [‐0.17, 0.06] |
| 1.17.2 Duloxetine | 6 | 2432 | Risk Difference (IV, Random, 95% CI) | 0.06 [0.03, 0.09] |
| 1.18 Insomnia Show forest plot | 9 | 5387 | Risk Difference (M‐H, Random, 95% CI) | 0.03 [0.01, 0.04] |
| 1.18.1 Desvenlafaxine | 1 | 82 | Risk Difference (M‐H, Random, 95% CI) | ‐0.08 [‐0.18, 0.03] |
| 1.18.2 Duloxetine | 4 | 1684 | Risk Difference (M‐H, Random, 95% CI) | 0.04 [0.01, 0.07] |
| 1.18.3 Milnacipran | 4 | 3621 | Risk Difference (M‐H, Random, 95% CI) | 0.03 [0.01, 0.04] |
