Opioids in chronic osteoarthritis pain - A systematic ... · 1 Opioids in chronic osteoarthritis pain - A systematic review and meta-analysis of efficacy and harms of randomized placebo-controlled

1

Opioids in chronic osteoarthritis pain - A systematic review and meta-analysis of efficacy and harms of randomized placebo-controlled studies of at least four weeks duration

R. Schaefert 1, P. Welsch 2, P. Klose 3, C. Sommer 4, F. Petzke 5, W. Häuser 6,7

1 Klinik für Allgemeine Innere Medizin und Psychosomatik, Universitätsklinikum

Heidelberg, Heidelberg, Germany

2 Stichting Rugzorg Nederland, Ede, The Netherlands

3 Abteilung für Natuheilkunde und Integrative Medizin, Kliniken Essen-Mitte, Essen,

Germany

4 Neurologische Klinik, Universitätsklinikum Würzburg, Germany

5 Schmerz-Tagesklinik und Ambulanz, Universitätsmedizin Göttingen, Göttingen,

Germany

6 Klinik und Poliklinik für Psychosomatische Medizin und Psychotherapie,

Technische Universität München, Germany

7 Innere Medizin I, Klinikum Saarbrücken gGmbH, Germany

Korrespondenzadresse:

PD Dr.med. Winfried Häuser

Innere Medizin 1

Klinikum Saarbrücken gGmbH

Winterberg 1

D - 66119 Saarbrücken

Germany

Tel: +49 681 9632020

Fax: +49 681 9632022

Email: [email protected]

mailto:[email protected]

2

Background: The efficacy, tolerability and safety of opioid therapy in chronic

osteoarthritis (OA) pain are under debate. We updated Cochrane systematic reviews

on the efficacy and safety of opioids in chronic OA pain published in 2008.

Methods: We screened Medline, Scopus, and the Cochrane Library (through October

2013), as well as reference sections of original studies and systematic reviews of

randomized controlled trials (RCTs) of opioids in chronic non-cancer pain. We

included double-blind randomized placebo-controlled studies 4 weeks. Relative risk

differences (RD) of categorical data and standardized mean differences (SMD) of

continuous variables were calculated using a random effects model.

Results: We included 20 RCTs with 33 treatment arms, with 8545 participants and a

median study duration of 12 (4 - 24) weeks. Six studies each tested oxycodone,

respectively tramadol, two studies each buprenorphine, hydromorphone, morphine,

respectively tapentadol, and one study each codeine, fentanyl, and oxymorphone.

Results are reported with [95% confidence intervals] Opioids were superior to

placebo in reducing pain intensity (SMD -0.22 [-0.28, -0.17]; p < 0.00001; 16 studies

with 6743 participants). Opioids were not superior to placebo in 50% pain reduction

(RD -0.01 [-0.07, 0.06], p = 0.82; two studies with 2709 participants). Opioids were

superior to placebo in reports of much or very much global improvement (RD 0.13

[0.05, 0.21]; p = 0.002; three studies with 2251 participants). Opioids were superior to

placebo in improving physical functioning (SMD -0.22 [-0.28, -0.17]; p < 0.00001; 14

studies with 5887 participants). Patients dropped out more frequently with opioids

than with placebo (RD 0.17 [0.14, 0.21], p < 0.00001; 15 studies with 6834

participants; number needed to harm 5 (4 - 6). There was no significant difference

between opioids and placebo in the frequency of serious adverse events (SAE) and

of deaths over the respective observation periods.

Conclusions: In short-term studies (4 - 12 weeks), opioids were superior in terms of

efficacy and inferior in terms of tolerability to placebo. The effect sizes of average

reduction of pain intensity and physical disability were small. Opioids and placebo did

not differ in terms of safety. The conclusion on the safety of opioids compared to

placebo is limited by the low number of serious adverse events and deaths. Short-

term opioid therapy in patients with chronic OA pain may be considered in selected

patients. No current evidence-based guideline recommends opioids as first-line

treatment option for chronic OA pain. To provide superior evidence for future

treatment guidelines, RCTs must directly compare existing pharmacological and non-

3

pharmacological therapies with each other, as well as administer them in various

combinations and sequences.

The English full-text version of this article is available at SpringerLink (under

“Supplemental”). This article is published with free access at Springerlink.com

Key words: Osteorthritis; chronic pain; systematic review; meta-analysis; efficacy;

tolerability; safety

4

Introduction

Osteoarthritis (OA) is the most common disease of joints in adults around the world

(10,24). In epidemiologic studies, OA is typically defined by radiographic findings and

consideration of symptoms (31). About one-third of all adults have radiological signs

of osteoarthritis (10). However, clinically significant osteoarthritis of the knee, hand,

or hip in terms of chronic pain and/ or disability was found in only 8.9% of the adult

population (2). The incidence and prevalence of OA are rising, likely related to the

aging of the population and increasing obesity (24). Non-pharmacological as well as

pharmacological modalities were recommended for OA by a recent guideline of the

American College of Rheumatology (ACR) (16). Opioid analgesics were strongly

recommended by the ACR in patients who were either not willing to undergo or had

contraindications for total joint arthroplasty after having failed medical therapy.

However, a Cochrane review on opioids in hip or knee OA pain published in 2009

concluded that the small to moderate beneficial effects of non-tramadol opioids were

outweighted by large increases in the risk of adverse events. Non-tramadol opioids

should therefore not be routinely used, even if osteoarthritic pain is severe (26).

The debate on the use of opioids in OA also depends on the duration of opioid use.

Short-term (< 4 weeks) opioid therapy might be appropriate in case of acute (on)

chronic OA pain from a clinical point of view. However, if long-term opioid therapy in

chronic OA pain is clinically useful, is under debate. Chronic opioid therapy has been

defined by daily or near-daily use of opioids for at least 90 days, but in practice often

used indefinitely (27). A systematic review on opioid therapy in chronic low back pain

distinguished between short-term (4 - 12 weeks), intermediate term (13 - 26 weeks)

and long-term (> 26 weeks) trials (4).

To our knowledge, the last systematic review of opioids in chronic OA pain searched

the literature until July 2008 and included short-term studies (< 4 weeks) into the

analyses of efficacy and harms. Studies with opioid agonists with additional mode of

action (e.g. tramadol, tapentadol) were excluded (24). In the meanwhile, new

randomized controlled trials (RCTs) with opioids in chronic OA pain have been

published.

Therefore, we updated the search of literature of systematic reviews on opioids in OA

pain for the update of the German 2008 guideline on the long-term administration of

opioids in chronic non-cancer pain (CNCP) (LONTS) (7). The objectives of this

5

review were to determine the efficacy, tolerability and safety of opioids compared to

placebo in adult patients with chronic OA pain in placebo-controlled RCTs 4 weeks.

Methods

The review was performed according to the PRISMA (Preferred Reporting Items for

Systematic Reviews and Meta-Analyses) statement (21) and the recommendations of

the Cochrane Collaboration (15).

Criteria for considering studies for this review

Types of studies

We included fully published double blind RCTs that compared any opioid to placebo

(pure or pseudo) for therapeutic purposes in OA pain. We included studies with a

parallel design and an enriched enrolment randomized withdrawal (EERW) design.

Studies with a cross-over design were included if a.) separated data of the two

periods were reported or b.) data were presented which excluded statistically

significant carry-over effect or c.) statistical adjustments were carried out in case of a

significant carry-over effect.

Study duration should be at least 4 weeks (tapering and maintenance phase for

parallel and cross-over design; double blind withdrawal phase for EERW design).

Studies should include at least 10 patients per treatment arm.

We grouped outcome measures according to the duration of postrandomization

follow-up, as proposed by Chaparro et al. (4): short-term (4 - 12 weeks), intermediate

(12 - 26 weeks) and long-term (> 26 weeks).

We had no restriction on the language of the publication.

We excluded studies which conducted a tapering phase after open-label run-in and a

consecutive double-blind parallel design with responders of the open-label run-in

period. We excluded studies with a duration of the tapering/ maintenance or

withdrawal period of less than 4 weeks, with an experimental design (i.e. if the

primary purpose was to study pain mechanisms and not pain relief) and studies

which were only published as abstracts. Furthermore, we excluded studies in which

different dosages of one opioid were compared without a placebo control group.

Types of participants

We included men and women of all ages and races or ethnicities diagnosed with

clinically or radiologically confirmed peripheral joint OA and associated pain of at

least three months duration. Trials exclusively including patients with inflammatory

6

arthritis, such as rheumatoid arthritis were not included. We excluded studies with

mixed study samples (participants with OA and low back pain) were if data of the two

groups were not presented separately.

Types of interventions

We included trials that examined the use of any opioid prescribed in an outpatient

setting, for a period of at least 4 weeks (titration and maintenance). We considered

trials with opioids given by oral or transdermal routes.

We included studies in which opioids were combined with abuse deterrent

formulations (ADFs) (e.g. naloxone).

We included studies with tramadol, a centrally acting, synthetic opioid analgesic with

two complementary mechanisms of action: binding of parent and M1 metabolite to μ -

opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin. We

included studies with tapentadol with two mechanisms of action: μ-receptor agonist

and norepinephrine reuptake inhibitor. We included both drugs into this review

because they are classified as opioids by German medicine agencies.

We considered trialswhich compared opioid with placebo:

We excluded trials that examined opioids given by intravenous route, including

implantable pumps, due to the invasive nature of the therapy and its limited clinical

relevance in the outpatient setting. In addition, the effectiveness of opioids used in

neuraxial implantable pumps has been discussed elsewhere (25). We excluded

studies in which the primary aim of the study was to test the efficacy of opioids as

rescue medication. We excluded studies with complete tapering off opioids after

open-label run-in followed by a randomized placebo-controlled parallel design.

We excluded studies in which drugs other than opioid agonists were used as a fixed

combination with opioids (e.g. tramadol with acetaminophen) because it is not

possible to detangle the effects of opioids from the one or the other analgesic.

Limited rescue medication with non-opioids was accepted.

We excluded studies in which a defined opioid was compared to the same opioid with

abuse deterrent formulations (ADFs) (e.g. oxycodone with and without naloxone) or

in which two opioids combined were compared with a single opioid.

We excluded studies in which opioids were compared to non-pharmacological

treatments. We excluded studies with propoxyphene because the drug has been

withdrawn from the market (United States Food and Drug Administration NEWS

RELEASE vom 19.11.2010).

http://www.fda.gov/

7

Types of outcome measures

The selection of outcomes was based on the recommendations of the ACTINPAIN

writing group of the International Association for the Study of Pain (IASP) Special

Interest Group (SIG) on Systematic Reviews in Pain Relief and the Cochrane Pain,

Palliative and Supportive Care Systematic Review Group editors for reporting meta-

analyses of RCTs in chronic pain (22). We included pain intensity as additional

outcome because most studies conducted before 2005 did not report responder

analyses (5,26).

Efficacy

1. Pain intensity ratings

2. Proportion of patients reporting 50% pain relief (responders)

3. Global improvement (Patient Global Impression of Change PGIC): Number of

patients reporting to be much or very much improved

4. Function: Examples of functional impairment outcomes that could be extracted

were as follows: Brief Pain Inventory (BPI); Fibromyalgia Impact Questionnaire

Subscale Physical Function (FIQ); Multidimensional Pain Inventory (MPI, physical

function); Western Ontario and McMaster Universities Arthritis Index (WOMAC);

Neck Disability Index (NDI); Oswestry Disability Index (ODI); Pain Disability Index

(PDI), physical disability; Roland Disability Questionnaire (RDQ); Short Form (SF)-36

or SF-12 (physical functioning scale). In case both, generic and disease specific

instruments were used, disease specific instruments were preferred (e.g. FIQ over

PDI, WOMAC over SF-36 physical functioning scale).

5. Proportion of patients who withdrew due to lack of efficacy

We excluded studies in which the primary outcome measure was not one of the five

outcomes of efficacy as defined above.

Tolerability

1.Proportion of patients who withdrew because of adverse events

Safety

1. Proportion of patients who experienced any SAE

2. Proportion of patients who died during study

Search methods for identification of studies

Electronic searches

The review updated and expanded the search of literature for the first version of the

German guideline on long-term administration of opiods (LONTS) which searched the

http://www.iasp-pain.org/

http://www.google.de/url?sa=t&rct=j&q=&esrc=s&frm=1&source=web&cd=2&ved=0CDQQFjAB&url=http%3A%2F%2Fwww.proz.com%2Fkudoz%2Fenglish_to_german%2Fmedical_general%2F3878318-patient_global_impression_of_change_pgic.html&ei=lHgbU-OMKYbRywPOt4GICg&usg=AFQjCNGKHludI2ZBPH2QA6gPk51_udiydg&bvm=bv.62578216,d.bGQ

8

literature until October 2008 (27). The updated and expanded search included

CENTRAL, Medline and Scopus from October 2008 to October 2013 and all types of

chronic non-cancer pain (CNCP). The search was conducted by PK. Our search

included all languages. The search strategy for Pubmed is detailed in the electronic

supplementary table 1.

Searching other resources

We searched bibliographies from reviewed articles and we retrieved relevant articles.

We screened the references of recent systematic reviews on long-term treatment of

opioids in CNCP (12,17,19,20) and in OA pain (5,26). We contacted the steering

committee of the update of the German guideline on long-term administration of

opioids (LONTS) to assist in locating fully published studies which we might have

missed by our search.

Data collection and analysis

Selection of studies

Two authors (PW, WH) independently screened titles, abstracts, and keywords of

trials that we identified by the search strategies to determine if our inclusion criteria

were met. We obtained the full text of trials that either appeared to meet our inclusion

criteria or for which we considered their inclusion was uncertain. We screened these

articles for inclusion and we resolved any disagreements through discussion.

Data extraction

Three pairs of authors (CS, WH; FP, WH; RS, WH) independently extracted data,

using the standardized forms on inclusion and exclusion criteria of the studies,

characteristics of participants, intervention group, clinical setting, interventions,

country of study, and study funding. If data were not available in a format that was

appropriate for data extraction, we did not contact the authors of the trial for further

clarification. We resolved any disagreements through discussion.

Dealing with missing data

If both, baseline observation carried forward (BOCF) data as well as last observation

carried forward (LOCF) data were reported for intention-to-treat (ITT) analysis, we

preferred BOCF data (23).

Where means or standard deviations (SD) were missing, we calculated them from t-

values, CIs or standard errors, as far as reported in the articles (15). If missing SDs

could not be calculated from these values, the study was excluded from analysis.

Measures of treatment effect

9

The effect measures of choice were absolute risk differences (RD) for dichotomous

data and standardized mean difference (SMD) for continuous data (pain intensity,

physical functioning) using a random effects model (method inverse variance). For

subgroup analyses of dichotomous outcomes we calculated risk ratios (RR). We

expressed uncertainty using 95% CIs. The threshold for “appreciable benefit” or

“appreciable harm” was set for categorical variables by a relative risk reduction

(RRR) or relative risk increase (RRI) >= 25% (4). We used Cohen’s categories to

evaluate the magnitude of the effect size, calculated by SMD, with Hedge’s g of 0.2 =

small, 0.5 = medium and 0.8 = large (6). We labelled g < 0.2 to be a ”not substantial”

effect size. We assumed a minimally important difference if there was small effect

size (9).

The numbers needed to treat for an additional beneficial outcome (NNTB) and the

numbers needed to treat for an additional harm (NNTH) for dichotomous variables

(50% pain reduction [responder], Patient Global Impression of Change [PGIC], drop

out due to adverse events, SAEs, death) were calculated by a calculator provided by

the Cochrane Musculoskeletal Group (personal communication).

Subgroup comparisons were performed by the test of interaction (1).

Unit-of-analysis issues

In the case of multiple opioid arms compared with one placebo group, we adjusted

the number of participants in the placebo group according to the number of opioid

arms for continuous outcomes.

Data synthesis

We pooled data from RCTs comparing opioids to placebo controls by a random-

effects model (method inverse variance). We used the I² statistic to describe the

percentage variability of effect estimates that is due to heterogeneity. I² values above

50% indicate high heterogeneity, between 25% and 50% moderate heterogeneity,

and below 25% low heterogeneity (15).

The risk of bias in each trial was assessed independently by two pairs of authors

(CS, WH; FP; WH; RS, WH) using eight aspects of bias recommended by the

Cochrane Collaboration considering (see figure 2 and see electronic supplementary

table 2) (4). We defined a study to have high quality (low risk of bias) when it fulfilled

six to eight, to have moderate quality study (moderate risk of bias) if it fulfilled three to

five and to have low quality (high risk of bias) if it fulfilled zero to two aspects.


10

We used the Grading of Recommendations Assessment, Development and

Evaluation (GRADE) to assess the overall quality evidence (13,15), defined as the

extent of confidence into the estimates of treatment benefits and harms. Quality

ratings were made separately for each of the eight quality indicators. The quality of

evidence was downgraded by one level for each of the following factors that were

encountered:

Limitations of study design: > 50% of the participants in low quality studies,

Inconsistency of results: I² > 50%

Indirectness: We assessed whether the question being addressed in this systematic

review was different from the available evidence regarding the population in routine

clinical care, if patients with clinically relevant somatic disease and/ or major mental

disorders (history of substance abuse or major depression) were excluded in 50%

of participants.

Imprecision: There was only one trial or when there was more than one trial, the total

number was < 400 patients or when 95% CI of the effect size included zero.

We categorized the quality of evidence as follows:

· High: further research is very unlikely to change the confidence in the estimate of

effect.

· Moderate: further research is likely to have an important impact in the confidence in

the estimate of effect.

· Low: 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: any estimate of effect is very uncertain.

Assessment of reporting biases

We used the Egger intercept test and the Begg rank correlation test at the

significance level p < 0.05, if at least 10 studies were available. The Begg test

examines the rank correlation between standardized intervention effect and its

standard error. An asymmetric funnel plot would give rise to such a correlation and

may be indicative of publication bias (3). In the Egger test, the standard normal

deviate is regressed on precision, defined as the inverse of the standard error. The

intercept in this regression corresponds to the slope in a weighted regression of the

effect size on the standard error (8).

Subgroup analysis

11

Subgroup analyses were a priori planned to assess the variations in effect sizes

(heterogeneity) by pooling study results of the relative effects of opioids compared to

placebo for the outcomes (pain intensity and drop out due to adverse events) for

different types of opioids (pure opioids versus opioids with additional modes of action

[tramadol, tapentadol]) and for treatment duration (short-term, intermediate-term and

long-term studies). At least two studies should be available for subgroup analysis.

Sensitivity analyses

We performed sensitivity analyses of all types of opioids pooled together compared

to placebo groups pooled together for the outcomes in studies in which we extracted

means and/ or SDs from figures or calculated SD from p-values.

Software

Comprehensive meta-analysis (Biostat, Englewood, NJ, USA) and RevMan Analysis

(RevMan 5.2) software of the Cochrane Collaboration were used for statistical

analyses.

Results

Literature search

After removing duplicates, the literature search produced unique 12601 citations.

Through screening, 12580 records were excluded. Twenty-one full-text articles were

assessed for eligibility. One study was excluded after full-text review. Twenty studies

with 33 treatment arms were included in the meta-analysis (see Figure 1).

Study characteristics (see table 1 and electronic supplementary table 3)

Study design: We included 20 RCTs with 33 treatment arms, with 8545 participants

and a median study duration of 12 (4 - 24) weeks. One study (5%) had a duration

12 weeks, namely 24 weeks (appendix reference 4). Fifteen (75.0%) studies had a

parallel, one (5.0%) study had a cross-over and four (20.0%) studies had an EERW

design. Fifteen (75.0%) studies were conducted in North America, four studies (20%)

in Europe and one study (5%) in different continents. Nineteen studies (50%) were

funded by the manufacturer of one of the tested drugs. One study was supported by

public funding.

Participants: Participants were diagnosed with OA of the hip and/ or knee. Seventeen

(85%) studies excluded patients with current and/ or a history of substance abuse

12

and/ or current major mental disorders and 18 (90%) studies excluded patients with

clinically relevant medical diseases. The range of the mean ages of participants in

the studies was 58-64 years. The participants were predominantly caucasian, the

gender ratio was nearly balanced.

Interventions: Six studies each tested oxycodone and tramadol, two studies each

buprenorphine, hydromorphine, morphine and tapentadol and one study each

codeine, fentanyl and oxymorphone. All oral opioids were administered by extended

release (ER) formulations except one four arm study which used in one treatment

arm immediate release morphine (appendix reference 6). 16 (80%) studies used a

flexible dosage of the opioid, the remaining ones used a fixed dosage. Five (25%)

studies did not report on rescue medication, three (15%) studies prohibited any

analgesic rescue medication and 12 (60%) studies allowed rescue medication

(acetaminophen, NSAIDs, short-acting opioids).

Study quality

Risk of bias could not be exactly assessed in all studies due to poor method

reporting. No study had a high study quality. Fourteen studies (70%) had a moderate,

five studies (20%) had a low study quality, and two studies (10%) had a very low

study quality (see Figure 2 for risk of bias graph and Figure 3 for risk of bias

summary). Detailed information regarding risk of bias assessments of every study are

given in the Electronic Supplementary Material table 4.

Synthesis of results

Parallel and cross-over design (Results are reported with 95% CI)

Sixteen studies with 6743 participants were entered into an analysis of mean pain

reduction at the end of the study. Opioids were superior to placebo (SMD -0.22 [-

0.28, -0.17]; p < 0.00001; I² = 21%) (moderate quality evidence). According to

Cohen’s categories the effects size was small (see Electronic Supplementary

Material figure 1). One study (appendix reference 2) did not report means and SDs,

but that tapentadol and oxycodone were not significantly superior to placebo.

Two studies with 2709 participants were entered into an analysis of 50% pain

reduction at the end of the study. Opioids were not superior to placebo (RD -0.01 [-

0.07, 0.06] p = 0.82, I² = 75%) (low quality evidence) (see Electronic Supplementary

Material figure 2).

13

Three studies with 2251 participants were entered into an analysis of Patients’ Global

Impression of Change (PGIC) reports to be much or very much improved at the end

of the study: Opioids were superior to placebo (RD 0.13 [0.05, 0.21]; p = 0.002; I² =

74%) (moderate quality evidence) (see Electronic Supplementary Material figure 3).

510/1018 (50.0%) of patients in opioid and 467/1233 (37.8%) of patients in placebo

groups reported to be much or very much improved (NNTB 8 [6-12]). According to

the predefined criteria there was an appreciable benefit by opioids (RRR 32 % [20%-

45%]).

Fourteen studies with 5887 participants were entered into an analysis of improved

physical functioning at the end of the study. Opioids were superior to placebo (SMD -

0.22 [-0.28, -0.17]; p < 0.00001; I² = 0%) (moderate quality evidence) (see Electronic

Supplementary Material figure 4). According to Cohen’s categories, the effect size

was small. Two studies did not report means and SDs. One study reported that

tramadol was superior to placebo (appendix reference 8). One study reported that

tapentadol and oxacodone were not superior to placebo (see appendix reference 2).

Fourteen studies with 6457 participants were entered into an analysis of drop outs

due to lack of efficacy. Patients dropped less frequently out in opioid than in placebo

group (RD -0.13 [.0.16, -0.10], p<0.0001, I²=72) (moderate quality evidence) (see

Electronic Supplementary Material figure 5). 386/3873 (10.0%) dropped out in opioid

and 596/2584 (23.1%) dropped out in placebo group (NNTB 8 [7-9]). According to the

predefined criteria there was an appreciable benefit by opioids (RRR 57 % [51%-

62%]).

Fifteen studies with 6834 participants were entered into an analysis of drop outs due

to adverse events. Patients dropped out more frequently with opioids than with

placebo (RD 0.17 [0.14, 0.21], p < 0.00001, I² = 77%) (moderate quality evidence)

(see Electronic Supplementary Material figure 6). 25.6% (1075/4207) of patients

dropped out in the opioid groups and 7.0% (184/2627) in placebo groups due to

adverse events (NNTH 5 [95% CI 4 - 6) (see Electronic Supplementary Material

figure 5). According to the predefined criteria there was an appreciable harm by

opioids (RRI 237 % [192%-291%]).

Eleven studies with 5520 participants were entered into an analysis of SAEs: There

was no significant difference between opioids and placebo (RD 0.00 [- 0.00, 0.01]; p



14

= 0.37; I² = 2%) (moderate quality evidence) (see Electronic Supplementary Material

figure 7).

Seven studies with 4694 participants were entered into an analysis of deaths. 1/2752

patients in opioid and 4/1942 in placebo groups dies during the study (RD - 0.00 [-

0.00, 0.00]; p = 0.88, I²=0%) (moderate quality evidence) (see Electronic

Supplementary Material figure 8).

EERW design

Three studies with 823 participants were entered into an analysis of mean pain

reduction from baseline to end of treatment. Opioids were superior to placebo (SMD -

0.26 [-0.49, -0.03]; p = 0.03; I² = 57%) (low quality evidence). According to Cohen’s

categories the effects size was small (see Electronic Supplementary Material figure

9).

One study with 344 participants was entered into a responder analysis of 50% pain

reduction at the end of the study. Opioid was not superior to placebo (RD 0.09 [-0.01,

0.20]; p = 0.08) (moderate quality evidence) (see Electronic Supplementary Material

figure10).

One study with 344 participants was entered into an analysis of physical functioning

at the end of the study. Opioid was not superior to placebo (SMD -0.13 [- 0.34, 0.08]

p = 0.24) (moderate quality evidence) (see Electronic Supplementary Material figure

11). One study reported that tramadol was superior to placebo (appendix reference

8) but did not provide means and SDs.

Four studies with 1178 participants were entered into an analysis of drop outs due to

lack of efficacy. Patients dropped less frequently out in opioid than in placebo group

(RD -0.13 [.0.18, -0.09], p<0.0001, I²=7) (moderate quality evidence) (see Electronic

Supplementary Material figure 12). 68/599 (11.4%) dropped out in opioid and

140/579 (24.2%) dropped out in placebo group (NNTB 8 [6-12]). According to the

predefined criteria there was an appreciable benefit by opioids (RRR 53 % [39%-

64%]).

Three studies with 826 participants were entered into an analysis of dropping out due

to adverse events. There was no significant difference between opioids and placebo

(RD 0.05 [-0.00, 0.11], p = 0.06, I² = 35%) (moderate quality evidence) (see

Electronic Supplementary Material figure 13).

Two studies with 756 participants were entered into an analysis of SAEs. There was

no significant difference between opioids and placebo (RD 0.01 [- 0.01, 0.03]; p =

15

0.40; I² = 0%) (moderate quality evidence) (see Electronic Supplementary Material

figure 14).

One study (appendix reference 10) with 412 participants explicitly stated that were no

deaths in both groups.

Subgroup and sensitivity analyses

In parallel and cross-over studies, opioids and opioids with additional mode of action

(tapentadol, tramadol) did not significantly differ in mean pain reduction (z= 0.01,

p=0.87). Thedrop out rates due to adverse events was higher with opioids than with

opioids with additional mode of action (z=3, p=0.003) (see table 2).

Removing two studies with means and SDs extracted from figures from analysis did

not change the significance and the magnitude of effect of pain reduction and

dropping out due to adverse events (details available on request).

Publication bias

The Kendall tau of the Begg rank correlation test of the outcome pain intensity

reduction of studies with a parallel and cross over design was significant (tau= -0.47,

P two-tailed = 0.0005). The Egger intercept of the outcome pain intensity of studies

with a parallel and cross over design was significant (intercept = -3.79, p two-tailed =

0.01). Both tests were indicative of a publication bias.

Discussion

Summary of main results

In short-term studies (4 - 12 weeks), opioids were superior in terms of efficacy and

inferior in terms of tolerability to placebo. Opioids and placebo did not differ in terms

of safety.The effect size of opioids on pain and physical function were small.

Comparison with other systematic reviews

The results of this systematic review on the efficacy, but also the limited tolerability of

opioids compared to placebo are consistent with the ones of previous systematic

reviews of Cochrane groups on opioids in OA pain. Cepeda and co-workers (

5) analysed 11 RCTs with a total of 1019 participants who received tramadol or

tramadol/ paracetamol and 920 participants who received placebo or active-control

irrespectively of study duration. Participants who received tramadol had less pain (-

8.5 units on a 0 to 100 scale; 95% CI -12.0 to -5.0) than patients who received

16

placebo. Of every 8 people who received tramadol or tramadol/ paracetamol, 1

(12.5%) stopped taking the medication because of adverse events, the NNTH was 8

(95% CI 7 to 12) for major adverse events.

Nüesch and coworkers (26) included ten trials with 2268 participants irrespectively of

study duration. Oral codeine was studied in three trials, transdermal fentanyl and oral

morphine in one trial each, oral oxycodone in four, and oral oxymorphone in two

trials. Overall, opioids were more effective than control interventions in terms of pain

relief (SMD -0.36, 95% CI -0.47 to -0.26) and improvement of function (SMD -0.33,

95% CI -0.45 to -0.21). The authors did not find substantial differences in effects

according to type of opioid, analgesic potency (strong or weak), daily dose and

duration of treatment. Adverse events were more frequent in patients receiving

opioids compared to control. The pooled risk ratio was 1.55 (95% CI 1.41 to 1.70) for

any adverse event (4 trials), 4.05 (95% CI 3.06 to 5.38) for dropouts due to adverse

events (10 trials), and 3.35 (95% CI 0.83 to 13.56) for SAEs (two trials).

Limitations

Only double-blind randomized placebo-controlled studies were included in this meta-

analysis, representing a high level in evidence based medicine. However, the

methodological quality of the included studies was predominantly at least moderate.

The blinding of outcome assessment was mostly unclear implying a high detection

bias. Complete data reporting was often doubtful, leading to a high attrition bias.

There was a high risk of selective reporting causing a relevant reporting bias. Almost

all studies were funded by the manufacturers of the tested drugs implying a high

funding bias.The external validity of the study results for OA-patients in routine

clinical care is limited, because no subgroup analyses of very aged patients (e.g. >75

years) was presented by any study. The Kendall tau of the Begg rank correlation test

of the outcome pain reduction and the Egger intercept of the outcome pain, both

were indicative for publication bias. Negative study results may not have been

published which can lead to an overestimation of the true intervention effect. On the

other hand, we might have underestimated the quality of studies because we did not

ask the authors for missing details. Summarizing, the methodological quality of the

studies and their reporting should be improved in future research.

The conclusion on the safety of opioids compared to placebo is limited by the low

number of serious adverse events and deaths.

17

Future research directions

The ability of systematic reviews of placebo-controlled studies to guide physicians

and patients in the choice of treatment options in chronic OA pain is very limited.

Head-to-head comparisons of opioids with other drugs have rarely been been

conducted in chronic OA pain (11,16). A comparative effectiveness review compared

Cox 1- and Cox 2-inhibitors (6) but did not include opioids. A recent systematic

review of head-to-head comparisons of opioids and non-opioid analgesics found low

quality evidence (five studies) that nonsteroidal agents were superior to tramadol in

pain reduction, improvement of physical function and tolerability (30). To provide a

superior evidence base for future treatment guidelines, additional RCTs must be

conducted in which existing drugs are directly compared with each other and

administered in various combinations. Additionally, whether non-pharmacological

approaches for the management of patients with chronic OA pain (eg, physical

therapy and life-style interventions) should be used before, in combination with, or

after pharmacological treatments, must be tested in clinical trials. Traditional RCTs

may not be the method of choice to answer all these questions; alternative

approaches should be developed and evaluated (eg, systematic comparative

effectiveness studies of health care registry data.

Conclusions for clinical practice

Opioids may be considered for the short-term treatment (4 - 24 weeks) of chronic OA

pain. However, clinicians should keep in mind that no current evidence-based

guideline recommends opioids as first-line treatment options for chronic OA pain

(11,16). In addition, recent data from the UK General Practice Research Database

indicated that the risk of fracture was increased during initiation of opioid therapy

(18).

The EULAR (European League Against Rheumatism) guideline recommended

patient information and education, lifestyle changes, exercise, weight loss, assistive

technology and adaptations, footwear and work as non-pharmacological treatments

(11). The ACR strongly recommended non-pharmacological therapies for the

management of knee OA such as aerobic, aquatic, and/ or resistance exercises as

well as weight loss for overweight patients. Non-pharmacological modalities

conditionally recommended for knee OA included medial wedge insoles for valgus

18

knee OA, subtalar strapped lateral insoles for varus knee OA, medially directed

patellar taping, manual therapy, walking aids, thermal agents, Tai Chi, self

management programs, and psychosocial interventions. Pharmacological modalities

conditionally recommended for the initial management of patients with knee OA

included acetaminophen, oral and topical NSAIDs (in combination with a proton-

pump inhibitor) and intraarticular corticosteroid injection. Intraarticular hyaluronate

injections, duloxetine, and opioids were conditionally recommended in patients who

had an inadequate response to initial therapy. Opioid analgesics were strongly

recommended in patients who were either not willing to undergo or had

contraindications for total joint arthroplasty after having failed medical therapy.

Recommendations for hip OA were similar to those for the management of knee OA

(16).

Long-term open-label studies demonstrated that a minority of patients with chronic

OA pain initially treated with opioids will experience a sustained (> 1 year) response

with no or tolerable side effects (14,29). Long-term ( 26 months) opioid therapy may

be offered to sustained responders to short-term opioid therapy and/ or to non-

responders to physical therapy and/ or life-style interventions or patients who are not

suited for total joint arthroplasty due to major medical diseases. However, the

potential benefits of long-term opioid therapy must be carefully weighted against the

potential risks of long-term opioid therapy such as aberrant drug use, increased

mortality, fractures and hypogonadism (15,18).

Achknowledgements

We thank Professor Sorgatz (Essen) for revieweing our extractions of the drop out

rates due to lack of efficacy.

19

Table 1: Overview of the randomized controlled trials in chronic osteoarthritis pain included into the systematic review (grouped by type of opioid in alphabetical order)

Buprenorphine

Reference Year Countries of study centers

Study design Population type Number of patients randomized

Interventions and control group

Duration of trial

Breivik 2010 Denmark, Finland, Norway, Sweden

Parallel Osteoarthritis pain 199

Stable dose NSAID or Coxib oral plus 7-day buprenorphine flexible 5 or 10 or 20 ug/h transdermal patch Stable dose NSAID or Coxib plus placebo transdermal patch

5 - 9 days screening 24 weeks titration and maintenance 4 weeks follow-up

Munera 2010 USA


7-day buprenorphine flexible 5 or 10 or 20 ug/h transdermal patch Placebo transdermal patch

1-week run-in period 3 weeks titration 1 week maintenance

Codeine




Duration of trial

Peloso Canada 2000


Codeine flexible 100 – 400 mg/d oral Placebo oral

Duration screening not reported 4 weeks titration and maintenance

20

Fentanyl




Duration of trial

Langford Great Britain 2006


Stable dosage of steroids or NSAIDS oral plus titration to individually optimal dosage of fentanyl 25,50,75 or 100 ug/h transdermal patch

Stable dosage of steroids or NSAIDS oral plus placebo transdermal patch

1 week screening 6 weeks titration and maintenance 3 days tapering off

Hydromorphone




Duration of trial

Rauck 2012 USA


Hydromorphone fixed 8 or 16 mg/d oral Placebo

≤ 2 weeks wash out ≤ 16 days titration 12 weeks maintenance ≤ 1 week taper

Vojtassak 2011 Slovakia


Hydromorphone fixed 32 mg/d oral Placebo

≤ 1 week screening 4 week titration 12 week maintenance 28 weeks open label

21

Morphine




Duration of trial (titration and maintenance)

Caldwell 2002 USA


Extended release morphine 30 mg/d once daily in the morning oral Extended release morphine 30 mg/d once daily in the evening oral Morphine 2x15 mg/d oral Placebo oral

Duration screening and wash-out not reported 4 weeks maintenance 26 weeks open label

Katz 2010 USA

Enriched-enrollment randomized withdrawal design

Osteoarthritis pain 547

Morphine and naltrexone extended release flexible 20 - 160 mg/d oral Placebo

Screening and wash-out ≤ 14 days ≤ 45 days open label titration 12 weeks double-blind withdrawal

22

Oxycodone


Study design

Population type Number of patients randomized



Caldwell 1999 USA

Enriched-enrollment randomized withdrawal


Oxycodone oral flexible 40 to 100 mg/d oral Placebo

Duration screening and wash-out not reported 4 weeks open label titration 4 weeks double-blind withdrawal

Friedmann USA 2011

Enriched-enrollment randomized withdrawal


Oxycodone oral flexible 10 - 80 mg/d oral

Duration screening and wash-out 4 - 10 days 2 weeks open label titration 12 weeks double-blind maintenance 6 months open label

Markenson 2005 USA


Oxycodone oral flexible up to 120 mg/d oral

Duration screening and wash-out not reported 13 weeks titration and maintenance

23

Oxymorphone


Study design




Matsumoto 2005 USA


Oxymorphone oral fixed 40 mg/d or 80 mg/ Oxycodone oral 40 mg/d Placebo

2 - 7 days wash-out 4 weeks fixed

Tapentadol




Duration of trial (weeks)

Afilalo 2010 Australia, Canada, New Zealand, USA

Parallel Osteoarthritis knee pain 1050

Tapentadol flexible 200 - 600 mg/d oral Oxycodon flexible 40 - 100 mg/d oral Placebo

< 2 weeks screening 3 - 7 days wash-out 3 weeks titration 12 weeks maintenance 10 - 14 days follow-up

Afilalo 2013 13 European countries


Tapentadol flexible 200 - 600 mg/d oral Oxycodon flexible 40 - 100 mg/d oral Placebo

Duration of screening not reported 3 - 7 days wash-out 3 weeks titration 12 weeks maintenance 2 weeks follow-up

24

Tramadol


Study design



Duration of trial (weeks)

Babul 2004 USA


Tramadol flexible 100 - 400 mg/d oral Placebo

3 - 7 days wash-out 1 week titration 12 weeks maintenance

Delemos 2011 USA


Tramadol fixed 100, 200 or 300 mg/d oral Placebo oral

2 - 7 days wash-out, 12 weeks maintenance, 1 week follow-up

Fishmann 2007 USA

Parallel Osteoarthritis knee or hip pain 552

Tramadol fixed 100, 200 or 300 mg/d oral Placebo

6 days titration 12 weeks maintenance

Fleischmann 2000 USA



10 days screening and wash-out 12 weeks titration and maintenance

Gana 2006 USA


Tramadol fixed 100, 200 or 300 or 400 mg/d oral Placebo

2 - 7 days wash-out 12 weeks maintenance 1 week follow-up

Thorne 2008 Canada

Cross-over Osteoarthritis 100


Up to 1 week wash-out 4 weeks each period 6 months open label

25

Table 2 : Effect sizes of diffent classes of opioids on selected outcome variables

Outcome

title

Number

of

studies

Number

of

patients

Effect size

[95% CI])

Heterog

eneity

I² [%]

Test for

overall

effect

p-value

Opioids

01 Pain 11 3509 SMD -0.23 (-0.32,

-0.14)

32 < 0.0001

02 Drop out

due to

adverse

events

8 3582 RR 4.68

(3,51,6.24)

72 < 0.0001

Opioids with additional mode of action *

01 Pain 6 3545 SMD -0.22 (-0,31,

-0.14)

14 < 0.0001

02 Drop out

due to

adverse

events

7 3618 RR 2.55

(2.06,3.14)

49 < 0.0001

Abbreviations: CI = Confidence interval; RR = Relative risk ; SMD = Standardized

mean difference; * tapentadol, tramadol

26

Figure 1: PRISMA Flow Diagram

Records identified through

database searching (n = 17 591)

CENTRAL: (n=3688) Medline: (n=6944) Scopus: (n=6959)

Scre

enin

g

Incl

ud

ed

Elig

ibili

ty

Iden

tifi

cati

on

Additional records identified through hand searching

(n = 52)

Records after duplicates removed (n = 12 601 )

Records screened (n = 12601 )

Records excluded (n =12 580)

Full-text articles assessed for eligibility

(n = 21 )

Full-text articles excluded, with reasons (n = 1)

Study design did not meet inclusion criteria (n=1)

Studies included in

qualitative synthesis (n = 20)

Studies included in quantitative synthesis

(meta-analysis) (n =20)

27

Figure 2: Risk of bias graph

Random sequence generation (selection bias)

Allocation concealment (selection bias)

Blinding of participants and personnel (performance bias)

Blinding of outcome assessment (detection bias)

Incomplete outcome data (attrition bias)

Selective reporting (reporting bias)

Selection bias

Funding bias

0% 25% 50% 75% 100%

Low risk of bias Unclear risk of bias High risk of bias

28

Figure 3: Risk of bias summary/ Study quality

(Study quality was defined according to the eight quality indicators as follows: high =

6 - 8, moderate = 3 – 5, low = 0 – 2,

29

Random

sequence g

enera

tion (

sele

ction b

ias)

Afilalo 2010 +

Afilalo 2013 ?

Babul 2004 +

Breivik 2010 +

Caldwell 1999 +

Caldwell 2002 ?

DeLemos 2011 +

Fishman 2007 +

Fleischmann 2000 +

Friedmann 2011 ?

Gana 2006 +

Katz 2010 +

Langford 2006 +

Markenson 2005 +

Matsumoto 2005 +

Munera 2010 ?

Peloso 2000 ?

Rauck 2013 ?

Thorne 2008 ?

Vojtassak 2011 +

Allo

ca

tio

n c

on

ce

alm

ent (s

ele

ctio

n b

ias)

+

?

?

+

+

?

+

+

?

?

+

?

+

+

?

?

?

?

?

?

Blin

din

g o

f p

art

icip

ants

an

d p

ers

on

ne

l (p

erf

orm

ance

bia

s)

?

+

+

+

+

+

+

+

+

?

+

+

+

?

+

+

+

+

+

?

Blin

din

g o

f o

utc

om

e a

sse

ssm

en

t (d

ete

ctio

n b

ias)

?

?

?

?

?

?

?

?

?

?

?

?

?

?

+

?

?

?

?

?

Inco

mp

lete

outc

om

e d

ata

(attritio

n b

ias)

?

?

?

?

?

?

?

?

?

?

?

?

?

?

?

?

–

?

?

?

Se

lective

rep

ort

ing (

repo

rtin

g b

ias)

+

–

–

?

–

–

?

–

?

–

?

+

–

?

–

+

–

?

?

+

Se

lection

bia

s

+

?

+

+

?

+

+

+

+

?

–

+

+

+

+

?

+

+

+

+

Fu

nd

ing

bia

s–

–

–

–

–

–

–

–

–

–

–

–

–

–

–

–

+

–

–

–

30

References

1. Altman DG, Bland JM. Interaction revisited: the difference between two

estimates. BMJ 2003;326(7382):219.

2. Andrianakos AA, Kontelis LK, Karamitsos DG. Prevalence of symptomatic knee,

hand and hip osteoarthritis in Greece. The ESORDIG study. J Rheumatol

2006;33:2507–2513.

3. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for

publication bias. Biometrics.1994;50:1088–1101.

4. Chaparro LE, Furlan AD, Deshpande A, Mailis-Gagnon A, Atlas S, Turk DC.

Opioids compared to placebo or other treatments for chronic low-back pain.

Cochrane Database Syst Rev 2013;8:CD004959.

5. Cepeda MS, Camargo F, Zea C, Valencia L. Tramadol for osteoarthritis. Cochrane

Database Syst Rev 2006;(3):CD005522.

6. Chou R, McDonagh MS, Nakamoto E, Griffin J. Analgesics for Osteoarthritis: An

Update of the 2006 Comparative Effectiveness Review. Comparative Effectiveness

Review No. 38. (Prepared by the Oregon Evidence-based Practice Center under

Contract No. HHSA 290 2007 10057 I) AHRQ Publication No. 11(12)-EHC076-EF.

Rockville, MD: Agency for Healthcare Research and Quality. October 2011.

www.effectivehealthcare.ahrq.gov/reports/final.cfm.Accessed February 1,2014

7. Cohen J. Statistical Power Analysis for the Behavoral Sciences. Hillsdale, NJ:

Lawrence Erlbaum Associates; 1988.

8. Egger M, Smith GD, Schneider M. Bias in meta-analysis detected by a simple,

graphical test. BMJ 1997;315:629–634

9. Fayers PM, Hays RD. Don't middle your MIDs: regression to the mean shrinks

estimates of minimally important differences. Qual Life Res 2014;23(1):1-4.

10. Felson DT. Epidemiology of knee and hip osteoarthritis. Epidemiol Rev.

1988;10:1–28.

11. Fernandes L, Hagen KB, Bijlsma JW, Andreassen O, Christensen P, Conaghan

PG, Doherty M, Geenen R, Hammond A, Kjeken I, Lohmander LS, Lund H, Mallen

CD, Nava T, Oliver S, Pavelka K, Pitsillidou I, da Silva JA, de la Torre J, Zanoli G,

Vliet Vlieland TP; European League Against Rheumatism (EULAR). EULAR

recommendations for the non-pharmacological core management of hip and knee

osteoarthritis. Ann Rheum Dis 2013;72(7):1125-35.

http://www.effectivehealthcare.ahrq.gov/reports/final.cfm.Accessed

31

12. Furlan AD, Sandoval JA, Mailis-Gagnon A, Tunks E. Opioids for chronic

noncancer pain: a meta-analysis of effectiveness and side effects. CMAJ

2006;174(11):1589-94.

13. Guyatt GH, Oxman AD, Kunz R, et al; GRADE Working Group. Going from

evidence to recommendations. BMJ 2008;336(7652):1049–1051.

14. Higgins JPT, Green S. Cochrane Handbook for systematic reviews of

intervention. Version 5.1.0. http://handbook.cochrane.org/

15. Häuser W, Bernardy K, Maier C. Long-term opioid therapy in chronic non-cancer

pain: A systematic review and meta-analysis of efficacy and harms in open-label

extension trials with a study duration of at least 26 weeks duration. Schmerz 2014, in

press.

16. Hochberg MC, Altman RD, April KT, Benkhalti M, Guyatt G, McGowan J,

Towheed T, Welch V, Wells G, Tugwell P; American College of Rheumatology.

American College of Rheumatology 2012 recommendations for the use of

nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and

knee. Arthritis Care Res (Hoboken) 2012;64(4):465-74.

17. Kissin I. Long-term opioid treatment of chronic nonmalignant pain: unproven

efficacy and neglected safety? J Pain Res 2013;6:513-29.

18. Li L, Setoguchi S, Cabral H, Jick S. Opioid use for noncancer pain and risk of

fracture in adults: a nested case-control study using the general practice

research database. Am J Epidemiol 2013 178(4):559-69.

19. Manchikanti L, Vallejo R, Manchikanti KN, Benyamin RM, Datta S, Christo PJ.

Effectiveness of long-term opioid therapy for chronic non-cancer pain. Pain Physician

2011;14(2):E133-56.

20. Michna E, Cheng WY, Korves C, Birnbaum H, Andrews R, Zhou Z, Joshi AV,

Schaaf D, Mardekian J, Sheng M. Systematic literature review and meta-analysis of

the efficacy and safety of prescription opioids, including abuse-deterrent formulations,

in non-cancer pain management. Pain Med 2014;15(1):79-92.

21. Moher D, Liberati A, Teztlaff J, Altman G and the PRISMA Group. Preferred

reporting items for systematic reviews and meta-analyses: The PRISMA Statement.

Ann Intern Med 2009;51:1-7.

http://handbook.cochrane.org/

32

22. Moore AR, Eccleston C, Derry S, Wiffen P, Bell RF, Straube S, McQuay H;

ACTINPAIN Writing Group of the IASP Special Interest Group on Systematic

Reviews in Pain Relief; Cochrane Pain, Palliative and Supportive Care Systematic

Review Group Editors. "Evidence" in chronic pain - establishing best practice in the

reporting of systematic reviews. Pain 2010;150(3):386-9.

23. Moore RA, Derry S, Wiffen PJ. Challenges in design and interpretation of chronic

pain trials. Br J Anaesth 2013;111(1):38-45.

24. Neogi T, Zhang Y. Epidemiology of osteoarthritis. Rheum Dis Clin North Am.

2013;39(1):1-19.

25. Noble M, Treadwell JR, Tregear SJ, Coates VH, Wiffen PJ, Akafomo C,

Schoelles KM. Long-term opioid management for chronic noncancer pain. Cochrane

Database Syst Rev 2010;(1):CD006605.

26. Nüesch E, Rutjes AW, Husni E, Welch V, Jüni P. Oral or transdermal opioids for

osteoarthritis of the knee or hip. Cochrane Database Syst Rev 2009;(4):CD003115.

27. Reinecke H, Sorgatz H; German Society for the Study of Pain (DGSS). [S3

guideline LONTS. Long-term administration of opioids for non-tumor pain]. Schmerz

2009;23(5):440-7.

28. Von Korff M, Kolodny A, Deyo RA, Chou R. Long-term opioid therapy

reconsidered. Ann Intern Med 2011;155(5):325-8.

29. Watson CP, Watt-Watson J, Chipman M. The long-term safety and efficacy of

opioids: a survey of 84 selected patients with intractable chronic noncancer pain.

Pain Res Manag 2010;15(4):213-7.

30. Welsch P, SOmmer C, Schiltenwolf M, Häöuser W. Opioids in chronic non-cancer

pain: Are opioids superior to non-opioid analgesics? A systematic review and meta-

analysis of efficacy and harms of randomized head-to head comparisons of opioids

versus non-opioid analgesics in studies of at least four weeks duration. Schmerz

2014, in press

31. Zacher J, Carl HD, Swoboda B, Backhaus M. [Imaging of osteoarthritis of the

peripheral joints]. Z Rheumatol 2007;66(3):257-8, 260-4, 266. German

33

Appendix references

1.Afilalo M, Etropolski MS, Kuperwasser B, Kelly K, Okamoto A, Van Hove I, Steup

A, Lange B, Rauschkolb C, Haeussler J. Efficacy and safety of Tapentadol extended

release compared with oxycodone controlled release for the management of

moderate to severe chronic pain related to osteoarthritis of the knee: a randomized,

double-blind, placebo- and active-controlled phase III study. Clin Drug Investig.

2010;30(8):489-505.

2. Afilalo M, Morlion B. Efficacy of tapentadol ER for managing moderate to severe

chronic pain. Pain Physician 2013;16(1):27-40.

3. Babul ND, Novek R, Chipman H, Roth SH, Gana T, Albert K. Efficacy and safety of

extended-release, once-daily tramadol in chronic pain: A randomized 12-week clinical

trial in osteoarthritis of the knee. J Pain Symptom Manage 2004; 28(1): 59-71

4. Breivik H, Ljosaa TM, Stengaard-Pedersen K. A 6-months, randomised, placebo-

controlled evaluation of efficacy and tolerability of a low-dose 7-day buprenorphine

transdermal patch in osteoarthritis patients naive to potent opioids. Scand J Pain

2010;1:122-41

5. Caldwell JR, Hale ME, Boyd RE, Hague JM, Iwan T, Shi M, Lacouture PG.

Treatment of osteoarthritis pain with controlled release oxycodone or fixed

combination oxycodone plus acetaminophen added to nonsteroidal antiinflammatory

drugs: A double blind, randomized, multicenter, placebo controlled trial.

J Rheumatol 1999; 26:862-869.

6. Caldwell JR, Rapoport RJ, Davis JC, Offenberg HL, Marker HW, Roth SH, Yuan

W, Eliot L, Babul N, Lynch PM. Efficacy and safety of a once-daily morphine

formulation in chronic, moderate-to-severe osteoarthritis pain: Results from a

randomized, placebo-controlled, doubleblind trial and an open-label extension trial. J

Pain Symptom Manage 2002; 23:278-291.

7. DeLemos BP, Xiang J, Benson C, Gana TJ, Pascual ML, Rosanna R, Fleming B.

Tramadol hydrochloride extended-release once-daily in the treatment of osteoarthritis

of the knee and/or hip: a double-blind, randomized, dose-ranging trial. Am J Ther

2011;18(3):216-26.

8. Fishman RL, Kistler CJ, Ellerbusch MT, Aparicio RT, Swami SS, Shirley ME, Jain

AK, Fortier L, Robertson S, Bouchard S. Efficacy and safety of 12 weeks of

osteoarthritic pain therapy with once-daily tramadol (Tramadol Contramid OAD). J

Opioid Manag 2007; 3(5):273-80.

http://www.ncbi.nlm.nih.gov/pubmed?term=DeLemos%20BP%5BAuthor%5D&cauthor=true&cauthor_uid=20215961

http://www.ncbi.nlm.nih.gov/pubmed?term=Xiang%20J%5BAuthor%5D&cauthor=true&cauthor_uid=20215961

http://www.ncbi.nlm.nih.gov/pubmed?term=Benson%20C%5BAuthor%5D&cauthor=true&cauthor_uid=20215961

http://www.ncbi.nlm.nih.gov/pubmed?term=Gana%20TJ%5BAuthor%5D&cauthor=true&cauthor_uid=20215961

http://www.ncbi.nlm.nih.gov/pubmed?term=Pascual%20ML%5BAuthor%5D&cauthor=true&cauthor_uid=20215961

http://www.ncbi.nlm.nih.gov/pubmed?term=Rosanna%20R%5BAuthor%5D&cauthor=true&cauthor_uid=20215961

http://www.ncbi.nlm.nih.gov/pubmed?term=Fleming%20B%5BAuthor%5D&cauthor=true&cauthor_uid=20215961

http://www.ncbi.nlm.nih.gov/pubmed/?term=delemos+BP

34

9. Fleischmann RM, Caldwell JR, Roth SH, Tesser JRP, Olson W, Kamin M.

Tramadol for the treatment of joint pain associated with osteoarthritis: a randomized,

double-blind, placebo-controlled trial. Curr Ther Res 2001; 62(2): 113-128.

10. Friedmann N, Klutzaritz V, Webster L. Efficacy and safety of an extended-release

oxycodone (Remoxy) formulation in patients with moderate to severe osteoarthritic

pain. J Opioid Manag 2011;7(3):193-202.

11. Gana TJ, Pascual ML,Fleming RR, Schein JR, Janagap CC, Xiang J. Extended-

release tramadol in the treatment of osteoarthritis: a multicenter, randomized, double-

blind, placebo-controlled clinical trial. Curr Med Res Opin 2006; 22(7):1391-1401.

12. Katz N, Hale M, Morris D. Morphine sulfate and naltrexone hydrochloride

extended release capsules in patients with chronic osteoarthritis pain. Postgrad Med

2010;122:112-18

13. Langford R, McKenna F, Ratcliffe S, Vojtassak J, Richarz U. Transdermal

fentanyl for improvement of pain and functioning in osteoarthritis: A randomized,

placebocontrolled trial. Arthritis Rheum 2006;54(6):1829–37.

14. Markenson JA, Croft J, Zhang PG, Richards P. Treatment of persistent pain

associated with osteoarthritis with controlled-release oxycodone tablets in a

randomized controlled clinical trial. Clin J Pain 2005;21(6): 524–35.

15. Matsumoto AK, Babul N, Ahdieh H. Oxymorphone extended-release tablets

relieve moderate to severe pain and improve physical function in osteoarthritis:

results of a randomized, double-blind, placebo- and active-controlled phase III trial.

Pain Med. 2005 Sep-Oct;6(5):357-66.

16. Munera C, Drehobl M, Sessler NE, Landau C. A randomized, placebo-controlled,

double-blinded, parallel-group, 5-week study of buprenorphine transdermal system in

adults with osteoarthritis. J Opioid Manag 2010;6:193-202.

17. Peloso PM, Bellamy N, Bensen W, Thomson GTD, Harsanyi Z, Babul N, Darke

AC. Double blind randomized placebo control trial of controlled release codeine in the

treatment of osteoarthritis of the hip or knee. J Rheumatol 2000;27: 76 4-7 71.

74.

18. Rauck R, Rapoport R, Thipphawong J. Results of a double-blind, placebo-

controlled, fixed-dose assessment of once-daily OROS® hydromorphone ER in

patients with moderate to severe pain associated with chronic osteoarthritis. Pain

Pract 2013;13(1):18-29.

19. Thorne C, Beaulieu AD, Callaghan DJ, O’Mahony WF, Bartlett JM, Knight R,

35

Kraag GR, Akhras R, Piraino PS, Eisenhoffer J, Harsanyi Z, Darke AC. A

randomized, double-blind, crossover comparison of the efficacy and safety of oral

controlled-release tramadol and placebo in patients with painful osteoarthritis. Pain

Res Manag 2008;13:93-102.

20. Vojtaššák J, Vojtaššák J, Jacobs A, Rynn L, Waechter S, Richarz U. A Phase

IIIb, Multicentre, Randomised, Parallel-Group, Placebo-Controlled, Double-Blind

Study to Investigate the Efficacy and Safety of OROS Hydromorphone in Subjects

with Moderate-to-Severe Chronic Pain Induced by Osteoarthritis of the Hip or the

Knee. Pain Res Treat 2011; 2011:239501

Excluded studies (with reason)

1.Burch F, Fishman R, Messina N, Corser B, Radulescu F, Sarbu A, Craciun-Nicodin

MM, Chiriac R, Beaulieu A, Rodrigues J, Beignot-Devalmont P, Duplan A, Robertson

S, Fortier L, Bouchard S. A comparison of the analgesic efficacy of Tramadol

Contramid OAD versus placebo in patients with pain due to osteoarthritis. J Pain

Symptom Manage 2007;34(3):328-38. (study design did not meet inclusion criteria)

36

Electronic supplementary tables Table 1: Search strategy PubMed November 18, 2013

Search Query Items found

#40 Search (#31 AND #34 AND #38) Filters: Publication date from 2008/10/01 to 2013/10/31

6938

#39 Search (#31 AND #34 AND #38) 22855

#38 Search (#35 OR #36 OR #37) 165885

#34 Search (#32 OR #33) 976115

#31 Search (#29 NOT #30) 2846830

#37 Search opiate[nm] OR anileridine[nm] OR carfentanil[nm] OR dezocine[nm] OR dihydroetorphine[nm] OR dihydrocodein[nm] OR dipipanone[nm] OR endomorphin[nm] OR eseroline[nm] OR hydroxycodeinone[nm] OR kaolin-pectin[nm] OR ketobemidone[nm] OR levomethadryl[nm] OR levomethadyl[nm] OR methynaloxone[nm] OR nocistatin[nm] OR oxycodein[nm] OR oxymorph[nm] OR paracymethadol[nm] OR paregoric[nm] OR protopine[nm] OR remifentanil[nm] OR sufentanyl[nm] OR tapentadol[nm]

2949

#36 Search Analgesics, Opioid[mh] OR Narcotics[mh] OR morphine derivatives[mh] OR narcotic[mh] OR opiate[mh] OR opioid[mh] OR acemethadone[mh] OR acetylmethadol[mh] OR alfentanil[mh] OR alphaprodine[mh] OR anileridine[mh] OR benzomorphan[mh] OR buprenorphine[mh] OR butorphanol[mh] OR carfentanil[mh] OR codeine[mh] OR dextromoramide[mh] OR dextropropoxyphene[mh] OR dezocine[mh] OR diacetylmorphine[mh] OR diamorphine[mh] OR dihydroetorphine[mh] OR dimepheptanol[mh] OR dionine[mh] OR diphenoxylate[mh] OR diprenorphine[mh] OR dihydrocodein[mh] OR dihydrohydroxycodeinone[mh] OR dihydromorphine[mh] OR dihydromorphinone[mh] OR dipipanone[mh] OR dynorphin[mh] OR endomorphin[mh] OR enkephalin[mh] OR eseroline[mh] OR etorphine[mh] OR ethylketocyclazocine[mh] OR ethylmorphine[mh] OR fenoperidine[mh] OR fentanyl[mh] OR heroin[mh] OR hydrocodon[mh] OR hydromorphon[mh] OR hydroxycodeinone[mh] OR isocodeine[mh] OR isonipecain[mh] OR isopromedol[mh] OR kaolin-pectin[mh] OR ketobemidone[mh] OR levallorphan[mh] OR levodroman[mh] OR levomethadryl[mh] OR levomethadyl[mh] OR levorphan[mh] OR meperidine[mh]

108754

http://www.ncbi.nlm.nih.gov/pubmed/advanced

http://www.ncbi.nlm.nih.gov/pubmed/?cmd=HistorySearch&querykey=40












37


OR meptazinol[mh] OR methadol[mh] OR methadone[mh] OR methadyl acetate [mh] OR morphia[mh] OR morphine[mh] OR methynaloxone[mh] OR nalbuphine[mh] OR nocistatin[mh] OR opium[mh] OR oxycodein[mh] OR oxycodone[mh] OR oxymorph[mh] OR pantopon[mh] OR papaveretum[mh] OR paracymethadol[mh] OR paregoric[mh] OR pentazocine[mh] OR pethidine[mh] OR phenazocine[mh] OR phenbenzorphan[mh] OR phenethylazocine[mh] OR phenoperidine[mh] OR pirinitramide[mh] OR promedol[mh] OR propoxyphene[mh] OR protopine[mh] OR pyrrolamidol[mh] OR remifentanil[mh] OR sufentanil[mh] OR sufentanyl[mh] OR talwin[mh] OR tapentadol[mh] OR thebaine[mh] OR theocodin[mh] OR tilidine[mh] OR tramadol[mh] OR trimeperidine[mh]

#35 Search Opioid Analgesics[tiab] OR Narcotics[tiab] OR morphine derivatives[tiab] OR narcotic[tiab] OR opiate[tiab] OR opioid[tiab] OR acemethadone[tiab] OR acetylmethadol[tiab] OR alfentanil[tiab] OR alphaprodine[tiab] OR anileridine[tiab] OR benzomorphan[tiab] OR buprenorphine[tiab] OR butorphanol[tiab] OR carfentanil[tiab] OR codeine[tiab] OR dextromoramide[tiab] OR dextropropoxyphene[tiab] OR dezocine[tiab] OR diacetylmorphine[tiab] OR diamorphine[tiab] OR dihydroetorphine[tiab] OR dimepheptanol[tiab] OR dionine[tiab] OR diphenoxylate[tiab] OR diprenorphine[tiab] OR dihydrocodein[tiab] OR dihydrohydroxycodeinone[tiab] OR dihydromorphine[tiab] OR dihydromorphinone[tiab] OR dipipanone[tiab] OR dynorphin[tiab] OR endomorphin[tiab] OR enkephalin[tiab] OR eseroline[tiab] OR etorphine[tiab] OR ethylketocyclazocine[tiab] OR ethylmorphine[tiab] OR fenoperidine[tiab] OR fentanyl[tiab] OR heroin[tiab] OR hydrocodon[tiab] OR hydromorphon[tiab] OR hydroxycodeinone[tiab] OR isocodeine[tiab] OR isonipecain[tiab] OR isopromedol[tiab] OR kaolin-pectin[tiab] OR ketobemidone[tiab] OR levallorphan[tiab] OR levodroman[tiab] OR levomethadryl[tiab] OR levomethadyl[tiab] OR levorphan[tiab] OR meperidine[tiab] OR meptazinol[tiab] OR methadol[tiab] OR methadone[tiab] OR methadyl acetate [tiab] OR morphia[tiab] OR morphine[tiab] OR methynaloxone[tiab] OR nalbuphine[tiab] OR nocistatin[tiab] OR opium[tiab] OR oxycodein[tiab] OR oxycodone[tiab] OR oxymorph[tiab] OR pantopon[tiab] OR papaveretum[tiab] OR paracymethadol[tiab] OR paregoric[tiab] OR pentazocine[tiab] OR pethidine[tiab] OR phenazocine[tiab]

141108



38


OR phenbenzorphan[tiab] OR phenethylazocine[tiab] OR phenoperidine[tiab] OR pirinitramide[tiab] OR promedol[tiab] OR propoxyphene[tiab] OR protopine[tiab] OR pyrrolamidol[tiab] OR remifentanil[tiab] OR sufentanil[tiab] OR sufentanyl[tiab] OR talwin[tiab] OR tapentadol[tiab] OR thebaine[tiab] OR theocodin[tiab] OR tilidine[tiab] OR tramadol[tiab] OR trimeperidine[tiab]

#33 Search chronic pain[mh] OR Chronic Disease[mh] OR Pain[mh] OR Pain Measurement[mh] OR Low Back pain[mh] OR Back Pain[mh] OR backache[mh] OR Osteoarthritis[mh] OR Rheumatoid arthritis[mh] OR Brachial Plexus Neuritis[mh] OR cervicobrachial pain syndrome[mh] OR Irritable bowel syndrome[mh] OR Irritable colon[mh] OR chronic pancreatitis[mh] OR Tension headache[mh] OR Headache[mh] OR Headache Disorders[mh] OR Temporomandibular joint syndrome[mh] OR globus syndrome[mh] OR Diabetic Neuropathies[mh] OR diabetic neuropath*[mh] OR Post herpetic neuralgia[mh] OR Postherpetic neuralgia[mh]OR neuropathic pain[mh] OR neuralgia[mh] OR polyneuropathies[mh] OR polyneuropathy[mh] OR Fibromyalgia[mh] OR Phantom Limb[mh] OR Phantom limb pain[mh] OR Cumulative Trauma Disorders[mh] OR Repetitive strain syndrome[mh] OR Whiplash Injuries[mh] OR Whiplash[mh]

704482

#32 Search chronic pain[tiab] OR Chronic Disease[tiab] OR Pain[tiab] OR Pain Measurement[tiab] OR Low Back pain[tiab] OR Back Pain[tiab] OR backache[tiab] OR Osteoarthritis[tiab] OR Rheumatoid arthritis[tiab] OR Brachial Plexus Neuritis[tiab] OR cervicobrachial pain syndrome[tiab] OR Irritable bowel syndrome[tiab] OR Irritable colon[tiab] OR chronic pancreatitis[tiab] OR Tension headache[tiab] OR Headache[tiab] OR Headache Disorders[tiab] OR Temporomandibular joint syndrom [tiab] OR globus syndrome[tiab] OR Diabetic Neuropathies[tiab] OR diabetic neuropath*[tiab] OR Post herpetic neuralgia[tiab] OR Postherpetic neuralgia[tiab]OR neuropathic pain[tiab] OR neuralgia[tiab] OR polyneuropathies[tiab] OR polyneuropathy[tiab] OR Fibromyalgia[tiab] OR Phantom Limb[tiab] OR Phantom limb pain[tiab] OR Cumulative Trauma Disorders[tiab] OR Repetitive strain syndrome[tiab] OR Whiplash Injuries[tiab] OR Whiplash[tiab]

572053

#30 Search animals[mh] NOT humans[mh] 3833757

#29 Search randomized controlled trial[pt] OR controlled 3308547









39


clinical trial[pt] OR randomized[tiab] OR placebo[tiab] OR drug therapy[sh] OR randomly[tiab] OR trial[tiab] OR groups[tiab] OR Systematic Review[pt] OR Systematic Review[tiab] OR Systematic Review[sh] OR Meta-Analysis[pt] OR Meta-Analysis[tiab] OR Meta-Analysis[sh] OR Cochrane Database Syst Rev[Journal]

40

41

Table 2. Criteria for risk of bias assessment for RCTs

1. Random sequence generation (selection bias)

Selection bias (biased allocation to interventions) due to inadequate generation

of a randomized sequence

There is a low risk of selection bias if the investigators describe a random component

in the sequence generation process such as: referring to a random number table,

using a computer random number generator, coin tossing, shuffling cards or

envelopes, throwing dice, drawing of lots or minimization (minimization may be

implemented without a random element, and this is considered to be equivalent to

being random).

There is a high risk of selection bias if the investigators describe a non-random

component in the sequence generation process such as: sequence generated by odd

or even date of birth, date (or day) of admission, hospital or clinic record number; or

allocation by judgement of the clinician, preference of the participant, results of a

laboratory test or a series of tests, or availability of the intervention.

2. Allocation concealment (selection bias)

Selection bias (biased allocation to interventions) due to inadequate

concealment of allocations prior to assignment

There is a low risk of selection bias if the participants and investigators enrolling

participants could not foresee assignment because one of the following, or an

equivalent method, was used to conceal allocation: central allocation (including

telephone, web-based and pharmacy-controlled randomization); sequentially

numbered drug containers of identical appearance; or sequentially numbered,

opaque, sealed envelopes.

There is a high risk of bias if participants or investigators enrolling participants could

possibly foresee assignments and thus introduce selection bias, such as allocation

based on: using an open randomallocation schedule (for example, a list of random

numbers); assignment envelopes were used without appropriate safeguards (for

example, if envelopes were unsealed or non-opaque or not sequentially numbered);

alternation or rotation; date of birth; case record number; or other explicitly

unconcealed procedures.

3. Blinding of participants and of personnel/ care providers (performance bias)

42

Performance bias due to knowledge of the allocated interventions by

participants and by personnel/care providers during the study

There is a low risk of performance bias if blinding of participants was ensured and it

was unlikely that the blinding could have been broken; or if there was no blinding or

incomplete blinding, but the review authors judge that the outcome is not likely to be

influenced by lack of blinding.

There is a low risk of performance bias if blinding of personnel was ensured and it

was unlikely that the blinding could have been broken; or if there was no blinding or

incomplete blinding, but the review authors judge that the outcome is not likely to be

influenced by lack of blinding.

4. Blinding of outcome assessor (detection bias)

Detection bias due to knowledge of the allocated interventions by outcome

assessors of patient reported outcomes

There is low risk of detection bias if the outcome assessor of patient-reported

outcomes is not the the clinical investigator but a statistician not involved in the

treatment of the patients. There is an unclear risk of bias if not details are reported

who was the outcome assessor. There is a high risk of bias if the outcome assessor

was involved in the treatment of the patients.

5. Incomplete outcome data (attrition bias)

Attrition bias due handling of incomplete outcome data

There is low risk of bias if all randomized patients were reported or analysed in the

group to which they were allocated by randomization and dropours were analysed by

baseline observation forward method (BOCF). There is an unclear risk of bias if all

randomized patients were reported or analysed in the group to which they were

allocated by randomization and dropouts were analysed by last observation

observation forward method (LOCF). There is a high risk of bias if there was no ITT-

analysis and only completers were reported.

6. Selective reporting (reporting bias)

Reporting bias due to selective outcome reporting

There is low risk of reporting bias if the study protocol is available and all of the

study’s pre-specified (primary and secondary) outcomes that are of interest in the

review have been reported in the pre-specified way, or if the study protocol is not

available but it is clear that the published reports include all expected outcomes,

43

including those that were pre-specified (convincing text of this nature may be

uncommon).

There is a high risk of reporting bias if not all of the study’s pre-specified primary

outcomes have been reported; one or more primary outcomes is reported using

measurements, analysis methods or subsets of the data (for example, subscales)

that were not pre-specified; one or more reported primary outcomes were not pre-

specified (unless clear justification for their reporting is provided, such as an

unexpected adverse effect); one or more outcomes of interest in the review are

reported incompletely so that they cannot be entered in a meta-analysis; the study

report fails to include results for a key outcome that would be expected to have been

reported for such a study.

7. Group similarity at baseline (selection bias)

Bias due to dissimilarity at baseline for the most important prognostic indicators.

There is low risk of bias if groups are similar at baseline for demographic factors,

value of main outcome measure(s), and important prognostic factors

8. Other bias (Funding bias)

We assumed a low risk of bias if the study was initiated by an investigator and the

study received no funding by a pharmaceutical company. We assumed a high risk of

bias if there was relationship of the authors with the pharmaceutical industry. We

extracted the following information about the relationship with the pharmaceutical

industry: author affiliation with industry, funding of study by industry, industry

providing the study drug or statistical analysis performed by an industry-affiliated

statistician. In case of affirmative response to any of these questions, we concluded

that there was a funding bias.

44

Table 3: Characteristics of included studies

Afilalo 2010

Methods Disease: Osteoarthritis pain

Study setting: 87 sites in US, 15 sites in Canada, 6 sites in new Zealand, 4 sites in Australia

Study design: Parallel design

Study duration: 3 weeks titration, 12 weeks maintenance

Participants Inclusion criteria: Age >= 40 years; diagnosis of osteoarthritis of the knee according to ACR criteria, functional capacity I-III, pain at the reference joints requiring the use of non-opioids or opioids at doses equivalent to <= 160 mg oral morphine/d for >=3 months prior to screening

Exclusion criteria: Presence of any clinically significant or unstable medical or psychiatric disease (e.g. history of substance abuse, chronic hepatitis B or C, HIV infection, uncontrolled hypertension, renal impairment (GFR < 60 ml/min), hepatic impairment (ALT or AST >= 3times the upper limit of normal)

Placebo: N=337; mean age 58.2 years; 59.3% female; 79.2% white. Severe pain 81.8 %

Tapentadol: N=344; mean age 58.4 years; 62.8% female; 75.6% white. Severe pain 81.8 %

Oxycodone: N=342;mean age 58.2 years; 59.1% female; 71.6% white. Severe pain 83.0%

Interventions Study medication: Tapentadol 200-500 mg/d (mean dosage approximately 350 mg/d); Oxycodon 40-100 mg/d (mean dosage approximately 70 mg/d), Placebo

Rescue medication: Paracetamol (up to 1000 mg/day for 3 consecutive days)

Allowed co-medication: Antidepressants for patients with controlled psychiatric or neurological diseases

Outcomes Pain: Pain intensity subscale of WOMAC at study

45

visit

Responder: 50% pain reduction NRS 0-10

PGIC: Much or very much improved

Function: Physical function subscale WOMAC *

Withdrawal due to adverse events: Reported

Serious adverse events: Reported

Death: Reported

Notes * The authors report ITT-analysis; however, the number of patients reported indicate rather per protocol analysis

46

Afilalo 2013


Study setting: 101 sites in 13 European countries;



Participants Inclusion criteria: Age >= 40 years; Patients diagnosed with osteoarthritis of the knee based on the American College of Rheumatology (ACR) criteria and functional capacity class of I- III;Patients taking analgesic medications for at least 3 months prior to screening and dissatisfied with their current therapy;Patients requiring opioid treatment must be taking daily doses of opioid- based analgesic, equivalent to <160 mg of oral morphine; Baseline score of >=5 on an 11-point numeric rating scale, calculated as the average pain intensity during the last 3 days prior to randomization

Exclusion criteria: History of alcohol and/or drug abuse in Investigator's judgment;Chronic hepatitis B or C, or HIV, presence of active hepatitis B or C within the past 3 months;Life-long history of seizure disorder or epilepsy;Uncontrolled hypertension;Patients with severely impaired renal function;Patients with moderate to severely impaired hepatic function or with laboratory values reflecting inadequate hepatic function; Treatment with neuroleptics, monoamine oxidase inhibitors, serotonin norepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants, anticonvulsants, or anti-parkinsonian drugs, treatment with any other analgesic therapy than investigational medication or rescue medication during the trial

Total sample: N=987; mean age 62.1 years; 60.4% female; 99.3% white. Severe pain 81.8 %

Interventions Study medication: Tapentadol 200-500 mg/d (mean daily dosage not reported); Oxycodon 40-100 mg/d (mean daily dosage not reported); Placebo

47

Rescue medication: No information given

Allowed com-medication: No information given

Outcomes Pain: Average pain intensity NRS 0-10; only LSMD vs placebo reported; no significant difference to placebo; data not usable for meta-analysis.

Responder: 50% pain reduction NRS 0-10

PGIC much or very much improved

Function: SF-36 physical functioning; only LSMD vs placebo reported; no significant difference to placebo; data not usable for meta-analysis.

Withdrawal due to adverse events: Reported for tapentadol and oxycodone, but not for placebo

Serious adverse events: Not reported

Death: Not explicitly stated

Notes The study was not published as a full paper; some data were presented in a pooled analysis of tapentadol studies in chronic pain. The authors stated: "Because the difference between the active comparator oxycodone and placebo was not statistically significant for either primary endpoint, this study must be considered a failed trial; hence, the lack of a statistically significant difference between tapentadol ER and placebo in the primary endpoint is not interpretable."

48

Babul 2004

Methods Diasease: Osteoarthritis pain

Study setting: 16 sites in US


Study duration: 3-7 days wash-out, 12 weeks titration and maintenance

Participants Inclusion criteria: At least 18 years of age and have Functional Class I–III, primary OA of the knee meeting ACR diagnostic criteria, defined by knee pain and recent radiographic evidence of osteophytes, plus at least one of the following: age 50 years, morning stiffness 30 minutes in duration, and/or crepitus; have involvement of at least one knee joint that has warranted treatment with acetaminophen, COX-2 inhibitors, NSAIDs, tramadol, or opioid analgesics for at least 75 of 90 days prior to the study; and have a baseline visual analogue scale (VAS) pain intensity score of 40 mm in the index joint.

Exclusion criteria: uncontrolled concomitant disease or chronic condition(s) that might interfere with the assessment of pain and other symptoms of OA; other prior disease or joint replacement at the index joint; likelihood of requiring a surgical procedure of the index joint(s) during the study; inflammatory arthritis, gout, pseudogout,or Paget’s disease that might interfere with the assessment of response; diagnosis of chronic pain syndrome; ACR or a clinical diagnosis of fibromyalgia; inability to discontinue acetaminophen, COX-2 inhibitors, NSAIDs (other than aspirin <=325 mg QD for cardiovascular prophylaxis), corticosteroids, or other analgesics for the duration of the double-blind study; use of oral, intramuscular, intravenous, or soft tissue corticosteroids within 1 month prior to the study; use of intra-articular corticosteroids in the index knee joint within 2 months prior to the study; intra-articular viscosupplementation in the index knee joint during the past 6 months, or intra-articular viscosupplementation in a non-index knee in the past 3 months; weight <= 100 lbs; history of clinically significant intolerance to

49

tramadol or a known hypersensitivity to opioid analgesics; and increased risk in terms of the precautions, warnings, and contraindications noted in the tramadol prescribing information.

Tramadol: N=124; mean age 61.2 years; 66.1% female; 78.2% white. Pain baseline 78.2 (±10)

Placebo:N=122; mean age 61.5 years; 56.6% female; 86.1 % white. Pain baseline 75.5 (±16.5)

Interventions Study medication: Upward titration up to tramadol 400mg/d (the mean tramadol dose was 276 mg )

Rescue medication: NSAIDs or other analgesics were not permitted during the washout period or double-blind period, except for acetaminophen up to 2000 mg per day for reasons other than for chronic pain, if absolutely necessary, and for no more than 3 consecutive days.

Allowed co-therapies: Glucosamine and chondroitin were permitted provided the patient was on stable doses for a minimum of 2 months prior to randomization and agreed to continue on the same dose for the duration of the study. Patients receiving physical therapy or using assistive devices upon entering the study were encouraged to continue these interventions throughout the study.

Outcomes Pain: Average daily pain intensity during the past 24 h VAS 0-100

Responder: No 50% pain reduction rates reported

PGIC: Not assessed

Function: The WOMAC (Western Ontario and McMaster Universities) OA Index Physical Function Subscale


Serious adverse events: Not explicitely reported


50

Breivik 2010


Study setting: 19 sites in Denmark, Finland, Norway, Sweden


Study duration: 24 weeks maintenance, follow-up after 4 weeks

Participants Inclusion criteria: Men and women over the age of 40 were included if they had a clinical diagnosis of osteoarthritis of the hip and/or knee, fulfilled the American College of Rheumatology (ACR) Criteria for osteoarthritis, had experienced pain from the relevant joint for at least one year prior to enrolment, had radiographic evidence of osteoarthritis of the hip and/or knee, as defined by Grades II to IV of the Kellgren and Lawrence scale, were taking NSAIDs or coxibs for their osteoarthritis pain for at least one month prior to the Screening Visit (visit 1), at a stable frequency and dose, and at least half the maximum allowed daily dose which gives an anti-inflammatory effect, they continued to experience at least moderate pain when walking on a flat surface, in spite of treatment with NSAIDs or coxibs, were willing to continue their treatment with NSAID or coxib, at a stable frequency and dose, until the end of the double-blind phase, those who had been using intermittently low-potent opioids (e.g. tramadol, low dose codeine) were willing to discontinue this regimen from the screening visit until the completion or discontinuation visit and take paracetamol tablets provided by the Sponsor as intermittent analgesic rescue, those who were receiving transcutaneous nerve stimulation (TENS) or biofeedback prior to study entry were willing to discontinue this therapy for the duration of the study.

Exclusion criteria: Patients were excluded if they had been treated with strong opioid analgesics (e.g. morphine, oxycodone, methadone, fentanyl-patch),were treated regularly with weak opioid analgesics such as tramadol, or codeine, for longer than three weeks prior to the screening visit; if any intermittent,

51

short-term, treatment with weak opioids could not be discontinued for the duration of the study; if they had a history of other chronic condition(s) for which they required frequent analgesic therapy (e.g., headaches, migraine, gout);were scheduled for any major surgery that would fall within the screening phase or the double-blind phase of the study; if transcutaneous nerve stimulation (TENS) or biofeedback prior to enrolment could not be discontinued for the duration of the study; if the investigator deemed that the patient had any contraindication to treatment with opioid medication, such as history of alcohol or substance abuse; if the patient had any other clinically significant disease or any reduced organ function; if the patient was using antidepressants, antiepileptic drugs, steroids, hypnotics (that may increase respiratory depression of buprenorphine); if the patient, or any close relatives, had long QT-syndrome, were on anti-arrhythmic medication (Class IA or Class III), or had any unstable or symptomatic cardiac abnormality.

Placebo: N=99; mean age 62.9 years; 64.7% female; 100% white. Pain baseline only reported in figure

Buprenorphine 5 or 10 or 20 ug/h: N=100; mean age 62.9 years; 72.0% female; 100% white. Pain baseline only reported in figure

Interventions Study medication: Titration to individually optimal dosage buprenorphine 5,10 or 20 ug/h; placebo

Rescue medication: Acetaminophen up to 4g/d

Allowed co-therapies: Stable dosage of NSAIDs

Outcomes Pain: Pain intensity NRS 0-10


PGIC: Much and very much improved

Function: WOMAC OA index of function


52


Death: Not explicitly stated: no deaths reported in section "serious adverse events"

53

Caldwell 1999



Study design: Enriched enrollment randomized withdrawal

Study duration: Open label titration for 30 days, 30 days double-blind withdrawal

Participants Inclusion criteria: Adult patients with moderate to severe average persistent daily pain > 1 month despite regular use of NSAIDS. The diagnosis of OA was based on 6 radiographic criteria.

Exclusion criteria: Ligitation related to pain or injury; intraarticular steroid injections within the last 6 weeks; active cancer; severe organic dysfunction; history of substance abuse

Oxycodone: N=34, mean age 57 years, race not reported. Pain baseline only reported in figure.

Placebo:N=36; mean age 58 years; 69% female, race not reported. Pain baseline only reported in figure.

Interventions Study medication: Oxycodone was adjusted (20 to 60 mg/d) in open label phase until pain intensity was less than moderate for several days in the absence of intolerable or unmanageable side effects (mean dosage 40 mg/d)

Rescue medication: No information provided.

Allowed co-therapies: NSAIDS were continued at prestudy dose, no other analgesics, stable steroid dose for at least 1 month.

Outcomes Pain: Mean global pain intensity at the end of double-blind phase compared to end of titration Pain Intensity NRS 0-10


PGIC: Not assessed

Function: Not assessed

54




Notes

55

Caldwell 2002




Study duration: 7 days days wash out, 4 weeks maintenance

Participants Inclusion criteria: Patients had to be at least 40 years of age and have both a clinical diagnosis and grade II-IV radiographic evidence of OA of the hip and/or knee; have had prior suboptimal analgesic response to treatment with NSAIDs and acetaminophen or had previously received intermittent opioid analgesic therapy; and have a baseline visual analogue scale (VAS) pain intensity score of 40 mm in the index joint.

Exclusion criteria: Patients with serious concomitant disease, chronic condition(s) that might interfere with the assessment of pain and other symptoms of OA, prior disease at the index joint, surgery or the likelihood of requiring a surgical procedure of the index joint(s) during the trial; diseases other than OA not well managed with treatment; weight 100 lbs; oral, intramuscular, intravenous, intra-articular, or soft tissue administration of steroids within 1 month of study drug administration (two months, if at index knee or hip joint); intra-articular viscosupplementation (in the index joint) within six months of trial treatment; opioid therapy for longer than three weeks prior to baseline; any history of substance abuse within two years prior to screening; and history of clinically significant intolerance to opioids or any known hypersensitivity to morphine or other opioid analgesics.

Extended release morphine 30 mg/d once daily in the morning: N=73; mean age 62.6 years; 59% female; 86% white. Pain baseline 62.6 (±9.5)

Extended release morphine 30 mg/d once daily in the evening: N=73; mean age

56

63.1years; 58% female; 82% white. Pain baseline 63.1 (±11.1)

Non-extended morphine 2x15 mg/d: N=76; mean age 61.9 years; 63% female; 90% white. Pain baseline 61.9 (±10.4)

Placebo:N=73; mean age 61.9 years; 70% female; 80 % white. Pain baseline 61.9 (±10.7)

Interventions Study medication: Extended release morphine 30 mg/d once daily in the morning (mean dosage not reported), extended release morphine 30 mg/d once daily in the evening (mean dosage not reported); Non-extended morphine 2x15 mg/d (mean dosage not reported); placebo twice/d

Rescue medication: Cardiovascular prophylactic doses of aspirin (up to 325 mg/day) and acetaminophen for non-OA symptomatology (up to 2000 mg/day for a maximum of 3 consecutive days) was prohibited in the double-blind trial. Acetaminophen had to be stopped 24 hours prior to efficacy assessments.

Allowed co-therapies: No information provided.

Outcomes Pain: Overall Arthritis Pain Intensity VAS 0-10


PGIC: Not assessed

Function: WOMAC Funcional Impairment subscale


Serious adverse events: Incompletely reported *


Notes * Details reported not sufficient to perform meta-analysis: "Six patients experienced a serious AE but only one (hospitalized for constipation) was thought to be possibly related to study drug (Avinza QPM); this patient withdrew from the trial due to this event.

57

DeLemos 2011



Study design: Parallel

Study duration: (1) 2-7 days wash-out, (2) 12 weeks maintenance, (3) 1 week follow-up

Participants Inclusion criteria: Aged 18-74 years with symptomatic (painful) OA of the kneehip and/or hipknee, radiographically confirmed ACR functional class I-III. Taken acetaminophen, NSAIDs, CO-2 inhibitor or an opioid at least 75 of 90 previous days to treat OA pain; moderate or severe OA pain that warranted treatment with COX-2-inhibitors, NSAIDs, acetaminophen, or opioid analgesics fort at least 75 of 90 days preceding the screening visit; baseline joint index pain of >= 40 on a 100 mm pain scale after wash-out. In addition, patients were required to be able to discontinue acetaminophen, NSAIDs, COX-2 inhibitors, opioids, and other analgesics during the study.

Exclusion criteria: Any medical condition other than OA which was not well controlled; inflammatroy arthritis, gout, pseudo-gout, or Paget disease; a chronic pain syndrome or fibromyalgia; prior joint replacement surgery at the index joint; history of substance abuse in the previous 6 months; use of antidepressants, anticonvulsants or other analgesics except acetaminophen.

Tramadol 100 mg/d: N=201; mean age 58.459.5 years; 62.458.2% female; 72.381.6% white. Pain baseline 298.4 (± 101.3)

Tramadol 200 mg/d: N=201; mean age 62.0 (± 9.9) years; 62.3% female; 78.4% white. Pain baseline 302.9 (± 96.1)

Tramadol 300 mg/d: N=201; mean age 59.7 years; 61.8% female; 80.9% white. Pain baseline 306.9 (± 107.3)

Placebo: N=200; mean age 58.9 years; 68.5% female; 82.5% white. Pain baseline 300.8 (±

58

103.5)

Interventions Study medication: Fixed dosage of 100, 200 or 300 mg tramadol/d; fixed dosage of placebo

Rescue medication: acetaminophen up to 2g/day for no more than 3 consecutive days for reasons other than OA or chronic pain. Use of acetaminophen was prohibited 48 h before each study visit.

Allowed co-therapies: No information provided

Outcomes Pain: WOMAC Pain Subscale


PGIC: Not assessed

Function: WOMAC OA physical function score 0-1700


Serious adverse events: Reported *

Death: Reported

Notes * Only treatment related SAE reported: Data not used for analysis

59

Fishmann 2007




Study duration: 6 days titration, 12 weeks maintenance

Participants Inclusion criteria: 40-75 years, diagnosis of OA according to ACR criteria; WOMAC OA Index pain score >= 150 mm;

Exclusion criteria: Arthritic conditions other than OA; history of seizures; evidence of effusion > 15 cc on physical examination; BMI >=38; major illnesses requiring hospitalization within 3 months before screening; unwillingness to discontinue pain medication or other medication taken for OA; previous or current substance abuse or dependence other than nicotine; significant bowel, renal or liver disease

Placebo: N=224; mean age 61 years; 61,6% female; race not reported. Pain baseline 30.1 (±8.9)

Tramadol 100 mg/d: N=103; mean age 63 years; 60.2% female; race not reported. Pain baseline 28.7 (±7.9)



Interventions Study medication: Tramadol fixed 100 mg/d or 200 mg/d or 300 mg/d

Rescue medication: Rescue medication of pain due to OA was not permitted.


Outcomes Pain: Relative percentage of pain improvement in WOMAC pain score from baseline

60


PGIC: Not reported

Function: WOMAC OA physical functioning score; no detailed outcomes reported *




Notes * The mean improvement in the WOMAC physical function score from baseline to end of the study was 46% for 300 mg/d (p=0.02 vs. placebo), 45% for 200 mg/d (p=0.045 vs. placebo) and 48% with 100 mg/d (p=0.03 vs. placebo) and 27% in placebo

61

Fleischmann 2000




Study duration: 10 days screening and wash-out,1 week titration and 11 weeks maintenance

Participants Inclusion criteria: aged 35 to 75 years with symptomatic (painful) OA of the knee for >=1 year were eligible for inclusion if they had used NSAlDs for >=3 months before study entry and were otherwise in good health. The diagnosis of OA was confirmed by demonstration of osteophytes on knee radiographs taken within a year before enrollment. Patients were required to have at least moderate pain (pain intensity r2 on a scale of 0 to 4, with 0 being the least and 4 being the greatest pain intensity) in the target knee when their current analgesic was discontinued.

Exclusion criteria: any other form of arthritis; major trauma, infection, or apparent avascular necrosis of the target knee within 6 months before study entry; or anatomical deformities of the knee that could interfere with assessment. In addition, patients were excluded if they underwent arthroscopic procedures within 6 months or surgical procedures on the target knee within a year before the study, or had knee replacements or were candidates for knee replacement within 1 year before the study. Patients who received intra-articular injections of corticosteroids in the knee within 1 month, hyaluronic acid injections in the knee or systemic corticosteroids within 3 months, or glucosamine within 10 days before the study were excluded. Also excluded were patients who, in the opinion of the investigator, should not have been enrolled in the study based on the precautions, warnings, or contraindications outlined in the tramadol package insert.

Placebo: N=66; mean age 62.5 years; 59.1% female; 86.4% white. Pain baseline 2.85 (± 0.63)

Tramadol: N=63; mean age 62.5 years; 65.1%

62

female; 95.2% white. Pain baseline 2.71 (± 0.63)

Interventions Study medication: Titration to individually optimal between 200 and 400 mg/d (mean dosage not reported)

Rescue medication: None allowed

Allowed co-therapies: Patients were instructed to maintain a constant level of activity throughout the study. Physiotherapy (ie, hot/cold packs and massages) initiated before the double-blind phase was continued throughout the study, although it could not be initiated during the double blind phase. Patients were not to use other adjunctive therapy (eg, topical therapy, acupuncture) during the study

Outcomes Pain: Pain intensity previous 24 hours NRS 0-4


PGIC: Not reported

Function: WOMAC OA function score




63

Friedmann 2011



Study design: Enriched enrollment randomized withdrawal design

Study duration: 4-10 days wash-out all medications (if >= 20mg Oxycodon or 200 mg Tramadol an opioid taper was required before), 2 weeks open label, 12 weeks double-blind withdrawal with option of dose escalation in the first 4 weeks

Participants Inclusion criteria: Male or female non-preganent women 40-75 years, moderate to severe pain due to OA for >=3 months owing to OA in the hip and or knee as demonstrated by clinical and radiological eveindence by the ACR-criteria; taking one or more of the following medications: NSAIds, COX2-inhibitors, opioids (>= 4 days/week for >= 4 weeks),NRS >= 5 after washout period ;

Exclusion criteria: Daily opioid dosage >=80 mg oxycodone equivalent for >=4 days/week during the week before initial screening; intararticular injections in the previous month; positive urine screening for opiates, amphetamines, cocaine, cannabinoids or methadone at baseline visit

Placebo: N=207; mean age 58.5 years; 68% female; 83% white. Pain baseline 7.6 (±1.36)

Oxycodone: N=205; mean age 58.0 years; 72% female; 82% white.Pain baseline 7.8 (±1.35)

Interventions Study medication: Titration to individually optimal up to 80 mg/d oxycodone (mean dosage 45 mg/d)

Rescue medication: Acetaminophen up to 3g/d

Allowed co-therapies: Stable dose of antidepressants, pregabalin, gabapentin, chondroitin

Outcomes Pain: Change in average pain intensity NRS 0-10 recorded via touch-phone

64


PGIC: Not reported

Function: WOMAC OA Index; no detailed outcomes reported *



Death: Reported

Notes * The mean change in the WOMAC subscales from prerandomisation to end of the study was only statistically significant for the pain subscale.

65

Gana 2006




Study duration: 2-7 days wash-out, 12 weeks maintenance, 1 week follow-up

Participants Inclusion criteria: aged 18-74 years with symptomatic (painful) OA of the knee or hip radiographically confirmed ACR functional class I-III. Taken acetaminophen, NSAIDs, CO-2 inhibitor or an opioid at least 75 of 90 previous days to treat OA pain; baseline joint index pain of >= 40 on a 100 mm pain scale after wash-out

Exclusion criteria: Any medical condition other than OA which that was not well controlled; any other form of arthritis or joint dsease at the index joint; a chronic pain syndrome or fibromyalgia; any contraindication for the use of tramadol; history of substance abuse in the previous 6 months; any condition that was likely to influence the absorption, efficacy, or safety of tramadol ER. Subjects were not permitted to take another investigational medication, a corticosteroid, a medication that could interact with tramadol (e.g., carbamazepine), or another medication for pain (e.g., analgesics, antidepressants) during the study use of antidepressants, anticonvulsants or other analgesics except acetaminophen

Placebo: N=205; mean age 56.4 (±9.8) years; 68.8% female; 81.5% white. Pain baseline 305.9 (± 95.2)

Tramadol ER 100 mg/d: N=202; mean age 58.4 (±10.9) years; 62.4% female; 72.3% white. Pain baseline 308.2 (±99.3)



66


Interventions Study medication: Fixed dosage of 100, 200, 300 or 400 mg tramadol/d, placebo

Rescue medication: acetaminophen up to 2g/day for no more than 3 consecutive days for reasons other than OA or chronic pain. Use of acetaminophen was prohibited 48 h before each study visit.

Allowed co-therapies: Subjects were not permitted to take another investigational medication, a corticosteroid, a medication that could interact with tramadol (e.g., carbamazepine), or another medication for pain (e.g., analgesics, antidepressants) during the study except acetaminoph

Outcomes Pain: WOMAC Osteoarthritis Pain Index 0-500


PGIC: Not assessed

Function: WOMAC OA function score 0-1700




67

Katz 2010


Study setting: Number of US sites not reported

Study design: Enriched-enrollment randomized withdrawal

Study duration: 7-14 days wash-out, <= 45 days titration, 12 weeks maintenance

Participants Inclusion criteria: Male and female subjects aged ≥21 years, OA (as defined by the American College of Rheumatology) of the hip or knee. Moderate-to-severe OA pain was defined as an average 24-hour pain intensity score of ≥5 on a scale of 0–10 at baseline visit following cessation of previous medication .Subjects must have suffered from chronic OA pain in the target joint for more than 3 months, and their pain must not have been adequately controlled with either nonopioid analgesics, tramadol or another opioid at a dose equivalent of <= 40 mg/d morphine for 3 months before beginning the study.

Exclusion criteria: History of drug or alcohol abuse within the last 5 years; positive urine toxicology test for illicit drugs or non prescribed controlled substances at screening; established history or uncontrolled major depressive disorder; any other chronic condition that would interfere with or confound the study results; history of rheumatoid or inflammatory rheumatoid arthritis

Morphine/Naloxone: N=171; mean age 54.2 years; 62% female; 74.9% white. Pain baseline 3.3 (± 1.3)

Placebo:N=73; mean age 54.7 years; 54.9% female; 69.9 % white, Pain baseline 3.2 (± 1.1)

Interventions Study medication: Dose titration of morphine, starting with 20 mg/d, increments up to 160 mg/d. Responders were defined by BPI score <=4 over the last 4 days before clinic visit and decline by >02 points from baseline

Rescue medication: Acetaminophen <= 3g/d.


68

Outcomes Pain: Average pain intensity NRS 0-10 of Brief Pain Inventory electronic diary

Responder: 50% pain reduction from the titration baseline visit

PGIC: Not assessed





69

Langford 2006


Study setting: Several European countries


Study duration: 6 weeks maintenance

Participants Inclusion criteria: Patients (at least 40 years of age) meeting the American College of Rheumatology diagnostic criteria for hip or knee OA and requiring joint replacement surgery, with radiographic evidence of disease in the affected joint(s);moderate or severe pain that was not adequately controlled with weak opioids, with or without paracetamol

Exclusion criteria: Patients who received any strong opioid in the 4 weeks before the study or had recently started a new therapy (e.g., physiotherapy or acupuncture) for their pain. Those patients deemed unsuitable for treatment with a strong opioid (e.g., because of suspected alcohol or drug abuse, or because they were considered at risk for respiratory depression)

Placebo: N=197; mean age 66 years; 68% female; race not reported. Pain baseline 73.3 (no SD reported)

Fentanyl: N=202; mean age 66 years; 65% female; race not reported. Pain baseline 73.1 (no SD reported)

Interventions Study medication: Stable dosage of steroids or NSAIDS plus titration to individually optimal dosage of fentanyl 25,50,75 or 100 ug/h (no average dosage reported); Stable dosage of steroids or NSAIDS plus placebo

Rescue medication: None

Allowed co-therapies: Paracetamol up to 4g/d allowed

Outcomes Pain: Average pain intensity score NRS 0-100


70

PGIC: Not assessed

Function: WOMAC physical functioning

Withdrawal due to adverse events: Not reported


Death: Reported

71

Markenson 2005

Methods Diasease: Osteoarthritis pain independent of location (~40% Back pain)



Study duration: 12 weeks titration and maintenance

Participants Inclusion criteria: OA, as defined by the American College of Rheumatology guidelines. Patients selected were experiencing moderate to severe pain in the most affected joint or region, as characterized by: 1) complaints of pain for at least 1 month before day 0 (baseline) or after the patient had discontinued their as necessary opioid; and 2) pain during the week before day 0 that was moderate to severe, defined as an average score of 5 or greater (3 or greater if receiving as necessary opioids) on a scale from 0 (no pain) to 10 (pain as bad as you can imagine). Eligible patients: 1) had been taking NSAIDs or APAP at a therapeutic and/or tolerated (but not as necessary) dose for at least 2 weeks before day 0; 2) were not taking NSAIDs because they were NSAIDintolerant or at high risk for toxicity or complications; or 3) were receiving as necessary oral opioid therapy that was equivalent to 60 mg of oxycodone per day (with or without NSAIDs or APAP for analgesia).

Exclusion criteria: allergic to opioids, were scheduled to have surgery during the study period, had unstable coexisting disease or active dysfunction, had active cancer, were pregnant or nursing, had a past or present history of substance abuse, were involved in litigation related to their pain, or had received intra-articular or intramuscular steroid injections involving the joint or site under evaluation within 6 weeks prior to baseline.

Oxycodone: N=56; mean age 62 years; 68% female; 93% white. Pain baseline 6.9 (± 1.5)

Placebo:N=51; mean age 64 years; 78% female;

72

94 % white. Pain baseline 6.3 (± 1.4)

Interventions Study medication: Upward titration up to 120 mg oxycodone/d (average dosage (44 ± 5 mg)

Rescue medication: No information provided

Allowed co-therapies: Patients were permitted to continue their stable NSAID (or APAP) regimen during the study; the dose could be decreased but could not be increased

Outcomes Pain: Average daily pain intensity during the past 24 h NRS 0-10 BPI

Responder: Not assessed

PGIC: Not assessed

Function: WOMAC physical functioning score




73

Matsumoto 2005


Study setting: Number of US sites not reported


Study duration: 2-7 days wash-out, 4 weeks maintenance

Participants Inclusion criteria: presence of typical knee or hip joint symptoms and signs and radiographic evidence of OA, with a minimum of grade 2 in the index joint using the Kellgren–Lawrence scale. Patients must have taken either acetaminophen, a conventional NSAID, a COX-2 inhibitor, or an opioid analgesic for at least 75 of 90 days before the screening visit and must have had a suboptimal response to these agents. Other inclusion criteria included age >40 years, use of a medically acceptable form of contraception or abstinence in women of childbearing test 7 days before first dose of study medication. Eligible patients entered a 2- to 7-day washout period during which all analgesic medications were discontinued. Patients were randomized when pain in the index joint reached 40

Exclusion criteria: inflammatory arthritis, gout, Paget’s disease, chronic pain syndrome, or fibromyalgia were excluded. Patients requiring knee or hip arthroplasty within 2 months of screening or anticipating any need for surgical procedures on the index joint during the study were also excluded. Other exclusion criteria included weight <100 pounds, difficulty swallowing capsules or tablets, prior history of substance or alcohol abuse, corticosteroid or investigational drug use within 1 month of first study treatment, and prior history of intolerance to opioids.

Oxymorphone 80 mg/d : N=121; mean age 61.4 years; 64.5% female; 87.6% white. Pain baseline not reported *

Oxymorphone 40 mg/d : N=119; mean age 63.4 years; 55.5% female; 81.5% white. Pain baseline

74

not reported *

Oxycodone 40 mg/d : N=125; mean age 62.7 years; 57.6% female; 89.6% white. Pain baseline not reported *

Placebo:N=124; mean age 61.7 years; 65.3% female; 86.3 % white, Pain baseline not reported *

Interventions Study medication: To improve tolerability, patients randomized to the oxymorphone ER 40 mg treatment group received oxymorphone ER 20 mg every 12 hours during weeks 1 and 2 and oxymorphone ER 40 mg every 12 hours during weeks 3 and 4. Similarly, patients randomized to oxycodone CR 20 mg received oxycodone CR 10 mg every 12 hours during weeks 1 and 2 and oxycodone CR 20 mg every 12 hours during weeks 3 and 4.



Outcomes Pain: WOMAC Pain score VAS 0-500 **


PGIC: Not assessed

Function: WOMAC Funcional Impairment subscale * and SF-36 physical component score ***


Serious adverse events: Incompletely Reported ****


Notes * "The mean baseline scores for the VAS were similar across all treatment groups"

** Data extracted from figures

*** Data of WOMAC only reported in figures; data of SF-36 reported by numbers and therefore chosen for meta-analysis

**** "Five patients had serious AEs that were not considered to be related to study medication."

75

76

Munera 2010




Study duration: 3 weeks titration, 1 week maintenance

Participants Inclusion criteria: Age >= 18 years; documented history and/or radiologic evidence of chronic osteoarthritis of the hip or knee; receiving opioid therapy for osteoarthritis-related pain within the past year or have experienced pain that was inadequately controlled with a full standard dose of NSAIDs; average pain intensity >=7

Exclusion criteria: receiving opioids at an average daily dose of greater than 90 mg of oral morphine equivalents or patients receiving more than 12 tablets or capsules per day of short-acting opioid-containing products;scheduled to have surgery (including dental) during the study period that involved the use of pre- and/or postoperative analgesics or anesthetics.

Placebo: N=163; mean age 62 years; 67% female; 87% white. Pain baseline not reported

Buprenorphine 5,10 or 20 ug/h: N=152; mean age 60 years; 67% female; 87% white. Pain baseline not reported

Interventions Study medication: Titration to individually optimal dosage buprenorphine 5,10 or 20 ug/h (no average dosage reported); placebo

Rescue medication: None

Allowed co-therapies: Aspirin as antithrombotic >=325 mg/d allowed

Outcomes Pain: Average pain intensity score NRS 0-10;


PGIC: Not assessed

77

Function: Not assessed



Death: Reported

78

Peloso 2000


Study setting: 4 sites in Canada


Study duration: 4 weeks maintenance

Participants Inclusion criteria: Age >= 35 years; primary osteoarthritis garde II defined by standard atlas of radiographs of the knee or hip with symptoms (pain, stiffness, disability requiring the use of acetaminophen, NSAIDS or opioid analgesics for the previous 3 months or longer.

Exclusion criteria: Allergy against analgesics,history of previous opioid abuse; secondary osteoarthritis; grade IV osteoarthritis awaiting surgery

Placebo: N=52; mean age 63.0 years; 65.7 % female; Race not reported, Pain baseline 53.2 (±24.5)

Codeine: N=51; mean age 60.1 years; 58.1% female; Race not reported. Pain baseline 58.2 (±18.9)

Interventions Study medication: Titration to individually optimal dosage of codeine 100-400 mg/d (mean daily dosage 159 ± 52 mg/d); placebo

Rescue medication: Acetaminophen


Outcomes Pain: Average pain intensity 24 h score VAS 0-100;


PGIC: Not assessed

Function: WOMAC physical function (VAS 0-1700)



79

Death: Reported

Notes

80

Rauck 2013


Study setting: Number of study sites in US not reported


Study duration: <= 16 days titration, 12 weeks maintenance, <=1 week taper

Participants Inclusion criteria: Male or female patients aged >= 21 years with OA of the hip or knee, reporting a target joint pain score of ‡ 5 on the NRS, who were unable to consistently control or treat their pain with nonopioid medications or who had received an opioid for pain treatment. Eligible patients were considered to be in good general health at the time of screening. based on results from medical history, physical examination, laboratory profile, and 12-lead electrocardiogram. Patients were required to have a primary diagnosis of Functional Class I–III OA of the knee or hip. In the case of OA of the knee, primary OA was characterized by knee pain, radiographic severity Grade II–IV, radiographic evidence (< 12 months) of target joint osteophytes, and at least one of the following symptoms: > 50 years of age, morning stiffness < 30 minutes in duration, or crepitus. In the case of OA of the hip, primary OA was characterized by articular hip pain, radiographic severity Grade II–IV, radiographic evidence (< 12 months) of target joint osteophytes, and target joint space narrowing.

Exclusion criteria: Patients with clinically significant intolerance to hydromorphone or other opioids were excluded from the study. In addition, those who had severe asthma; were pregnant or breastfeeding; were being treated with monoamine oxidase inhibitors; or had a history of drug or analgesic abuse, dependence, or misuse, or alcohol abuse within the last 5 years were not eligible. Patients were also excluded if they had a

81

chronic pain syndrome that could interfere with the study’s assessment of pain or other symptoms of OA (eg, fibromyalgia), a documented history of uncontrolled inflammatory arthritis (eg, rheumatoid arthritis), inflammatory arthritis dependent on nonsteroidal anti-inflammatory drugs (NSAIDs), significant clinical abnormalities in laboratory analyses, including hematology and urinanalysis, or other conditions that might interfere with dose administration. This study also excluded patients who were unable to wash out other opioids before the start of the study or who participated in a previous controlled-release hydromorphone HCl study

Hydromorphone 8 mg: N=319; mean age 59.7 years; 64.6% female; 88.3% white. Pain baseline 7.2 (±1.5)

Hydromorphone 16 mg: N=330; mean age 59.5 years; 64.2% female; 86.1% white. Pain baseline 7.5 (±1.4)

Placebo:N=332; mean age 60 years; 63% female; 88.3 % white. Pain baseline 7.4 (±1.4)

Interventions Study medication: Hydromorphone 8 mg, Hydromorphone 16 mg, Placebo

Rescue medication: Acetaminophen (< 2,000 mg daily) was permitted as supplemental analgesia during the titration, maintenance, and taper phases.


Outcomes Pain: Mean change from average pain intensity baseline NRS 0-10


PGIC: Not assessed





82

Notes This study did not meet the primary endpoint of improvement in pain intensity as analyzed with the primary imputation method, BOCF.

83

Thorne 2008


Study setting: 6 sites in Canada

Study design: Cross over

Study duration: (1) Analgesic wash-out for 2-7 days; Up to 1 week wash-out, (2) 4 weeks each periodAfter four weeks, patients crossed over to the alternate treatment for another four weeks.

Participants Inclusion criteria: Men and nonpregnant, non-nursing women over the age of 18 years, diagnosed with OA and requiring the use of acetaminophen,anti-inflammatory agents or combination opioid and nonopioid analgesics for at least three months were eligible for the present study. OA was defined by the presence of hip and/or knee symptoms (pain, stiffness, disability) and signs (bony crepitus), as well as radiographic evidence of OA in the medial and/or lateral tibiofemoral compartment (with or without patellofemoral OA), or in the hip. Radiographic evidence was defined by the presence of at least one of the following: osteophytes, joint space narrowing, periarticular sclerosis or subchondral cysts, with a minimum grade 2 severity, as illustrated in the Atlas of Standard Radiographs of Arthritis . Ptients with more advanced grades were eligible if they were not awaiting surgery. Patients using only acetaminophen at the time of enrollment were required to have pain of at least moderate intensity (a 2 or greater on a 0 to 4 ordinal pain scale) at both visits 1 and 2. Patients treated with any other opioid or nonopioid analgesic were required to have at least moderate pain (a 2 or greater on a 0 to 4 ordinal pain scale) after a two to seven day washout period at visit 2.

Exclusion criteria: intolerance to any opioid, tramadol or acetaminophen; Patients who required more than eight tablets per day of acetaminophen plus codeine, or its analgesic equivalent, or with a history of drug or alcohol abuse were also excluded. The following medical conditions were exclusionary: any other form of joint disease or previous replacement of the study joint, renal or

84

hepatic impairment (alanine aminotransferase or aspartate aminotransferase more than two times the upper limit of the normal range), shortened gastrointestinal transit time, peptic ulcer disease, inflammatory disease of the gastrointestinal tract, cardiac or respiratory conditions that put the patient at risk for respiratory depression, a history of seizures or a recognized risk for seizure, and any other condition that would adversely affect the patient’s safety or obscure the assessment of efficacy. Patients receiving monoamine oxidase inhibitors, carbamazepine, quinidine, selective serotonin reuptake inhibitors or tricyclic antidepressants, cyclobenzaprine, promethazine, neuroleptics, warfarin or digoxin were excluded. Patients who received an investigational drug within the last month were also ineligible.

Total sample: N=100; mean age 61 years; 55% female; race not reported. Pain baseline 50.8 (±17.9)

Interventions Study medication: Tramadol flexible 100-400 mg/d placebo (average dosage 340 mg/d)

Rescue medication: Acetaminophen up to 2.6 g/d


Outcomes Pain: Average pain intensity last 24 hours VAS 0-100


PGIC: Not assessed

Function: WOMAC physical function subscale




Notes ""An analysis of carry-over effect found no significance"

85

Vojtassak 2011


Study setting: 18 sites in four European countries (Czech republic, Romania, Slovakia, UK)



Participants Inclusion criteria: Male and female subjects aged ≥40 years, with moderate-to-severe pain induced byOA (as defined by the American College of Rheumatology) of the hip or knee. Moderate-to-severe OA pain was defined as a mean weekly score of ≥5 on a scale of 0–10 for “pain on average” on the BPI scale, which was calculated as a mean of the pain assessments collected at screening visit (week −1), telephone call (week –0.5), and baseline visit (week 0).Subjects must have suffered from chronic OA pain in the target joint for more than 3 months, and their pain must not have been adequately controlled with daily analgesic (NSAIDs or paracetamol) treatment for the month before beginning the study.

Exclusion criteria: regular treatment with an opioid in the 4 weeks before the screening visit—infrequent use of tramadol, codeine, tilidine, or dihydrocodeine for no more than 10 days in the 4 weeks before the screening visit was acceptable, but subjects were to stop any use of weak opioids at the screening visit, another type of continuous pain that stood out in comparison with OA pain such as fibromyalgia, cervical radiculopathy, or chronic low back pain, any of the following 6 months before entering study: major trauma to target joints, infection in target joints, radiologically apparent avascular necrosis in target joints, hyaluronan injections in the target joints, arthrodesis in the year or arthroscopy in the 2 months before entering study, planned treatment that could have altered the degree of pain within the study period, subjects who were being treated with buprenorphine,

86

nalbuphine, or pentazocine; corticosteroid injections in the 3 months before the start of the study.

Hydromorphone: N=139; mean age 65 years; 77% female; 100% white. Pain baseline 6.6 (±1.04)

Placebo:N=149; mean age 66 years; 68% female; 100 % white. Pain baseline 6.5 (±0.94)

Interventions Study medication: Hydromorphone. Treatment comprised a 4-week titration phase and a 12-week maintenance phase. In the event of unsatisfactory pain control, subjects had their dose titrated 3-4 days after randomisation until week 4 of the study with intervals of at least 3-4 days between dose increments. Possible doses were 4mg, 8mg, 12 mg, 16mg, 24 mg, and a maximum daily dose of 32 mg. There followed a 12-week maintenance phase on as stable a dose as possible. If a dose of 32mg did not provide sufficient analgesia, subjects were withdrawn owing to lack of efficacy and had their dose tapered off by reducing their dose in specified increments every 2 days..



Outcomes Pain: Average pain intensity NRS 0-10 of Brief Pain Inventory


PGIC: Not assessed





87

Table 4: Risk of bias assessment of RCTs with opioids in chronic osteoarthritis pain

inlcuded into the review

Afilalo 2010

Bias Authors'

judgement Support for judgement


Low risk Computer-generated randomization list


Low risk Randomization was implemented by interactive voice response system


Unclear risk We had insufficient information to permit judgement.


Unclear risk No details provided. Outcomes assessors could be bias based on the side effects profile of tapentadol.


Unclear risk ITT-analysis according to LOCF

Selective reporting (reporting bias) Low risk NCT00421928; All outcomes as reported in the protocol were published

Selection bias Low risk No significant baseline differences in demographic and clinical variables between the three groups

Funding bias High risk Funding by pharmaceutical industry; 8 of 9 authors affiliated with industry

88

Afilalo 2013

Bias Authors'



Unclear risk "Study medication assigned to patients by chance"


Unclear risk "Study medication assigned to patients by chance"


Unclear risk "Neither patient nor investigator knows which patient gets which study medication"


Unclear risk We had insufficient information to permit judgement.Outcomes assessors could be biased by the side effects profile of tapentadol.


Unclear risk ITT-analysis according to LOCF

Selective reporting (reporting bias) High risk NCT00486811; drop out rates due to serious adverse events for placebo group not reported; serious adverse events not reported

Selection bias Unclear risk Demographic and clinical data of study samples were not reported separately

Funding bias High risk The two authors were clinical investigators of the study. Study sponsored by pharmaceutical company.

89

Babul 2004

Bias Authors'



Low risk "A list of randomization numbers based on a computer-generated randomization schedule was prepared"




Low risk "identical appearing placebo"


Unclear risk We had insufficient information to permit judgement.Outcome assessors could be biased by the side effects of tramadol


Unclear risk ITT, method not reported

Selective reporting (reporting bias) High risk No protocol reported by the authors; SAE not reported


Funding bias High risk No information on study sponsoring provided. The study was managed by SCIREX Corporation,Horsham, PA, a commercial scientific research service;

90

Breivik 2010

Bias Authors'



Low risk "Validated computer system with randomised numbers"


Low risk "All patients, investigators, and study centre and Sponsor personnel were blinded to the medication codes."


Low risk " They were identical in appearance, packed in a labelled foil pouch, containing coded treatment group identification"


Unclear risk No details provided. Outcomes assessors could be biased on the side effects profile of buprenorphine.


Unclear risk ITT-analysis, method not reported

Selective reporting (reporting bias) Unclear risk No protocol reported by the authors

Selection bias Low risk No significant baseline differences in demographic and clinical variables between the groups

Funding bias High risk One of six authors (senior author) affiliated with pharmaceutical company

91

Caldwell 1999

Bias Authors'



Low risk "Centralized randomization code provided by the sponsor"


Low risk "Blocks of study medication blister packs were assigned to study centers in sequential ascending order"


Low risk " The double dummy technique was used to blind the study medications for differences in appearance and dosing frequency


Unclear risk No details provided. Outcomes assessors could be biased by the side effects profile of oxycodone.


Unclear risk ITT-analysis, LCOF

Selective reporting (reporting bias) High risk No protocol reported by the authors; SAE not reported

Selection bias Unclear risk No significant baseline differences in demographic variables between the three groups. Pain baseline not reported.

Funding bias High risk Funded by pharmaceutical industry; one author (senior author) affiliated with drug manufacturer

92

Caldwell 2002

Bias Authors'







Low risk "Placebo Avinza and placebo MSC matched the appearance of the respective active treatments"


Unclear risk No details reported. Outcome assessors may have been unblinded by the side effects of opioids


Unclear risk ITT-analysis, no details reported

Selective reporting (reporting bias) High risk No protocol reported by the authors; serious adverse events insufficiently reported


Funding bias High risk The affiliation of 4 of 9 study authors was the pharmaceutical company which sponsored the study

93

DeLemos 2011

Bias Authors'



Low risk " a randomization schedule was generated"


Low risk "Interactive voice-response system to asign randomization numbers to subjects"


Low risk "Tablets were similar in appearance and size"


Unclear risk We had insufficient information to permit judgement. The outcome assessor could be blinded by the side effects of tramadol.


Unclear risk ITT-analysis, methods not reported

Selective reporting (reporting bias) Unclear risk No protocol reported by authors


Funding bias High risk Study funded by pharmaceutical industry; 7 of 8 authors affiliated with drug manufacturer

94

Fishmann 2007

Bias Authors'



Low risk "Centralized computer-generated randomization list"


Low risk "Patients and personel remained blinded to treatment assignments"


Low risk Double dummy technique


Unclear risk Outcome assessors could be unblinded by side effects of tramadol


Unclear risk ITT-analysis, the primary method of imputation used for missing data was LOCF

Selective reporting (reporting bias) High risk No protocol reported by authors; data of outcome physical functioning not suited for meta-analysis


Funding bias High risk The affiliation of 3 of 10 study authors was the pharmaceutical company which sponsored the study

95

Fleishmann 2010

Bias Authors'



Low risk Study medications were randomly assigned by a computer to a numerical list for each site, and patients were enrolled sequentially using the list.




Low risk "The tramadol 50-mg capsules were identical in appearance to the placebo capsules".


Unclear risk We had insufficient information to permit judgement. The outcome assessor could be unblinded by the side effects of tramadol.


Unclear risk ITT-analysis, methods not reported




96

Friedmann 2011

Bias Authors'











Unclear risk ITT-analysis by LOCF

Selective reporting (reporting bias) High risk No means and SDs of secondary outcomes reported; outcomes of function could not be used for meta-analysis

Selection bias Unclear risk No significant baseline differences in demographic and clinical variables between the group

Funding bias High risk Authors affiliated with commercial companies

97

Gana 2006

Bias Authors'



Low risk " a randomization schedule was generated"


Low risk "Interactive voice-response system to asign randomization numbers to subjects"


Low risk "Tablets were similar in appearance and size"


Unclear risk We had insufficient information to permit judgement. The outcome assessor could be unblinded by the side effects of tramadol.


Unclear risk ITT-analysis by LOCF


Selection bias High risk Significant differences between the groups in pain baseline


98

Katz 2010

Bias Authors'



Low risk "The outpatient site contacted the interactive Web Response System..."




Low risk ""Both drug and placebo were packaged so as to be blinded to..."


Unclear risk No information provided. Outcomes assessors could be biased by the side effects profile of morphine.


Unclear risk ITT-analysis of primary outcomes by BOCF and of secondary outcomes by LOCF

Selective reporting (reporting bias) Low risk The trial was registered at clinicaltrials.gov (NCT004200992); the primary and the secondary outcomes were consistent in the protocol compared with the publication


Funding bias High risk The study and the writing of the manuscript were sponsored by the manufacturer of the drug.

99

Langford 2006

Bias Authors'



Low risk "Randomization was performed using a computer generated list and stratified by target joint"


Low risk "Participants were assigned consecutive treatment codes, and investigators were unaware of the treatment allocation"


Low risk "TDF and placebo patches were identical."


Unclear risk We had insufficient information to permit judgement.Outcomes assessors could be biased by the side effects profile of fentanyl.


Unclear risk ITT-analysis according to LCOF method

Selective reporting (reporting bias) High risk No protocol available in clinicaltrials.gov; drop out rates due to adverse events not reported


Funding bias High risk The affiliation of 1 of 5 study authors (senior author) was the pharmaceutical company which sponsored the study

100

Markenson 2005

Bias Authors'



Low risk The computer-generated randomization code and study drug bottles labelled with randomization numbers were supplied by the sponsor.


Low risk Study drug bottles labeled with randomization numbers were supplied by the sponsor






Unclear risk ITT by LOCF

Selective reporting (reporting bias) Unclear risk No protocol reported by the authors


Funding bias High risk The affiliation of 2 of 4 study authors (senior author) was the pharmaceutical company which sponsored the study

101

102

Matsumoto 2005

Bias Authors' judgement

Support for judgement


Low risk "The list of randomization numbers was based on a computergenerated randomization schedule."




Low risk "Study enrollees, study personnel, and investigators were blinded to the identity of the treatments. The statisticians who analyzed the data remained blinded to the identity of the treatments until all data were entered into the database and the database was locked."


Low risk "Study enrollees, study personnel, and investigators were blinded to the identity of the treatments. The statisticians who analyzed the data remained blinded to the identity of the treatments until all data were entered into the database and the database was loc


Unclear risk ITT by LCOF

Selective reporting (reporting bias) High risk The authors did not provide a protocol; SAE incompletely reported *


Funding bias High risk Study funded by manufacturer of the drug

103

Munera 2010

Bias Authors'

judgement

Support for

judgement

Random

sequence

generation

(selection

bias)

Unclear risk We had

insufficient

information to

permit

judgement.

Allocation

concealment

(selection

bias)

Unclear risk We had

insufficient

information to

permit

judgement.

Blinding of

participants

and

personnel

(performance

bias)

Low risk "Patients

received

identical

looking

patches"

Blinding of

outcome

assessment

(detection

bias)

Unclear risk No details

provided.

Outcomes

assessors could

be biased by

the side effects

profile of

buprenorphine

Incomplete

outcome data

(attrition

bias)

Unclear risk ITT-analysis,

details not

reported

Selective

reporting

(reporting

bias)

Low risk NCT00455520;

the primary

and the

secondary

outcomes were

consistent in

the protocol

compared with

the publication

Selection

bias Unclear risk

Pain baseline

not reported

Funding bias High risk Funding by

pharmaceutical

industry; 3 of 4

104

authors

affiliated with

industry

105

Peloso 2000

Bias Authors'

judgement

Support for

judgement

Random

sequence

generation

(selection

bias)

Unclear risk We had

insufficient

information to

permit

judgement.

Allocation

concealment

(selection

bias)

Unclear risk We had

insufficient

information to

permit

judgement.

Blinding of

participants

and

personnel

(performance

bias)

Low risk "Identical

appearing

placebo"

Blinding of

outcome

assessment

(detection

bias)

Unclear risk No details

provided.

Outcomes

assessors

could be bias

based on the

side effects

profile of

codeine.

Incomplete

outcome data

(attrition

bias)

High risk Completer

analysis

Selective

reporting

(reporting

bias)

High risk No protocol

reported by the

authors. SAE

not reported

Selection

bias Low risk

No significant

baseline

differences in

demographic

and clinical

variables

between the

groups

Funding bias Low risk No funding by

pharmaceutical

industry

106

reported; no

authors

affiliated with

industry

107

Rauck 2013

Bias Authors'


Random sequence generation

(selection bias) Unclear risk

We had insufficient information to

permit judgement.

Allocation concealment (selection

bias) Unclear risk


permit judgement.

Blinding of participants and personnel

(performance bias) Low risk

"Identical appearing placebo"

Blinding of outcome assessment

(detection bias) Unclear risk

No details provided. Outcomes

assessors could be bias based on

the side effects profile of codeine.

Incomplete outcome data (attrition

bias) High risk

Completer analysis

Selective reporting (reporting bias) High risk No protocol reported by the

authors. SAE not reported

Selection bias Low risk No significant baseline differences

in demographic and clinical

variables between the groups

Funding bias Low risk No funding by pharmaceutical

industry reported; no authors

affiliated with industry

108

Thorne 2008

Bias Authors'



(selection bias) Unclear risk


permit judgement.


bias) Unclear risk


permit judgement.


(performance bias) Low risk

"Matching placebo tablets"



No information provided.

Outcomes assessors could be bias

based on the side effects profile of

tramadol


bias) Unclear risk

ITT-analysis, method not reported

Selective reporting (reporting bias) Unclear risk No study protocol reported by

authors

Selection bias Low risk Cross over design

Funding bias High risk Funding by pharmaceutical

industry; 4/9 authors affiliated with

industry

109

Vojtassasak 2011

Bias Authors'



(selection bias) Low risk

"computer-generated randomisation

schedule prepared by an

independent statistician"


bias) Unclear risk

"The investigator and the subject

were blinded to treatment

allocation". No further information

provided


(performance bias) Unclear risk

The authors did not report the

physical characteristics of the

placebos.




permit judgement.Outcomes

assessors could be bias based on

the side effects profile of

hydromorphone


bias) Unclear risk

ITT-analysis, No further

information provided

Selective reporting (reporting bias) Low risk No protocol reported by the

authors. By search in clinicaltrials.

gov: NCT00980798. the primary

and the secondary outcomes were

consistent in the protocol compared

with the publication

Selection bias Low risk No significant baseline differences

in demographic and clinical

variables between the three groups

Funding bias High risk Funding by pharmaceutical

industry; 3 of five authors affiliated

with industry

110

Evidence report – Forest Plots of standardised mean differences and risk differences of opioids compared to placebo on selected outcomes

Parallel or cross over design

Figure 1 (Electronic Supplementary Material): Effect estimates (standardised mean

differences) of mean pain intensity reduction at end of treatment

111

Study or Subgroup

1.1.1 Buprenorphine

Breivik 2010

Munera 2010Subtotal (95% CI)

Heterogeneity: Tau² = 0.00; Chi² = 0.17, df = 1 (P = 0.68); I² = 0%

Test for overall effect: Z = 2.18 (P = 0.03)

1.1.2 Codeine

Peloso 2000Subtotal (95% CI)

Heterogeneity: Not applicable


1.1.3 Fentanyl

Langford 2006Subtotal (95% CI)



1.1.4 Hydromorphone

Rauck 2013

Rauck 2013

Vojtassak 2011Subtotal (95% CI)



1.1.5 Morphine

Caldwell 2002

Caldwell 2002

Caldwell 2002Subtotal (95% CI)



1.1.6 Oxycodone

Afilalo 2010

Markenson 2005

Matsumoto 2005Subtotal (95% CI)



1.1.7 Oxymorphone

Matsumoto 2005



Test for overall effect: Z = 4.12 (P < 0.0001)

1.1.8 Tapentadol

Afilalo 2010

Afilalo 2010Subtotal (95% CI)



1.1.9 Tramadol

Babul 2004

DeLemos 2011

DeLemos 2011

DeLemos 2011

Fishman 2007

Fishman 2007

Fishman 2007

Fleischmann 2000

Gana 2006

Gana 2006

Gana 2006

Gana 2006

Thorne 2008Subtotal (95% CI)



Total (95% CI)



Test for subgroup differences: Chi² = 15.03, df = 8 (P = 0.06), I² = 46.8%

Mean

-3.2

-1.84

32.5

-23.6

-2.5

-2

-2.4

-26.7

-23.1

-22.8

-1.05

-1.7

-90

-118

-104

-1.16

0

-29

-90.4

-82.5

-117.8

-46

-42.8

-41.6

2.1

-111.5

-107.2

-103.9

-107.8

38.2

SD

3.8

2.68

21.4

25.6

2.9

2.86

2.1

29.9

29.9

29.9

0.67

2.2

112

110

109

0.67

0

76.2

125.6

125.6

125.9

39.9

46.4

50.2

1.06

123.3

122.2

123.3

123.7

22.7

Total

100

149249

3131

202202

330

319

138787

73

76

73222

92

56

125273

121

121242

149

0149

124

199

201

199

105

107

103

63

201

202

201

202

1002007

4162

Mean

-2.3

-1.4

47.7

-17.9

-1.9

-1.9

-2.6

-14.6

-14.6

-14.6

-0.88

-0.6

-60

-60

-60

-0.88

0

-18.7

-94.9

-94.9

-94.9

-32.3

-32.3

-32.3

2.48

-74.2

-74.2

-74.2

-74.2

47.7

SD

3.7

2.67

24.7

26.7

2.86

2.86

2.3

29.9

29.9

29.9

0.69

2.9

111

111

111

0.69

0

73.9

125.9

125.9

125.9

38.2

48.2

48.2

1.13

121.7

121.7

121.7

121.7

25.7

Total

99

162261

3535

197197

166

165

149480

24

25

2473

158

51

124333

62

62124

158

0158

122

67

67

66

76

76

75

66

51

51

51

52

100920

2581

Weight

3.5%

4.9%8.4%

1.3%1.3%

5.8%5.8%

6.2%

6.2%

4.6%17.0%

1.5%

1.5%

1.5%4.4%

4.0%

2.1%

4.2%10.2%

2.9%

3.0%5.9%

4.8%

4.8%

4.1%

3.5%

3.5%

3.5%

3.2%

3.2%

3.1%

2.4%

3.0%

3.0%

3.0%

3.0%

3.5%42.1%

100.0%

IV, Random, 95% CI

-0.24 [-0.52, 0.04]

-0.16 [-0.39, 0.06]-0.19 [-0.37, -0.02]

-0.65 [-1.14, -0.15]-0.65 [-1.14, -0.15]

-0.22 [-0.41, -0.02]-0.22 [-0.41, -0.02]

-0.21 [-0.39, -0.02]

-0.03 [-0.22, 0.15]

0.09 [-0.14, 0.32]-0.06 [-0.23, 0.10]

-0.40 [-0.87, 0.06]

-0.28 [-0.74, 0.17]

-0.27 [-0.73, 0.19]-0.32 [-0.58, -0.05]

-0.25 [-0.51, 0.01]

-0.43 [-0.81, -0.04]

-0.27 [-0.52, -0.02]-0.29 [-0.45, -0.13]

-0.52 [-0.83, -0.21]

-0.40 [-0.71, -0.09]-0.46 [-0.68, -0.24]

-0.41 [-0.64, -0.18]

Not estimable-0.41 [-0.64, -0.18]

-0.14 [-0.39, 0.11]

0.04 [-0.24, 0.31]

0.10 [-0.18, 0.38]

-0.18 [-0.46, 0.10]

-0.35 [-0.65, -0.05]

-0.22 [-0.52, 0.07]

-0.19 [-0.49, 0.11]

-0.34 [-0.69, 0.00]

-0.30 [-0.61, 0.01]

-0.27 [-0.58, 0.04]

-0.24 [-0.55, 0.07]

-0.27 [-0.58, 0.03]

-0.39 [-0.67, -0.11]-0.20 [-0.28, -0.12]

-0.22 [-0.28, -0.17]

Opioids Placebo Std. Mean Difference Std. Mean Difference

IV, Random, 95% CI

-1 -0.5 0 0.5 1Favours opioids Favours placebo

Figure 2 (Electronic Supplementary Material): Effect estimates (risk difference) of 50% pain

reduction at end of treatment

112

Study or Subgroup

1.2.1 Oxycodone

Afilalo 2010


Total events



1.2.2 Tapentadol

Afilalo 2010

Afilalo 2010

Afilalo 2013


Total events



Total (95% CI)

Total events




Events

59

73

132

0

110

0

99

209

341

Total

342

331673

0

344

0

344688

1361

Events

82

91

173

0

82

0

91

173

346

Total

337

337674

0

337

0

337674

1348

Weight

25.8%

25.0%50.8%

24.6%

24.6%49.2%

100.0%

IV, Random, 95% CI

-0.07 [-0.13, -0.01]

-0.05 [-0.11, 0.02]-0.06 [-0.11, -0.02]

Not estimable

0.08 [0.01, 0.14]

Not estimable

0.02 [-0.05, 0.09]0.05 [-0.01, 0.10]

-0.01 [-0.07, 0.06]

Opioids Placebo Risk Difference Risk Difference

IV, Random, 95% CI

-0.5 -0.25 0 0.25 0.5Placebo Opioids

113

Figure 3 (Electronic Supplementary Material): Effect estimates (risk difference) of

Patient Global Impression of Change (PGIC): reports to be much or very much improved at

end of treatment

Study or Subgroup

1.3.1 Buprenorphine

Breivik 2010Subtotal (95% CI)

Total events



1.3.2 Tapentadol

Afilalo 2010

Afilalo 2010

Afilalo 2013


Total events



1.3.3 Oxycodone

Afilalo 2010


Total events



Total (95% CI)

Total events




Events

36

36

0

151

0

139

290

94

90

184

510

Total

100100

0

258

0

248506

200

212412

1018

Events

19

19

0

97

0

127

224

97

127

224

467

Total

9999

0

273

0

294567

273

294567

1233

Weight

16.8%16.8%

21.2%

21.0%42.2%

20.4%

20.6%41.0%

100.0%

IV, Random, 95% CI

0.17 [0.05, 0.29]0.17 [0.05, 0.29]

Not estimable

0.23 [0.15, 0.31]

Not estimable

0.13 [0.04, 0.21]0.18 [0.08, 0.28]

0.11 [0.03, 0.20]

-0.01 [-0.09, 0.08]0.05 [-0.07, 0.17]

0.13 [0.05, 0.21]


IV, Random, 95% CI

-0.5 -0.25 0 0.25 0.5Placebo Opioids


114


differences) of physical function improvement at end of treatment

115

Figure 5 (Electronic Supplementary Material): Effect estimates (risk difference) of dropping

out due to lack of efficacy during study

116

Study or Subgroup

1.8.1 Buprenorphine

Breivik 2010Subtotal (95% CI)

Total events



1.8.2 Codeine

Peloso 2000Subtotal (95% CI)

Total events



1.8.3 Fentanyl


Total events



1.8.4 Hydromorphone

Rauck 2013

Rauck 2013


Total events



1.8.5 Morphine

Caldwell 2002

Caldwell 2002

Caldwell 2002Subtotal (95% CI)

Total events



1.8.6 Oxycodone

Afilalo 2010

Markenson 2005


Total events



1.8.7 Oxymorphone

Matsumoto 2005


Total events



1.8.8 Tapentadol


Total events



1.8.9 Tramadol

Babul 2004

Fishman 2007

Fishman 2007

Fishman 2007

Fleischmann 2000

Gana 2006

Gana 2006

Gana 2006

Gana 2006


Total events



Total (95% CI)

Total events

Heterogeneity: Tau² = 0.00; Chi² = 85.36, df = 24 (P < 0.00001); I² = 72%



Events

7

7

1

1

15

15

30

49

5

84

9

12

8

29

7

9

9

25

5

13

18

15

15

19

21

11

11

28

31

29

18

23

1

192

386

Total

100100

5151

202202

330

319

139788

73

73

76222

332

56

121509

121

125246

334334

124

106

111

108

63

203

203

204

205

941421

3873

Events

12

12

5

5

64

64

42

41

16

99

5

4

5

14

56

34

34

124

17

17

34

56

56

45

15

15

15

49

11

11

12

12

3

188

596

Total

9999

5252

197197

166

166

149481

24

25

2574

337

51

124512

62

62124

337337

122

76

76

75

66

51

51

51

52

88708

2584

Weight

4.7%4.7%

4.5%4.5%

4.9%4.9%

4.9%

4.8%

5.4%15.2%

2.3%

2.5%

2.4%7.3%

5.8%

2.6%

4.4%12.8%

3.7%

3.5%7.1%

5.8%5.8%

3.9%

3.6%

4.0%

3.9%

2.6%

3.5%

3.5%

3.5%

3.5%

5.8%37.8%

100.0%

IV, Random, 95% CI

-0.05 [-0.13, 0.03]-0.05 [-0.13, 0.03]

-0.08 [-0.17, 0.01]-0.08 [-0.17, 0.01]

-0.25 [-0.33, -0.18]-0.25 [-0.33, -0.18]

-0.16 [-0.24, -0.09]

-0.09 [-0.17, -0.02]

-0.07 [-0.13, -0.01]-0.11 [-0.16, -0.05]

-0.09 [-0.26, 0.09]

0.00 [-0.16, 0.17]

-0.09 [-0.27, 0.08]-0.06 [-0.16, 0.04]

-0.15 [-0.19, -0.10]

-0.51 [-0.67, -0.34]

-0.20 [-0.29, -0.11]-0.26 [-0.42, -0.11]

-0.23 [-0.35, -0.12]

-0.17 [-0.29, -0.05]-0.20 [-0.29, -0.12]

-0.12 [-0.17, -0.08]-0.12 [-0.17, -0.08]

-0.22 [-0.32, -0.11]

0.00 [-0.12, 0.12]

-0.10 [-0.20, 0.01]

-0.10 [-0.21, 0.01]

-0.30 [-0.46, -0.14]

-0.06 [-0.19, 0.06]

-0.07 [-0.20, 0.05]

-0.15 [-0.27, -0.02]

-0.12 [-0.24, 0.00]

-0.02 [-0.07, 0.02]-0.10 [-0.16, -0.05]

-0.13 [-0.16, -0.10]


IV, Random, 95% CI

-1 -0.5 0 0.5 1Favours placebo Favours opioid

117


out due to adverse events during study

118

119

Figure 7 (Electronic Supplementary Material): Effect estimates (risk difference) of serious

adverse events during study

Study or Subgroup

1.6.1 Buprenorphine

Breivik 2010


Total events



1.6.2 Fentanyl


Total events



1.6.3 Hydromorphone

Rauck 2013

Rauck 2013


Total events



1.6.4 Oxycodone

Afilalo 2010

Markenson 2005Subtotal (95% CI)

Total events



1.6.5 Tapentadol

Afilalo 2010


Total events



1.6.6 Tramadol

Fishman 2007

Fleischmann 2000

Gana 2006

Gana 2006

Gana 2006

Gana 2006


Total events



Total (95% CI)

Total events




Events

5

0

5

6

6

13

8

10

31

10

3

13

4

0

4

2

0

4

3

3

6

0

18

77

Total

100

152252

202202

330

319

139788

342

56398

344

0344

325

63

201

201

202

202

941288

3272

Events

4

2

6

2

2

3

2

9

14

6

0

6

6

0

6

2

2

0

1

0

1

1

7

41

Total

99

163262

197197

166

166

149481

337

51388

337

0337

224

66

51

51

51

52

88583

2248

Weight

1.5%

10.8%12.3%

6.4%6.4%

5.6%

8.3%

1.5%15.4%

9.1%

1.1%10.2%

14.2%

14.2%

20.3%

1.9%

4.3%

2.8%

4.7%

2.5%

5.2%41.6%

100.0%

M-H, Random, 95% CI

0.01 [-0.05, 0.07]

-0.01 [-0.03, 0.01]-0.01 [-0.03, 0.01]

0.02 [-0.01, 0.05]0.02 [-0.01, 0.05]

0.02 [-0.01, 0.05]

0.01 [-0.01, 0.04]

0.01 [-0.05, 0.07]0.02 [-0.00, 0.03]

0.01 [-0.01, 0.03]

0.05 [-0.01, 0.12]0.02 [-0.01, 0.05]

-0.01 [-0.02, 0.01]

Not estimable-0.01 [-0.02, 0.01]

-0.00 [-0.02, 0.01]

-0.03 [-0.08, 0.02]

0.02 [-0.01, 0.05]

-0.00 [-0.05, 0.04]

0.01 [-0.02, 0.05]

0.01 [-0.03, 0.05]

-0.01 [-0.04, 0.02]-0.00 [-0.01, 0.01]

0.00 [-0.00, 0.01]


M-H, Random, 95% CI

-0.2 -0.1 0 0.1 0.2Favours placebo Favours opioid

120

Figure 8 (Electronic Supplementary Material): Effect estimates (risk difference) of death

during study

121

Forest Plots of standardised mean differences and risk differences of opioids compared to placebo on selected outcomes

EERW design


differences) of mean pain intensity reduction at end of treatment

Study or Subgroup

2.2.3 Morphine

Katz 2010Subtotal (95% CI)



2.2.4 Oxycodone

Caldwell 1999

Friedmann 2011Subtotal (95% CI)



Total (95% CI)



Test for subgroup differences: Chi² = 0.73, df = 1 (P = 0.39), I² = 0%

Mean

-0.4

0.44

-0.7

SD

1.3

0.76

2.05

Total

170170

34

203237

407

Mean

-0.2

1

-0.3

SD

1.3

0.78

2.48

Total

173173

36

207243

416

Weight

40.5%40.5%

16.6%

42.9%59.5%

100.0%

IV, Random, 95% CI

-0.15 [-0.37, 0.06]-0.15 [-0.37, 0.06]

-0.72 [-1.20, -0.23]

-0.18 [-0.37, 0.02]-0.40 [-0.92, 0.12]

-0.26 [-0.49, -0.03]

Opioid Placebo Std. Mean Difference Std. Mean Difference

IV, Random, 95% CI

-4 -2 0 2 4Opioid Placebo

122

Figure 10 (Electronic Supplementary Material): Effect estimates (risk difference) of 50% pain

reduction at end of treatment

Study or Subgroup

2.4.3 Morphine


Total events



Total (95% CI)

Total events



Test for subgroup differences: Not applicable

Events

97

97

97

Total

171171

171

Events

82

82

82

Total

173173

173

Weight

100.0%100.0%

100.0%

IV, Random, 95% CI

0.09 [-0.01, 0.20]0.09 [-0.01, 0.20]

0.09 [-0.01, 0.20]

Opioid Placebo Risk Difference Risk Difference

IV, Random, 95% CI

-10 -5 0 5 10Favours placebo Favours opioid

123


differences) of physical function improvementat end of treatment

124


out due to lack of efficacy during study

Study or Subgroup

2.5.1 Buprenorphine


Total events



2.5.2 Morphine


Total events



2.5.3 Oxycodone

Caldwell 1999

Caldwell 1999


Total events



2.5.4 Tramadol

Subtotal (95% CI)

Total events


Test for overall effect: Not applicable

Total (95% CI)

Total events




Events

43

43

6

6

3

4

12

19

0

68

Total

152152

171171

34

37

205276

0

599

Events

57

57

32

32

7

6

38

51

0

140

Total

163163

173173

18

18

207243

0

579

Weight

16.2%16.2%

37.6%37.6%

3.0%

3.1%

40.0%46.2%

100.0%

IV, Random, 95% CI

-0.07 [-0.17, 0.04]-0.07 [-0.17, 0.04]

-0.15 [-0.21, -0.09]-0.15 [-0.21, -0.09]

-0.30 [-0.55, -0.06]

-0.23 [-0.46, 0.01]

-0.13 [-0.19, -0.06]-0.16 [-0.24, -0.07]

Not estimable

-0.13 [-0.18, -0.09]


IV, Random, 95% CI

-1 -0.5 0 0.5 1Favours placebo Favours opioid

125


out due to adverse events during study

Study or Subgroup

2.8.3 Morphine


Total events



2.8.4 Oxycodone

Caldwell 1999


Total events



Total (95% CI)

Total events




Events

18

18

3

43

46

64

Total

171171

34

205239

410

Events

13

13

3

22

25

38

Total

173173

36

207243

416

Weight

45.5%45.5%

15.6%

38.9%54.5%

100.0%

IV, Random, 95% CI

0.03 [-0.03, 0.09]0.03 [-0.03, 0.09]

0.00 [-0.13, 0.14]

0.10 [0.03, 0.17]0.07 [-0.02, 0.16]

0.05 [-0.00, 0.11]


IV, Random, 95% CI

-0.5 -0.25 0 0.25 0.5Placebo Opioid

126

Figure 14 (Electronic Supplementary Material): Effect estimates (risk difference) of serious

adverse events during study

Study or Subgroup

2.9.3 Morphine


Total events



2.9.4 Oxycodone


Total events



Total (95% CI)

Total events




Events

9

9

5

5

14

Total

171171

205205

376

Events

11

11

2

2

13

Total

173173

207207

380

Weight

20.3%20.3%

79.7%79.7%

100.0%

IV, Random, 95% CI

-0.01 [-0.06, 0.04]-0.01 [-0.06, 0.04]

0.01 [-0.01, 0.04]0.01 [-0.01, 0.04]

0.01 [-0.01, 0.03]


IV, Random, 95% CI

-0.5 -0.25 0 0.25 0.5Placebo Opioid

Documents

Opioids in chronic osteoarthritis pain - A systematic ... · 1 Opioids in chronic osteoarthritis pain - A systematic review and meta-analysis of efficacy and harms of randomized placebo-controlled