1 Opioids in chronic osteoarthritis pain - A systematic review

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
5
Neurologische Klinik, Universitätsklinikum Würzburg, Germany
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]
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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. Shortterm 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 non2
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
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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
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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
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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).
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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 metaanalyses 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
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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 tvalues, 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
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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 randomeffects 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.
9
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
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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
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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).
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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
13
= 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 =
14
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
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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 metaanalysis, 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.
16
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
17
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 protonpump 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 nonresponders 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.
18
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)
Reference
Year
Countries of
study centers
Study design
Breivik
2010
Denmark,
Finland,
Norway,
Sweden
Parallel
Munera
2010
USA
Buprenorphine
Population
type
Number of
patients
randomized
Osteoarthritis
pain
199
Parallel
Osteoarthritis
pain
315
Reference
Year
Countries of
study centers
Study design
Peloso
Parallel
Canada
2000
Codeine
Population
type
Number of
patients
randomized
Osteoarthritis
pain
Interventions
and control
group
Duration of trial
Stable dose
NSAID or
Coxib oral
plus 7-day
buprenorphine
flexible 5 or 10
or 20 ug/h
transdermal
patch
5 - 9 days
screening
24 weeks
titration and
maintenance
4 weeks followup
Stable dose
NSAID or
Coxib plus
placebo
transdermal
patch
7-day
buprenorphine
flexible 5 or 10
or 20 ug/h
transdermal
patch
Placebo
transdermal
patch
Interventions
and control
group
Duration of trial
Codeine
flexible 100 –
400 mg/d oral
Duration
screening not
reported
4 weeks
titration and
maintenance
103
Placebo oral
19
1-week run-in
period
3 weeks
titration
1 week
maintenance
Reference
Year
Countries of
study centers
Study design
Langford
Great Britain
2006
Parallel
Fentanyl
Population
type
Number of
patients
randomized
Osteoarthritis
pain
399
Interventions
and control
group
Duration of trial
Stable dosage
of steroids or
NSAIDS oral
plus titration to
individually
optimal
dosage of
fentanyl
25,50,75 or
100 ug/h
transdermal
patch
1 week
screening
6 weeks
titration and
maintenance
3 days tapering
off
Stable dosage
of steroids or
NSAIDS oral
plus placebo
transdermal
patch
Reference
Year
Countries of
study centers
Study design
Rauck
2012
USA
Parallel
Vojtassak
2011
Slovakia
Parallel
Hydromorphone
Population
Interventions
type
and control
Number of
group
patients
randomized
Osteoarthritis
Hydromorphone
pain
fixed 8 or 16
mg/d oral
981
Placebo
Osteoarthritis
pain
278
20
Duration of trial
≤ 2 weeks
wash out
≤ 16 days
titration
12 weeks
maintenance
≤ 1 week taper
Hydromorphone ≤ 1 week
fixed 32 mg/d
screening
oral
4 week titration
Placebo
12 week
maintenance
28 weeks open
label
Reference
Year
Countries of
study centers
Caldwell
2002
USA
Study design
Parallel
Morphine
Population type
Number of
patients
randomized
Osteoarthritis
pain
295
Katz
2010
USA
Enrichedenrollment
randomized
withdrawal
design
Osteoarthritis
pain
547
Interventions
and control
group
Duration of trial
(titration and
maintenance)
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
Morphine and
naltrexone
extended
release flexible
20 - 160 mg/d
oral
Duration
screening and
wash-out not
reported
4 weeks
maintenance
Placebo
21
26 weeks open
label
Screening and
wash-out ≤ 14
days
≤ 45 days open
label titration
12 weeks
double-blind
withdrawal
Reference
Year
Countries of
study
centers
Caldwell
1999
USA
Study
design
Friedmann
USA
2011
Enrichedenrollment
randomized
withdrawal
Enrichedenrollment
randomized
withdrawal
Oxycodone
Population
Interventions and
type
control group
Number of
patients
randomized
Osteoarthritis
Oxycodone oral
pain
flexible 40 to 100
mg/d oral
107
Placebo
Osteoarthritis
pain
Oxycodone oral
flexible 10 - 80 mg/d
oral
412
Duration of
trial (titration
and
maintenance)
Duration
screening
and wash-out
not reported
4 weeks
open label
titration
4 weeks
double-blind
withdrawal
Duration
screening
and wash-out
4 - 10 days
2 weeks
open label
titration
Markenson
2005
USA
Parallel
Osteoarthritis
pain
107
22
Oxycodone oral
flexible up to 120
mg/d oral
12 weeks
double-blind
maintenance
6 months
open label
Duration
screening
and wash-out
not reported
13 weeks
titration and
maintenance
Reference
Study
Year
design
Countries of
study centers
Matsumoto
2005
USA
Parallel
Oxymorphone
Population
Interventions and
type
control group
Number of
patients
randomized
Osteoarthritis
Oxymorphone oral
pain
fixed 40 mg/d or 80
mg/
489
Oxycodone oral 40
mg/d
Placebo
Reference
Year
Countries of
study centers
Study design
Afilalo
2010
Australia,
Canada, New
Zealand, USA
Parallel
Afilalo
2013
13 European
countries
Parallel
Tapentadol
Population
type
Number of
patients
randomized
Osteoarthritis
knee pain
1050
4 weeks fixed
Duration of trial
(weeks)
Tapentadol
flexible 200 600 mg/d oral
< 2 weeks
screening
3 - 7 days
wash-out
3 weeks
titration
12 weeks
maintenance
10 - 14 days
follow-up
Duration of
screening not
reported
3 - 7 days
wash-out
Tapentadol
flexible 200 600 mg/d oral
Oxycodon
flexible 40 100 mg/d oral
Placebo
23
2 - 7 days
wash-out
Interventions
and control
group
Oxycodon
flexible 40 100 mg/d oral
Placebo
Osteoarthritis
knee pain
987
Duration of
trial (titration
and
maintenance)
3 weeks
titration
12 weeks
maintenance
2 weeks followup
Reference
Study
Year
design
Countries of
study centers
Babul
Parallel
2004
USA
Tramadol
Population type
Number of
patients
randomized
Osteoarthritis
knee pain
246
Delemos
2011
USA
Parallel
Osteoarthritis
pain
806
Tramadol fixed 100,
200 or 300 mg/d oral
Placebo oral
Fishmann
2007
USA
Parallel
Tramadol fixed 100,
200 or 300 mg/d oral
Placebo
Fleischmann
2000
USA
Parallel
Osteoarthritis
knee or hip
pain
552
Osteoarthritis
knee or hip
pain
129
Gana
2006
USA
Parallel
Osteoarthritis
knee or hip
pain
1020
Tramadol fixed 100,
200 or 300 or 400
mg/d oral
Placebo
Thorne
2008
Canada
Cross-over
Osteoarthritis
100
Tramadol flexible
100 - 400 mg/d oral
Placebo
24
Interventions and
control group
Duration of
trial (weeks)
Tramadol flexible
100 - 400 mg/d oral
Placebo
3 - 7 days
wash-out
1 week
titration
12 weeks
maintenance
2 - 7 days
wash-out,
12 weeks
maintenance,
1 week
follow-up
6 days
titration
12 weeks
maintenance
10 days
screening
and wash-out
12 weeks
titration and
maintenance
2 - 7 days
wash-out
12 weeks
maintenance
1 week
follow-up
Up to 1 week
wash-out
4 weeks
each period
6 months
open label
Tramadol flexible
100 - 400 mg/d oral
Placebo
Table 2 : Effect sizes of diffent classes of opioids on selected outcome variables
Outcome
Number
Number
Effect size
title
of
of
[95% CI])
studies
patients
Test for
Heterog overall
eneity
effect
I² [%]
p-value
32
< 0.0001
72
< 0.0001
14
< 0.0001
49
< 0.0001
Opioids
01 Pain
11
3509
SMD -0.23 (-0.32,
-0.14)
02 Drop out
8
3582
due to
RR 4.68
(3,51,6.24)
adverse
events
01 Pain
6
3545
Opioids with
additional mode
of action *
SMD -0.22 (-0,31,
-0.14)
02 Drop out
due to
7
3618
RR 2.55
(2.06,3.14)
adverse
events
Abbreviations: CI = Confidence interval; RR = Relative risk ; SMD = Standardized
mean difference; * tapentadol, tramadol
25
Figure 1: PRISMA Flow Diagram
Identification
Records identified through
database searching
(n = 17 591)
CENTRAL: (n=3688)
Medline: (n=6944)
Scopus: (n=6959)
Additional records identified
through hand searching
(n = 52)
Screening
Records after duplicates removed
(n = 12 601 )
Records screened
(n = 12601 )
Included
Eligibility
Full-text articles assessed
for eligibility
(n = 21 )
Studies included in
qualitative synthesis
(n = 20)
Studies included in
quantitative synthesis
(meta-analysis)
(n =20)
26
Records excluded
(n =12 580)
Full-text articles excluded, with
reasons
(n = 1)
Study design did not meet
inclusion criteria (n=1)
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%
Low risk of bias
Unclear risk of bias
27
25%
50%
High risk of bias
75%
100%
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,
28
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
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
?
?
+
?
?
?
+
–
29
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11. Gana TJ, Pascual ML,Fleming RR, Schein JR, Janagap CC, Xiang J. Extendedrelease tramadol in the treatment of osteoarthritis: a multicenter, randomized, doubleblind, 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, placebocontrolled, 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,
34
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)
35
Electronic supplementary tables
Table 1: Search strategy PubMed November 18, 2013
Search
Query
#40 Search (#31 AND #34 AND #38) Filters: Publication date from
2008/10/01 to 2013/10/31
#39 Search (#31 AND #34 AND #38)
Items
found
6938
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
36
Search
Query
Items
found
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 kaolinpectin[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]
37
141108
Search
Query
Items
found
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
38
Search
Query
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 MetaAnalysis[pt] OR Meta-Analysis[tiab] OR Meta-Analysis[sh]
OR Cochrane Database Syst Rev[Journal]
39
Items
found
40
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)
41
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 ITTanalysis 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,
42
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 prespecified (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.
43
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
Participants
Study duration: 3 weeks titration, 12 weeks
maintenance
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 %
Interventions
Oxycodone: N=342;mean age 58.2 years;
59.1% female; 71.6% white. Severe pain 83.0%
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)
Outcomes
Allowed co-medication: Antidepressants for
patients with controlled psychiatric or neurological
diseases
Pain: Pain intensity subscale of WOMAC at study
44
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
Notes
Death: Reported
* The authors report ITT-analysis; however, the
number of patients reported indicate rather per
protocol analysis
45
Afilalo 2013
Methods
Disease: Osteoarthritis pain
Study setting: 101 sites in 13 European
countries;
Study design: Parallel design
Participants
Study duration: 3 weeks titration, 12 weeks
maintenance
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 IIII;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 opioidbased 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
Interventions
Total sample: N=987; mean age 62.1 years;
60.4% female; 99.3% white. Severe pain 81.8 %
Study medication: Tapentadol 200-500 mg/d
(mean daily dosage not reported); Oxycodon 40100 mg/d (mean daily dosage not reported);
Placebo
46
Rescue medication: No information given
Outcomes
Allowed com-medication: No information given
Pain: Average pain intensity NRS 0-10; only
LSMD vs placebo reported; no significant
difference to placebo; data not usable for metaanalysis.
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
Notes
Death: Not explicitly stated
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."
47
Babul 2004
Methods
Diasease: Osteoarthritis pain
Study setting: 16 sites in US
Study design: Parallel design
Participants
Study duration: 3-7 days wash-out, 12 weeks
titration and maintenance
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 intraarticular viscosupplementation in a non-index
knee in the past 3 months; weight <= 100 lbs;
history of clinically significant intolerance to
48
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)
Interventions
Placebo:N=122; mean age 61.5 years; 56.6%
female; 86.1 % white. Pain baseline 75.5 (±16.5)
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.
Outcomes
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.
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
Withdrawal due to adverse events: Reported
Serious adverse events: Not explicitely reported
Death: Not explicitly stated
49
Breivik 2010
Methods
Disease: Osteoarthritis pain
Study setting: 19 sites in Denmark, Finland,
Norway, Sweden
Study design: Parallel design
Participants
Study duration: 24 weeks maintenance, followup after 4 weeks
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,
50
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
Interventions
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
Study medication: Titration to individually
optimal dosage buprenorphine 5,10 or 20 ug/h;
placebo
Rescue medication: Acetaminophen up to 4g/d
Outcomes
Allowed co-therapies: Stable dosage of NSAIDs
Pain: Pain intensity NRS 0-10
Responder: No 50% pain reduction rates
reported
PGIC: Much and very much improved
Function: WOMAC OA index of function
Withdrawal due to adverse events: Reported
51
Serious adverse events: Reported
Death: Not explicitly stated: no deaths reported in
section "serious adverse events"
52
Caldwell 1999
Methods
Disease: Osteoarthritis pain
Study setting: 9 sites in US
Study design: Enriched enrollment randomized
withdrawal
Participants
Study duration: Open label titration for 30 days,
30 days double-blind withdrawal
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.
Interventions
Placebo:N=36; mean age 58 years; 69% female,
race not reported. Pain baseline only reported in
figure.
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.
Outcomes
Allowed co-therapies: NSAIDS were continued
at prestudy dose, no other analgesics, stable
steroid dose for at least 1 month.
Pain: Mean global pain intensity at the end of
double-blind phase compared to end of titration
Pain Intensity NRS 0-10
Responder: No 50% pain reduction rates
reported
PGIC: Not assessed
Function: Not assessed
53
Withdrawal due to adverse events: Reported
Serious adverse events: Not reported
Death: Not explicitly stated
Notes
54
Caldwell 2002
Methods
Disease: Osteoarthritis pain
Study setting: 16 sites in US
Study design: Parallel design
Participants
Study duration: 7 days days wash out, 4 weeks
maintenance
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
55
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)
Interventions
Placebo:N=73; mean age 61.9 years; 70%
female; 80 % white. Pain baseline 61.9 (±10.7)
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.
Outcomes
Allowed co-therapies: No information provided.
Pain: Overall Arthritis Pain Intensity VAS 0-10
Responder: No 50% pain reduction rates
reported
PGIC: Not assessed
Function: WOMAC Funcional Impairment
subscale
Withdrawal due to adverse events: Reported
Serious adverse events: Incompletely reported
*
Notes
Death: Not explicitly stated
* Details reported not sufficient to perform metaanalysis: "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.
56
DeLemos 2011
Methods
Diasease: Osteoarthritis pain
Study setting: 70 sites in US
Study design: Parallel
Participants
Study duration: (1) 2-7 days wash-out, (2) 12
weeks maintenance, (3) 1 week follow-up
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 washout. 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 (±
57
Interventions
103.5)
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.
Outcomes
Allowed co-therapies: No information provided
Pain: WOMAC Pain Subscale
Responder: No 50% pain reduction rates
reported
PGIC: Not assessed
Function: WOMAC OA physical function score
0-1700
Withdrawal due to adverse events: Reported
Serious adverse events: Reported *
Notes
Death: Reported
* Only treatment related SAE reported: Data not
used for analysis
58
Fishmann 2007
Methods
Diasease: Osteoarthritis pain
Study setting: 74 sites in US
Study design: Parallel
Participants
Study duration: 6 days titration, 12 weeks
maintenance
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)
Tramadol 200 mg/d: N=107; mean age 61
years; 59.8% female; race not reported. Pain
baseline 28.4 (±8.2)
Interventions
Tramadol 300 mg/d: N=105; mean age 60
years; 65.7% female; race not reported. Pain
baseline 31.4 (±8.7)
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
Allowed co-therapies: No information provided
Pain: Relative percentage of pain improvement in
WOMAC pain score from baseline
59
Responder: No 50% pain reduction rates
reported
PGIC: Not reported
Function: WOMAC OA physical functioning
score; no detailed outcomes reported *
Withdrawal due to adverse events: Reported
Serious adverse events: Reported
Notes
Death: Not explicitly stated
* 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
60
Fleischmann 2000
Methods
Diasease: Osteoarthritis pain
Study setting: 12 sites in US
Study design: Parallel
Participants
Study duration: 10 days screening and washout,1 week titration and 11 weeks maintenance
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%
61
Interventions
female; 95.2% white. Pain baseline 2.71 (± 0.63)
Study medication: Titration to individually
optimal between 200 and 400 mg/d (mean
dosage not reported)
Rescue medication: None allowed
Outcomes
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
Pain: Pain intensity previous 24 hours NRS 0-4
Responder: No 50% pain reduction rates
reported
PGIC: Not reported
Function: WOMAC OA function score
Withdrawal due to adverse events: Reported
Serious adverse events: Reported
Death: Not explicitly stated
62
Friedmann 2011
Methods
Diasease: Osteoarthritis pain
Study setting: 62 sites in US
Study design: Enriched enrollment randomized
withdrawal design
Participants
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
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)
Interventions
Oxycodone: N=205; mean age 58.0 years; 72%
female; 82% white.Pain baseline 7.8 (±1.35)
Study medication: Titration to individually
optimal up to 80 mg/d oxycodone (mean dosage
45 mg/d)
Rescue medication: Acetaminophen up to 3g/d
Outcomes
Allowed co-therapies: Stable dose of
antidepressants, pregabalin, gabapentin,
chondroitin
Pain: Change in average pain intensity NRS 0-10
recorded via touch-phone
63
Responder: No 50% pain reduction rates
reported
PGIC: Not reported
Function: WOMAC OA Index; no detailed
outcomes reported *
Withdrawal due to adverse events: Reported
Serious adverse events: Reported
Notes
Death: Reported
* The mean change in the WOMAC subscales
from prerandomisation to end of the study was
only statistically significant for the pain subscale.
64
Gana 2006
Methods
Diasease: Osteoarthritis pain
Study setting: 46 sites in US
Study design: Parallel
Participants
Study duration: 2-7 days wash-out, 12 weeks
maintenance, 1 week follow-up
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)
Tramadol ER 200 mg/d: N=201; mean age 59.1
(±9.9) years; 63.7% female; 76.1% white. Pain
baseline 315.2 (±92.4)
Tramadol ER 300 mg/d: N=201; mean age 58.5
(±9.4) years; 59.2% female; 81.6% white. Pain
baseline 296.6 (±96.3)
65
Interventions
Tramadol ER 400 mg/d: N=202; mean age 58.4
(±9.7) years; 57.9% female; 79.7% white. Pain
baseline 298.0 (±93.7)
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.
Outcomes
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
Pain: WOMAC Osteoarthritis Pain Index 0-500
Responder: No 50% pain reduction rates
reported
PGIC: Not assessed
Function: WOMAC OA function score 0-1700
Withdrawal due to adverse events: Reported
Serious adverse events: Reported
Death: Not explicitly stated
66
Katz 2010
Methods
Diasease: Osteoarthritis pain
Study setting: Number of US sites not reported
Study design: Enriched-enrollment randomized
withdrawal
Participants
Study duration: 7-14 days wash-out, <= 45 days
titration, 12 weeks maintenance
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)
Interventions
Placebo:N=73; mean age 54.7 years; 54.9%
female; 69.9 % white, Pain baseline 3.2 (± 1.1)
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.
Allowed co-therapies: No information provided.
67
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
Function: WOMAC Funcional Impairment
subscale
Withdrawal due to adverse events: Reported
Serious adverse events: Reported
Death: Not explicitly stated
68
Langford 2006
Methods
Diasease: Osteoarthritis pain
Study setting: Several European countries
Study design: Parallel design
Participants
Study duration: 6 weeks maintenance
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)
Interventions
Fentanyl: N=202; mean age 66 years; 65%
female; race not reported. Pain baseline 73.1 (no
SD reported)
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
Outcomes
Allowed co-therapies: Paracetamol up to 4g/d
allowed
Pain: Average pain intensity score NRS 0-100
Responder: No 50% pain reduction rates
reported
69
PGIC: Not assessed
Function: WOMAC physical functioning
Withdrawal due to adverse events: Not
reported
Serious adverse events: Reported
Death: Reported
70
Markenson 2005
Methods
Diasease: Osteoarthritis pain independent of
location (~40% Back pain)
Study setting: 9 sites in US
Study design: Parallel design
Participants
Study duration: 12 weeks titration and
maintenance
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;
71
Interventions
94 % white. Pain baseline 6.3 (± 1.4)
Study medication: Upward titration up to 120
mg oxycodone/d (average dosage (44 ± 5 mg)
Rescue medication: No information provided
Outcomes
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
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
Withdrawal due to adverse events: Reported
Serious adverse events: Reported
Death: Not explicitly stated
72
Matsumoto 2005
Methods
Diasease: Osteoarthritis pain
Study setting: Number of US sites not reported
Study design: Parallel
Participants
Study duration: 2-7 days wash-out, 4 weeks
maintenance
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
73
not reported *
Oxycodone 40 mg/d : N=125; mean age 62.7
years; 57.6% female; 89.6% white. Pain baseline
not reported *
Interventions
Placebo:N=124; mean age 61.7 years; 65.3%
female; 86.3 % white, Pain baseline not reported
*
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.
Rescue medication: No information provided.
Outcomes
Allowed co-therapies: No information provided.
Pain: WOMAC Pain score VAS 0-500 **
Responder: Not assessed
PGIC: Not assessed
Function: WOMAC Funcional Impairment
subscale * and SF-36 physical component score
***
Withdrawal due to adverse events: Reported
Serious adverse events: Incompletely Reported
****
Notes
Death: Not explicitly stated
* "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."
74
75
Munera 2010
Methods
Diasease: Osteoarthritis pain
Study setting: 22 sites in US
Study design: Parallel design
Participants
Study duration: 3 weeks titration, 1 week
maintenance
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 shortacting 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
Interventions
Buprenorphine 5,10 or 20 ug/h: N=152; mean
age 60 years; 67% female; 87% white. Pain
baseline not reported
Study medication: Titration to individually
optimal dosage buprenorphine 5,10 or 20 ug/h
(no average dosage reported); placebo
Rescue medication: None
Outcomes
Allowed co-therapies: Aspirin as antithrombotic
>=325 mg/d allowed
Pain: Average pain intensity score NRS 0-10;
Responder: No 50% pain reduction rates
reported
PGIC: Not assessed
76
Function: Not assessed
Withdrawal due to adverse events: Reported
Serious adverse events: Reported
Death: Reported
77
Peloso 2000
Methods
Diasease: Osteoarthritis pain
Study setting: 4 sites in Canada
Study design: Parallel design
Participants
Study duration: 4 weeks maintenance
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)
Interventions
Codeine: N=51; mean age 60.1 years; 58.1%
female; Race not reported. Pain baseline 58.2
(±18.9)
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
Allowed co-therapies: No information provided
Pain: Average pain intensity 24 h score VAS 0100;
Responder: Not assessed
PGIC: Not assessed
Function: WOMAC physical function (VAS 01700)
Withdrawal due to adverse events: Reported
Serious adverse events: Not reported
78
Death: Reported
Notes
79
Rauck 2013
Methods
Diasease: Osteoarthritis pain
Study setting: Number of study sites in US not
reported
Study design: Parallel design
Participants
Study duration: <= 16 days titration, 12 weeks
maintenance, <=1 week taper
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 12lead 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
80
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 antiinflammatory 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 controlledrelease 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)
Interventions
Placebo:N=332; mean age 60 years; 63%
female; 88.3 % white. Pain baseline 7.4 (±1.4)
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
Allowed co-therapies: No information provided.
Pain: Mean change from average pain intensity
baseline NRS 0-10
Responder: No 50% pain reduction rates
reported
PGIC: Not assessed
Function: WOMAC Funcional Impairment
subscale
Withdrawal due to adverse events: Reported
Serious adverse events: Reported
Death: Not explicitly stated
81
Notes
This study did not meet the primary endpoint of
improvement in pain intensity as analyzed with
the primary
imputation method, BOCF.
82
Thorne 2008
Methods
Diasease: Osteoarthritis pain
Study setting: 6 sites in Canada
Study design: Cross over
Participants
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.
Inclusion criteria: Men and nonpregnant, nonnursing 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
83
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.
Interventions
Total sample: N=100; mean age 61 years; 55%
female; race not reported. Pain baseline 50.8
(±17.9)
Study medication: Tramadol flexible 100-400
mg/d placebo (average dosage 340 mg/d)
Rescue medication: Acetaminophen up to 2.6
g/d
Outcomes
Allowed co-therapies: No information provided.
Pain: Average pain intensity last 24 hours VAS 0100
Responder: No 50% pain reduction rates
reported
PGIC: Not assessed
Function: WOMAC physical function subscale
Withdrawal due to adverse events: Reported
Serious adverse events: Reported
Notes
Death: Not explicitly stated
""An analysis of carry-over effect found no
significance"
84
Vojtassak 2011
Methods
Diasease: Osteoarthritis pain
Study setting: 18 sites in four European
countries (Czech republic, Romania, Slovakia,
UK)
Study design: Parallel design
Participants
Study duration: 4 weeks titration, 12 weeks
maintenance
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-tosevere 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,
85
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)
Interventions
Placebo:N=149; mean age 66 years; 68%
female; 100 % white. Pain baseline 6.5 (±0.94)
Study medication: Hydromorphone. Treatment
comprised a 4-week titration phase and a 12week 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..
Rescue medication: No information provided.
Outcomes
Allowed co-therapies: No information provided.
Pain: Average pain intensity NRS 0-10 of Brief
Pain Inventory
Responder: No 50% pain reduction rates
reported
PGIC: Not assessed
Function: WOMAC Funcional Impairment
subscale
Withdrawal due to adverse events: Reported
Serious adverse events: Reported
Death: Not explicitly stated
86
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
Random sequence generation
(selection bias)
Allocation concealment (selection
bias)
Low risk
Blinding of participants and
personnel (performance bias)
Blinding of outcome assessment
(detection bias)
Unclear risk
Incomplete outcome data (attrition
bias)
Selective reporting (reporting bias)
Unclear risk
ITT-analysis according to LOCF
Low risk
Selection bias
Low risk
Funding bias
High risk
NCT00421928; All outcomes as
reported in the protocol were
published
No significant baseline
differences in demographic and
clinical variables between the
three groups
Funding by pharmaceutical
industry; 8 of 9 authors affiliated
with industry
Low risk
Unclear risk
87
Computer-generated
randomization list
Randomization was
implemented by interactive
voice response system
We had insufficient information
to permit judgement.
No details provided. Outcomes
assessors could be bias based
on the side effects profile of
tapentadol.
Afilalo 2013
Bias
Authors'
judgement
Support for judgement
Random sequence generation
(selection bias)
Allocation concealment (selection
bias)
Blinding of participants and
personnel (performance bias)
Unclear risk
Blinding of outcome assessment
(detection bias)
Unclear risk
Incomplete outcome data (attrition
bias)
Selective reporting (reporting bias)
Unclear risk
ITT-analysis according to LOCF
High risk
Selection bias
Unclear risk
Funding bias
High risk
NCT00486811; drop out rates
due to serious adverse events
for placebo group not reported;
serious adverse events not
reported
Demographic and clinical data
of study samples were not
reported separately
The two authors were clinical
investigators of the study. Study
sponsored by pharmaceutical
company.
Unclear risk
Unclear risk
88
"Study medication assigned to
patients by chance"
"Study medication assigned to
patients by chance"
"Neither patient nor investigator
knows which patient gets which
study medication"
We had insufficient information
to permit judgement.Outcomes
assessors could be biased by
the side effects profile of
tapentadol.
Babul 2004
Bias
Authors'
judgement
Random sequence generation
(selection bias)
Low risk
Allocation concealment (selection
bias)
Blinding of participants and
personnel (performance bias)
Blinding of outcome assessment
(detection bias)
Unclear risk
Support for judgement
"A list of randomization numbers
based on a computer-generated
randomization
schedule was prepared"
We had insufficient information
to permit judgement.
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
Incomplete outcome data (attrition
bias)
Selective reporting (reporting bias)
Unclear risk
ITT, method not reported
High risk
Selection bias
Low risk
Funding bias
High risk
No protocol reported by the
authors; SAE not reported
No significant baseline
differences in demographic and
clinical variables between the
three groups
No information on study
sponsoring provided. The study
was managed by SCIREX
Corporation,Horsham, PA, a
commercial scientific research
service;
89
Breivik 2010
Bias
Authors'
judgement
Random sequence generation
(selection bias)
Allocation concealment (selection
bias)
Low risk
Blinding of participants and
personnel (performance bias)
Low risk
Blinding of outcome assessment
(detection bias)
Unclear risk
Incomplete outcome data (attrition
bias)
Selective reporting (reporting bias)
Unclear risk
Selection bias
Low risk
Funding bias
High risk
Low risk
Unclear risk
90
Support for judgement
"Validated computer system
with randomised numbers"
"All patients, investigators, and
study centre and Sponsor
personnel were blinded to the
medication codes."
" They were identical in
appearance, packed in a
labelled foil pouch, containing
coded
treatment group identification"
No details provided. Outcomes
assessors could be biased on
the side effects profile of
buprenorphine.
ITT-analysis, method not
reported
No protocol reported by the
authors
No significant baseline
differences in demographic and
clinical variables between the
groups
One of six authors (senior
author) affiliated with
pharmaceutical company
Caldwell 1999
Bias
Authors'
judgement
Support for judgement
Random sequence generation
(selection bias)
Allocation concealment (selection
bias)
Low risk
Blinding of participants and
personnel (performance bias)
Low risk
Blinding of outcome assessment
(detection bias)
Unclear risk
Incomplete outcome data (attrition
bias)
Selective reporting (reporting bias)
Unclear risk
ITT-analysis, LCOF
High risk
Selection bias
Unclear risk
Funding bias
High risk
No protocol reported by the
authors; SAE not reported
No significant baseline
differences in demographic
variables between the three
groups. Pain baseline not
reported.
Funded by pharmaceutical
industry; one author (senior
author) affiliated with drug
manufacturer
Low risk
91
"Centralized randomization code
provided by the sponsor"
"Blocks of study medication
blister packs were assigned to
study centers in sequential
ascending order"
" The double dummy technique
was used to blind the study
medications for differences in
appearance and dosing
frequency
No details provided. Outcomes
assessors could be biased by
the side effects profile of
oxycodone.
Caldwell 2002
Bias
Authors'
judgement
Support for judgement
Random sequence generation
(selection bias)
Allocation concealment (selection
bias)
Blinding of participants and
personnel (performance bias)
Unclear risk
Blinding of outcome assessment
(detection bias)
Unclear risk
Incomplete outcome data (attrition
bias)
Selective reporting (reporting bias)
Unclear risk
ITT-analysis, no details reported
High risk
Selection bias
Low risk
Funding bias
High risk
No protocol reported by the
authors; serious adverse events
insufficiently reported
No significant baseline
differences in demographic and
clinical variables between the
three groups
The affiliation of 4 of 9 study
authors was the pharmaceutical
company which sponsored the
study
Unclear risk
Low risk
92
We had insufficient information
to permit judgement.
We had insufficient information
to permit judgement.
"Placebo Avinza and placebo
MSC matched the appearance
of the respective active
treatments"
No details reported. Outcome
assessors may have been
unblinded by the side effects of
opioids
DeLemos 2011
Bias
Authors'
judgement
Support for judgement
Random sequence generation
(selection bias)
Allocation concealment (selection
bias)
Low risk
Blinding of participants and
personnel (performance bias)
Blinding of outcome assessment
(detection bias)
Low risk
Incomplete outcome data (attrition
bias)
Selective reporting (reporting bias)
Unclear risk
Unclear risk
No protocol reported by authors
Selection bias
Low risk
Funding bias
High risk
No significant baseline
differences in demographic and
clinical variables between the
groups
Study funded by pharmaceutical
industry; 7 of 8 authors affiliated
with drug manufacturer
Low risk
Unclear risk
93
" a randomization schedule was
generated"
"Interactive voice-response
system to asign randomization
numbers to subjects"
"Tablets were similar in
appearance and size"
We had insufficient information
to permit judgement. The
outcome assessor could be
blinded by the side effects of
tramadol.
ITT-analysis, methods not
reported
Fishmann 2007
Bias
Authors'
judgement
Support for judgement
Random sequence generation
(selection bias)
Allocation concealment (selection
bias)
Low risk
Blinding of participants and
personnel (performance bias)
Blinding of outcome assessment
(detection bias)
Low risk
Double dummy technique
Unclear risk
Incomplete outcome data (attrition
bias)
Unclear risk
Selective reporting (reporting bias)
High risk
Selection bias
Low risk
Funding bias
High risk
Outcome assessors could be
unblinded by side effects of
tramadol
ITT-analysis, the primary
method of imputation used for
missing data was LOCF
No protocol reported by authors;
data of outcome physical
functioning not suited for metaanalysis
No significant baseline
differences in demographic and
clinical variables between the
three groups
The affiliation of 3 of 10 study
authors was the pharmaceutical
company which sponsored the
study
Low risk
94
"Centralized computergenerated randomization list"
"Patients and personel
remained blinded to treatment
assignments"
Fleishmann 2010
Bias
Authors'
judgement
Support for judgement
Random sequence generation
(selection bias)
Low risk
Allocation concealment (selection
bias)
Blinding of participants and
personnel (performance bias)
Unclear risk
Blinding of outcome assessment
(detection bias)
Unclear risk
Incomplete outcome data (attrition
bias)
Selective reporting (reporting bias)
Unclear risk
Unclear risk
No protocol reported by authors
Selection bias
Low risk
Funding bias
High risk
No significant baseline
differences in demographic and
clinical variables between the
groups
Study funded by pharmaceutical
industry; 2 of 6 authors affiliated
with drug manufacturer
Low risk
95
Study medications were
randomly assigned by a
computer to a numerical list for
each site, and patients were
enrolled sequentially using the
list.
We had insufficient information
to permit judgement.
"The tramadol 50-mg capsules
were identical in appearance to
the placebo capsules".
We had insufficient information
to permit judgement. The
outcome assessor could be
unblinded by the side effects of
tramadol.
ITT-analysis, methods not
reported
Friedmann 2011
Bias
Authors'
judgement
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)
Unclear risk
Selection bias
Unclear risk
Funding bias
High risk
Unclear risk
Unclear risk
Unclear risk
Support for judgement
We had insufficient information
to permit judgement.
We had insufficient information
to permit judgement.
We had insufficient information
to permit judgement.
We had insufficient information
to permit judgement.
Unclear risk
ITT-analysis by LOCF
High risk
No means and SDs of
secondary outcomes reported;
outcomes of function could not
be used for meta-analysis
No significant baseline
differences in demographic and
clinical variables between the
group
Authors affiliated with
commercial companies
96
Gana 2006
Bias
Authors'
judgement
Support for judgement
Random sequence generation
(selection bias)
Allocation concealment (selection
bias)
Low risk
Blinding of participants and
personnel (performance bias)
Blinding of outcome assessment
(detection bias)
Low risk
Incomplete outcome data (attrition
bias)
Selective reporting (reporting bias)
Unclear risk
ITT-analysis by LOCF
Unclear risk
No protocol reported by authors
Selection bias
High risk
Funding bias
High risk
Significant differences between
the groups in pain baseline
Study funded by pharmaceutical
industry; 7 of 8 authors affiliated
with drug manufacturer
Low risk
Unclear risk
97
" a randomization schedule was
generated"
"Interactive voice-response
system to asign randomization
numbers to subjects"
"Tablets were similar in
appearance and size"
We had insufficient information
to permit judgement. The
outcome assessor could be
unblinded by the side effects of
tramadol.
Katz 2010
Bias
Authors'
judgement
Random sequence generation
(selection bias)
Low risk
Allocation concealment (selection
bias)
Blinding of participants and
personnel (performance bias)
Unclear risk
Blinding of outcome assessment
(detection bias)
Unclear risk
Incomplete outcome data (attrition
bias)
Unclear risk
Selective reporting (reporting bias)
Low risk
Selection bias
Low risk
Funding bias
High risk
Low risk
98
Support for judgement
"The outpatient site contacted
the interactive Web Response
System..."
We had insufficient information
to permit judgement.
""Both drug and placebo were
packaged so as to be blinded
to..."
No information provided.
Outcomes assessors could be
biased by the side effects profile
of morphine.
ITT-analysis of primary
outcomes by BOCF and of
secondary outcomes by LOCF
The trial was registered at
clinicaltrials.gov
(NCT004200992); the primary
and the secondary
outcomes were consistent in the
protocol compared with the
publication
No significant baseline
differences in demographic and
clinical variables between the
three groups
The study and the writing of the
manuscript were sponsored by
the manufacturer of the drug.
Langford 2006
Bias
Authors'
judgement
Random sequence generation
(selection bias)
Low risk
Allocation concealment (selection
bias)
Low risk
Blinding of participants and
personnel (performance bias)
Blinding of outcome assessment
(detection bias)
Low risk
Incomplete outcome data (attrition
bias)
Selective reporting (reporting bias)
Unclear risk
Selection bias
Low risk
Funding bias
High risk
Unclear risk
High risk
99
Support for judgement
"Randomization was performed
using a computer generated list
and stratified by target joint"
"Participants were assigned
consecutive treatment codes,
and investigators were unaware
of the treatment allocation"
"TDF and placebo patches were
identical."
We had insufficient information
to permit judgement.Outcomes
assessors could be biased by
the side effects profile of
fentanyl.
ITT-analysis according to LCOF
method
No protocol available in
clinicaltrials.gov; drop out rates
due to adverse events not
reported
No significant baseline
differences in demographic and
clinical variables between the
three groups
The affiliation of 1 of 5 study
authors (senior author) was the
pharmaceutical company which
sponsored the study
Markenson 2005
Bias
Authors'
judgement
Random sequence generation
(selection bias)
Low risk
Allocation concealment (selection
bias)
Low risk
Blinding of participants and
personnel (performance bias)
Blinding of outcome assessment
(detection bias)
Incomplete outcome data (attrition
bias)
Selective reporting (reporting bias)
Unclear risk
Selection bias
Low risk
Funding bias
High risk
Unclear risk
Support for judgement
The computer-generated
randomization code and study
drug bottles labelled with
randomization numbers were
supplied by the sponsor.
Study drug bottles labeled with
randomization numbers were
supplied by the sponsor
We had insufficient information
to permit judgement.
We had insufficient information
to permit judgement.
Unclear risk
ITT by LOCF
Unclear risk
No protocol reported by the
authors
No significant baseline
differences in demographic and
clinical variables between the
three groups
The affiliation of 2 of 4 study
authors (senior author) was the
pharmaceutical company which
sponsored the study
100
101
Matsumoto 2005
Bias
Authors'
judgement
Support for judgement
Random sequence generation
(selection bias)
Low risk
Allocation concealment (selection
bias)
Blinding of participants and
personnel (performance bias)
Unclear risk
Blinding of outcome assessment
(detection bias)
Low risk
Incomplete outcome data (attrition
bias)
Selective reporting (reporting bias)
Unclear risk
ITT by LCOF
High risk
Selection bias
Low risk
Funding bias
High risk
The authors did not provide a
protocol; SAE incompletely
reported *
No significant baseline
differences in demographic and
clinical variables between the
groups
Study funded by manufacturer
of the drug
Low risk
102
"The list of randomization
numbers was based on a
computergenerated
randomization schedule."
We had insufficient information
to permit judgement.
"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."
"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
Munera 2010
Bias
Authors'
judgement
Support for
judgement
We had
insufficient
information to
permit
judgement.
We had
insufficient
information to
permit
judgement.
Random
sequence
generation
(selection
bias)
Allocation
concealment
(selection
bias)
Unclear risk
Blinding of
participants
and
personnel
(performance
bias)
Blinding of
outcome
assessment
(detection
bias)
Low risk
"Patients
received
identical
looking
patches"
Unclear risk
No details
provided.
Outcomes
assessors could
be biased by
the side effects
profile of
buprenorphine
Incomplete
outcome data
(attrition
bias)
Selective
reporting
(reporting
bias)
Unclear risk
ITT-analysis,
details not
reported
Low risk
Selection
bias
Funding bias
Unclear risk
NCT00455520;
the primary
and the
secondary
outcomes were
consistent in
the protocol
compared with
the publication
Pain baseline
not reported
Funding by
pharmaceutical
industry; 3 of 4
Unclear risk
High risk
103
authors
affiliated with
industry
104
Peloso 2000
Bias
Authors'
judgement
Random
sequence
generation
(selection
bias)
Allocation
concealment
(selection
bias)
Unclear risk
Blinding of
participants
and
personnel
(performance
bias)
Blinding of
outcome
assessment
(detection
bias)
Low risk
Incomplete
outcome data
(attrition
bias)
Selective
reporting
(reporting
bias)
Selection
bias
High risk
Funding bias
Low risk
Unclear risk
Support for
judgement
We had
insufficient
information to
permit
judgement.
We had
insufficient
information to
permit
judgement.
"Identical
appearing
placebo"
Unclear risk
No details
provided.
Outcomes
assessors
could be bias
based on the
side effects
profile of
codeine.
Completer
analysis
High risk
Low risk
No protocol
reported by the
authors. SAE
not reported
No significant
baseline
differences in
demographic
and clinical
variables
between the
groups
No funding by
pharmaceutical
industry
105
reported; no
authors
affiliated with
industry
106
Rauck 2013
Bias
Authors'
judgement
Random sequence generation
(selection bias)
Allocation concealment (selection
bias)
Blinding of participants and personnel
(performance bias)
Blinding of outcome assessment
(detection bias)
Unclear risk
Unclear risk
Support for judgement
We had insufficient information to
permit judgement.
We had insufficient information to
permit judgement.
Low risk
"Identical appearing placebo"
Unclear risk
No details provided. Outcomes
assessors could be bias based on
the side effects profile of codeine.
Incomplete outcome data (attrition
bias)
Selective reporting (reporting bias)
High risk
Completer analysis
High risk
Selection bias
Low risk
Funding bias
Low risk
No protocol reported by the
authors. SAE not reported
No significant baseline differences
in demographic and clinical
variables between the groups
No funding by pharmaceutical
industry reported; no authors
affiliated with industry
107
Thorne 2008
Bias
Authors'
judgement
Random sequence generation
(selection bias)
Allocation concealment (selection
bias)
Blinding of participants and personnel
(performance bias)
Blinding of outcome assessment
(detection bias)
Unclear risk
Unclear risk
Support for judgement
We had insufficient information to
permit judgement.
We had insufficient information to
permit judgement.
Low risk
"Matching placebo tablets"
Unclear risk
No information provided.
Outcomes assessors could be bias
based on the side effects profile of
tramadol
Incomplete outcome data (attrition
bias)
Selective reporting (reporting bias)
Unclear risk
ITT-analysis, method not reported
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
108
Vojtassasak 2011
Bias
Authors'
judgement
Random sequence generation
(selection bias)
Low risk
Allocation concealment (selection
bias)
Unclear risk
Blinding of participants and personnel
(performance bias)
Unclear risk
Blinding of outcome assessment
(detection bias)
Unclear risk
Incomplete outcome data (attrition
bias)
Selective reporting (reporting bias)
Unclear risk
Selection bias
Low risk
Funding bias
High risk
Low risk
109
Support for judgement
"computer-generated randomisation
schedule prepared by an
independent statistician"
"The investigator and the subject
were blinded to treatment
allocation". No further information
provided
The authors did not report the
physical characteristics of the
placebos.
We had insufficient information to
permit judgement.Outcomes
assessors could be bias based on
the side effects profile of
hydromorphone
ITT-analysis, No further
information provided
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
No significant baseline differences
in demographic and clinical
variables between the three groups
Funding by pharmaceutical
industry; 3 of five authors affiliated
with industry
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
110
Opioids
Placebo
Std. Mean Difference
Study or Subgroup
Mean
SD Total Mean
SD Total Weight
IV, Random, 95% CI
1.1.1 Buprenorphine
Breivik 2010
-3.2
3.8
100
-2.3
3.7
99
3.5%
-0.24 [-0.52, 0.04]
Munera 2010
-1.84 2.68
149
-1.4 2.67
162
4.9%
-0.16 [-0.39, 0.06]
Subtotal (95% CI)
249
261
8.4%
-0.19 [-0.37, -0.02]
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 2000
32.5 21.4
31
Subtotal (95% CI)
31
Heterogeneity: Not applicable
Test for overall effect: Z = 2.55 (P = 0.01)
47.7
24.7
35
35
1.3%
1.3%
-0.65 [-1.14, -0.15]
-0.65 [-1.14, -0.15]
-17.9
26.7
197
197
5.8%
5.8%
-0.22 [-0.41, -0.02]
-0.22 [-0.41, -0.02]
6.2%
6.2%
4.6%
17.0%
-0.21 [-0.39, -0.02]
-0.03 [-0.22, 0.15]
0.09 [-0.14, 0.32]
-0.06 [-0.23, 0.10]
1.5%
1.5%
1.5%
4.4%
-0.40 [-0.87, 0.06]
-0.28 [-0.74, 0.17]
-0.27 [-0.73, 0.19]
-0.32 [-0.58, -0.05]
4.0%
2.1%
4.2%
10.2%
-0.25 [-0.51, 0.01]
-0.43 [-0.81, -0.04]
-0.27 [-0.52, -0.02]
-0.29 [-0.45, -0.13]
2.9%
3.0%
5.9%
-0.52 [-0.83, -0.21]
-0.40 [-0.71, -0.09]
-0.46 [-0.68, -0.24]
4.8%
4.8%
-0.41 [-0.64, -0.18]
Not estimable
-0.41 [-0.64, -0.18]
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%
-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]
Total (95% CI)
4162
2581 100.0%
Heterogeneity: Tau² = 0.01; Chi² = 35.47, df = 28 (P = 0.16); I² = 21%
Test for overall effect: Z = 7.51 (P < 0.00001)
Test for subgroup differences: Chi² = 15.03, df = 8 (P = 0.06), I² = 46.8%
-0.22 [-0.28, -0.17]
1.1.3 Fentanyl
Langford 2006
-23.6 25.6
202
Subtotal (95% CI)
202
Heterogeneity: Not applicable
Test for overall effect: Z = 2.17 (P = 0.03)
1.1.4 Hydromorphone
Rauck 2013
-2.5
2.9
330
-1.9 2.86
166
Rauck 2013
-2 2.86
319
-1.9 2.86
165
Vojtassak 2011
-2.4
2.1
138
-2.6
2.3
149
Subtotal (95% CI)
787
480
Heterogeneity: Tau² = 0.01; Chi² = 4.05, df = 2 (P = 0.13); I² = 51%
Test for overall effect: Z = 0.72 (P = 0.47)
1.1.5 Morphine
Caldwell 2002
-26.7 29.9
73 -14.6 29.9
24
Caldwell 2002
-23.1 29.9
76 -14.6 29.9
25
Caldwell 2002
-22.8 29.9
73 -14.6 29.9
24
Subtotal (95% CI)
222
73
Heterogeneity: Tau² = 0.00; Chi² = 0.19, df = 2 (P = 0.91); I² = 0%
Test for overall effect: Z = 2.34 (P = 0.02)
1.1.6 Oxycodone
Afilalo 2010
-1.05 0.67
92 -0.88 0.69
158
Markenson 2005
-1.7
2.2
56
-0.6
2.9
51
Matsumoto 2005
-90
112 125
-60
111
124
Subtotal (95% CI)
273
333
Heterogeneity: Tau² = 0.00; Chi² = 0.62, df = 2 (P = 0.73); I² = 0%
Test for overall effect: Z = 3.48 (P = 0.0005)
1.1.7 Oxymorphone
Matsumoto 2005
-118
110
121
-60
111
62
Matsumoto 2005
-104
109
121
-60
111
62
Subtotal (95% CI)
242
124
Heterogeneity: Tau² = 0.00; Chi² = 0.31, df = 1 (P = 0.58); I² = 0%
Test for overall effect: Z = 4.12 (P < 0.0001)
1.1.8 Tapentadol
Afilalo 2010
-1.16 0.67
149
Afilalo 2010
0
0
0
Subtotal (95% CI)
149
Heterogeneity: Not applicable
Test for overall effect: Z = 3.56 (P = 0.0004)
-0.88
0
0.69
0
158
0
158
1.1.9 Tramadol
Babul 2004
-29 76.2
124 -18.7 73.9
122
DeLemos 2011
-90.4 125.6
199 -94.9 125.9
67
DeLemos 2011
-82.5 125.6
201 -94.9 125.9
67
DeLemos 2011
-117.8 125.9
199 -94.9 125.9
66
Fishman 2007
-46 39.9
105 -32.3 38.2
76
Fishman 2007
-42.8 46.4
107 -32.3 48.2
76
Fishman 2007
-41.6 50.2
103 -32.3 48.2
75
Fleischmann 2000
2.1 1.06
63 2.48 1.13
66
Gana 2006
-111.5 123.3
201 -74.2 121.7
51
Gana 2006
-107.2 122.2
202 -74.2 121.7
51
Gana 2006
-103.9 123.3
201 -74.2 121.7
51
Gana 2006
-107.8 123.7
202 -74.2 121.7
52
Thorne 2008
38.2 22.7
100 47.7 25.7
100
Subtotal (95% CI)
2007
920
Heterogeneity: Tau² = 0.00; Chi² = 11.83, df = 12 (P = 0.46); I² = 0%
Test for overall effect: Z = 4.87 (P < 0.00001)
Std. Mean Difference
IV, Random, 95% CI
-1
-0.5
0
0.5
1
Favours opioids Favours placebo
Figure 2 (Electronic Supplementary Material): Effect estimates (risk difference) of 50% pain
reduction at end of treatment
111
Opioids
Placebo
Risk Difference
Study or Subgroup
Events Total Events Total Weight IV, Random, 95% CI
1.2.1 Oxycodone
Afilalo 2010
59 342
82 337 25.8%
-0.07 [-0.13, -0.01]
Afilalo 2013
73 331
91 337 25.0%
-0.05 [-0.11, 0.02]
Subtotal (95% CI)
673
674
50.8%
-0.06 [-0.11, -0.02]
Total events
132
173
Heterogeneity: Tau² = 0.00; Chi² = 0.22, df = 1 (P = 0.64); I² = 0%
Test for overall effect: Z = 2.68 (P = 0.007)
1.2.2 Tapentadol
Afilalo 2010
0
0
0
0
Afilalo 2010
110 344
82 337 24.6%
Afilalo 2013
0
0
0
0
Afilalo 2013
99 344
91 337 24.6%
Subtotal (95% CI)
688
674
49.2%
Total events
209
173
Heterogeneity: Tau² = 0.00; Chi² = 1.46, df = 1 (P = 0.23); I² = 31%
Test for overall effect: Z = 1.61 (P = 0.11)
Not estimable
0.08 [0.01, 0.14]
Not estimable
0.02 [-0.05, 0.09]
0.05 [-0.01, 0.10]
Total (95% CI)
1361
1348 100.0%
-0.01 [-0.07, 0.06]
Total events
341
346
Heterogeneity: Tau² = 0.00; Chi² = 12.24, df = 3 (P = 0.007); I² = 75%
Test for overall effect: Z = 0.22 (P = 0.82)
Test for subgroup differences: Chi² = 8.48, df = 1 (P = 0.004), I² = 88.2%
112
Risk Difference
IV, Random, 95% CI
-0.5 -0.25 0 0.25 0.5
Placebo Opioids
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
Opioids
Placebo
Study or Subgroup
Events Total Events Total Weight
1.3.1 Buprenorphine
Breivik 2010
36 100
19
99 16.8%
Subtotal (95% CI)
100
99 16.8%
Total events
36
19
Heterogeneity: Not applicable
Test for overall effect: Z = 2.70 (P = 0.007)
1.3.2 Tapentadol
Afilalo 2010
0
0
0
0
Afilalo 2010
151
258
97
273 21.2%
Afilalo 2013
0
0
0
0
Afilalo 2013
139
248
127 294 21.0%
Subtotal (95% CI)
506
567
42.2%
Total events
290
224
Heterogeneity: Tau² = 0.00; Chi² = 2.85, df = 1 (P = 0.09); I² = 65%
Test for overall effect: Z = 3.54 (P = 0.0004)
1.3.3 Oxycodone
Afilalo 2010
94
200
97
273 20.4%
Afilalo 2013
90
212
127
294 20.6%
Subtotal (95% CI)
412
567
41.0%
Total events
184
224
Heterogeneity: Tau² = 0.01; Chi² = 3.66, df = 1 (P = 0.06); I² = 73%
Test for overall effect: Z = 0.87 (P = 0.38)
Risk Difference
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]
Total (95% CI)
1018
1233 100.0%
0.13 [0.05, 0.21]
Total events
510
467
Heterogeneity: Tau² = 0.01; Chi² = 15.55, df = 4 (P = 0.004); I² = 74%
Test for overall effect: Z = 3.05 (P = 0.002)
Test for subgroup differences: Chi² = 2.83, df = 2 (P = 0.24), I² = 29.3%
113
Risk Difference
IV, Random, 95% CI
-0.5 -0.25 0 0.25 0.5
Placebo Opioids
Figure 4 (Electronic Supplementary Material): Effect estimates (standardised mean
differences) of physical function improvement at end of treatment
114
Figure 5 (Electronic Supplementary Material): Effect estimates (risk difference) of dropping
out due to lack of efficacy during study
115
Opioids
Placebo
Study or Subgroup
Events Total Events Total Weight
1.8.1 Buprenorphine
Breivik 2010
7 100
12
99
4.7%
Subtotal (95% CI)
100
99
4.7%
Total events
7
12
Heterogeneity: Not applicable
Test for overall effect: Z = 1.23 (P = 0.22)
1.8.2 Codeine
Peloso 2000
1
51
Subtotal (95% CI)
51
Total events
1
Heterogeneity: Not applicable
Test for overall effect: Z = 1.69 (P = 0.09)
5
Risk Difference
IV, Random, 95% CI
Risk Difference
IV, Random, 95% CI
-0.05 [-0.13, 0.03]
-0.05 [-0.13, 0.03]
52
52
4.5%
4.5%
-0.08 [-0.17, 0.01]
-0.08 [-0.17, 0.01]
197
197
4.9%
4.9%
-0.25 [-0.33, -0.18]
-0.25 [-0.33, -0.18]
5
1.8.3 Fentanyl
Langford 2006
15
202
64
Subtotal (95% CI)
202
Total events
15
64
Heterogeneity: Not applicable
Test for overall effect: Z = 6.57 (P < 0.00001)
1.8.4 Hydromorphone
Rauck 2013
30
330
42 166
4.9%
-0.16 [-0.24, -0.09]
Rauck 2013
49 319
41 166
4.8%
-0.09 [-0.17, -0.02]
Vojtassak 2011
5 139
16 149
5.4%
-0.07 [-0.13, -0.01]
Subtotal (95% CI)
788
481 15.2%
-0.11 [-0.16, -0.05]
Total events
84
99
Heterogeneity: Tau² = 0.00; Chi² = 3.69, df = 2 (P = 0.16); I² = 46%
Test for overall effect: Z = 3.85 (P = 0.0001)
1.8.5 Morphine
Caldwell 2002
9
73
5
24
2.3%
Caldwell 2002
12
73
4
25
2.5%
Caldwell 2002
8
76
5
25
2.4%
Subtotal (95% CI)
222
74
7.3%
Total events
29
14
Heterogeneity: Tau² = 0.00; Chi² = 0.80, df = 2 (P = 0.67); I² = 0%
Test for overall effect: Z = 1.12 (P = 0.26)
-0.09 [-0.26, 0.09]
0.00 [-0.16, 0.17]
-0.09 [-0.27, 0.08]
-0.06 [-0.16, 0.04]
1.8.6 Oxycodone
Afilalo 2010
7 332
56 337
5.8%
-0.15 [-0.19, -0.10]
Markenson 2005
9
56
34
51
2.6%
-0.51 [-0.67, -0.34]
Matsumoto 2005
9 121
34 124
4.4%
-0.20 [-0.29, -0.11]
Subtotal (95% CI)
509
512 12.8%
-0.26 [-0.42, -0.11]
Total events
25
124
Heterogeneity: Tau² = 0.02; Chi² = 18.36, df = 2 (P = 0.0001); I² = 89%
Test for overall effect: Z = 3.29 (P = 0.0010)
1.8.7 Oxymorphone
Matsumoto 2005
5 121
17
62
3.7%
Matsumoto 2005
13
125
17
62
3.5%
Subtotal (95% CI)
246
124
7.1%
Total events
18
34
Heterogeneity: Tau² = 0.00; Chi² = 0.52, df = 1 (P = 0.47); I² = 0%
Test for overall effect: Z = 4.70 (P < 0.00001)
1.8.8 Tapentadol
Afilalo 2010
15
334
56
Subtotal (95% CI)
334
Total events
15
56
Heterogeneity: Not applicable
Test for overall effect: Z = 5.22 (P < 0.00001)
337
337
5.8%
5.8%
-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]
1.8.9 Tramadol
Babul 2004
19 124
45 122
3.9%
-0.22 [-0.32, -0.11]
Fishman 2007
21
106
15
76
3.6%
0.00 [-0.12, 0.12]
Fishman 2007
11
111
15
76
4.0%
-0.10 [-0.20, 0.01]
Fishman 2007
11 108
15
75
3.9%
-0.10 [-0.21, 0.01]
Fleischmann 2000
28
63
49
66
2.6%
-0.30 [-0.46, -0.14]
Gana 2006
31
203
11
51
3.5%
-0.06 [-0.19, 0.06]
Gana 2006
29 203
11
51
3.5%
-0.07 [-0.20, 0.05]
Gana 2006
18
204
12
51
3.5%
-0.15 [-0.27, -0.02]
Gana 2006
23
205
12
52
3.5%
-0.12 [-0.24, 0.00]
Thorne 2008
1
94
3
88
5.8%
-0.02 [-0.07, 0.02]
Subtotal (95% CI)
1421
708
37.8%
-0.10 [-0.16, -0.05]
Total events
192
188
Heterogeneity: Tau² = 0.00; Chi² = 23.26, df = 9 (P = 0.006); I² = 61%
Test for overall effect: Z = 3.80 (P = 0.0001)
Total (95% CI)
3873
2584 100.0%
-0.13 [-0.16, -0.10]
Total events
386
596
Heterogeneity: Tau² = 0.00; Chi² = 85.36, df = 24 (P < 0.00001); I² = 72%
-1
-0.5
0
0.5
1
Test for overall effect: Z = 7.49 (P < 0.00001)
Favours placebo Favours opioid
Test for subgroup differences: Chi² = 24.37, df = 8 (P = 0.002), I² = 67.2%
116
Figure 6 (Electronic Supplementary Material): Effect estimates (risk difference) of dropping
out due to adverse events during study
117
118
Figure 7 (Electronic Supplementary Material): Effect estimates (risk difference) of serious
adverse events during study
Opioids
Placebo
Risk Difference
Study or Subgroup
Events Total Events Total Weight M-H, Random, 95% CI
1.6.1 Buprenorphine
Breivik 2010
5
100
4
99
1.5%
0.01 [-0.05, 0.07]
Munera 2010
0
152
2
163 10.8%
-0.01 [-0.03, 0.01]
Subtotal (95% CI)
252
262
12.3%
-0.01 [-0.03, 0.01]
Total events
5
6
Heterogeneity: Tau² = 0.00; Chi² = 0.84, df = 1 (P = 0.36); I² = 0%
Test for overall effect: Z = 0.98 (P = 0.33)
1.6.2 Fentanyl
Langford 2006
6
202
Subtotal (95% CI)
202
Total events
6
Heterogeneity: Not applicable
Test for overall effect: Z = 1.40 (P = 0.16)
2
197
197
6.4%
6.4%
0.02 [-0.01, 0.05]
0.02 [-0.01, 0.05]
2
1.6.3 Hydromorphone
Rauck 2013
13
330
3
166
5.6%
Rauck 2013
8 319
2 166
8.3%
Vojtassak 2011
10
139
9
149
1.5%
Subtotal (95% CI)
788
481
15.4%
Total events
31
14
Heterogeneity: Tau² = 0.00; Chi² = 0.21, df = 2 (P = 0.90); I² = 0%
Test for overall effect: Z = 1.77 (P = 0.08)
1.6.4 Oxycodone
Afilalo 2010
10 342
6 337
9.1%
Markenson 2005
3
56
0
51
1.1%
Subtotal (95% CI)
398
388 10.2%
Total events
13
6
Heterogeneity: Tau² = 0.00; Chi² = 1.35, df = 1 (P = 0.24); I² = 26%
Test for overall effect: Z = 1.17 (P = 0.24)
1.6.5 Tapentadol
Afilalo 2010
4
344
Afilalo 2010
0
0
Subtotal (95% CI)
344
Total events
4
Heterogeneity: Not applicable
Test for overall effect: Z = 0.67 (P = 0.50)
Risk Difference
M-H, Random, 95% CI
6
0
337
0
337
14.2%
14.2%
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]
6
1.6.6 Tramadol
Fishman 2007
2
325
2
224 20.3%
Fleischmann 2000
0
63
2
66
1.9%
Gana 2006
4
201
0
51
4.3%
Gana 2006
3 201
1
51
2.8%
Gana 2006
3
202
0
51
4.7%
Gana 2006
6 202
1
52
2.5%
Thorne 2008
0
94
1
88
5.2%
Subtotal (95% CI)
1288
583
41.6%
Total events
18
7
Heterogeneity: Tau² = 0.00; Chi² = 4.52, df = 6 (P = 0.61); I² = 0%
Test for overall effect: Z = 0.03 (P = 0.97)
-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]
Total (95% CI)
3272
2248 100.0%
0.00 [-0.00, 0.01]
Total events
77
41
Heterogeneity: Tau² = 0.00; Chi² = 15.28, df = 15 (P = 0.43); I² = 2%
-0.2 -0.1 0 0.1 0.2
Test for overall effect: Z = 0.90 (P = 0.37)
Favours placebo Favours opioid
Test for subgroup differences: Chi² = 7.42, df = 5 (P = 0.19), I² = 32.6%
119
Figure 8 (Electronic Supplementary Material): Effect estimates (risk difference) of death
during study
120
Forest Plots of standardised mean differences and risk differences
of opioids compared to placebo on selected outcomes
EERW design
Figure 9 (Electronic Supplementary Material): Effect estimates (standardised mean
differences) of mean pain intensity reduction at end of treatment
Opioid
Placebo
Std. Mean Difference
Study or Subgroup
Mean SD Total Mean SD Total Weight
IV, Random, 95% CI
2.2.3 Morphine
Katz 2010
-0.4 1.3
170
-0.2 1.3
173 40.5%
-0.15 [-0.37, 0.06]
Subtotal (95% CI)
170
173 40.5%
-0.15 [-0.37, 0.06]
Heterogeneity: Not applicable
Test for overall effect: Z = 1.42 (P = 0.16)
2.2.4 Oxycodone
Caldwell 1999
0.44 0.76
34
1 0.78
36 16.6%
Friedmann 2011
-0.7 2.05
203
-0.3 2.48
207 42.9%
Subtotal (95% CI)
237
243
59.5%
Heterogeneity: Tau² = 0.11; Chi² = 4.17, df = 1 (P = 0.04); I² = 76%
Test for overall effect: Z = 1.49 (P = 0.14)
Total (95% CI)
407
416 100.0%
Heterogeneity: Tau² = 0.02; Chi² = 4.63, df = 2 (P = 0.10); I² = 57%
Test for overall effect: Z = 2.17 (P = 0.03)
Test for subgroup differences: Chi² = 0.73, df = 1 (P = 0.39), I² = 0%
121
Std. Mean Difference
IV, Random, 95% CI
-0.72 [-1.20, -0.23]
-0.18 [-0.37, 0.02]
-0.40 [-0.92, 0.12]
-0.26 [-0.49, -0.03]
-4
-2 0 2 4
Opioid Placebo
Figure 10 (Electronic Supplementary Material): Effect estimates (risk difference) of 50% pain
reduction at end of treatment
Opioid
Placebo
Study or Subgroup
Events Total Events Total Weight
2.4.3 Morphine
Katz 2010
97 171
82 173 100.0%
Subtotal (95% CI)
171
173 100.0%
Total events
97
82
Heterogeneity: Not applicable
Test for overall effect: Z = 1.74 (P = 0.08)
Total (95% CI)
171
Total events
97
82
Heterogeneity: Not applicable
Test for overall effect: Z = 1.74 (P = 0.08)
Test for subgroup differences: Not applicable
173 100.0%
Risk Difference
IV, Random, 95% CI
Risk Difference
IV, Random, 95% CI
0.09 [-0.01, 0.20]
0.09 [-0.01, 0.20]
0.09 [-0.01, 0.20]
-10
-5
0
5
10
Favours placebo Favours opioid
122
Figure 11 (Electronic Supplementary Material): Effect estimates (standardised mean
differences) of physical function improvementat end of treatment
123
Figure 12 (Electronic Supplementary Material): Effect estimates (risk difference) of dropping
out due to lack of efficacy during study
Opioid
Placebo
Study or Subgroup
Events Total Events Total Weight
2.5.1 Buprenorphine
Munera 2010
43
152
57
163 16.2%
Subtotal (95% CI)
152
163
16.2%
Total events
43
57
Heterogeneity: Not applicable
Test for overall effect: Z = 1.28 (P = 0.20)
2.5.2 Morphine
Katz 2010
6
171
32
Subtotal (95% CI)
171
Total events
6
32
Heterogeneity: Not applicable
Test for overall effect: Z = 4.58 (P < 0.00001)
173
173
37.6%
37.6%
Risk Difference
IV, Random, 95% CI
Risk Difference
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]
2.5.3 Oxycodone
Caldwell 1999
3
34
7
18
3.0%
-0.30 [-0.55, -0.06]
Caldwell 1999
4
37
6
18
3.1%
-0.23 [-0.46, 0.01]
Friedmann 2011
12
205
38
207 40.0%
-0.13 [-0.19, -0.06]
Subtotal (95% CI)
276
243
46.2%
-0.16 [-0.24, -0.07]
Total events
19
51
Heterogeneity: Tau² = 0.00; Chi² = 2.37, df = 2 (P = 0.31); I² = 16%
Test for overall effect: Z = 3.56 (P = 0.0004)
2.5.4 Tramadol
Subtotal (95% CI)
0
Total events
0
Heterogeneity: Not applicable
Test for overall effect: Not applicable
0
Not estimable
0
Total (95% CI)
599
579 100.0%
-0.13 [-0.18, -0.09]
Total events
68
140
Heterogeneity: Tau² = 0.00; Chi² = 4.31, df = 4 (P = 0.37); I² = 7%
-1
-0.5
0
0.5
1
Test for overall effect: Z = 6.12 (P < 0.00001)
Favours placebo Favours opioid
Test for subgroup differences: Chi² = 2.16, df = 2 (P = 0.34), I² = 7.2%
124
Figure 13 (Electronic Supplementary Material): Effect estimates (risk difference) of dropping
out due to adverse events during study
Opioid
Placebo
Study or Subgroup
Events Total Events Total Weight
2.8.3 Morphine
Katz 2010
18 171
13 173 45.5%
Subtotal (95% CI)
171
173
45.5%
Total events
18
13
Heterogeneity: Not applicable
Test for overall effect: Z = 0.98 (P = 0.33)
2.8.4 Oxycodone
Caldwell 1999
3
34
3
36 15.6%
Friedmann 2011
43 205
22 207 38.9%
Subtotal (95% CI)
239
243
54.5%
Total events
46
25
Heterogeneity: Tau² = 0.00; Chi² = 1.69, df = 1 (P = 0.19); I² = 41%
Test for overall effect: Z = 1.52 (P = 0.13)
Risk Difference
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]
Total (95% CI)
410
416 100.0%
0.05 [-0.00, 0.11]
Total events
64
38
Heterogeneity: Tau² = 0.00; Chi² = 3.06, df = 2 (P = 0.22); I² = 35%
Test for overall effect: Z = 1.89 (P = 0.06)
Test for subgroup differences: Chi² = 0.52, df = 1 (P = 0.47), I² = 0%
125
Risk Difference
IV, Random, 95% CI
-0.5 -0.25 0 0.25 0.5
Placebo Opioid
Figure 14 (Electronic Supplementary Material): Effect estimates (risk difference) of serious
adverse events during study
Opioid
Placebo
Study or Subgroup
Events Total Events Total Weight
2.9.3 Morphine
Katz 2010
9 171
11 173 20.3%
Subtotal (95% CI)
171
173
20.3%
Total events
9
11
Heterogeneity: Not applicable
Test for overall effect: Z = 0.43 (P = 0.66)
2.9.4 Oxycodone
Friedmann 2011
5 205
Subtotal (95% CI)
205
Total events
5
Heterogeneity: Not applicable
Test for overall effect: Z = 1.16 (P = 0.25)
2
207
207
79.7%
79.7%
Risk Difference
IV, Random, 95% CI
Risk Difference
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]
2
Total (95% CI)
376
380 100.0%
0.01 [-0.01, 0.03]
Total events
14
13
Heterogeneity: Tau² = 0.00; Chi² = 0.83, df = 1 (P = 0.36); I² = 0%
Test for overall effect: Z = 0.84 (P = 0.40)
Test for subgroup differences: Chi² = 0.83, df = 1 (P = 0.36), I² = 0%
126
-0.5 -0.25 0 0.25 0.5
Placebo Opioid