Topical capsaicin (high concentration) for chronic neuropathic pain in adults

Sheena Derry; Andrew SC Rice; Peter Cole; Toni Tan; R Andrew Moore

doi:10.1002/14651858.CD007393.pub4

Capsaicina tópica (alta concentración) para el dolor neuropático crónico en adultos

Appendices

Appendix 1. CENTRAL search strategy

MeSH descriptor Capsaicin (400)
(capsaicin OR capsaicine OR capsici OR axsain OR capsidol OR capsig OR capsin OR capsina OR capsiplast OR capzasin‐P OR dolorac OR gelcen OR katrum OR "No pain‐HP" OR priltam OR "R‐gel" OR zacin OR zostrix OR capsicum):TI,AB,KY (763)
1 OR 2 (763)
exp MeSH descriptor Administration, topical (13012)
(topical* OR cutaneous OR dermal OR transcutaneous OR transdermal OR percutaneous OR skin OR massage OR embrocation OR gel OR ointment OR aerosol OR cream OR crème OR lotion OR foam OR liniment OR spray OR rub OR balm OR salve OR emulsion OR oil OR patch OR plaster):TI,AB,KY (79078)
4 OR 5 (81831)
MeSH descriptor Diabetic neuropathies EXPLODE ALL TREES (1017)
MESH DESCRIPTOR Peripheral Nervous System Diseases EXPLODE ALL TREES (2878)
MESH DESCRIPTOR Neuralgia EXPLODE ALL TREES (694)
((neuropath* OR diabet* post‐herpetic OR neuralgia OR phantom OR stump)):TI,AB,KY (7096)
7 OR 8 OR 9 OR 10 (8623)
3 AND 6 AND 11 (108)
2012 TO 2016:YR (192843)
12 AND 13 (40)

Appendix 2. MEDLINE search strategy (via Ovid)

Capsaicin/ (1149)
(capsaicin OR capsaicine OR capsici OR axsain OR capsidol OR capsig OR capsin OR capsina OR capsiplast OR capzasin‐P OR dolorac OR gelcen OR katrum OR "No pain‐HP" OR priltam OR "R‐gel" OR zacin OR zostrix OR capsicum).mp. (2436)
1 or 2 (2436)
exp Administration, topical/ (10094)
(topical* OR cutaneous OR dermal OR transcutaneous OR transdermal OR percutaneous OR skin OR massage OR embrocation OR gel OR ointment OR aerosol OR cream OR creme OR lotion OR foam OR liniment OR spray OR rub OR balm OR salve OR emulsion OR oil OR patch OR plaster).mp. (191041)
4 or 5 (193874)
exp Diabetic neuropathies/ (2906)
exp Peripheral Nervous System Diseases/ (166699)
exp Neuralgia/ (3473)
(neuropath* OR diabet* post‐herpetic OR neuralgia OR phantom OR stump).mp. (28080)
7 or 8 or 9 or 10 (36908)
randomized controlled trial.pt. (83324)
controlled clinical trial.pt. (6282)
randomized.ab. (75790)
placebo.ab. (25769)
drug therapy.fs. (304825)
randomly.ab. (49098)
trial.ab. (78401)
groups.ab. (275092)
12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 (637615)
3 AND 6 AND 11 AND 20 (94)

Appendix 3. EMBASE search strategy (via Ovid)

Capsaicin/ (13552)
(capsaicin or capsaicine or capsici or axsain or capsidol or capsig or capsin or capsina or capsiplast or capzasin‐P or dolorac or gelcen or katrum or "No pain‐HP" or priltam or "R‐gel" or zacin or zostrix or capsicum).mp. (17641)
1 or 2 (17641)
exp Topical Drug Administration/ (28821)
(topical* or cutaneous or dermal or transcutaneous or transdermal or percutaneous or skin or massage or embrocation or gel or ointment or aerosol or cream or creme or lotion or foam or liniment v spray or rub or balm or salve or emulsion or oil or patch or plaster).mp. (1410353)
4 or 5 (1417324)
exp Diabetic Neuropathies/ (14444)
exp Peripheral Nervous System Diseases/ (43680)
exp Neuralgia/ (63962)
(neuropath* or diabet* post‐herpetic or neuralgia or phantom or stump).mp. (252239)
7 or 8 or 9 or 10 (276770)
Randomized controlled trial/ (348956)
Double‐blind procedure/ (102583)
Crossover‐procedure/ (41951)
(random* or factorial* or crossover* or cross over* or cross‐over* or placebo* or (doubl* adj blind*) or assign* or allocat*).tw. (1194868)
12 or 13 or 14 or 15 (1262910)
3 and 6 and 11 and 16 (359)
limit 17 to yr="2012‐Current" (124)

Appendix 4. 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, Higgins 2011).

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 5. Summary of outcomes in individual studies: efficacy

Study ID

Treatment

Clinical improvement

Backonja 2008

(1) Capsaicin patch 8%, n = 206

(2) Control patch, n = 196

Over 2 to 12 weeks

≥ 30% pain reduction from baseline:

(1) 91/206, (2) 69/196

(Participants with ≥ 50% pain reduction from baseline ‐ no significant difference between groups)

≥ 2 points reduction in pain from baseline:

(1) 87/206, (2) 55/196

At 12 weeks

PGIC (slightly/much/very much improved):

(1) 114/206, (2) 85/196

Over 2 to 8 weeks

≥ 30% pain reduction from baseline:

(1) 87/206, (2) 63/196

≥ 2 points reduction in pain from baseline:

(1) 82/206, (2) 51/196

At 8 weeks

PGIC (slightly/much/very much improved):

(1) 109/206, (2) 83/196

Bischoff 2014

(1) Capsaicin patch 8% 60 min, n = 24 (23 treated)

(2) Placebo patch 60 min, n = 22

No responder outcomes reported. No significant difference in the summed pain intensity difference (from baseline) between groups at 4, 8, or 12 weeks after treatment in completers

Clifford 2012

(1) Capsaicin patch 8% 30 min, n = 167

(2) Capsaicin patch 8% 60 min, n = 165

(3) Control patch 30 min, n = 73

(4) Control patch 60 min, n = 89

Over 2 to 12 weeks

≥ 30% pain reduction from baseline:

(1) 65/167, (2) 79/165, (3) 19/73, (4) 40/89

At 12 weeks

PGIC (slightly, much, very much improved):

(1) 109/167, (2) 114/165, (3) 33/73, (4) 56/89

Irving 2011

(1) Capsaicin patch 8%, n = 212

(2) Control patch, n = 204

At 12 weeks

≥ 50% pain reduction from baseline:

(1) 64/212, (2) 43/204

≥ 30% pain reduction from baseline:

(1) 100/212, (2) 71/204

At 12 weeks

PGIC (much and very much improved):

(1) 83/212, (2) 50/204

≥ 2 points reduction in pain from baseline:

(1) 91/212, (2) 59/204

Over 2 to 8 weeks

≥ 50% pain reduction from baseline:

(1) 61/212, (2) 41/204

≥ 30% pain reduction from baseline:

(1) 98/212, (2) 69/204

At 8 weeks

PGIC (much and very much improved):

(1) 71/212, (2) 49/204

≥ 2 points reduction in pain from baseline:

(1) 89/212, (2) 53/204

Simpson 2008

(1) Capsaicin patch 8% 30 min, n = 72

(2) Capsaicin patch 8% 60 min, n = 78

(3) Capsaicin patch 8% 90 min, n = 75

(4) Control patch, n = 82

Over 2 to 12 weeks

≥ 30% pain reduction from baseline:

(1) 30/72, (2) 19/78, (3) 27/75, (4) 15/82

(capsaicin combined 76/225)

At 12 weeks

PGIC (much and very much improved):

(1) 23/72, (2) 18/78, (3) 20/75, (4) 9/82

(capsaicin combined 61/225)

STEP 2014

(1) Capsaicin patch 8%, 30 min, n = 186

(2) Placebo patch, n = 183

Over 2 to 8 weeks

≥ 50% pain reduction from baseline:

(1) 39/186, (2) 33/183

≥ 30% pain reduction from baseline:

(1) 74/186, (2) 60/183

At 8 weeks

PGIC (much and very much improved), using ITT denominators:

(1) 71/186, (2) 52/183

Over 2 to 12 weeks

≥ 50% pain reduction from baseline:

(1) 41/186, (2) 35/183

≥ 30% pain reduction from baseline:

(1) 76/186, (2) 58/183

At 12 weeks

PGIC (much and very much improved), using ITT denominators:

(1) 68/186, (2) 51/183

Webster 2010a

(1) Capsaicin patch 8% 30 min, n = 72

(2) Capsaicin patch 8% 60 min, n = 77

(3) Capsaicin patch 8% 90 min, n = 73

(4) Control patch, 30, 60, 90 min pooled for analysis, n = 77

Over 2 to 8 weeks

≥ 50% pain reduction from baseline:

(1) 17/72, (2) 21/77, (3) 17/73, (4) 8/77

≥ 30% pain reduction from baseline:

(1) 27/72, (2) 27/77, (3) 29/73, (4) 22/77

At 12 weeks

PGIC (slight, much and very much improved):

(1+2+3) 122/222 (capsaicin combined), (4) 32/77

Webster 2010b

(1) Capsaicin patch 8%, n = 102

(2) Control patch, n = 53

Over 2 to 12 weeks

≥ 50% pain reduction from baseline:

(1) 40/102, (2) 19/53

≥ 30% pain reduction from baseline:

(1) 50/102, (2) 26/53

At 12 weeks

PGIC (much and very much improved):

(1) 41/102, (2) 15/53

Over 2 to 8 weeks

≥ 50% pain reduction from baseline:

(1) 37/102, (2) 19/53

≥ 30% pain reduction from baseline:

(1) 50/102, (2) 24/53

At 8 weeks

PGIC (much and very much improved):

(1) 43/102, (2) 14/53

ITT: intention‐to‐treat; min: minute; n: number of participants in treatment arm; PGIC: Patient Global Impression of Change.

Appendix 6. Summary of outcomes in individual studies: adverse events and withdrawals

Study ID

Treatment

Local AEs

Systemic AEs

Serious AEs

Withdrawals/exclusions

Backonja 2008

(1) Capsaicin patch 8%, n = 206

(2) Control patch, n = 196

Mostly transient, mild to moderate

Erythema:

(1) 193/205, (2) 128/197

Pain:

(1) 114/205, (2) 43/197

Papules:

(1) 20/205, (2) 6/197

Pruritus:

(1) 10/205, (2) 6/197

Oedema:

(1) 12/205, (2) 2/197

Nausea, vomiting, nasopharyngitis, sinusitis, back pain, dizziness, headache, worsening of PHN, hypertension ‐ all reported at < 5% per group, with no clear difference between groups

(1) 10/205, (2) 6/197

(1 in capsaicin group judged related to medication)

AE:

(1) 1/205, (2) 0/197

LoE:

(1) 10/205, (2) 9/197

Lost to follow‐up:

(1) 3/205, (2) 2/197

Other:

(1) 5/205, (2) 7/197

Bischoff 2014

(1) Capsaicin patch 8% 60 min, n = 24 (23 treated)

(2) Placebo patch 60 min, n = 22

Pain:

(1) 12/23, (2) 6/20

Erythema:

(1) 9/23, (2) 3/20

Burning sensation:

(1) 12/23, (2) 1/20

None

AE:

(1) 1/23 (due to pain during application), (2) 0/22

LoE:

(1) 0.23, (2) 2/22 (began new analgesic treatment)

Lost to follow‐up:

(1) 0/23, (2) 2/22

Clifford 2012

(1) Capsaicin patch 8% 30 min, n = 167

(2) Capsaicin patch 8% 60 min, n = 165
(3) Control patch 30 min, n = 73

(4) Control patch 60 min, n = 89

Generally mild or moderate. Groups combined

Erythema:

(1+2) 176/332, (3+4) 58/162

Pain:

(1+2) 274/332, (3+4) 62/162

Papules:

(1+2) 12/332, (3+4) 0/162

Pruritus:

(1+2) 12/332, (3+4) 2/162

Oedema:

(1+2) 4/332, (3+4) 5/162

Diarrhoea, nausea, respiratory tract infection, pain, worsening neuropathy ‐ all reported, generally < 5% per group

Approximately 6% in all groups with "infections and infestations"

1 death in capsaicin 60 min group (judged unrelated)

AE:

(1) 0/167, (2) 2/165 (1 death), (3) 0/72, (4) 1/90
All judged unrelated

LoE:

(1) 0/167, (2) 1/165, (3) 0/73, (4) 1/89

Lost to follow‐up:

(1) 3/167, (2) 2/165, (3) 2/73, (4) 0/89

Other:

(1) 8/167, (2) 6/165, (3) 0/73, (4) 6/89

Irving 2011

(1) Capsaicin patch 8%, n = 212

(2) Control patch, n = 204

Most mild or moderate

Erythema:

(1) 194/212, (2) 141/204

Pain:

(1) 134/212, (2) 57/204

Papules:

(1) 15/212, (2) 5/204

Pruritus:

(1) 6/212, (2) 3/204

Oedema:

(1) 13/212, (2) 0/204

Nausea, vomiting, sinusitis, respiratory tract infection, musculoskeletal disorders, dizziness, headache ‐ all reported, most < 5% per group

(1) 11/212 (1 death), (2) 8/204

None considered drug‐related

AE:

(1) 4/212 (1 death), (2) 3/304
All SAE and considered not related to treatment

LoE:

(1) 1/212, (2) 5/204

Lost to follow‐up:

(1) 4/212, (2) 5/204

Other:

(1) 11/212, (2) 5/204

Simpson 2008

(1) Capsaicin patch 8% 30 min, n = 72

(2) Capsaicin patch 8% 60 min, n = 78

(3) Capsaicin patch 8% 90 min, n = 75

(4) Control patch, n = 82

Self‐limiting and mild to moderate

Pain:

(1) 47/225, (2) 7/82

Papules:

(1) 11/225, (2) 1/82

Pruritus:

(1) 39/225, (2) 5/82

Swelling:

(1) 29/225, (2) 7/82

Diarrhoea, nausea, vomiting, fatigue, infections, musculoskeletal disorders, dizziness, headache, psychiatric disorders ‐ all reported, < 5% per group

(1) 1/225, (2) 2/82

All deaths, all judged unrelated to study medication

AE:

(1) 3/225 (1 death), (2) 3/82 (2 deaths)

LoE:

(1) 1/225, (2) 2/82

Lost to follow‐up:

(1) 13/225, (2) 4/82

Other:

(1) 5/225, (2) 2/82

STEP 2014

(1) Capsaicin patch 8%, 30 min, n = 186

(2) Placebo patch, n = 183

Mostly mild or moderate

Application site pain and reactions overall:

(1) 63/186, (2) 15/183

Pain:

(1) 18/186, (2) 4/183

Burning sensation:

(1) 26/186, (2) 5/183

Musculoskeletal disorders, infections, respiratory disorders, gastrointestinal disorders

(1) 2/186, (2) 7/183

AE:

(1) 0/186,

(2) 1/183

Lost to follow‐up:

(1) 2/186,

(2) 1/183

Participant decision:

(1) 7/186,

(2) 6/183

Webster 2010a

(1) Capsaicin patch 8% 30 min, n = 72

(2) Capsaicin patch 8% 60 min, n = 77

(3) Capsaicin patch 8% 90 min, n = 73

(4) Control patch, 30, 60, 90 min pooled for analysis, n = 77

Transient and mild to moderate

Pain:

(1) 1/222, (2) 2/77

Papules:

(1) 3/222, (2) 2/77

Pruritus:

(1) 17/222, (2) 9/77

Swelling:

(1) 3/222, (2) 5/77

Diarrhoea, nausea, vomiting, infections, musculoskeletal disorders, dizziness, headache, cough ‐ all reported, mostly < 5% per group

(1+2+3) 10/222 (1 death), (4) 3/77

None considered related to study medication

AE:

(1+2+3) 2/222, (4) 1/77 (death)

LoE:

(1+2+3) 4/222, (4) 0/77

Lost to follow‐up

(1+2+3) 7/222, (4) 1/77

Other:

(1+2+3) 9/222, (4) 2/77

Webster 2010b

(1) Capsaicin patch 8%, n = 102

(2) Control patch, n = 53

Transient and mild to moderate

Erythema:

(1) 4/102, (2) 0/53

Pain:

(1) 4/102, (2) 2/53

Papules:

(1) 4/102, (2) 2/53

Pruritus:

(1) 17/102, (2) 6/53

Swelling:

(1) 10/102, (2) 1/53

Nausea, infections, musculoskeletal disorders, dizziness, cough, nasopharyngitis, hypertension ‐ all reported, mostly < 5% per group

(1) 7/102, (2) 0/53

None considered related to study medication

AE:

None in either group

LoE:

(1) 3/102, (2) 7/53

Lost to follow‐up:

(1) 5/102, (2) 0/53

Other:

(1) 3/102, (2) 3/53

AE: adverse event; LoE: lack of efficacy; n: number of participants in treatment arm; PHN: postherpetic neuralgia; SAE: serious adverse event

Appendix 7. Patch tolerability

Study ID

Treatment

Completed < 90% application time

Dermal irritation score > 2 at 2 hours

Rescue medication days 0 to 5

Backonja 2008

(1) Capsaicin patch 8%, n = 206

(2) Control patch, n = 196

(1) 1/206,

(2) 2/196

"Common but mild, transient and self‐limited"

(1) 99/206,

(2) 32/196

Bischoff 2014

(1) Capsaicin patch 8% 60 min, n = 24 (23 treated)

(2) Placebo patch 60 min, n = 22

Not reported

1 participant in (1) had patch removed early

No data

Clifford 2012

(1) Capsaicin patch 8% 30 min, n = 167

(2) Capsaicin patch 8% 60 min, n = 165

(3) Control patch 30 min, n = 73

(4) Control patch 60 min, n = 89

(1+2) 10/332,

(3+4) 0/162

(1+2) 13/332,

(3+4) 0/162

(1+2) 246/332,

(3+4) 53/162

Irving 2011

(1) Capsaicin patch 8%, n = 212

(2) Control patch, n = 204

(1) 4/212,

(2) 0/204

(1) 6/212,

(2) 1/204

(1) 112/212,

(2) 43/204

Simpson 2008

(1) Capsaicin patch 8% 30 min, n = 72

(2) Capsaicin patch 8% 60 min, n = 78

(3) Capsaicin patch 8% 90 min, n = 75

(4) Control patch, n = 82

(1) 0/72,

(2) 0/78,

(3) 2/75,

(4) 0/82

> 0 at 2 hours:

(1+2+3) 92/225,

(4) 23/82

(1+2+3) 124/225,

(4) 19/82

STEP 2014

(1) Capsaicin patch 8%, 30 min, n = 186

(2) Placebo patch, n = 183

No data

Dermal irritation (scale 0 to 7) score ≥ 4 (definite oedema) at 15 and 60 min after patch removal

(1) 0/186, (2) 2/183

(1) 35/186, (2) 10/183

Webster 2010a

(1) Capsaicin patch 8% 30 min, n = 72

(2) Capsaicin patch 8% 60 min, n = 77

(3) Capsaicin patch 8% 90 min, n = 73

(4) Control patch, 30, 60, 90 min pooled for analysis, n = 77

(1) 0/73,

(2) 1/77,

(3) 0/73,

(4) 0/77

> 0 at 2 hours:

(1+2+3) 87/222,

(4) 5/77

(1+2+3) 12/222,

(4) 3/77

Webster 2010b

(1) Capsaicin patch 8%, n = 102

(2) Control patch, n = 53

(1) 4/102,

(2) 0/53

(1) 53/102, (2) 2/53

(1) 12/102, (2) 1/53

min: minutes; n: number of participants in treatment arm

Figure 1

Study flow diagram.

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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 High‐concentration (8%) capsaicin versus control (single dose), outcome: 1.1 Postherpetic neuralgia ‐ at least 50% pain intensity reduction over weeks 2 to 8.

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Figure 4

Forest plot of comparison: 1 High‐concentration (8%) capsaicin versus control (single dose), outcome: 1.5 Postherpetic neuralgia ‐ Patient Global Impression of Change much or very much improved at 8 and 12 weeks.

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Figure 5

Forest plot of comparison: 1 High‐concentration (8%) capsaicin versus control (single dose), outcome: 1.6 HIV‐neuropathy ‐ at least 30% pain intensity reduction over weeks 2 to 12.

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Figure 6

Forest plot of comparison: 1 High‐concentration (8%) capsaicin versus control (single dose), outcome: 1.10 Serious adverse events.

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Analysis 1.1

Comparison 1: High‐concentration (8%) capsaicin versus control (single dose), Outcome 1: Postherpetic neuralgia (PHN) ‐ at least 50% pain intensity reduction over weeks 2 to 8

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Analysis 1.2

Comparison 1: High‐concentration (8%) capsaicin versus control (single dose), Outcome 2: PHN ‐ at least 50% pain intensity reduction over 2 to 12 weeks

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Analysis 1.3

Comparison 1: High‐concentration (8%) capsaicin versus control (single dose), Outcome 3: PHN ‐ at least 30% pain intensity reduction over weeks 2 to 8

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Analysis 1.4

Comparison 1: High‐concentration (8%) capsaicin versus control (single dose), Outcome 4: PHN ‐ at least 30% pain intensity reduction over weeks 2 to 12

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Analysis 1.5

Comparison 1: High‐concentration (8%) capsaicin versus control (single dose), Outcome 5: PHN ‐ Patient Global Impression of ChangePGIC much or very much improved at 8 and 12 weeks

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Analysis 1.6

Comparison 1: High‐concentration (8%) capsaicin versus control (single dose), Outcome 6: HIV‐neuropathy ‐ at least 30% pain intensity reduction over weeks 2 to 12

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Analysis 1.7

Comparison 1: High‐concentration (8%) capsaicin versus control (single dose), Outcome 7: Local skin reactions ‐ group 1

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Analysis 1.8

Comparison 1: High‐concentration (8%) capsaicin versus control (single dose), Outcome 8: Local skin reactions ‐ group 2

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Analysis 1.9

Comparison 1: High‐concentration (8%) capsaicin versus control (single dose), Outcome 9: Patch tolerability

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Analysis 1.10

Comparison 1: High‐concentration (8%) capsaicin versus control (single dose), Outcome 10: Serious adverse events

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Analysis 1.11

Comparison 1: High‐concentration (8%) capsaicin versus control (single dose), Outcome 11: Withdrawals

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Summary of findings 1. High‐concentration (8%) capsaicin patch compared with control patch (0.4%) for postherpetic neuralgia

Outcomes	Outcome with intervention	Outcome with comparator	RR, NNT, NNH, NNTp (95% CI)	Number of studies, participants, events	Quality of the evidence (GRADE)	Comments
High‐concentration (8%) capsaicin patch compared with control patch (0.4%) for postherpetic neuralgia
Patient or population: adults with postherpetic neuralgia Settings: community Intervention: high‐concentration (8%) capsaicin patch, single application Comparison: control patch (0.4% capsaicin), single application
Substantial benefit
PGICvery much improved, week 8 and week 12	No data	No data	‐	‐	Very low	No data
Moderate benefit
PGICmuch or very much improved, week 8	360 in 1000	250 in 1000	RR 1.4 (1.1 to 1.8) NNT 8.8 (5.3 to 26)	2 studies, 571 participants, 178 events	Moderate	Downgraded 1 level due to susceptibility to publication bias
PGIC much or very much improved, week 12	390 in 1000	250 in 1000	RR 1.6 (1.2 to 2.0) NNT 7.0 (4.6 to 15)	2 studies, 571 participants, 189 events	Moderate	Downgraded 1 level due to susceptibility to publication bias
Harm ‐ all conditions combined
Withdrawals due to lack of efficacy	15 in 1000	31 in 1000	RR 0.58 (0.32 to 1.04) NNTp 64 (34 to 610)	6 studies, 2073 participants, 44 events	Moderate	Downgraded 1 level due to imprecision (few events, wide CI)
Withdrawals due to adverse events	8.0 in 1000	9.2 in 1000	RR 0.80 (0.36 to 1.8) NNTp not calculated	8 studies, 2487 participants, 21 events	Moderate	Downgraded 1 level due to sparse data (few events)
Serious adverse events	35 in 1000	32 in 1000	RR 1.1 (0.70 to 1.8) NNH not calculated	7 studies, 1993 participants, 67 events	Moderate	Downgraded 1 level due to sparse data (few events)
Death	4 events	2 events	Not calculated	8 studies, 2487 participants	Very low	Downgraded 3 levels as only six events, so no better grading possibleNo death was judged related to study medication by study authors
CI: confidence interval; NNH: number needed to treat for one additional harmful outcome; NNT: number needed to treat for one additional beneficial outcome; NNTp: number needed to treat to prevent one withdrawal event; 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.

Summary of findings 1. High‐concentration (8%) capsaicin patch compared with control patch (0.4%) for postherpetic neuralgia

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Comparison 1. High‐concentration (8%) capsaicin versus control (single dose)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Postherpetic neuralgia (PHN) ‐ at least 50% pain intensity reduction over weeks 2 to 8 Show forest plot	3	870	Risk Ratio (M‐H, Fixed, 95% CI)	1.44 [1.12, 1.86]

1.1.1 Using 30‐minute application	1	97	Risk Ratio (M‐H, Fixed, 95% CI)	2.95 [0.73, 11.88]
1.1.2 Using 60‐minute application	3	674	Risk Ratio (M‐H, Fixed, 95% CI)	1.34 [1.03, 1.75]
1.1.3 Using 90‐minute application	1	99	Risk Ratio (M‐H, Fixed, 95% CI)	2.02 [0.64, 6.33]
1.2 PHN ‐ at least 50% pain intensity reduction over 2 to 12 weeks Show forest plot	2	571	Risk Ratio (M‐H, Fixed, 95% CI)	1.31 [1.00, 1.71]

1.3 PHN ‐ at least 30% pain intensity reduction over weeks 2 to 8 Show forest plot	4	1268	Risk Ratio (M‐H, Fixed, 95% CI)	1.31 [1.13, 1.52]

1.3.1 Using 30‐minute application	1	97	Risk Ratio (M‐H, Fixed, 95% CI)	1.34 [0.67, 2.69]
1.3.2 Using 60‐minute application	4	1072	Risk Ratio (M‐H, Fixed, 95% CI)	1.30 [1.12, 1.52]
1.3.3 Using 90‐minute application	1	99	Risk Ratio (M‐H, Fixed, 95% CI)	1.48 [0.74, 2.95]
1.4 PHN ‐ at least 30% pain intensity reduction over weeks 2 to 12 Show forest plot	3	973	Risk Ratio (M‐H, Fixed, 95% CI)	1.25 [1.07, 1.45]

1.5 PHN ‐ Patient Global Impression of ChangePGIC much or very much improved at 8 and 12 weeks Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.5.1 At 8 weeks	2	571	Risk Ratio (M‐H, Fixed, 95% CI)	1.42 [1.10, 1.84]
1.5.2 At 12 weeks	2	571	Risk Ratio (M‐H, Fixed, 95% CI)	1.55 [1.20, 1.99]
1.6 HIV‐neuropathy ‐ at least 30% pain intensity reduction over weeks 2 to 12 Show forest plot	2	801	Risk Ratio (M‐H, Fixed, 95% CI)	1.35 [1.09, 1.68]

1.6.1 Using 30‐minute application	2	340	Risk Ratio (M‐H, Fixed, 95% CI)	1.67 [1.14, 2.46]
1.6.2 Using 60‐minute application	2	359	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.84, 1.44]
1.6.3 Using 90‐minute application	1	102	Risk Ratio (M‐H, Fixed, 95% CI)	1.94 [0.83, 4.53]
1.7 Local skin reactions ‐ group 1 Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.7.1 Erythema	4	1355	Risk Ratio (M‐H, Fixed, 95% CI)	1.42 [1.32, 1.54]
1.7.2 Pain	4	1355	Risk Ratio (M‐H, Fixed, 95% CI)	2.26 [1.98, 2.59]
1.7.3 Papules	3	1312	Risk Ratio (M‐H, Fixed, 95% CI)	3.58 [1.87, 6.85]
1.7.4 Pruritus	3	1312	Risk Ratio (M‐H, Fixed, 95% CI)	1.99 [0.98, 4.03]
1.7.5 Oedema	3	1312	Risk Ratio (M‐H, Fixed, 95% CI)	2.98 [1.44, 6.18]
1.8 Local skin reactions ‐ group 2 Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.8.1 Erythema	1	129	Risk Ratio (M‐H, Fixed, 95% CI)	6.31 [0.35, 114.82]
1.8.2 Pain	4	1105	Risk Ratio (M‐H, Fixed, 95% CI)	2.39 [1.41, 4.05]
1.8.3 Papules	3	735	Risk Ratio (M‐H, Fixed, 95% CI)	1.58 [0.59, 4.24]
1.8.4 Pruritus	3	735	Risk Ratio (M‐H, Fixed, 95% CI)	1.57 [0.98, 2.50]
1.8.5 Oedema	3	735	Risk Ratio (M‐H, Fixed, 95% CI)	1.34 [0.75, 2.39]
1.9 Patch tolerability Show forest plot	7		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.9.1 < 90% of application time	6	2074	Risk Ratio (M‐H, Fixed, 95% CI)	3.27 [1.17, 9.15]
1.9.2 Dermal irritation score > 2 at 2 hours	3	1065	Risk Ratio (M‐H, Fixed, 95% CI)	11.80 [4.04, 34.48]
1.9.3 Dermal irritation score > 0 at 2 hours	2	606	Risk Ratio (M‐H, Fixed, 95% CI)	2.28 [1.60, 3.26]
1.9.4 Pain medication 0 to 5 days	7	2442	Risk Ratio (M‐H, Fixed, 95% CI)	2.52 [2.18, 2.92]
1.10 Serious adverse events Show forest plot	7	1993	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [0.70, 1.86]

1.11 Withdrawals Show forest plot	8		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.11.1 Adverse events	8	2487	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.36, 1.78]
1.11.2 Lack of efficacy	6	2073	Risk Ratio (M‐H, Fixed, 95% CI)	0.57 [0.32, 1.02]

Comparison 1. High‐concentration (8%) capsaicin versus control (single dose)

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The Cochrane Library

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Capsaicina tópica (alta concentración) para el dolor neuropático crónico en adultos

Appendices

Appendix 1. CENTRAL search strategy

Appendix 2. MEDLINE search strategy (via Ovid)

Appendix 3. EMBASE search strategy (via Ovid)

Appendix 4. GRADE: criteria for assigning grade of evidence

Appendix 5. Summary of outcomes in individual studies: efficacy

Appendix 6. Summary of outcomes in individual studies: adverse events and withdrawals

Appendix 7. Patch tolerability

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Appendices

Appendix 1. CENTRAL search strategy

Appendix 2. MEDLINE search strategy (via Ovid)

Appendix 3. EMBASE search strategy (via Ovid)

Appendix 4. GRADE: criteria for assigning grade of evidence

Appendix 5. Summary of outcomes in individual studies: efficacy

Appendix 6. Summary of outcomes in individual studies: adverse events and withdrawals

Appendix 7. Patch tolerability

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