Oral or transdermal opioids for osteoarthritis of the knee or hip

Eveline Nüesch; Anne WS Rutjes; Elaine Husni; Vivian Welch; Peter Jüni

doi:10.1002/14651858.CD003115.pub3

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Figure 1

Study flow chart

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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.

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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.

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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.

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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.

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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.

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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

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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.

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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.

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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.

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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.

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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.

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Analysis 1.1

Comparison 1 Opioids versus placebo, Outcome 1 Pain.

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Analysis 1.2

Comparison 1 Opioids versus placebo, Outcome 2 Function.

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Analysis 1.3

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

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Analysis 1.4

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

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Analysis 1.5

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

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Analysis 1.6

Comparison 1 Opioids versus placebo, Outcome 6 Withdrawal symptoms.

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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.

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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

Table 1. Stratified analyses: pain

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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

Table 2. Stratified analyses: function

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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]

Comparison 1. Opioids versus placebo

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