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Study flow chart
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Figure 1

Study flow chart

Methodological characteristics and source of funding of included trials. (+) indicates low risk of bias, (?) unclear and (‐) a high risk of bias on a specific item.
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Figure 2

Methodological characteristics and source of funding of included trials. (+) indicates low risk of bias, (?) unclear and (‐) a high risk of bias on a specific item.

Forest plot of 10 trials comparing the effects of any type of opioids and control (placebo or no intervention) on knee or hip pain. Values on x‐axis denote standardised mean differences. The plot is stratified according to type of opioids. Matsumoto 2005 contributed with two comparisons and the standard error was inflated and the number of patients in the placebo group was halfed to avoid duplicate counting of patients when including both comparisons in the overall meta‐analysis. Data relating to the 3, 3, 3, and 2 active intervention arms in Caldwell 2002, Chindalore 2005, Kivitz 2006, and Matsumoto 2005, respectively, were pooled.
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Figure 3

Forest plot of 10 trials comparing the effects of any type of opioids and control (placebo or no intervention) on knee or hip pain. Values on x‐axis denote standardised mean differences. The plot is stratified according to type of opioids. Matsumoto 2005 contributed with two comparisons and the standard error was inflated and the number of patients in the placebo group was halfed to avoid duplicate counting of patients when including both comparisons in the overall meta‐analysis. Data relating to the 3, 3, 3, and 2 active intervention arms in Caldwell 2002, Chindalore 2005, Kivitz 2006, and Matsumoto 2005, respectively, were pooled.

Funnel plot for effects on knee or hip pain. 
 Numbers on x‐axis refer to standardised mean differences (SMDs), on y‐axis to standard errors of SMDs.
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Figure 4

Funnel plot for effects on knee or hip pain.
Numbers on x‐axis refer to standardised mean differences (SMDs), on y‐axis to standard errors of SMDs.

Standardised mean differences of knee or hip pain (y‐axis) are plotted against total daily dose of morphine equivalents (x‐axis). The size of the circles is proportional to the random‐effects weights that were used in the meta‐regression. The dotted line indicates predicted treatment effects (regression line) from uni‐variable meta‐regression by using daily morphine equivalence doses the explanatory variable, and dashed lines represent the 95% CIs.
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Figure 5

Standardised mean differences of knee or hip pain (y‐axis) are plotted against total daily dose of morphine equivalents (x‐axis). The size of the circles is proportional to the random‐effects weights that were used in the meta‐regression. The dotted line indicates predicted treatment effects (regression line) from uni‐variable meta‐regression by using daily morphine equivalence doses the explanatory variable, and dashed lines represent the 95% CIs.

Forest plot of 7 trials comparing the effects of any type of opioids and control (placebo or no intervention) on function. Values on x‐axis denote standardised mean differences. The plot is stratified according to type of opioids. Matsumoto 2005 contributed with two comparisons and the standard error was inflated and the number of patients in the placebo group was halved to avoid duplicate counting of patients when including both comparisons in the overall meta‐analysis. Data relating to the 3, 3, and 2 active intervention arms in Caldwell 2002, Kivitz 2006, and Matsumoto 2005, respectively, were pooled.
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Figure 6

Forest plot of 7 trials comparing the effects of any type of opioids and control (placebo or no intervention) on function. Values on x‐axis denote standardised mean differences. The plot is stratified according to type of opioids. Matsumoto 2005 contributed with two comparisons and the standard error was inflated and the number of patients in the placebo group was halved to avoid duplicate counting of patients when including both comparisons in the overall meta‐analysis. Data relating to the 3, 3, and 2 active intervention arms in Caldwell 2002, Kivitz 2006, and Matsumoto 2005, respectively, were pooled.

Funnel plot for effects on functioning of the knee or hip. 
 Numbers on x‐axis refer to standardised mean differences (SMDs), on y‐axis to standard errors of SMDs
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Figure 7

Funnel plot for effects on functioning of the knee or hip.
Numbers on x‐axis refer to standardised mean differences (SMDs), on y‐axis to standard errors of SMDs

Standardised mean differences of function (y‐axis) are plotted against total daily dose of morphine equivalents (x‐axis). The size of the circles is proportional to the random‐effects weights that were used in the meta‐regression. The dotted line indicates predicted treatment effects (regression line) from uni‐variable meta‐regression by using daily morphine equivalence doses the explanatory variable, and dashed lines represent the 95% CIs.
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Figure 8

Standardised mean differences of function (y‐axis) are plotted against total daily dose of morphine equivalents (x‐axis). The size of the circles is proportional to the random‐effects weights that were used in the meta‐regression. The dotted line indicates predicted treatment effects (regression line) from uni‐variable meta‐regression by using daily morphine equivalence doses the explanatory variable, and dashed lines represent the 95% CIs.

Forest plot of 4 trials comparing patients experiencing any adverse event between any opioid and control (placebo or no intervention). Values on x‐axis denote risks ratios. The plot is stratified according to type of opioid. Matsumoto 2005 contributed with two comparisons and the number of patients in the placebo group was halved to avoid duplicate counting of patients when including both comparisons in the overall meta‐analysis.
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Figure 9

Forest plot of 4 trials comparing patients experiencing any adverse event between any opioid and control (placebo or no intervention). Values on x‐axis denote risks ratios. The plot is stratified according to type of opioid. Matsumoto 2005 contributed with two comparisons and the number of patients in the placebo group was halved to avoid duplicate counting of patients when including both comparisons in the overall meta‐analysis.

Forest plot of 10 trials comparing patients withdrawn or dropped out because of adverse events between any opioid and control (placebo or no intervention). Values on x‐axis denote risks ratios. The plot is stratified according to type of opioid. Matsumoto 2005 contributed with two comparisons and the number of patients in the placebo group was halved to avoid duplicate counting of patients when including both comparisons in the overall meta‐analysis. The risk ratio in one trial could not be estimated because no withdrawals or dropouts because of adverse events occurred in either group.
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Figure 10

Forest plot of 10 trials comparing patients withdrawn or dropped out because of adverse events between any opioid and control (placebo or no intervention). Values on x‐axis denote risks ratios. The plot is stratified according to type of opioid. Matsumoto 2005 contributed with two comparisons and the number of patients in the placebo group was halved to avoid duplicate counting of patients when including both comparisons in the overall meta‐analysis. The risk ratio in one trial could not be estimated because no withdrawals or dropouts because of adverse events occurred in either group.

Risk ratios of patients withdrawn or dropped out because of adverse events between opioids and control groups (y‐axis) are plotted against total daily dose of morphine equivalents (x‐axis). The size of the circles is proportional to the random‐effects weights that were used in the meta‐regression. The dotted line indicates predicted treatment effects (regression line) from uni‐variable meta‐regression by using daily morphine equivalence doses the explanatory variable, and dashed lines represent the 95% CIs.
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Figure 11

Risk ratios of patients withdrawn or dropped out because of adverse events between opioids and control groups (y‐axis) are plotted against total daily dose of morphine equivalents (x‐axis). The size of the circles is proportional to the random‐effects weights that were used in the meta‐regression. The dotted line indicates predicted treatment effects (regression line) from uni‐variable meta‐regression by using daily morphine equivalence doses the explanatory variable, and dashed lines represent the 95% CIs.

Forest plot of 3 trials comparing patients experiencing any serious adverse event between any opioid and control (placebo or no intervention). Values on x‐axis denote risks ratios. The plot is stratified according to type of opioid. The risk ratio in one trial could not be estimated because no serious adverse event occurred in either group.
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Figure 12

Forest plot of 3 trials comparing patients experiencing any serious adverse event between any opioid and control (placebo or no intervention). Values on x‐axis denote risks ratios. The plot is stratified according to type of opioid. The risk ratio in one trial could not be estimated because no serious adverse event occurred in either group.

Comparison 1 Opioids versus placebo, Outcome 1 Pain.
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Analysis 1.1

Comparison 1 Opioids versus placebo, Outcome 1 Pain.

Comparison 1 Opioids versus placebo, Outcome 2 Function.
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Analysis 1.2

Comparison 1 Opioids versus placebo, Outcome 2 Function.

Comparison 1 Opioids versus placebo, Outcome 3 Number of patients experiencing any adverse event.
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Analysis 1.3

Comparison 1 Opioids versus placebo, Outcome 3 Number of patients experiencing any adverse event.

Comparison 1 Opioids versus placebo, Outcome 4 Number of patients who withdrew because of adverse events.
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Analysis 1.4

Comparison 1 Opioids versus placebo, Outcome 4 Number of patients who withdrew because of adverse events.

Comparison 1 Opioids versus placebo, Outcome 5 Number of patients experiencing any serious adverse event.
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Analysis 1.5

Comparison 1 Opioids versus placebo, Outcome 5 Number of patients experiencing any serious adverse event.

Comparison 1 Opioids versus placebo, Outcome 6 Withdrawal symptoms.
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Analysis 1.6

Comparison 1 Opioids versus placebo, Outcome 6 Withdrawal symptoms.

Oral or transdermal opioids compared with placebo for osteoarthritis of the knee or hip

Patient or population: Patients with osteoarthritis of the knee or hip

Settings: Various orthopedic or rheumatology clinics

Intervention: Oral or transdermal opioids

Comparison: Placebo

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Placebo

Opioids

Pain intensity

Various pain scales.

(median follow‐up: 4 weeks)

‐1.8 cm change
on 10 cm VAS1

29% improvement

‐2.7 cm change
(Δ ‐0.9 cm,‐1.2 to ‐0.7)2

44% improvement
(Δ 15%, 11% to 20%)3

SMD ‐0.36 (‐0.47 to ‐0.26)

2268
(10)

++++
high

NNT: 8 (95% CI 7 to 11)4

Function

Various validated function scales.

(median follow‐up: 4 weeks)

‐1.2 units
on WOMAC (range 0 to 10)1

21% improvement

‐1.9 units on WOMAC
(Δ ‐0.7, ‐1.0 to ‐0.5)5

34% improvement
(Δ 13%, 9% to 18%)6

SMD ‐0.33 (‐0.45 to ‐0.21)

1794
(7)

++++
high

NNT: 10 (95% CI 8 to 15)7

Number of patients experiencing any adverse event

(median follow‐up: 4 weeks)

150 per 1000 patient‐years8

233 per 1000 patient‐years
(212 to 255)

RR 1.55 (1.41 to 1.70)

1080
(4)

+++O
moderate9

NNH: 12 (95% CI 10 to 16)

Number of patients who withdrew because of adverse events

(median follow‐up: 4 weeks)

17 per 1000 patient‐years8

69 per 1000 patient‐years
(52 to 91)

RR 4.05 (3.06 to 5.38)

2403
(10)

++++
high

NNH: 19 (95% CI 13 to 29)

Number of patients experiencing any serious adverse event

(median follow‐up: 4 weeks)

4 per 1000 patient‐years8

13 per 1000 patient‐years
(3 to 54)

RR 3.35 (0.83 to 13.56)

681
(3)

++OO
low10

Little evidence of harmful effect [NNH: not statistically significant].

Withdrawal symptoms

Short Opiate Withdrawal Scale.

(follow‐up: 8 weeks)

0.9 units
(range 0 to 3)

0.7 units
(Δ 0.3, 0.2 to 0.4)

69% increase
(46 to 92%)11

SMD 0.60 (0.42 to 0.79)

499
(1)

++OO
low12

No evidence‐based assumption could be made for the calculation of NNH.

*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; RR: Risk ratio; SMD: Standardised mean difference; GRADE: GRADE Working Group grades of evidence (see explanations); NNT: number needed to treat; NNH: number needed to harm.

GRADE Working Group grades of evidence
High quality (++++): Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality (+++O): Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality (++OO): Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality (+OOO): We are very uncertain about the estimate.

1 Median reduction as observed across placebo groups in large osteoarthritis trials (see methods section, Nüesch 2009).
2 Standardised mean differences (SMDs) were back‐transformed onto a 10 cm visual analogue scale (VAS) on the basis of a typical pooled SD of 2.5 cm in large trials that assessed pain using a VAS and expressed as change based on an assumed standardised reduction of 0.72 standard deviation units in the control group.
3 Percentage of improvement was calculated based on median observed pain at baseline across control groups of large osteoarthritis trials of 6.1 cm on 10 cm VAS (Nüesch 2009).
4 Absolute response risks for pain in the control groups were assumed 31% (see methods section).
5 Standardised mean differences (SMDs) were back‐transformed onto a standardised WOMAC disability score ranging from 0 to 10 on the basis of a typical pooled SD of 2.1 in trials that assessed function using WOMAC disability scores and expressed as change based on an assumed standardised reduction of 0.58 standard deviation units in the control group.
6 Percentage of improvement was calculated based on median observed WOMAC function scores at baseline across control groups of large osteoarthritis trials of 5.6 units (Nüesch 2009).
7 Absolute response risks for function in the control groups were assumed 26% (see methods section).
8 Median control risk across placebo groups in large osteoarthritis trials (see methods section, Nüesch 2009).
9 Downgraded (1 level) because: 4 out of 10 studies reported this outcome, possibly leading to selective outcome reporting bias.
10 Downgraded (2 levels) because: 3 out of 10 studies reported this outcome, possibly leading to selective outcome reporting bias, the confidence interval of the pooled estimate is wide and crossed no difference.
11 Percentage of improvement was calculated based on observed withdrawal symptom scores in the placebo group of 0.39.
12 Downgraded (2 levels) because the outcome was assessed by a single trial assessing transdermal fentanyl therapy, and 8 weeks follow‐up duration considered short for this outcome.

Figures and Tables -
Table 1. Stratified analyses: pain

Variable

Number of
studies

N of patients
opioids

N of patients
control

Pain intensity
SMD (95% CI)

Hetero‐
geneity
I2 (%)

P‐value*

All trials

10

1541

727

‐0.36 (‐0.47 to ‐0.26)

18%

Analgesic potency

0.74

   Weak

3

79

100

‐0.51 (‐1.01 to ‐0.01)

55%

   Strong

7

1462

627

‐0.38 (‐0.49 to ‐0.26)

19%

Route of administration

 

 

 

 

 

0.14

   Oral

9

1339

530

‐0.42 (‐0.54 to ‐0.31)

12%

 

   Transdermal

1

202

197

‐0.22 (‐0.42 to ‐0.03)

N/A

 

Allocation concealment

 

 

 

 

 

0.96

   Adequate

4

583

384

‐0.42 (‐0.64 to ‐0.20)

56%

 

   Inadequate or unclear

6

958

343

‐0.38 (‐0.52 to ‐0.25)

3%

 

Type of control intervention

 

 

 

 

 

0.53

   Placebo

8

1493

662

‐0.40 (‐0.52 to ‐0.28)

30%

 

   No intervention

2

48

65

‐0.33 (‐0.93 to  0.28)

35%

 

Number of patients randomised

 

 

 

 

 

0.15

   > 200

5

1351

527

‐0.33 (‐0.44 to ‐0.23)

0%

 

   ≤ 200

5

190

200

‐0.55 (‐0.83 to ‐0.27)

42%

 

Duration of treatment

 

 

 

 

 

0.23

   > 1 month

2

258

248

‐0.27 (‐0.44 to ‐0.09)

0%

 

   ≤ 1 month

8

1283

479

‐0.43 (‐0.56 to ‐0.29)

23%

 

Use of analgesic co‐interventions

0.66

   Similar between groups

3

289

283

‐0.41 (‐0.71 to ‐0.11)

56%

   Unclear

7

1252

444

‐0.40 (‐0.53 to ‐0.28)

14%

*P‐value for interaction

Figures and Tables -
Table 1. Stratified analyses: pain
Table 2. Stratified analyses: function

Variable

Number of
studies

N of patients
opioids

N of patients
control

Function
SMD (95% CI)

Hetero‐
geneity
I2 (%)

P‐value*

All trials

7

1172

622

‐0.33 (‐0.45 to ‐0.21)

24%

Analgesic potency

 

 

 

 

 

0.68

   Weak

2

74

95

‐0.42 (‐0.74 to ‐0.10)

6%

 

   Strong

5

1098

527

‐0.35 (‐0.48 to ‐0.21)

34%

 

Route of administration

 

 

 

 

 

0.58

   Oral

6

970

425

‐0.38 (‐0.53 to ‐0.23)

28%

 

   Transdermal

1

202

197

‐0.28 (‐0.48 to ‐0.09)

N/A

 

Allocation concealment

 

 

 

 

 

0.60

   Adequate

3

528

335

‐0.43 (‐0.68 to ‐0.18)

62%

 

   Inadequate or unclear

4

644

287

‐0.31 (‐0.45 to ‐0.16)

0%

 

Type of control intervention

 

 

 

 

 

0.83

   Placebo

6

1129

562

‐0.36 (‐0.50 to ‐0.23)

32%

 

   No intervention

1

43

60

‐0.29 (‐0.68 to  0.11)

N/A

 

Number of patients randomised

 

 

 

 

 

0.09

   > 200

4

1042

476

‐0.29 (‐0.41 to ‐0.18)

0%

 

   ≤ 200

3

130

146

‐0.56 (‐0.88 to ‐0.25)

39%

 

Duration of treatment

 

 

 

 

 

0.55

   > 1 month

2

258

248

‐0.51 (‐1.01 to ‐0.01)

81%

 

   ≤ 1 month

5

914

374

‐0.32 (‐0.44 to ‐0.19)

0%

 

Use of analgesic co‐interventions

0.29

   Similar between groups

3

289

283

‐0.53 (‐0.88 to ‐0.18)

67%

   Unclear

4

883

339

‐0.30 (‐0.43 to ‐0.17)

0%

*P‐value for interaction

Figures and Tables -
Table 2. Stratified analyses: function
Comparison 1. Opioids versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Pain Show forest plot

10

2268

Std. Mean Difference (Random, 95% CI)

‐0.36 [‐0.47, ‐0.26]

1.1 Codeine

3

179

Std. Mean Difference (Random, 95% CI)

‐0.51 [‐1.01, ‐0.01]

1.2 Fentanyl

1

399

Std. Mean Difference (Random, 95% CI)

‐0.22 [‐0.42, ‐0.03]

1.3 Morphine

1

295

Std. Mean Difference (Random, 95% CI)

‐0.32 [‐0.59, ‐0.06]

1.4 Oxycodone

4

750

Std. Mean Difference (Random, 95% CI)

‐0.42 [‐0.65, ‐0.20]

1.5 Oxymorphone

2

645

Std. Mean Difference (Random, 95% CI)

‐0.39 [‐0.58, ‐0.21]

2 Function Show forest plot

7

1794

Std. Mean Difference (Random, 95% CI)

‐0.33 [‐0.45, ‐0.21]

2.1 Codeine

2

169

Std. Mean Difference (Random, 95% CI)

‐0.42 [‐0.74, ‐0.10]

2.2 Fentanyl

1

399

Std. Mean Difference (Random, 95% CI)

‐0.28 [‐0.48, ‐0.09]

2.3 Morphine

1

295

Std. Mean Difference (Random, 95% CI)

‐0.29 [‐0.56, ‐0.03]

2.4 Oxycodone

2

286

Std. Mean Difference (Random, 95% CI)

‐0.44 [‐1.12, 0.24]

2.5 Oxymorphone

2

645

Std. Mean Difference (Random, 95% CI)

‐0.32 [‐0.50, ‐0.13]

3 Number of patients experiencing any adverse event Show forest plot

4

1080

Risk Ratio (IV, Random, 95% CI)

1.55 [1.41, 1.70]

3.1 Codeine

1

66

Risk Ratio (IV, Random, 95% CI)

1.28 [0.94, 1.75]

3.2 Fentanyl

1

416

Risk Ratio (IV, Random, 95% CI)

1.55 [1.33, 1.81]

3.3 Oxycodone

2

294

Risk Ratio (IV, Random, 95% CI)

1.62 [1.36, 1.92]

3.4 Oxymorphone

1

304

Risk Ratio (IV, Random, 95% CI)

1.59 [1.28, 1.97]

4 Number of patients who withdrew because of adverse events Show forest plot

10

2403

Risk Ratio (IV, Random, 95% CI)

4.05 [3.06, 5.38]

4.1 Codeine

3

277

Risk Ratio (IV, Random, 95% CI)

3.67 [2.16, 6.24]

4.2 Fentanyl

1

399

Risk Ratio (IV, Random, 95% CI)

2.63 [1.64, 4.23]

4.3 Morphine

1

295

Risk Ratio (IV, Random, 95% CI)

3.49 [1.45, 8.39]

4.4 Oxycodone

4

758

Risk Ratio (IV, Random, 95% CI)

7.75 [3.76, 15.97]

4.5 Oxymorphone

2

674

Risk Ratio (IV, Random, 95% CI)

5.32 [2.93, 9.68]

5 Number of patients experiencing any serious adverse event Show forest plot

3

681

Risk Ratio (IV, Random, 95% CI)

3.35 [0.83, 13.56]

5.1 Codeine

1

158

Risk Ratio (IV, Random, 95% CI)

0.0 [0.0, 0.0]

5.2 Fentanyl

1

416

Risk Ratio (IV, Random, 95% CI)

2.78 [0.57, 13.60]

5.3 Oxycodone

1

107

Risk Ratio (IV, Random, 95% CI)

6.39 [0.34, 120.71]

6 Withdrawal symptoms Show forest plot

1

499

Std. Mean Difference (IV, Fixed, 95% CI)

0.60 [0.42, 0.79]

Figures and Tables -
Comparison 1. Opioids versus placebo