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

Oral or transdermal opioids for osteoarthritis of the knee or hip

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Referencias

References to studies included in this review

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otras referencias

Caldwell JR, Rapoport RJ, Davis JC, Offenberg HL, Marker HW, Roth SH, et al. Efficacy and safety of a once‐daily morphine formulation in chronic, moderate‐to‐severe osteoarthritis pain: Results from a randomized, placebo‐controlled, double‐blind trial and an open‐label extension trial. Journal of Pain and Symptom Management 2002;23(4):278‐91.

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References to studies excluded from this review

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otras referencias

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References to studies awaiting assessment

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Additional references

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

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Caldwell 2002

Methods	Randomised controlled trial 4‐arm parallel group design Trial duration: 4 weeks Multicentre trial No power calculation reported
Participants	Patients with prior suboptimal analgesic response to NSAIDs/paracetamol or previous intermittent opioid therapy were eligible 295 patients with knee and/or hip osteoarthritis were reported at baseline Number of females: 184 of 295 (62%) Average age: 62 years
Interventions	Experimental interventions a) oral morphine (Avinza), 30mg once daily in the morning b) oral morphine (Avinza), 30mg once daily in the evening c) oral morphine sulphate (Contin), 15mg twice daily Control intervention Placebo, twice daily Treatment duration: 4 weeks No analgesics other than study drugs allowed
Outcomes	Extracted pain outcome: global pain after 4 weeks Extracted function outcome: WOMAC disability subscore after 4 weeks Primary outcome: WOMAC OA index
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	No information provided.
Allocation concealment?	Unclear risk	No information provided.
Described as double‐blind?	Low risk
Blinding of patients?	Low risk
Blinding of physicians?	Unclear risk	No information provided.
Blinding of outcome assessors?	Low risk
Interventions reported as indistinguishable?	High risk
Double‐dummy technique used?	Low risk
Intention‐to‐treat analysis performed? Pain	High risk	No information on exclusions available.
Intention‐to‐treat analysis performed? Function	High risk	No information on exclusions available.
No funding by commercial organisation?	High risk	Sponsor: Elan

Chindalore 2005

Methods	Randomised controlled trial 4‐arm parallel group design Trial duration: 4 weeks Randomisation stratified according to gender Multicentre trial with 37 centres No power calculation reported
Participants	Patients with moderate to severe hip or knee pain while taking ≥1 oral analgesic medication were eligible 362 patients were randomised 360 patients with hip or knee osteoarthritis were reported at baseline Number of females: 249 of 360 (69%) Average age: 54 years
Interventions	Experimental interventions a) oral oxycodone, 10mg 4‐times daily b) oral oxycodone, 2.5 mg 4‐times daily, plus naltrexone, 0.001 mg 4‐times daily (Oxytrex) c) oral oxycodone, 2.5 mg 4‐times daily, plus natronex, 0.001 mg twice daily (Oxytrex) Control intervention Placebo, twice daily Treatment duration: 3 weeks Analgesics other than study drugs allowed, but it was unclear whether intake was similar between groups
Outcomes	Extracted pain outcome: global pain after 4 weeks Extracted function outcome: WOMAC disability subscore after 4 weeks Primary outcome: pain intensity during the past 24 hours
Notes	For WOMAC disability, insufficient data were reported to calculate standardised mean differences and it was therefore not included in the meta‐analysis
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	No information provided.
Allocation concealment?	Unclear risk	No information provided.
Described as double‐blind?	Low risk
Blinding of patients?	Low risk
Blinding of physicians?	Low risk
Blinding of outcome assessors?	Low risk
Interventions reported as indistinguishable?	Low risk
Double‐dummy technique used?	High risk
Intention‐to‐treat analysis performed? Pain	High risk	1 of 310 patients (0.3%) excluded in experimental groups, 1 of 52 patients (1.9%) excluded in control group.
Intention‐to‐treat analysis performed? Function	High risk	1 of 310 patients (0.3%) excluded in experimental groups, 1 of 52 (1.9%) patients excluded in control group.
No funding by commercial organisation?	High risk	Sponsor: Pain Therapeutics

Kivitz 2006

Methods	Randomised controlled trial 4‐arm parallel group design Trial duration: 2 weeks Multicentre trial Power calculation reported
Participants	Patients with suboptimal analgesic response to NSAIDs/paracetamol or previous opioid therapy were eligible 370 patients were randomised 370 patients with knee or hip osteoarthritis were reported at baseline Affected joints: 297 knees and 73 hips Number of females: 224 of 370 (61%)
Interventions	Experimental interventions a) oral extended‐release oxymorphone, 10mg twice daily b) oral extended‐release oxymorphone, 40mg twice daily c) oral extended‐release oxymorphone, 50mg twice daily Control intervention Placebo, twice daily Treatment duration: 2 weeks No analgesics other than study drugs allowed.
Outcomes	Extracted pain outcome: global pain after 2 weeks. Extracted function outcome: WOMAC disability subscore after 2 weeks Primary outcome: change in pain intensity
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk
Allocation concealment?	Low risk
Described as double‐blind?	Low risk
Blinding of patients?	Low risk
Blinding of physicians?	Low risk
Blinding of outcome assessors?	Low risk
Interventions reported as indistinguishable?	High risk
Double‐dummy technique used?	Low risk
Intention‐to‐treat analysis performed? Pain	High risk	9 of 279 patients (0.7%) excluded in experimental groups, 4 of 91 patients (4.4%) excluded in control group.
Intention‐to‐treat analysis performed? Function	High risk	9 of 279 patients (0.7%) excluded in experimental groups, 4 of 91 patients (4.4%) excluded in control group.
No funding by commercial organisation?	High risk	Sponsor: Endo Pharmaceuticals Inc, Penwest Pharmaceuticals Co.

Kjaersgaard‐Andersen 1990

Methods	Randomised controlled trial 2‐arm parallel group design Trial duration: 4 weeks Multicentre trial with 7 centres Power calculation reported
Participants	Patients with chronic pain requiring analgesic treatment were eligible 158 patients with hip osteoarthritis were reported at baseline Affected joints: 158 hips Number of females: 72 of 158 (46%) Average age: 66 years Average BMI: 26 kg/m²
Interventions	Experimental intervention Oral codeine 60 mg plus paracetamol 1000 mg, 3 times daily Control intervention Paracetamol 1000 mg, 3 times daily Treatment duration: 4 weeks No analgesics other than study drugs allowed
Outcomes	Extracted pain outcome: global pain after 4 weeks Extracted function outcome: patient's global assessment after 4 weeks
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	No information provided.
Allocation concealment?	Unclear risk	No information provided.
Described as double‐blind?	Low risk
Blinding of patients?	Low risk
Blinding of physicians?	Unclear risk	No information provided.
Blinding of outcome assessors?	Low risk
Interventions reported as indistinguishable?	Low risk
Double‐dummy technique used?	High risk
Intention‐to‐treat analysis performed? Pain	High risk	43 of 83 patients (52%) excluded in experimental group, 18 of 75 patients (24%) excluded in control group.
Intention‐to‐treat analysis performed? Function	High risk	40 of 83 patients (48%) excluded in experimental group, 15 of 75 patients (20%) excluded in control group.
No funding by commercial organisation?	Unclear risk	No information provided.

Langford 2006

Methods	Randomised controlled trial 2‐arm parallel group design Trial duration: 8 weeks Randomisation stratified according to target joint (knee/hip) Multicentre trial Power calculation reported
Participants	Patients without adequate pain control under weak opioid treatment (with and without paracetamol) were eligible 416 patients were randomised 399 patients with knee or hip osteoarthritis were reported at baseline Affected joints: 211 knees and 188 hips Number of females: 265 of 399 (66%)
Interventions	Experimental intervention Transdermal fentanyl (Durogesic), median dosage 25μg/hour Control intervention Placebo Treatment duration: 6 weeks Analgesics other than study drugs allowed and intake assessed, but unclear whether intake was similar between groups
Outcomes	Extracted pain outcome: global pain after 8 weeks Extracted function outcome: WOMAC disability subscore after 8 weeks Primary outcome: pain relief on VAS
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk
Allocation concealment?	Low risk
Described as double‐blind?	Low risk
Blinding of patients?	Low risk
Blinding of physicians?	Low risk
Blinding of outcome assessors?	Unclear risk	No information provided.
Interventions reported as indistinguishable?	Low risk
Double‐dummy technique used?	High risk
Intention‐to‐treat analysis performed? Pain	High risk	No information on exclusions available.
Intention‐to‐treat analysis performed? Function	High risk	No information on exclusions available.
No funding by commercial organisation?	High risk	Sponsor: Janssen‐Cilag

Markenson 2005

Methods	Randomised controlled trial 2‐arm parallel group design Trial duration: 13 weeks Multicentre trial with 9 centres Power calculation reported
Participants	Patients with moderate to severe pain while taking NSAIDs/paracetamol, with contraindications to NSAID therapy or with previous oral opioid therapy were eligible 109 patients were randomised 107 patients with osteoarthritis were reported at baseline Affected joints: 33 knees, 19 hips, and 57 other joints Number of females: 78 of 107 (73%) Average age: 63 years
Interventions	Experimental intervention Oral oxycodone (OxyContin), 10mg twice daily Control intervention Placebo, twice daily Treatment duration: 13 weeks Analgesics other than study drugs allowed and intake assessed, but unclear whether intake was similar
Outcomes	Extracted pain outcome: global pain after 13 weeks Extracted function outcome: WOMAC global scale after 13 weeks
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk
Allocation concealment?	Low risk
Described as double‐blind?	Low risk
Blinding of patients?	Low risk
Blinding of physicians?	Low risk
Blinding of outcome assessors?	Low risk
Interventions reported as indistinguishable?	Low risk
Double‐dummy technique used?	High risk
Intention‐to‐treat analysis performed? Pain	High risk	No information on exclusions available.
Intention‐to‐treat analysis performed? Function	High risk	No information on exclusions available.
No funding by commercial organisation?	High risk	Sponsor: Purdue Pharma

Matsumoto 2005

Methods	Randomised controlled trial 4‐arm parallel group design Trial duration: 4 weeks Simple randomisation Multicentre trial Power calculation reported
Participants	Patients with suboptimal analgesic response to NSAIDs, paracetamol, or opioids were eligible 491 patients were randomised 489 patients with OA were reported at baseline Affected joints: 373 knees and 116 hips Number of females: 297 of 489 (61%) Average age: 62 years Average BMI: 34 kg/m²
Interventions	Experimental interventions a) Oral extended‐release oxymorphone, 20mg twice daily b) Oral extended‐release oxymorphone, 40mg twice daily c) Oral controlled‐release oxycodone, 20mg twice daily Control intervention Placebo, twice daily Treatment duration: 4 weeks No analgesics other than study drugs allowed
Outcomes	Extracted pain outcome: WOMAC pain subscore after 4 weeks Extracted function outcome: WOMAC disability subscore after 4 weeks Primary outcome: change in arthritis pain intensity
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk
Allocation concealment?	Unclear risk	No information provided.
Described as double‐blind?	Low risk
Blinding of patients?	Low risk
Blinding of physicians?	Low risk
Blinding of outcome assessors?	Low risk
Interventions reported as indistinguishable?	Low risk
Double‐dummy technique used?	High risk
Intention‐to‐treat analysis performed? Pain	High risk	19 of 367 patients (5.2%) excluded in experimental groups, 5 of 124 (4.0%) patients excluded in control group.
Intention‐to‐treat analysis performed? Function	High risk	19 of 367 patients (5.2%) excluded in experimental groups, 5 of 124 (4.0%) patients excluded in control group.
No funding by commercial organisation?	High risk	Sponsors: TheraQuest Biosciences, Endo Pharmaceuticals, Penwest Pharmaceuticals Co.

Peloso 2000

Methods	Randomised controlled trial 2‐arm parallel group design Trial duration: 4 weeks Multicentre trial with 4 centres Power calculation reported
Participants	Patients with osteoarthritis symptoms requiring therapy with paracetamol, anti‐inflammatory agents or opioids were eligible. 103 patients were randomised 103 patients with osteoarthritis were reported at baseline Affected joints: 94 knees and 49 hips Number of females: 64 of 103 (62%) Average age: 62 years Average BMI: 34 kg/m² Average disease duration: 10.3 years
Interventions	Experimental intervention Oral codeine (Contin), 100mg twice daily Control intervention Placebo, twice daily Treatment duration: 4 weeks Analgesics other than study drugs allowed and intake assessed, but unclear whether intake was similar between groups
Outcomes	Extracted pain outcome: global pain after 4 weeks Extracted function outcome: WOMAC disability subscore after 4 weeks Primary outcome: WOMAC pain and overall pain intensity
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	No information provided.
Allocation concealment?	Unclear risk	No information provided.
Described as double‐blind?	Low risk
Blinding of patients?	Low risk
Blinding of physicians?	Unclear risk	No information provided.
Blinding of outcome assessors?	Unclear risk	No information provided.
Interventions reported as indistinguishable?	Low risk
Double‐dummy technique used?	High risk
Intention‐to‐treat analysis performed? Pain	High risk	20 of 51 patients (39%) excluded in experimental group, 17 of 52 patients (33%) excluded in control group.
Intention‐to‐treat analysis performed? Function	High risk	20 of 51 patients (39%) excluded in experimental group, 17 of 52 patients (33%) excluded in control group.
No funding by commercial organisation?	High risk	Sponsor: Purdue Frederick

Quiding 1992

Methods	Randomised controlled trial 3‐arm crossover design Trial duration: 1 week No power calculation reported
Participants	Patients in need of analgesic medication for hip osteoarthritis were eligible 27 patients were randomised 26 patients with OA were reported at baseline Affected joints: 26 hips Number of females: 22 of 26 (85%) Average age: 53 years
Interventions	Experimental intervention 30 mg oral codeine plus 200 mg ibuprofen, 6 times in 32 hours Control intervention 200 mg ibuprofen, 6 times in 32 hours Treatment duration: 32 hours No analgesics other than study drugs allowed
Outcomes	Extracted pain outcome: global pain after 1 week No function outcome reported No primary outcome reported
Notes	1 trial arm excluded from review
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	No information provided.
Allocation concealment?	Unclear risk	No information provided.
Described as double‐blind?	Low risk
Blinding of patients?	Low risk
Blinding of physicians?	Unclear risk	No information provided.
Blinding of outcome assessors?	Low risk
Interventions reported as indistinguishable?	High risk
Double‐dummy technique used?	Low risk
Intention‐to‐treat analysis performed? Pain	Unclear risk	No information on exclusions available.
Intention‐to‐treat analysis performed? Function	Unclear risk	Not applicable, no function outcome reported.
No funding by commercial organisation?	Unclear risk	No information provided.

Zautra 2005

Methods	Randomised controlled trial 2‐arm parallel group design Trial duration: 13 weeks Multicentre trial with 9 centres No power calculation reported
Participants	107 patients were randomised 104 patients with knee osteoarthritis were reported at baseline Number of females: 76 of 104 (73%) Average age: 63 years
Interventions	Experimental intervention Oral oxycodone (Oxycontin), 10mg twice daily Control intervention Placebo, twice daily Treatment duration: 13 weeks Analgesics other than study drugs allowed, but it was unclear whether intake was similar between groups
Outcomes	Extracted pain outcome: global pain after 13 weeks No function outcome reported Primary outcome: coping efficacy and arthritis helplessness
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	No information provided.
Allocation concealment?	Low risk
Described as double‐blind?	Low risk
Blinding of patients?	Low risk
Blinding of physicians?	Low risk
Blinding of outcome assessors?	Low risk
Interventions reported as indistinguishable?	Low risk
Double‐dummy technique used?	High risk
Intention‐to‐treat analysis performed? Pain	High risk	1 of 56 patients (1.8%) excluded in experimental group, 2 of 51 patients (3.9%) excluded in control group.
Intention‐to‐treat analysis performed? Function	Unclear risk	Not applicable, no function outcome reported.
No funding by commercial organisation?	High risk	Sponsor: Purdue Pharma

Characteristics of excluded studies [ordered by study ID]

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Study	Reason for exclusion
Adams 2006	Only active control interventions.
Andrei 1984	Percentage of patients with knee or hip osteoarthritis 17% (5/30).
Boureau 1990	Only active control interventions.
Brooks 1982	Percentage of patients with osteoarthritis 50%, no information about joints involved.
Burch 2004	No randomised controlled trial.
Caldwell 1999	Percentage of patients with knee or hip osteoarthritis likely to be below 50%.
Choquette 2008	No randomised controlled trial.
Doak 1992	Crossover trial providing pooled results only.
Fancourt 1984	Mixed population of rheumatoid arthritis and osteoarthritis, no information about number of patients with osteoarthritis.
Gazi 2005	Only active control interventions.
Hale 2007	Only active control interventions.
Le Loet 2005	Not randomised controlled trial.
McIlwain 2005	Not randomised controlled trial.
Mitchell 1984	Mixed population of rheumatoid arthritis and osteoarthritis, no information about number of patients with osteoarthritis.
Neubauer 1983	Percentage of patients with osteoarthritis 15% (5/33).
Rosenthal 2007	Not randomised controlled trial.
Roth 2000	Percentage of patients with knee or hip osteoarthritis likely to be below 50%.
Salzman 1983	Only active control interventions.
Tassain 2003	Percentage of patients with osteoarthritis 7% (2/28).
Torres 2001	Not randomised controlled trial.
Vignon 1999	Comparison of combination of dextropropoxyphene, acetaminophen, and caffeine with placebo.
Vlok 1987	Crossover trial providing pooled results only.
Wallace 1994	Crossover trial providing pooled results only.
Wang 1965	Percentage of patients with osteoarthritis 6% (2/34).

Characteristics of studies awaiting assessment [ordered by study ID]

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Kroner 1991

Methods	Randomised controlled trial 2‐arm parallel group design Trial duration: 3 weeks Multicentre trial
Participants	131 patients with hip osteoarthritis were reported at baseline Number of females: 70 of 131 (53%)
Interventions	Experimental intervention Codeine 30mg plus paracetamol 500mg Control intervention Paracetamol 500mg Treatment duration: 3 weeks
Outcomes	Assessed efficacy outcomes: pain intensity, pain relief, patient's evaluation of the effect of treatment Assessed safety outcomes: number of patients withdrawn due to adverse events, serious adverse events
Notes	Insufficient data provided in published abstract, no full‐text article available. Awaiting author response.

Data and analyses

Open in table viewer

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]
Open in figure viewer Analysis 1.1 Comparison 1 Opioids versus placebo, Outcome 1 Pain.
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]
Open in figure viewer Analysis 1.2 Comparison 1 Opioids versus placebo, Outcome 2 Function.
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]
Open in figure viewer Analysis 1.3 Comparison 1 Opioids versus placebo, Outcome 3 Number of patients experiencing any adverse event.
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]
Open in figure viewer Analysis 1.4 Comparison 1 Opioids versus placebo, Outcome 4 Number of patients who withdrew because of adverse events.
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]
Open in figure viewer Analysis 1.5 Comparison 1 Opioids versus placebo, Outcome 5 Number of patients experiencing any serious adverse event.
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]
Open in figure viewer Analysis 1.6 Comparison 1 Opioids versus placebo, Outcome 6 Withdrawal symptoms.

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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Referencias

References to studies included in this review

Caldwell 2002 {published data only}

Chindalore 2005 {published data only}

Kivitz 2006 {published data only}

Kjaersgaard‐Andersen 1990 {published data only}

Langford 2006 {published data only}

Markenson 2005 {published data only}

Matsumoto 2005 {published data only}

Peloso 2000 {published data only}

Quiding 1992 {published data only}

Zautra 2005 {published data only}

References to studies excluded from this review

Adams 2006 {published data only}

Andrei 1984 {published data only}

Boureau 1990 {published data only}

Brooks 1982 {published data only}

Burch 2004 {published data only}

Caldwell 1999 {published data only}

Choquette 2008 {published data only}

Doak 1992 {published data only}

Fancourt 1984 {published data only}

Gazi 2005 {published data only}

Hale 2007 {published data only}

Le Loet 2005 {published data only}

McIlwain 2005 {published data only}

Mitchell 1984 {published data only}

Neubauer 1983 {published data only}

Rosenthal 2007 {published data only}

Roth 2000 {published data only}

Salzman 1983 {published data only}

Tassain 2003 {published data only}

Torres 2001 {published data only}

Vignon 1999 {published data only}

Vlok 1987 {published data only}

Wallace 1994 {published data only}

Wang 1965 {published data only}

References to studies awaiting assessment

Kroner 1991 {published data only}

Additional references

ACR OA 2000

Altman 1986

Altman 1996

Avouac 2007

Bellamy 1995

Caldwell 2005

Cepeda 2006

Chinn 2000

Clegg 2006

Cohen 1988

DerSimonian 1986

Dickersin 1994

Eccles 1998

Egger 2001

Egger 2003

Eriksen 2006

Furlan 2006

Gossop 1990

Guyatt 2008

Gøtzsche 2007

Higgins 2003

Higgins 2008

Jüni 2001

Jüni 2006

Kalso 2004

Loeser 2001

Maier 2002

Nüesch 2009

Pham 2004

Reichenbach 2007

Rücker 2008

Schug 2006

Shang 2005

Stein 1996

Sterne 2001

Thompson 1999

Von Korff 2004

Zhang 2008