Tramadol for neuropathic pain in adults

Rudolf Martin Duehmke; Sheena Derry; Philip J Wiffen; Rae F Bell; Dominic Aldington; R Andrew Moore

doi:10.1002/14651858.CD003726.pub4

Tramadol untuk sakit neuropatik dalam kalangan orang dewasa

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Referencias

References to studies included in this review

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Treede RD, Jensen TS, Campbell JN, Cruccu G, Dostrovsky JO, Griffin JW, et al. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology 2008;70(18):1630‐5. [DOI: 10.1212/01.wnl.0000282763.29778.59]

Turner RM, Bird SM, Higgins JP. The impact of study size on meta‐analyses: examination of underpowered studies in Cochrane reviews. PLoS One 2013;8(3):e59202. [DOI: 10.1371/journal.pone.0059202]

van Hecke O, Austin SK, Khan RA, Smith BH, Torrance N. Neuropathic pain in the general population: a systematic review of epidemiological studies. Pain 2014;155(4):654‐62. [DOI: 10.1016/j.pain.2013.11.013]

van Hoek AJ, Gay N, Melegaro A, Opstelten W, Edmunds WJ. Estimating the cost‐effectiveness of vaccination against herpes zoster in England and Wales. Vaccine 2009;27(9):1454‐67. [DOI: 10.1016/j.vaccine.2008.12.024]

von Hehn CA, Baron R, Woolf CJ. Deconstructing the neuropathic pain phenotype to reveal neural mechanisms. Neuron 2012;73(4):638‐52. [DOI: 10.1016/j.neuron.2012.02.008]

Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990‐2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380(9859):2163‐96. [DOI: 10.1016/S0140‐6736(12)61729‐2]

World Health Organization (WHO). WHO analgesic ladder. www.who.int/cancer/palliative/painladder/en/ (accessed 9 January 2017).

Wiffen PJ, Derry S, Moore RA, Aldington D, Cole P, Rice ASC, et al. Antiepileptic drugs for neuropathic pain and fibromyalgia ‐ an overview of Cochrane reviews. Cochrane Database of Systematic Reviews 2013, Issue 11. [DOI: 10.1002/14651858.CD010567.pub2]

References to other published versions of this review

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otras referencias

Dühmke R, Hollingshead J, Cornblath D. Tramadol for neuropathic pain. Cochrane Database of Systematic Reviews 2002, Issue 2. [DOI: 10.1002/14651858.CD003726]

Dühmke RM, Cornblath DD, Hollingshead JRF. Tramadol for neuropathic pain. Cochrane Database of Systematic Reviews 2004, Issue 2. [DOI: 10.1002/14651858.CD003726.pub2]

Hollingshead J, Dühmke RM, Cornblath DR. Tramadol for neuropathic pain. Cochrane Database of Systematic Reviews 2006, Issue 3. [DOI: 10.1002/14651858.CD003726.pub3]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

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Arbaiza 2007

Methods	Randomised ("matched pair"), double‐blind, parallel‐group, placebo‐controlled Duration: 45 days Assessed at baseline, 15, 30, 45 days
Participants	Cancer‐related or cancer treatment‐related neuropathic pain of ≥ moderate intensity for ≥ 3 months, aged 18‐60 years Exclusion: pain mainly somatic, visceral or sympathetically maintained; scheduled for surgery, radiotherapy, chemotherapy, hormone therapy; use of tricyclic antidepressants, tramadol or any opioid; respiratory failure, chronic obstructive pulmonary disease, intracranial hypertension; Hx psychiatric illness or dependency on alcohol or drugs N = 36 M 14, F 22 Mean age 50 years Mean baseline PI: 7/10
Interventions	Tramadol 1 mg/kg bodyweight every 6 h; increased to 1.5 mg/kg every 6 h if relief inadequate, n = 18 Placebo, n = 18 Participants could continue with previous antiepileptic analgesic therapy ‐ and could reduce dose during study Rescue medication: paracetamol 500 mg/d
Outcomes	PI: 0‐10 NRS Reduction in use of antiepileptics: 0 = no need for antiepileptics, 5 = 100% analgesic use at first assessment Adverse events
Notes	Peru. Sponsor: Grunenthal Laboratories, Peru
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants with similar pain syndromes were paired, then "randomly assigned using a computer program"
Allocation concealment (selection bias)	Unclear risk	Method not described, but effectively, the first of pair was randomised, leaving a possibility of unconcealed allocation
Blinding (performance bias and detection bias) All outcomes	Low risk	Treatments supplied in identical 10 ml bottles, "distinguished only by labels"
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Imputation not mentioned, approximately 30% withdrawals, with different reasons between groups
Size	High risk	< 50 participants per treatment arm (18)

Boureau 2003

Methods	Multicentre, randomised, double‐blind, parallel‐group, placebo‐controlled Duration 6 weeks Assessments at 1, 8, 15, 22, 43 days
Participants	Postherpetic neuralgia ≥ 3 months and ≤ 1 year, PI ≥ 40/100, aged 18‐85 years Exclusion: seizures; cerebral tumour or recent cranial trauma; severe hepatic, renal, cardiac, respiratory pathology; contraindication to tramadol or opioids; Hx depression, drug abuse N = 127 (125 in ITT population, 108 in PP) M 35, F 92 Mean age ˜67 years (35‐85) Mean baseline PI: 60/100
Interventions	Tramadol SR 100 mg taken in evening, n = 64 Placebo, n = 63 Dose could be increased to maximum 400 mg (≤ 75 years) or 300 mg (75+ years) taken as divided dose in morning and evening Rescue medication: paracetamol to maximum 3 g/d No MAO within 15 days, or antidepressants, anticonvulsants, opioid analgesics or local/general anaesthetics within 7 days
Outcomes	PI in last 24 h (daily): 100 mm VAS, 5‐point VRS PGE: % reduction from baseline Use of rescue medication Adverse events
Notes	France. Sponsor: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated 4‐block centralised randomisation list
Allocation concealment (selection bias)	Unclear risk	Method not described
Blinding (performance bias and detection bias) All outcomes	Low risk	"treatments were identical with regard to appearance"
Incomplete outcome data (attrition bias) All outcomes	High risk	Missing data on VAS and VRS over the 6th week were replaced by data available from the last 7 observations before the final visit (or the visit before premature discontinuation), not including more than 13 days before the end visit. Essentially an LOCF analysis
Size	Unclear risk	50‐199 participants per treatment arm (63, 64)

Harati 1998

Methods	Multicenter, randomised, double‐blind, placebo‐controlled, parallel‐group Duration: 6 weeks Assessed at 1, 14, 28, 42 days
Participants	Peripheral diabetic neuropathy (HbA1 < 14%), distal, symmetric, > 3 months, PI moderate without analgesics, aged 18 years and over Exclusion: contraindication or previous use of tramadol; cause other than diabetes; other pain > neuropathic pain; clinically significant medical conditions; use of multiple daily doses of opioids or regular mexiletine; amputations; open ulcers; Hx drug or alcohol abuse N = 131 (127 for efficacy) M 78, F 53 Mean age 57 years (32‐85) Baseline pain 2.5 (scale 0‐4)
Interventions	Tramadol starting at 50 mg/d, increasing to 200 mg/d on day 10, then increased again as required from day 14 to maximum 400 mg/d by day 28, then stable; minimum 100 mg/d from day 14 to end of study, n = 65 Placebo, n = 66 Divided doses, given 4 x daily Mean dose tramadol at end of study 210 ± 113 mg/day Tricyclics and antiepileptics discontinued ≥ 21 days; shorter acting analgesics discontinued ≥ 7 days before start Rescue medication: "No pain medications other than the study medications were permitted"
Outcomes	PI at end of study (5‐point scale, 0‐4) PR (6‐point scale, ‐1 to 4) Adverse events
Notes	USA. Sponsor: Ortho‐McNeil Pharmaceutical, Raritan, NJ (research grant)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer random‐number generator
Allocation concealment (selection bias)	Low risk	Double‐blind code numbers assigned sequentially
Blinding (performance bias and detection bias) All outcomes	Low risk	Identically appearing capsules, indistinguishable
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Imputation not mentioned, approximately 30% withdrawals, with different reasons between groups
Size	Unclear risk	50‐199 participants per treatment arm (65, 66)

Norrbrink 2009

Methods	Randomised, double‐blind, placebo‐controlled, parallel‐group Duration: 4 weeks Assessed at baseline and week 4 (daily pain diary)
Participants	Spinal cord injury ≥ 12 months, "at or below level of lesion neuropathic pain" ≥ 6 months, PI > 3 (Borg's Category Ratio), aged 18‐70 years Exclusion: cognitive impairment; previous treatment with tramadol; intolerance to opioids in past Current use of opioids or antidepressants considered on individual basis N = 35 M 28, F 7 Mean age 51 years (SD 11) Mean 15 years post injury Some differences in baseline characteristics ‐ level of injury, baseline PI Worst PI at baseline: 7‐9/10, but general PI 4‐7/10
Interventions	Tramadol 50 mg x 3 daily, n = 23 Placebo, n = 12 Dose increased every 5 days by 50 mg (1 tablet) to maximum of 400 mg/d (or 8 placebo tablets) until optimal pain relief or intolerable adverse events Stable pain medication allowed without change to dosage (20/35 took concomitant pain medication)
Outcomes	Daily PI: complete relief = 10 PGIC Adverse events
Notes	Sweden. Sponsor: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method not described
Allocation concealment (selection bias)	Low risk	"sealed coded envelopes" provided by third party
Blinding (performance bias and detection bias) All outcomes	Low risk	"identical in appearance"
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	ITT analysis with LOCF
Size	High risk	< 50 participants per treatment arm (12, 23)

Sindrup 1999

Methods	Randomised, double‐blind, placebo‐controlled, cross‐over Duration: 2 x 4 weeks with washout of ≥ 1 week between periods Assessed at end of treatment periods
Participants	Polyneuropathy > 6 months, PI without treatment ≥ 4/10, aged 20‐80 years Exclusion: pain from other causes; previous allergy to tramadol; intolerance to tramadol or other opioids; use of MAO inhibitors; epilepsy; severe terminal illness N = 45 (34 provided data for both periods) M 27, F 18 Median age 58 years (range 26‐77) Median baseline PI: 6/10
Interventions	Tramadol SR, titrated to 100‐200 mg twice daily over at least 1 week Placebo (22 participants took tramadol first, 23 placebo first) Rescue medication: up to 6 x paracetamol 500 mg/d Existing pain medication slowly discontinued over a maximum of 1 week
Outcomes	Daily PI: NRS 0‐10 (also paraesthesia and touch‐evoked pain) used to calculate median for each week Use of rescue medication Adverse events Preference at end of study
Notes	Denmark. Sponsor: Grunenthal GmbH
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"computer generated randomisation code with a block size of six"
Allocation concealment (selection bias)	Low risk	"sealed envelopes", participants numbered consecutively and treated with drugs with corresponding randomisation number
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Method not described
Incomplete outcome data (attrition bias) All outcomes	High risk	LOCF imputation, efficacy data only for participants providing data for both phases; reasons for withdrawals per treatment arm not fully reported
Size	High risk	< 50 participants per treatment arm (≤ 43, 40)

Sindrup 2012

Methods	Multicentre, randomised, double‐blind, active‐ and placebo‐controlled, cross‐over Duration: 3 x 4 weeks with washout of 1‐2 weeks between periods Assessed weekly and at end of each treatment period
Participants	Polyneuropathy (distal, symmetric) > 6 months, PI ≥ 4/10, aged 18‐74 years Exclusion: pain from other causes; psychiatric disease; raised creatinine or liver enzymes; chronic disease affecting drug absorption; HbA1c > 12%; QT interval > 500 ms; contraindication to opioids, tramadol, paracetamol; Hx drug or alcohol abuse; use of other analgesics or MAO inhibitors or non‐pharmacological pain therapy N = 64 (48 completed) M 44, F 20 Mean age 58 years (38‐75) Baseline PI: 6/10
Interventions	Tramadol SR 100 mg/d, increasing to 200‐400 mg/d GRT9906 (experimental drug) 60 mg/d, increasing to 120‐240 mg/d Placebo Dose increased over 1 week, then kept constant for remaining 3 weeks Most participants took maximum dose Rescue medication: paracetamol up to 6 x 500 mg/d
Outcomes	Daily PI: (NRS 0‐10), then averaged over last 3 days of each period, and for each week ≥ 50% and ≥ 30% reduction in pain at end of each period PGIC (7‐point scale; 1 = very much better) Use of rescue medication Adverse events
Notes	Denmark, Germany. Sponsor: Grunenthal GmbH
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"the randomization list was generated via computer"
Allocation concealment (selection bias)	Low risk	Each site given "a unique series of numbers which were assigned to each trial patient in ascending order and marked at the corresponding drug packages"
Blinding (performance bias and detection bias) All outcomes	Low risk	The three treatments "had identical appearance and weight and were dosed similarly"
Incomplete outcome data (attrition bias) All outcomes	High risk	Completer analysis used for PP analysis of dichotomous efficacy data.
Size	High risk	< 50 participants per treatment arm for efficacy data (maximum 56 for safety data)

F: female; HbA1c: glycosylated haemoglobin; Hx: history of; LOCF: last observation carried forward; M: male; MAO: monoamine oxidase; N: number of participants in study; n: number of participants in treatment arm; NRS: numerical rating scale; PGIC: Patient Global Impression of Change; PI: pain intensity; PP: per protocol; PR: pain relief; SD: standard deviation; SR: sustained‐release; VAS: visual analogue scale; VRS: verbal rating scale.

Characteristics of excluded studies [ordered by study ID]

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Study	Reason for exclusion
Ashry 2001	Commentary on Harati 1998
Attal 2001	Review article
Benedetti 1998	Investigates buprenorphine, not tramadol
Erdine 1997	Short conference abstract with inadequate method description and no usable data
Gobel 1995	Open‐label study
Harati 1999	Correspondence with no new trial data
Harati 2000	Follow up to Harati 1998. Not randomised or controlled
Herrera Silva 2001	Review article
Leppert 2001	Open‐label study
Moulin 1999	Correspondence with no new trial data
NCT00610155	7‐day treatment periods, < 10 participants per treatment arm
Saxena 2013	Open‐label cohort study
Xiao 2004	Observational study. Not a randomised controlled trial

Characteristics of studies awaiting assessment [ordered by study ID]

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Ho 2009

Methods	Enriched enrolment, randomised withdrawal design. Single‐blind run‐in phases in which participants were treated with gabapentin then active placebo. Responders were randomised to a double‐blind, 3‐period cross‐over of gabapentin, tramadol, and active placebo Participants with PI ≤ 7.5/10 at end of Period A could proceed to Period B Participants whose average pain scores at end of Period B were ≥ 3 and increased by ≥ 30% from Period A could proceed to randomisation and a double‐blind cross‐over phase Duration: Period A: 1 week; Period B: 2 weeks; double‐blind: 3 x 2‐week periods (1‐week titration, 1‐week stable), each followed by 1‐week washout
Participants	Idiopathic small fibre neuropathy ≥ 2 months, self‐reported gabapentin responders (on stable dose 900 ‐ 4800 mg/d), PI > 3 to ≤ 7.5 on medication, aged ≥ 18 years Exclusion: allergies to any study drug; Hx fibromyalgia, epilepsy; cancer within 5 years; pernicious anaemia; HIV infection; multi‐organ autoimmune disease; peripheral vascular disease; renal or hepatic disease; use of insulin or antiglycaemic drugs N = 59 entered run‐in A, 48 entered run‐in B M 21, F 20 Mean age 60 years N = 18 randomised M 10, F 8 Mean age 59 years Baseline PI: 4.9/10 Baseline PGIC 5.5 (after B)
Interventions	Period A: gabapentin at pre‐study dose + matching active placebo (diphenhydramine). Pain scores ≤ 7.5/10 entered period B Period B: gabapentin at pre‐study dose + matching active placebo (diphenhydramine) with tapering off gabapentin. Pain scores ≥ 3/10 and increasing by ≥ 30% entered treatment period Treatment period (2‐week test and 1‐week washout in multiple cross‐overs): Tramadol 50 mg x 4 daily Gabapentin pre‐study dose Placebo (diphenhydramine 50 mg at bedtime) Rescue medication: 325 mg tablets (probably paracetamol) ‐ limit not specified If still inadequate, additional 400 mg gabapentin every 8 h, up to 1200 every 24 h
Outcomes	Daily PI: (NRS 0‐10), averaged over 24 h. If rescue medication or additional gabapentin taken, used score before first rescue dose of the day PGIC (7‐point scale; 1 = very much better) Adverse events
Notes	USA. Sponsor: Merck Research Laboratories

F: female; Hx: history of; M: male; N: number of participants in study; NRS: numerical rating scale; PGIC: Patient Global Impression of Change; PI: pain intensity.

Data and analyses

Open in table viewer

Comparison 1. Tramadol versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Participants with ≥ 50% pain intensity reduction Show forest plot	3	265	Risk Ratio (M‐H, Random, 95% CI)	2.16 [1.02, 4.58]
Open in figure viewer Analysis 1.1 Comparison 1 Tramadol versus placebo, Outcome 1 Participants with ≥ 50% pain intensity reduction.
2 Withdrawal due to adverse events Show forest plot	6	485	Risk Ratio (M‐H, Fixed, 95% CI)	4.08 [1.99, 8.37]
Open in figure viewer Analysis 1.2 Comparison 1 Tramadol versus placebo, Outcome 2 Withdrawal due to adverse events.
3 All cause withdrawal Show forest plot	3	202	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.75, 1.76]
Open in figure viewer Analysis 1.3 Comparison 1 Tramadol versus placebo, Outcome 3 All cause withdrawal.
4 Participants with any adverse event Show forest plot	4	266	Risk Ratio (M‐H, Fixed, 95% CI)	1.61 [1.22, 2.13]
Open in figure viewer Analysis 1.4 Comparison 1 Tramadol versus placebo, Outcome 4 Participants with any adverse event.
5 Participants with specific adverse events Show forest plot	6		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.5 Comparison 1 Tramadol versus placebo, Outcome 5 Participants with specific adverse events.
5.1 Nausea	6	508	Risk Ratio (M‐H, Fixed, 95% CI)	3.62 [2.23, 5.88]
5.2 Constipation	5	381	Risk Ratio (M‐H, Fixed, 95% CI)	4.11 [2.36, 7.16]
5.3 Tiredness/fatigue/somnolence	4	345	Risk Ratio (M‐H, Fixed, 95% CI)	3.22 [1.93, 5.36]
5.4 Dizziness	3	214	Risk Ratio (M‐H, Fixed, 95% CI)	3.72 [1.94, 7.12]
5.5 Dry mouth	3	214	Risk Ratio (M‐H, Fixed, 95% CI)	2.44 [1.35, 4.42]

Figure 1

Study flow diagram for the updated search

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 3

Forest plot of comparison: 1 Tramadol versus placebo, outcome: 1.1 Participants with ≥ 50% pain intensity reduction.

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Analysis 1.1

Comparison 1 Tramadol versus placebo, Outcome 1 Participants with ≥ 50% pain intensity reduction.

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Analysis 1.2

Comparison 1 Tramadol versus placebo, Outcome 2 Withdrawal due to adverse events.

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Analysis 1.3

Comparison 1 Tramadol versus placebo, Outcome 3 All cause withdrawal.

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Analysis 1.4

Comparison 1 Tramadol versus placebo, Outcome 4 Participants with any adverse event.

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Analysis 1.5

Comparison 1 Tramadol versus placebo, Outcome 5 Participants with specific adverse events.

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Summary of findings for the main comparison. Tramadol compared with placebo for neuropathic pain

Tramadol compared with placebo for neuropathic pain
Patient or population: adults with neuropathic pain (any origin) Settings: community Intervention: oral tramadol (typically started at a dose of about 100 mg daily and increased over 1 to 2 weeks to a maximum of 400 mg daily) Comparison: placebo
Outcomes (at trial end)	Probable outcome with tramadol	Probable outcome with placebo	Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
At least 30% reduction in pain	Not analysed	Not analysed	Not analysed	157 participants (2 studies) 60 events	Low quality¹	‐
At least 50% reduction in pain	530 per 1000	300 per 1000	RR 2.2 (1.02, 4.6) NNT 4.4 (2.9 to 8.8)	265 participants (3 studies) 110 events	Low quality¹	‐
PGIC much or very much improved	Not analysed	Not analysed	Not analysed	35 participants (1 study) 4 events	Very low quality²	‐
Withdrawal due to adverse event	160 per 100	30 per 1000	RR 4.1 (2.0 to 8.4) NNH 8.2 (5.8 to 14)	485 participants (6 studies) 45 events	Low quality¹	‐
Participants experiencing any adverse event	580 per 1000	340 per 1000	RR 1.6 (1.2 to 2.1) NNH 4.2 (2.8 to 8.3)	266 participants (4 studies) 123 events	Low quality¹	‐
Serious adverse events	4 serious adverse events reported in total			Not all studies reported specifically on serious adverse events	Very low quality²	‐
Death	No data	No data	Not calculated	No data	Very low quality³	‐
CI: confidence interval; NNH: number needed to treat for one additional harmful outcome; PGIC: Patient Global Impression of Change; RR: risk ratio
Descriptors for levels of evidence (EPOC 2015): High quality: this research provides a very good indication of the likely effect. The likelihood that the effect will be substantially different^† is low. Moderate quality: this research provides a good indication of the likely effect. The likelihood that the effect will be substantially different^† is moderate. Low quality: this research provides some indication of the likely effect. However, the likelihood that it will be substantially different^† is high. Very low quality: this research does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different^† is very high. ^† Substantially different: a large enough difference that it might affect a decision.
¹Downgraded 2 levels due to small number of studies and participants and relatively few events, and several sources of potential bias. ²Downgraded 3 levels due to small number of studies, and participants and events, and several sources of potential bias. ³No events.

Summary of findings for the main comparison. Tramadol compared with placebo for neuropathic pain

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Comparison 1. Tramadol versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Participants with ≥ 50% pain intensity reduction Show forest plot	3	265	Risk Ratio (M‐H, Random, 95% CI)	2.16 [1.02, 4.58]

2 Withdrawal due to adverse events Show forest plot	6	485	Risk Ratio (M‐H, Fixed, 95% CI)	4.08 [1.99, 8.37]

3 All cause withdrawal Show forest plot	3	202	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.75, 1.76]

4 Participants with any adverse event Show forest plot	4	266	Risk Ratio (M‐H, Fixed, 95% CI)	1.61 [1.22, 2.13]

5 Participants with specific adverse events Show forest plot	6		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1 Nausea	6	508	Risk Ratio (M‐H, Fixed, 95% CI)	3.62 [2.23, 5.88]
5.2 Constipation	5	381	Risk Ratio (M‐H, Fixed, 95% CI)	4.11 [2.36, 7.16]
5.3 Tiredness/fatigue/somnolence	4	345	Risk Ratio (M‐H, Fixed, 95% CI)	3.22 [1.93, 5.36]
5.4 Dizziness	3	214	Risk Ratio (M‐H, Fixed, 95% CI)	3.72 [1.94, 7.12]
5.5 Dry mouth	3	214	Risk Ratio (M‐H, Fixed, 95% CI)	2.44 [1.35, 4.42]

Comparison 1. Tramadol versus placebo

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Referencias

References to studies included in this review

Arbaiza 2007 {published data only}

Boureau 2003 {published data only}

Harati 1998 {published data only}

Norrbrink 2009 {published data only}

Sindrup 1999 {published data only}

Sindrup 2012 {published data only}

References to studies excluded from this review

Ashry 2001 {published data only}

Attal 2001 {published data only}

Benedetti 1998 {published data only}

Erdine 1997 {published data only}

Gobel 1995 {published data only}

Harati 1999 {published data only}

Harati 2000 {published data only}

Herrera Silva 2001 {published data only}

Leppert 2001 {published data only}

Moulin 1999 {published data only}

NCT00610155 {published data only}

Saxena 2013 {published data only}

Xiao 2004 {published data only}

References to studies awaiting assessment

Ho 2009 {published data only}

Additional references

AlBalawi 2013

Baron 2012

Beakley 2015

Berger 2004

Berger 2009

Berger 2012

Bouhassira 2008

Bozkurt 2005

Brok 2009

Bush 2015

CADTH 2015

Calvo 2012

Cepeda 2006

Chaparro 2012

Dechartres 2013

Dechartres 2014

Demant 2014

Derry 2012

Derry 2013

Derry 2014

Dworkin 2008

Dworkin 2013

Edwards 2002

EPOC 2015

Finnerup 2013

Finnerup 2015

Gan 2007

Gaskell 2016

Grond 2004

Gustorff 2008

Guyatt 2013a

Guyatt 2013b

Hall 2008

Helfert 2015

Higgins 2003

Higgins 2011

Hoffman 2010

Jadad 1996

Jensen 2011

Kalso 2013

Katusic 1991

Koopman 2009

L'Abbé 1987

Lintz 1998

Lunn 2014

Martindale 2016

McQuay 1996

McQuay 1998

McQuay 2007

Moher 2009

Moore 1997

Moore 1998

Moore 2008