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Forest plot of comparison: 1 Rubefacient versus placebo, outcome: 1.1 Clinical success (e.g. 50% reduction in pain).
Figures and Tables -
Figure 1

Forest plot of comparison: 1 Rubefacient versus placebo, outcome: 1.1 Clinical success (e.g. 50% reduction in pain).

Forest plot of comparison: 1 Rubefacient versus placebo, outcome: 1.4 Adverse events.
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Figure 2

Forest plot of comparison: 1 Rubefacient versus placebo, outcome: 1.4 Adverse events.

Forest plot of comparison: 1 Rubefacient versus placebo, outcome: 1.2 Withdrawals.
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Figure 3

Forest plot of comparison: 1 Rubefacient versus placebo, outcome: 1.2 Withdrawals.

Comparison 1 Rubefacient versus placebo, Outcome 1 Clinical success (e.g. 50% reduction in pain).
Figures and Tables -
Analysis 1.1

Comparison 1 Rubefacient versus placebo, Outcome 1 Clinical success (e.g. 50% reduction in pain).

Comparison 1 Rubefacient versus placebo, Outcome 2 Adverse events.
Figures and Tables -
Analysis 1.2

Comparison 1 Rubefacient versus placebo, Outcome 2 Adverse events.

Comparison 1 Rubefacient versus placebo, Outcome 3 Withdrawals.
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Analysis 1.3

Comparison 1 Rubefacient versus placebo, Outcome 3 Withdrawals.

Comparison 2 Rubefacient versus active control, Outcome 1 Clinical success (e.g. 50% reduction in pain).
Figures and Tables -
Analysis 2.1

Comparison 2 Rubefacient versus active control, Outcome 1 Clinical success (e.g. 50% reduction in pain).

Comparison 2 Rubefacient versus active control, Outcome 2 Adverse events.
Figures and Tables -
Analysis 2.2

Comparison 2 Rubefacient versus active control, Outcome 2 Adverse events.

Comparison 2 Rubefacient versus active control, Outcome 3 Withdrawals.
Figures and Tables -
Analysis 2.3

Comparison 2 Rubefacient versus active control, Outcome 3 Withdrawals.

Table 1. Summary of outcomes ‐ efficacy and rescue medication

Analgesia

Study ID

Treatment

Outcome measure

Success

Rescue Medication

Acute

Diebschlag 1987

(1) Salicylate, adrenal extract, and mucopolysaccharide ointment (Mobilat)

(2) Placebo ointment

Movement pain on 100 mm VAS at:

(a) 8 days

(b) 15 days

No dichotomous data

(a) Significant difference in favour of (1)

(b) Significant difference in favour of (1)

No data

Frahm 1993

(1) Salicylate and mucopolysaccharide cream (Movelat)

(2) Placebo cream

Movement pain on 100 mm VAS at:

(a) 9 days

(b) 11 days

No dichotomous data

(a) Significant difference in favour of (1)

(b) No significant difference

No data

Ginsberg 1987

(1) Salicylate and capsicum oleoresin ointment (Rado‐Salil)

(2) Placebo ointment

Patient global assessment ('excellent' or 'good') at:

(a) 3 days

(b) 14 days

(a)

(1) 5/20

(2) 0/20

(b)

(1) 10/20

(2) 2/20

Total number of rescue tablets (250 mg paracetamol) used:

(1) 24

(2) 36

Ibanez 1988

(1) Salicylate spray

(2) Fepradinol spray active control

'Cure' at 12 days

(1) 23/35

(2) 85/102

No data

Lester 1981

(1) Salicylate, adrenal extract, and mucopolysaccharide gel (Movelat)

(2) Placebo gel

Relief of pain by 7 days

(1) 18/20

(2) 13/22

No data

Rothhaar 1982

(1) Salicylate gel (Reparil‐Gel)

(2) Placebo gel

Patient global assessment ('very good' or 'good') at 9 days

(1) 37/39

(2) 3/42

No data

Stam 2001

(1) Salicylate, nicotinate, capsicum oleoresin, and histamine gel (Cremor Capsici Compositus FNA)

(2) Herbal gel (Spiroflor SRL) active control

80% reduction in pain on 100 mm VAS at 7 days

(1) 41/78

(2) 40/83

Number using rescue medication (paracetamol):

(1) 65/82

(2) 56/75

Chronic

Algozzine 1982

(1) Salicylate cream (Myoflex)

(2) Placebo cream

Pain relief score at 7 days favours (1) or (2)

(1) 10/26

(2) 8/26

No data

Camus 1975

(1) Salicylate and myrtecaine cream (Algesal Suractive)

(2) Placebo cream

Improvement in rest pain score at 10 days

(1) 8/10

(2) 3/10

No data

Geller 1980

(1) Salicylate and heparin gel (Dolo‐Menthoneurin)

(2) Etofenamate gel active control

Patient global score ('very good' or 'good') after phase 1 at 7 days

(1) 24/25

(2) 8/25

No data

Golden 1978

(1) Salicylate cream (Aspercreme) + placebo tablets

(2) Aspirin tablets + placebo cream active control

Patient global assessment of pain relief ('excellent' or 'good') at 7 days

(1) 13/20

(2) 10/20

No data

Lobo 2004

(1) Salicylate cream (Theraflex‐TMJ)
(2) Placebo cream

Spontaneous pain VAS (10 cm) at:

(a) 15 days

(b) 10 days

No dichotomous data

(a) Significant difference in favour of (1)

(b) No significant difference

No data

Rutner 1995

(1) Salicylate gel (Phardol‐Mono)

(2) Placebo gel

Drop‐out 'pain free' by day 14

(1) 21/54

(2) 18/59

No data

Shackel 1997

(1) Salicylate gel

(2) Placebo gel

Patient global assessment ('very good' or 'good') at 28 days

(1) 22/58

(2) 21/56

Number using rescue medication (paracetamol):

(1) 43/56

(2) 39/55

Average dose (mg/day):

(1) 555

(2) 600

von Bach 1979

(1) Salicylate and nonivamide in heparin and salicylate ointment (Enelbin‐Rheuma)

(2) Salicylate in heparin and salicylate ointment active control

Global assessment ('very good' or 'good') at 14 days

(1) 27/50

(2) 10/50

No data

Wanet 1979

(1) Salicylate and myrtecaine cream (Algesal Suractive)

(2) Placebo cream

Rest pain score at 15 days

(1) 15/32

(2) 4/24

No data

Figures and Tables -
Table 1. Summary of outcomes ‐ efficacy and rescue medication
Table 2. Summary of outcomes ‐ withdrawals and adverse events

Withdrawals and exclusions

Adverse events

Study ID

Treatment

All withdrawals and exclusions

Lack of efficacy

Adverse events

All adverse events

Local adverse events

Algozzine 1982

(1) Salicylate cream (Myoflex)

(2) Placebo cream

1/26

unrelated to study

(1) 0/25

(2) 0/25

(1) 0/25

(2) 0/25

(1) 0/25

(2) 0/25

(1) 0/25

(1) 0/25

Camus 1975

(1) Salicylate and myrtecaine cream (Algesal Suractive)

(2) Placebo cream

No data

No data

No data

No data

No data

Diebschlag 1987

(1) Salicylate, adrenal extract, and mucopolysaccharide ointment (Mobilat)

(2) Placebo ointment

No data

No data

(1) 0/40

(2) 0/40

(1) 0/40

(2) 0/40

(1) 0/40

(2) 0/40

Frahm 1993

(1) Salicylate and mucopolysaccharide cream (Movelat)

(2) Placebo cream

7/16

violation of protocol

(1) 0/78

(2) 0/78

(1) 0/78

(2) 0/78

(1) 0/78

(2) 1/78

(1) 0/78

(2) 1/78

Geller 1980

(1) Salicylate and heparin gel (Dolo‐Menthoneurin)

(2) Etofenamate gel active control

Phase 1:

(1) 0/25

(2) 0/25

Phase 1:

(1) 0/25

(2) 0/25

Phase 1:

(1) 0/25

(2) 0/25

Phase 2:

(1) 0/25

(2) 0/25

Phases 1 and 2 combined:

(1) 2/50

(2) 2/50

Phases 1 and 2 combined:

(1) 2/50

(2) 2/50

Ginsberg 1987

(1) Salicylate and capsicum oleoresin ointment (Rado‐Salil)

(2) Placebo ointment

No data

No data

No data

(1) 4/20

(2) 1/20

(1) 4/20

(2) 1/20

Golden 1978

(1) Salicylate cream (Aspercreme) + placebo tablets

(2) Aspirin tablets + placebo cream active control

(1) 1/20

(2) 8/20

(1) 1/20

(2) 2/20

(1) 0/20

(2) 6/20

(1) 3/20

(2) 12/20

(1) 0/20

(2) 0/20

Ibanez 1988

(1) Salicylate spray

(2) Fepradinol spray active control

No data

No data

(1) 0/35

(2) 0/102

(1) 0/35

(2) 0/102

(1) 0/35

(2) 0/102

Lester 1981

(1) Salicylate, adrenal extract, and mucopolysaccharide gel (Movelat)

(2) Placebo gel

8/50

4 excluded due to fractures, 4 lost to follow‐up

No data

No data

(1) 0/20

(2) 2/22

(1) 0/20

(2) 2/22

Lobo 2004

(1) Salicylate cream (Theraflex‐TMJ)
(2) Placebo cream

No data

No data

No data

(1) 2/26

(2) 2/26

(1) 2/26

(2) 2/26

Rothhaar 1982

(1) Salicylate gel (Reparil‐Gel)

(2) Placebo gel

(1) 13/50

11 with no data, rest lack of efficacy

(2) 24/50

8 with no data, rest lack of efficacy

(1) 2/39

(2) 16/42

(1) 0/39

(2) 0/42

(1) 0/39

(2) 0/42

(1) 0/39

(2) 0/42

Rutner 1995

(1) Salicylate gel (Phardol‐Mono)

(2) Placebo gel

7/136

lost to follow‐up

No data

No data

(1) 1/54

unrelated disc prolapse

(2) 0/59

(1) 0/54

(2) 0/59

Shackel 1997

(1) Salicylate gel

(2) Placebo gel

(1) 15/58

14 withdrew during trial, 1 lost to follow‐up

(2) 10/58

2 withdrew before treatment, 7 withdrew during trial, 1 lost to follow‐up

(1) 3/58
(2) 2/56

(1) 10/58
(2) 1/56

(1) 48/58
(2) 29/56

Total number of adverse events:

(1) 80

(2) 27

Stam 2001

(1) Salicylate, nicotinate, capsicum oleoresin, and histamine gel (Cremor Capsici Compositus FNA)

(2) Herbal gel (Spiroflor SRL) active control

(1) 4/78

lost to follow‐up

(2) 2/83

1 death, 1 lost to follow‐up

No data

(1) 8/74

(2) 1/82

unrelated death

(1) 19/74

(2) 10/82

(1) 18/74

(2) 3/81

von Bach 1979

(1) Salicylate and nonivamide in heparin and salicylate ointment (Enelbin‐Rheuma)

(2) Salicylate in heparin and salicylate ointment active control

(1) 0/50

(2) 2/50

(1) 1/50

(2) 0/50

(1) 0/50

(2) 2/50

(1) 0/50

(2) 2/50

(1) 0/50

(2) 2/50

Wanet 1979

(1) Salicylate and myrtecaine cream (Algesal Suractive)

(2) Placebo cream

No data

No data

No data

No data

No data

Figures and Tables -
Table 2. Summary of outcomes ‐ withdrawals and adverse events
Table 3. Sensitivity analyses ‐ acute efficacy

Subgroup

Studies

Participants

Fixed‐effect RR (95% CI)

NNT (95% CI)

All acute studies

4

324

1.9 (1.5 to 2.5)

3.2 (2.4 to 4.9)

Excluding Lester 19811

3

282

2.0 (1.5 to 2.7)

3.2 (2.4 to 5.0)

Excluding validity < 9

3

243

1.3 (1.01 to 1.7)

not calculated

Excluding quality < 3 or validity < 9

2

201

1.2 (0.90 to 1.7)

not calculated

Outcomes ≥ 7 days

3

202

1.8 (1.4 to 2.4)

3.1 (2.3 to 4.8)

Outcomes ≥ 7 days2

4

324

2.0 (1.5 to 2.5)

3.1 (2.3 to 4.4)

1. Quality score < 3, outcome measure unspecified 'improvement'

2. Including additional data at 14 days from Ginsberg 1987

Figures and Tables -
Table 3. Sensitivity analyses ‐ acute efficacy
Table 4. Sensitivity analyses ‐ chronic efficacy

Subgroup

Studies

Participants

Fixed‐effect RR (95% CI)

NNT (95% CI)

All chronic studies

6

429*

1.6 (1.2 to 2.0)

6.2 (4.0 to 13)

Excluding von Bach 19791

5

329*

1.4 (1.03 to 1.8)

8.8 (4.7 to 70)

Excluding Shackel 19972

5

315*

1.9 (1.4 to 2.5)

4.6 (3.2 to 8.5)

Group size ≥ 40

3

327

1.5 (1.1 to 2.0)

7.4 (4.2 to 31)

Outcome measure global assessment or categorical score

4

290

1.8 (1.3 to 2.5)

4.8 (3.2 to 10)

Duration ≥ 14 days

4

383

1.6 (1.2 to 2.1)

6.3 (4.0 to 16)

* Including 26 patients in a crossover trial (Algozzine 1982)

1. Lower dose salicylate control

2. Application to a site remote from pain

Figures and Tables -
Table 4. Sensitivity analyses ‐ chronic efficacy
Table 5. Sensitivity analyses ‐ adverse events and withdrawals

Event rate (%)

Subgroup

Rubefacient

Placebo

Studies (with ≥ 1 event)

Participants (in studies with ≥ 1 event)

Fixed effect RR (95% CI)

NNH (95% CI)

Any adverse event

All studies

74/484 (15%)

47/500 (9%)

8

773

1.6 (1.2 to 2.0)

13 (7.9 to 43)

All studies excluding Shackel 19971

26/426 (6%)

18/44 (4%)

7

659

1.5 (0.88 to 2.6)

not calculated

All studies excluding Stam 20012 and von Bach 19793

55/360 (15%)

35/368 (10%)

6

517

1.5 (1.1 to 2.0)

12 (6.8 to 67)

Acute studies only

23/271 (8%)

14/284 (5%)

4

394

1.7 (0.96 to 3.2)

not calculated

Acute excluding Stam 20012

4/197 (2%)

4/202 (2%)

3

238

1.03 (0.30 to 3.5)

not calculated

Chronic studies only

51/213 (24%)

33/216 (15%)

4

379

1.5 (1.1 to 2.0)

10 (5.5 to 68)

Chronic excluding Shackel 19971

3/155 (2%)

4/160 (3%)

3

265

0.82 (0.23 to 2.9)

not calculated

Chronic excluding von Bach 19793

51/163 (31%)

31/166 (19%)

3

279

1.6 (1.2 to 2.1)

6.7 (3.9 to 23)

Local adverse events

All studies

24/426 (6%)

11/443 (2%)

6

545

2.2 (1.1 to 4.1)

20 (11 to 140)

All studies excluding Stam 20012 and von Bach 19793

6/302 (2%)

6/312 (2%)

4

290

1.02 (0.37 to 2.8)

not calculated

Acute studies only

22/271 (8%)

7/283(2%)

4

393

3.1 (1.4 to 6.7)

13 (7.5 to 37)

Acute excluding Stam 20012

4/197 (2%)

4/202 (2%)

3

238

1.03 (0.30 to 3.5)

not calculated

Withdrawals due to adverse events

All studies

18/364 (5%)

4/373 (1%)

3

370

4.2 (1.5 to 12)

13 (7.9 to 35)

Chronic studies only

10/133 (8%)

3/131 (2%)

2

214

2.9 (0.88 to 9.7)

not calculated

1. High event rate

2. Herbal control

3. Lower dose salicylate control

Figures and Tables -
Table 5. Sensitivity analyses ‐ adverse events and withdrawals
Table 6. Random‐effects model

Outcome

Fixed‐effect RR estimate (95% CI)

Random‐effects RR estimate (95% CI)

Acute efficacy

1.9 (1.5 to 2.5)

2.7 (1.05 to 7.0)

Chronic efficacy

1.6 (1.2 to 2.0)

1.6 (1.1 to 2.4)

Any adverse events

1.6 (1.2 to 2.0)

1.6 (1.3 to 2.1)

Local adverse events

2.2 (1.1 to 4.1)

1.3 (0.35 to 4.7)

All withdrawals

0.85 (0.57 to 1.3)

0.92 (0.41 to 2.1)

Withdrawal due to adverse events

4.2 (1.5 to 12)

3.4 (0.40 to 28)

Figures and Tables -
Table 6. Random‐effects model
Comparison 1. Rubefacient versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Clinical success (e.g. 50% reduction in pain) Show forest plot

10

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

1.1 Acute conditions

4

324

Risk Ratio (M‐H, Fixed, 95% CI)

1.93 [1.51, 2.46]

1.2 Chronic conditions

6

455

Risk Ratio (M‐H, Fixed, 95% CI)

1.58 [1.22, 2.04]

2 Adverse events Show forest plot

11

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

2.1 Any adverse event

11

984

Risk Ratio (M‐H, Fixed, 95% CI)

1.56 [1.19, 2.04]

2.2 Local adverse events

10

869

Risk Ratio (M‐H, Fixed, 95% CI)

2.15 [1.12, 4.12]

3 Withdrawals Show forest plot

7

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

3.1 Lack of efficacy

5

501

Risk Ratio (M‐H, Fixed, 95% CI)

0.36 [0.15, 0.87]

3.2 Adverse events

7

737

Risk Ratio (M‐H, Fixed, 95% CI)

4.19 [1.52, 11.56]

Figures and Tables -
Comparison 1. Rubefacient versus placebo
Comparison 2. Rubefacient versus active control

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Clinical success (e.g. 50% reduction in pain) Show forest plot

3

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

1.1 Acute

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

1.2 Chronic

2

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2 Adverse events Show forest plot

3

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

2.1 Any adverse events

3

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2.2 Local adverse events

3

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3 Withdrawals Show forest plot

3

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

3.1 Lack of efficacy

2

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3.2 Adverse events

3

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Figures and Tables -
Comparison 2. Rubefacient versus active control