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Le tramadol pour les douleurs neuropathiques chez l'adulte

Appendices

Appendix 1. Methodological considerations for chronic pain

There have been several recent changes in how the efficacy of conventional and unconventional treatments is assessed in chronic painful conditions. The outcomes are now better defined, particularly with new criteria for what constitutes moderate or substantial benefit (Dworkin 2008); older trials may only report participants with 'any improvement'. Newer trials tend to be larger, avoiding problems from the random play of chance. Newer trials also tend to be of longer duration, up to 12 weeks, and longer trials provide a more rigorous and valid assessment of efficacy in chronic conditions. New standards have evolved for assessing efficacy in neuropathic pain, and we are now applying stricter criteria for the inclusion of trials and assessment of outcomes, and are more aware of problems that may affect our overall assessment. To summarise some of the recent insights that must be considered in this new review:

  1. Pain results tend to have a U‐shaped distribution rather than a bell‐shaped distribution. This is true in acute pain (Moore 2011a; Moore 2011b), back pain (Moore 2010c), and arthritis (Moore 2010d), as well as in fibromyalgia (Straube 2010); in all cases average results usually describe the experience of almost no‐one in the trial. Data expressed as averages are potentially misleading, unless they can be proven to be suitable.

  2. As a consequence, we have to depend on dichotomous results (the individual either has or does not have the outcome) usually from pain changes or patient global assessments. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) group has helped with their definitions of minimal, moderate, and substantial improvement (Dworkin 2008). In arthritis, trials of less than 12 weeks' duration, and especially those shorter than eight weeks, overestimate the effect of treatment (Moore 2010c); the effect is particularly strong for less effective analgesics, and this may also be relevant in neuropathic‐type pain.

  3. The proportion of patients with at least moderate benefit can be small, even with an effective medicine, falling from 60% with an effective medicine in arthritis to 30% in fibromyalgia (Moore 2009; Moore 2010c; Moore 2010d; Moore 2013b; Moore 2014b; Straube 2008; Sultan 2008). A Cochrane Review of pregabalin in neuropathic pain and fibromyalgia demonstrated different response rates for different types of chronic pain (higher in diabetic neuropathy and postherpetic neuralgia and lower in central pain and fibromyalgia) (Moore 2009). This indicates that different neuropathic pain conditions should be treated separately from one another, and that pooling should not be done unless there are good grounds for doing so.

  4. Individual patient analyses indicate that patients who get good pain relief (moderate or better) have major benefits in many other outcomes, affecting quality of life in a significant way (Moore 2010b; Moore 2014a).

  5. Imputation methods such as last observation carried forward (LOCF), used when participants withdraw from clinical trials, can overstate drug efficacy especially when adverse event withdrawals with drug are greater than those with placebo (Moore 2012).

Appendix 2. CENTRAL search strategy (via CRSO)

  1. MESH DESCRIPTOR Tramadol (757)

  2. (tramadol* or tramal* or ultram or zamadol or zydol):TI,AB,KY (2227)

  3. 1 OR 2 (2227)

  4. MESH DESCRIPTOR Neuralgia EXPLODE ALL TREES (718)

  5. MESH DESCRIPTOR Peripheral Nervous System Diseases EXPLODE ALL TREES (2963)

  6. MESH DESCRIPTOR Somatosensory Disorders EXPLODE ALL TREES (796)

  7. ((pain* or discomfort*) adj10 (central or complex or nerv* or neuralg* or neuropath*)):TI,AB,KY (3875)

  8. ((neur* or nerv*) adj6 (compress* or damag*)):TI,AB,KY (721)

  9. 4 OR 5 OR 6 OR 7 OR 8 (7310)

  10. 3 AND 9 (151)

Appendix 3. MEDLINE search strategy (via Ovid)

  1. Tramadol/ (2637)

  2. (tramadol* or tramal* or ultram or zamadol or zydol).mp. (3719)

  3. 1 or 2 (3719)

  4. exp NEURALGIA/ (17673)

  5. exp PERIPHERAL NERVOUS SYSTEM DISEASES/ (137699)

  6. exp SOMATOSENSORY DISORDERS/ (20383)

  7. ((pain* or discomfort*) adj10 (central or complex or nerv* or neuralg* or neuropath*)).mp. (49191)

  8. ((neur* or nerv*) adj6 (compress* or damag*)).mp. (57636)

  9. 4 or 5 or 6 or 7 or 8 (222483)

  10. randomized controlled trial.pt. (469510)

  11. randomized.ab. (359272)

  12. placebo.ab. (177279)

  13. drug therapy.fs. (2035842)

  14. randomly.ab. (250055)

  15. trial.ab. (379955)

  16. groups.ab. (1554754)

  17. 10 or 11 or 12 or 13 or 14 or 15 or 16 (3875115)

  18. 3 and 9 and 17 (388)

Appendix 4. Embase search strategy (via Ovid)

  1. Tramadol/ (16416)

  2. (tramadol* or tramal* or ultram or zamadol or zydol).mp. (16918)

  3. 1 or 2 (16918)

  4. exp neuropathy/ (465954)

  5. exp peripheral neuropathy/ (61799)

  6. postherpetic neuralgia/ or neuralgia/ or trigeminus neuralgia/ (20978)

  7. exp somatosensory disorder/ (82589)

  8. ((pain* or discomfort*) adj10 (central or complex or nerv* or neuralg* or neuropath*)).mp. (93462)

  9. ((neur* or nerv*) adj6 (compress* or damag*)).mp. (80148)

  10. 4 or 5 or 6 or 7 or 8 or 9 (327771)

  11. random*.ti,ab. (1153236)

  12. factorial*.ti,ab. (29202)

  13. (crossover* or cross over* or cross‐over*).ti,ab. (85870)

  14. placebo*.ti,ab. (249172)

  15. (doubl* adj blind*).ti,ab. (175156)

  16. assign*.ti,ab. (302886)

  17. allocat*.ti,ab. (111144)

  18. Randomized Controlled Trial/ (463655)

  19. Double‐blind procedure/ (138148)

  20. Crossover Procedure/ (53925)

  21. 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 (1623468)

  22. 3 and 10 and 21 (737)

Appendix 5. Clinical trials registers search strategy

Conditions: neuropathic pain OR neuralgia OR neuropathy OR phantom OR stump

Intervention: tramadol

Limits: Adult and Senior

ClinicalTrials.gov identified 8 studies.

apps.who.int/trialsearch/ identified 3 studies.

Appendix 6. GRADE: criteria for assigning grade of evidence

The GRADE system uses the following criteria for assigning a quality level to a body of evidence (Chapter 12, Schünemann 2011a).

  • High: randomised trials; or double‐upgraded observational studies

  • Moderate: downgraded randomised trials; or upgraded observational studies

  • Low: double‐downgraded randomised trials; or observational studies

  • Very low: triple‐downgraded randomised trials; or downgraded observational studies; or case series/case reports

Factors that may decrease the quality level of a body of evidence are:

  • limitations in the design and implementation of available studies suggesting high likelihood of bias;

  • indirectness of evidence (indirect population, intervention, control, outcomes);

  • unexplained heterogeneity or inconsistency of results (including problems with subgroup analyses);

  • imprecision of results (wide confidence intervals).

  • high probability of publication bias.

Factors that may increase the quality level of a body of evidence are:

  • large magnitude of effect;

  • all plausible confounding would reduce a demonstrated effect or suggest a spurious effect when results show no effect;

  • dose‐response gradient.

Appendix 7. Summary of outcomes in individual studies: efficacy

Study

Treatment

Pain outcome

Other efficacy outcome

Arbaiza 2007

Peru

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

Mean PI at 45 days:
Tramadol 2.9
Placebo 4.3

% reduction:
Tramadol 57%
Placebo 39%

Use of antiepileptic drugs reduced in tramadol group, but not in placebo group

Significant improvements with tramadol versus placebo for Karnofsky score, ADL, sleep, but not appetite, anxiety, depression

Boureau 2003

France

Tramadol SR 100 mg taken in evening, n = 64
Placebo, n = 63

Dose could be increased to max 400 mg (≤ 75 years) or 300 mg (75+ years) taken as divided dose in morning and evening

≥ 50% PIR (PP population, LOCF)
Tramadol 77.3% = 41/53
Placebo 56.3% = 31/55

Mean PI on day 43 (ITT population, similar for PP population):
Tramadol 25/100
Placebo 34/100

QoL improved for both groups, but no significant difference

Harati 1998

USA

Tramadol 100 mg to 200 mg daily, titrated from 50 mg daily over maximum 28 days, n = 65
Placebo, n = 66

Mean (SD) PR at end of study (scale ‐1 to 4):
Tramadol 2.1 (± 0.2)
Placebo 0.9 (± 0.2)

Mean PI at end of study (scale 0 to 4):
Tramadol 1.4 (± 0.1)
Placebo 2.2 (± 0.1)

Subset of participants with severe/extreme pain after washout:
"Improved" (not defined) at final visit
Tramadol 25/28
Placebo 12/33

Norrbrink 2009

Sweden

Tramadol 150 mg to 400 mg daily, n = 23
Placebo, n = 12

PGIC "much improved or very much improved"
Tramadol 4/23
Placebo 0/12
(No participants had very much improved; 3 tramadol and 1 placebo had minimally improved)

Proportion of participants reporting decreased pain intensity larger with tramadol than placebo

Sindrup 1999

Denmark

Tramadol SR 200 mg to 400 mg daily, titrated over at least one week
Placebo

N = 45 (34 in both periods of cross‐over)

≥ 50% PIR (participants in both periods)
Tramadol 11/34
Placebo 3/33

≥ 30% PIR (participants in both periods)
Tramadol 13/34
Placebo 4/33

PI reduced from ≥ 3/10 to < 3/10 by 4th week:
Tramadol 6/34
Placebo 2/34 (both these participants had same response with tramadol)

Sindrup 2012

Denmark, Germany

Tramadol SR 200 mg to 400 mg daily, titrated over one week
GRT9906 120 mg to 240 mg daily, titrated over one week
Placebo

N = 64 (48 completed cross‐over)

PP (completer) population

≥ 50% PIR:
Tramadol 18/45
GRT9906 18/45
Placebo 6/45

≥ 30% PIR:
Tramadol 32/45
GRT9906 25/45
Placebo 11/45

PGIC ‐ mean score at end of study:
Tramadol 2.4 (SD 1.1)
GRT9906 2.4 (SD 1.1)
Placebo 3.8 (SD 1.6)

Full analysis set
Mean change from baseline:
Tramadol ‐2.4 (SD 2.1)
GRT9906 ‐2.3 (SD 2.0)
Placebo ‐0.7 (SD 1.8)

ADL: activities of daily living; h: hour; ITT: intention to treat; LOCF: last observation carried forward; N: number of participants in study; n: number of participants in treatment arm; PGIC: Patient Global Impression of Change; PI: pain intensity; PIR: pain intensity reduction; PP: per protocol; SD: standard deviation; SR: sustained release.

Appendix 8. Summary of outcomes in individual studies: adverse events, withdrawals

Study

Treatment

Adverse events

Specific adverse events

Withdrawals

Arbaiza 2007

Peru

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

Any AE:
Tramadol 12/18
Placebo 4/18

No SAE reported

Events with tramadol: nausea, somnolence, constipation, dry mouth, general malaise, dizziness, tiredness, sweaty hands

Most common:
Nausea and constipation
Tramadol 11/18
Placebo 3/18
Vomiting
Tramadol 7/18
Placebo 1/18

All cause:
Tramadol 5/18
Placebo 6/18

LoE:
Tramadol 2/18
Placebo 6/18

AE:
Tramadol 3/18
Placebo 0/18

Boureau 2003

France

Tramadol SR 100 mg taken in evening, n = 64
Placebo, n = 63

Dose could be increased to max 400 mg (≤ 75 years) or 300 mg (75+ years) taken as divided dose in morning and evening

Any AE:
Tramadol 19/64
Placebo 20/63
Mostly mild in placebo group, moderate in tramadol group

SAE:
3 participants had SAE ‐ unclear which group, but probably tramadol
(1 participant on tramadol had two SAE, both judged unrelated to treatment)

Tramadol: mostly digestive system (11), body as a whole (6), nervous system (6)
Placebo: mostly digestive system (5), body as a whole (6), nervous system (5), respiratory system (5)

Nausea:
Tramadol 12.5% = 8/64
Placebo 3.2% = 2/63

AE:
Tramadol 6/64 (5 nausea)
Placebo 0/63

All cause:
Tramadol 11/64
Placebo 5/63

(Note: denominators uncertain)

Harati 1998

USA

Tramadol 100 mg to 200 mg daily, titrated from 50 mg daily over maximum 28 days, n = 65
Placebo, n = 66

Participants with any AE not reported

No SAE reported

AEs occurring in ≥ 5% reported

Nausea:
Tramadol 15/65
Placebo 2/66
Constipation:
Tramadol 14/65
Placebo 2/66
Headache:
Tramadol 11/65
Placebo 3/66
Somnolence:
Tramadol 8/65
Placebo 4/66
Dyspepsia:
Tramadol 6/65
Placebo 2/66
'Flu symptoms:
Tramadol 4/65
Placebo 6/66
Rhinitis:
Tramadol 3/65
Placebo 5/66
Diarrhoea:
Tramadol 2/65
Placebo 5/66

Pruritus, rash, fatigue, dizziness, vomiting each reported by 3 or 4 participants in tramadol group

All cause:
Tramadol 20/65
Placebo 25/66

LoE:
Tramadol 9/65
Placebo 22/66

AE:
Tramadol 9/65 (mostly nausea and dyspepsia)
Placebo 1/66

Norrbrink 2009

Sweden

Tramadol 150 mg to 400 mg daily, n = 23
Placebo, n = 12

Any AE:
Tramadol 21/23
Placebo 7/12

More moderate or severe with tramadol

No SAE reported

Tiredness:
Tramadol 17/23
Placebo 2/12
Dry mouth:
Tramadol 12/23
Placebo 3/12
Dizziness:
Tramadol 12/23
Placebo 3/12
Sweating:
Tramadol 9/23
Placebo 3/12
Constipation:
Tramadol 8/23
Placebo 4/12
Nausea:
Tramadol 9/23
Placebo 3/12
Voiding dysfunction:
Tramadol 1/23
Placebo 0/12

All cause:
Tramadol 11/23
Placebo 2/12

All AE, 1 judged unrelated to drug

Sindrup 1999

Denmark

Tramadol SR 200 mg to 400 mg daily, titrated over at least one week
Placebo

N = 45 (34 in both periods of cross‐over)

Any AE:
Tramadol 28/34
Placebo 12/34

No SAE reported

Tiredness:
Tramadol 19/34
Placebo 4/34
Dizziness:
Tramadol 15/34
Placebo 2/34
Dry mouth:
Tramadol 17/34
Placebo 6/34
Sweating:
Tramadol 14/34
Placebo 6/34
Constipation:
Tramadol 10/34
Placebo 2/34
Micturation problems:
Tramadol 6/34
Placebo 1/34
Nausea:
Tramadol 11/34
Placebo 3/34

Tramadol AEs mild or moderate
Placebo AEs mainly mild

All cause (both periods):
Tramadol 8/43
Placebo 3/40
(Does not appear to include 4 participants who provided data for analyses but did not complete ‐ 2 for LoE, 2 logistic problems)

LoE:
2 participants in second period ‐ group unclear

AE:
Tramadol 5/23 (first period), 2/20 (second period)
Placebo 2/22 (first period)

Sindrup 2012
Denmark, Germany

Tramadol SR 200 mg to 400 mg daily, titrated over one week
GRT9906 120 mg to 240 mg daily, titrated over one week
Placebo

N = 64 (48 completed cross‐over)

Any AE not reported

SAE:
Tramadol 1/56 (vertigo)
GRT9906 1/58
Placebo 0/55

Nausea:
Tramadol 14/56
Placebo 4/55
Constipation:
Tramadol 14/56
Placebo 1/55
Dry mouth:
Tramadol 4/56
Placebo 2/55
Vomiting:
Tramadol 6/56
Placebo 0/55
Diarrhoea:
Tramadol 3/56
Placebo 4/55
Fatigue:
Tramadol 15/56
Placebo 6/55
Drug withdrawal syndrome:
Tramadol 5/56
Placebo 0/55
Dizziness:
Tramadol 14/56
Placebo 4/55
Headache:
Tramadol 7/56
Placebo 3/55
Sleep disorder:
Tramadol 14/56
Placebo 3/55

All cause:
16 ‐ not reported per treatment group

AE:
Tramadol 4/56
GRT9906 4/58
Placebo 2/55

LoE:
Tramadol 0/56
GRT9906 1/58
Placebo 0/55

Participant withdrew consent:
Tramadol 5/56
GRT9906 3/58
Placebo 0/55

Protocol violation:
Tramadol 0/56
GRT9906 2/58
Placebo 1/55

Note participants could terminate for more than one reason, so unclear how many withdrew in each phase

AE: adverse event; hour: h; LoE: lack of efficacy; N: number of participants in study; n: number of participants in treatment arm; SAE: serious adverse event; SR: sustained release.

Study flow diagram for the updated search
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Figure 1

Study flow diagram for the updated search

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Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
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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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Forest plot of comparison: 1 Tramadol versus placebo, outcome: 1.1 Participants with ≥ 50% pain intensity reduction.
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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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Comparison 1 Tramadol versus placebo, Outcome 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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Comparison 1 Tramadol versus placebo, Outcome 2 Withdrawal due to adverse events.
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Analysis 1.2

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

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Comparison 1 Tramadol versus placebo, Outcome 3 All cause withdrawal.
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Analysis 1.3

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

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Comparison 1 Tramadol versus placebo, Outcome 4 Participants with any adverse event.
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Analysis 1.4

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

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

Figuras y tablas -
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]
Figuras y tablas -
Comparison 1. Tramadol versus placebo
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