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1
Opioids in chronic neuropathic pain - A systematic review and meta-analysis of
efficacy, tolerability and safety in randomized placebo-controlled studies of at least
four weeks duration
C. Sommer 1, P. Welsch 2, P. Klose 3, R. Schaefert 4, F. Petzke 5, W. Häuser 6,7
1 Neurologische Klinik, Universitätsklinikum Würzburg, Würzburg, Germany
2 Stichting Rugzorg Nederland, Ede, The Netherlands
3 Abteilung für Naturheilkunde und Integrative Medizin, Kliniken Essen-Mitte, Essen,
Germany
4 Klinik für Allgemeine Innere Medizin und Psychosomatik, Universitätsklinikum
Heidelberg, Heidelberg, Germany
5 Schmerz-Tagesklinik und Ambulanz, Universitätsmedizin Göttingen, Göttingen,
Germany
6 Klinik und Poliklinik für Psychosomatische Medizin und Psychotherapie, Technische
Universität München, Germany
7 Innere Medizin I, Klinikum Saarbrücken gGmbH, Germany
Korrespondenzadresse:
PD Dr. med. Winfried Häuser
Klinikum Saarbrücken gGmbH
Innere Medizin 1
Winterberg 1
D-66119 Saarbrücken
Germany
Tel: +49 681 9632020
Fax: +49 681 9632022
Email: [email protected]
2
Background: The efficacy and safety of opioid therapy in chronic neuropathic pain
(CNP) is under debate. We updated a recent Cochrane systematic review on the
efficacy, tolerability and safety of opioids in CNP.
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 CNP. We included double-blind
randomized placebo-controlled studies of at least four weeks duration. Risk
differences (RD) of categorical data and standardized mean differences (SMD) of
continuous variables were calculated using a random effects model.
Results: We included twelve RCTs with 1192 participants. The included diagnostic
entities were painful diabetic neuropathy (four studies), postherpetic neuralgia (three
studies), mixed polyneuropathic pain (two studies) and lumbar root, spinal cord injury
and post-amputation pain in one study each. Mean study duration was six (4 - 12)
weeks. Four studies tested morphine, three studies tramadol, two studies oxycodone
and one study tapentadol. These are the pooled results of studies with a parallel or
cross-over design: Opioids were superior to placebo in reducing pain intensity (SMD -
0.64 [95% confidence interval [CI] -0.81, -0.46]; p < 0.0001; eleven studies with 1040
participants). Opioids were not superior to placebo in 50% pain reduction (RD 0.16
[95% CI -0.04, 0.35], p = 0.11; one study with 93 participants). Opioids were not
superior to placebo in reports of much or very much improvement (RD 0.17 [95% CI -
0.01, 0.36]; p = 0.07; one study with 53 participants). Opioids were superior to
placebo in improving physical functioning (SMD -0.28 [95% CI -0.43, -0.13]; p <
0.0001; seven studies with 680 participants). Patients dropped out less frequently
with opioids than with placebo due to lack of efficacy (RD -0.07 [95% CI -0.13, -0.02],
p=0.008, six studies with 656 participants). Patients dropped out more frequently with
opioids than with placebo due to adverse events (RD 0.08 [95% CI 0.05, 0.12], p <
0.0001; ten studies with 1018 participants; number needed to harm 11 [95% CI 8 -
17]). There was no significant difference between opioids and placebo in the
frequency of serious adverse events and of deaths.
Conclusions: In short-term studies (4 - 12 weeks) in CNP, opioids were superior to
placebo in terms of efficacy and inferior in terms of tolerability. Opioids and placebo
did not differ in terms of safety. The conclusion on the safety of opioids compared to
placebo in CNP is limited by the low number of serious adverse events and deaths.
Short-term opioid therapy may be considered in selected patients with CNP.
3
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: Systematic review; meta-analysis; opioids; chronic neuropathic pain
4
Introduction
Chronic neuropathic pain (CNP) may result from a large variety of insults to the
peripheral or central somatosensory nervous system, including trauma, inflammation,
ischemia, and metabolic and neoplastic disorders. Common examples of peripheral
neuropathic pain include diabetic and postsurgical neuropathy. Central neuropathic
pain includes post-stroke pain, pain in multiple sclerosis, and pain after spinal cord
injury. The main clinical characteristics of neuropathic pain are a burning, aching, or
shooting quality, and abnormal sensitivity of the painful site to normally innocuous
stimuli (14). Estimates of the prevalence of chronic pain with neuropathic
characteristics range from 6.9% - 10% in the general population (22). However,
specific conditions with neuropathic pain can be rare, like postherpetic neuralgia with
a prevalence of 0.09% and trigeminal neuralgia with 0,07% (22), which makes it
difficult to collect large homogenous study cohorts.
The drug therapy of CNP is under debate (1,7,10). There is a lack of definitive
evidence regarding the efficacy of opioids in reducing neuropathic pain (14). A recent
systematic Cochrane reviews on opioids in neuropathic pain searched the literature
until October 2012. The review included short-term studies (< 4 weeks) into the
analyses of efficacy and harms and excluded studies with tramadol and tapentadol
(14).
For the revision of the German 2008 guideline on the long-term administration of
opioids in chronic non-cancer pain (CNCP) (LONTS) (19) we updated the search of
literature of systematic review on opioids in CNP. The objectives of this review were
to determine the efficacy, tolerability and safety of opioids (including tapentadol and
tramadol) compared to placebo in patients of any age with CNP in randomized
placebo-controlled studies with a duration of four or more weeks.
.
5
Methods
The review was performed according to the PRISMA (Preferred
Reporting Items for Systematic Reviews and Meta-Analyses) statement (15) and the
recommendations of the Cochrane Collaboration (13).
Criteria for considering studies for this review
Types of studies
We included fully published randomised double-blind controlled trials (RCT) that
compared any opioid to placebo (pure or pseudo) for therapeutic purposes in CNP.
We included studies with a parallel design and an enriched enrolment 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 effects or c.) statistical adjustments were carried out
in case of a significant carry-over effect.
Study duration should be at least 4 weeks (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 timing of post-randomization follow-
up: short-term (four to twelve weeks), intermediate (12 - 26 weeks) and long-term
(longer than 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 maintenance or withdrawal period of
less than four weeks, with an experimental design (i.e. if the primary purpose was to
study pain mechanisms and not pain relief) and studies and studies which were only
published as abstracts. We excluded studies in which different dosages of one opioid
were compared without a control group.
Types of participants
We included men and women of all ages and races or ethnicities diagnosed with
central or peripheral neuropathic pain of any etiology of least three months duration.
Types of interventions
We considered trials with opioids given by oral and transdermal routes.
6
We included studies in which opioids were combined with abuse deterrent
formulations (ADFs) (e.g. naloxone). We also 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 inhibition of
reuptake of norepinephrine and serotonin. We included studies with tapentadol, a
drug with two mechanisms of action: μ-receptor agonist and norepinephrine reuptake
inhibitor. The reason for including both drugs into this review was that they are
classified as opioids by German medicine agencies.
We considered trials with the following comparisons:
1. Opioids compared to placebo;
We excluded trials that examined opioids given by intravenous route and intrathecal
implantable pumps, due to the invasive nature of the therapy and its limited clinical
relevance in the outpatient setting. We did not assess the effectiveness of opioids
used in neuraxial implantable pumps as this has been discussed elsewhere (18). We
excluded studies in which drugs other than opioid agonists were combined with
opioids (e.g. tramadol with acetaminophen) except as a rescue medication because it
is not possible to detangle the effects of opioids from the other analgesic. 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 without a placebo
group. We excluded studies in which opioids and placebo were compared as add-on
to other drug therapies or vice versa. 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). We excluded
studies with opioid receptor agonist / NMDA antagonists (e.g. levorphanol) because
these drugs are not available in Germany.
Types of outcome measures
The selection of outcomes was based on the recommendations of the ACTINPAIN
writing group of the International Association for the Study of Pain (IASP) Special
Interest Group (SIG) on Systematic Reviews in Pain Relief and the Cochrane Pain,
Palliative and Supportive Care Systematic Review Group editors for reporting meta-
analyses of RCTs in chronic pain (16,17). We included pain intensity as additional
7
outcome because most studies conducted before 2005 did not report responder
analyses (14).
Efficacy
1. Pain intensity ratings
2. Proportion of patients reporting 50% pain relief (responders)
3. Global improvement: 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
Tolerability
1. Proportion of patients who withdrew because of adverse events
Safety
1. Proportion of patients who experienced any serious adverse events (SAE).
2. Proportion of patients who died during study
We excluded studies in which the primary outcome measure was not one of the five
outcomes of efficacy as defined above.
Search methods for identification of studies
Electronic searches
The review updated and expanded the search of literature of the first version of the
German guideline on the long-term administration of opiods (LONTS), which
searched the literature until October 2008 (19). The updated and expanded search
included CENTRAL, Medline and Scopus from October 2008 to October 2013 and all
types of CNCP. The search was conducted by PK. Our search included all
languages.
Searching other resources
8
The search strategy has been detailed in another paper of this issue (20).
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 the references met the
inclusion criteria. We obtained the full text of trials that either appeared to meet
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 studies,
characteristics of participants, intervention group, clinical setting, interventions,
country of study, and sponsorship of study. 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 (17).
Where means or standard deviations (SD) were missing, we calculated them from t-
values, CIs or standard errors, where reported in articles (13). Where missing SDs
could not be calculated fromt values, the study was excluded from analysis.
Measures of treatment effect
The effect measures of choice were absolute risk difference (RD) for dichotomous
data and standardised 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% confidence intervals (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).
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, PGIC, drop out due to adverse events, serious adverse events,
death) by a calculator provided by the Cochrane Musculoskeletal Group.
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
participants in the different opioid arms for continuous outcomes.
Data synthesis
We pooled data from trials comparing opioids to controls by a random-effects
methods 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 (12).
The risk of bias in each trial was assessed independently by two pairs of authors
(CS, WH; FP; WH; RS, WH) using eight domains recommended by the Cochrane
Collaboration: selection bias, performance bias, detection bias, attrition bias,
reporting bias, selection bias, performance bias, detection bias and funding bias (19).
We defined a high quality study (low risk of bias) that fulfilled six to eight, a moderate
quality study (moderate risk of bias) that fulfilled three to five and a low quality study
(high risk of bias) that fulfilled zero to two of the eight validity criteria (4). We used
Grading of Recommendations Assessment, Development and Evaluation (GRADE)
approach to assess the overall quality evidence (13,), defined as the extent of
confidence into the estimates of treatment benefits and harms. Quality ratings were
made separately for each of the eight outcomes. 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 of 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
10
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 the 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
For analyses without substantial heterogeneity (I² < 50%) and at least 10 studies, we
used the Egger intercept test and the Begg rank correlation test at the significance
level p< 0.05. 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
Subgroups were a priori planned to assess the variations in effect size
(heterogeneity) for all types of opioids pooled together compared to placebo groups
pooled together for the outcomes (pain intensity and drop out due to adverse events)
for different types of chronic neuropathic pain, different types of opioids (pure opioids
versus opioids with additional modes of action [tramadol, tapentadol], studies with
and without industry sponsoring and treatment duration (short-term, intermediate-
term and long-term studies). At least two studies should be available for subgroup
analysis.
Sensitivity analysis
11
We performed sensitivity analysis 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
Search
After removing duplicates, the literature search produced unique 12601 citations.
Through screening, 12589 records were excluded. Twelve full-text articles were
assessed for eligibility. No study was excluded after full-text review. Twelve studies
with 12 treatment arms were included in the meta-analysis (see Figure 1).
Study characteristics (see table 1 and supplementary table 1).
Study design: The 12 studies included 1192 (35 - 395) patients. Median study
duration was 6 (4 - 12) weeks. No study had a duration > 12 weeks. Eight (66.7%)
studies had a cross-over, 3 (25%) studies had a parallel and one (8.3%) study had an
enriched enrolment randomized withdrawal design. Nine (75.0%) studies were
conducted in North America and three studies (25.0%) in Europe. Six studies (50%)
were funded by the manufacturer of one of the drugs tested.
Participants: Participants were diagnosed with painful diabetic neuropathy (four
studies), postherpetic neuralgia (three studies), mixed polyneuropathic pain (two
studies) and in one study each with lumbar root, spinal cord injury and
postamputation pain. Only adults were included into the studies. The range of the
mean ages of participants in the studies was 51 - 71 years. The participants were
predominantly Caucasians, the gender ratio was nearly balanced. Nine (80%) studies
each excluded patients with current and/or a history of substance abuse and/or
current major mental disorders and all studies excluded patients with clinically
relevant medical diseases.
Interventions: Four studies tested morphine, three studies tramadol, two studies
oxycodone and one study tapentadol. All studies used a flexible dosage of the opioid.
The opioids were administered by extended release formulations in all studies. Two
12
(16.7%) studies did not report on or prohibited rescue medication. Eight (66.7%)
studies allowed rescue medication (acetaminophen, NSAIDs, short-acting opioids).
Quality of evidence
Risk of bias could not be properly assessed in all studies due to poor method
reporting. Two studies each (16.7%) had a low or high and eight studies (75.0%) had
a moderate study quality (see Figure 2, Figure 3 for risk of bias summary and graph).
Detailed information regarding risk of bias assessments of every study are given in
the Electronic Supplementary Material table 2.
Synthesis of results
Parallel and cross-over design (Results are reported with 95% CI)
Eleven studies with 1040 participants were entered into an analysis of mean pain
reduction at the end of the study. Opioids were superior to placebo (SMD -0.64 [-
0.81, -0.46]; p < 0.0001; I² = 45) (moderate quality evidence). According to Cohen’s
categories the effects size was moderate (see Electronic Supplementary Material
figure 1).
One study with 93 participants was entered into an analysis of 50% pain reduction at
the end of the study. Opioid was not superior to placebo (RD 0.16 [-0.04, 0.35], p =
0.11, I² = 51) (low quality evidence) (see Electronic Supplementary Material figure 2).
One study with 35 participants was entered into an analysis of reports to be much or
very much improved at the end of the study. Opioids were not superior to placebo
(RD 0.17 [-0.01, 0.36]; p = 0.07) (very low quality evidence) (see Electronic
Supplementary Material figure 3).
Seven studies with 680 participants were entered into an analysis of physical function
at the end of the study. Opioids were superior to placebo (SMD -0.28 [-0.43, -0.13]; p
= 0.0003]; I² = 0) (moderate quality evidence) (see Electronic Supplementary Material
figure 4). According to Cohen’s categories, the effect size was small. Two studies
(appendix references 1,12), which reported no significant differences between opioid
and placebo, could not be entered in meta-analysis because no means, SDs, p- or t-
values were reported.
Patients dropped out less frequently with opioids than with placebo due to lack of
efficacy (RD -0.07 [ -0.13, -0.02], p=0.008, six studies with 656 participants)
(moderate quality evidence) (see Electronic supplementary figure 5). 11/330 (3.3%)
13
of patients dropped out in opioid and 44/326 (13.5%) dropped out in placebo group
(NNTB 10 [95% CI 7-17]). According to the predefined criteria, there was an
appreciable additional benefit by opioids (RRR 75% [53% - 87%]).
Ten studies with 1018 participants were entered into an analysis of dropping out due
to adverse events. Patients dropped out more frequently with opioids than with
placebo (RD 0.08 [0.05, 0.12], p < 0.0001, I² = 0) (moderate quality evidence) (see
Electronic Supplementary Material figure 6). 70/524 (13.3%) of patients dropped out
in the opioid groups and 20/494 (4.0%) in the placebo groups due to adverse events
(NNH 11 [95% CI 8 - 17]). According to the predefined criteria, there was no
appreciable additional harm by opioids (RRI 230% [104% - 434%]).
Three studies with 357 participants were entered into an analysis of serious adverse
events. There was no significant difference between opioids and placebo (RD -0.01 [-
0.09, 0.07] p = 0.78; I² = 63) (very low quality evidence) (see Electronic
Supplementary Material figure 7).
One study with 159 participants was entered into an analysis of deaths. 1/82 patients
died in opioid and 0/77 patients died in placebo groups (p = 0.48) (very low quality
evidence).
EERW design
One study with 200 participants was entered into an analysis of 50% pain reduction
maintenance from randomization to the end of study. Opioid was superior to placebo
(RD 0.23 [0.09, 0.36] p = 0.01 (very low quality evidence). 55/93 (59.1%) of patients
in the opioid group and 39/107 (36.4%) of patients in the placebo group reported a
50% pain reduction maintenance (NNTB 4 [95% CI 3 - 11) (see Electronic
Supplementary Material figure 8). According to the predefined criteria, there was an
appreciable additional benefit by opioids (RRI 62% [20% - 119%]).
One study with 357 participants was entered into an analysis of reports to be much or
very much improved at the end of the study. Opioid was superior to placebo (RD 0.26
[0.16, 0.36]; p < 0.0001) (very low quality evidence) (see Electronic Supplementary
Material figure 9). 116/180 (64.4%) of patients in the opioid group and 68/177
(38.4%) of patients in the placebo group reported to be much or very much improved
(NNTB 4 [95% CI 3 - 6). According to the predefined criteria, there was an
appreciable additional benefit by opioids (RRI 68% [35% - 108%].
One study with 389 participants was entered into an analysis of dropping out due to
adverse events. Patients dropped out more frequently with opioids than with placebo
14
(RD 0.07 [0.01, 0.13], p = 0.03) (very low quality evidence) (see Electronic
Supplementary Material figure10). 29/196 (14.8%) of patients dropped out in opioid
group and 15/193 (7.8%) in placebo group (NNTH 14 [95% CI 8 - 128]). According to
the predefined criteria, there was an appreciable additional harm by opioids (RRI
90% [5% - 244%]).
One study with 389 participants was entered into an analysis of serious adverse
events. There were more SAE in the opioid than in the placebo groups (RD 0.04
[0.00, 0.07]; p = 0.05) (very low quality evidence) (see Electronic Supplementary
Material figure 11). 10/196 (5.1%) of patients in opiod group and 3/193 (1.6%) of
patients in placebo group reported serious adverse events. (NNTH 28 [95% CI 28-
14400]). According to the predefined criteria, there was no appreciable additional
harm by opioids (RRI 228% [-8% - 1000%]) because the confidence interval included
zero..
No deaths were reported in both groups.
Subgroup and sensitivity analyses
In three parallel or cross-over studies of painful diabetic neuropathy, opioids were
superior in pain reduction and in improving physical function and inferior in tolerability
if compared to placebo (see table 2).
In three parallel or cross-over studies of chronic postherpetic neuralgia, opioids were
superior in pain reduction, but not in improving physical function compared to
placebo. Opioids were inferior in tolerability compared to placebo (see table 2).
Studies with and without industry sponsoring did not differ in their effect sizes on pain
(z=0.74, p=0.46).. The drop out rate due to adverse events was higher in studies
without industry sponsoring than without industry sponsoring (z=3.41, p=0.0006).(see
table 3).
Publication bias
The Kendall tau of the Begg rank correlation test of the outcome dropping out due to
adverse events was not significant (tau = -0.27, P two-tailed = 0.24). The Egger
intercept of the outcome pain was not significant (intercept = -2.44, p two-tailed =
0.27).
15
Discussion
Summary of main results
In short-term studies in patients with CNP (4 - 12 weeks), opioids were superior to
placebo in terms of efficacy and inferior in terms of tolerability. Opioids and placebo
did not differ in terms of safety. Sufficient data (> one RCT, > 400 patients included)
were only available for painful diabetic neuropathy and postherpetic neuralgia pain.
No studies with opioids are available for other types of chronic polyneuropathic pain,
e.g. in HIV, alcoholic or by chemotherapy-induced PNP. The evidence on opioids on
central neuropathic pain syndromes assessed in this review (spinal cord injury and
postamputation pain) is based on one study each with small sample size. There are
no RCTs with opioids available on other types of central CNP such as post stroke
pain. In short, the efficacy of opioids in all types of CNP has not been demonstrated
until now.
Comparison with other systematic reviews
Our results on the efficacy in terms of pain reduction and tolerability of opioids in
CNP are mainly in line with those of a Cochrane review which included fourteen
studies (845 participants, average 60 participants per study with duration lasting 1 to
12 weeks; most studies lasted less than six weeks). The authors did not include
studies with tramadol and tapentadol (14). Seven RCTs were included in the
Cochrane and in our review. Meta-analysis of the Cochrane group demonstrated at
least 33% pain relief in 57% of participants receiving an opioid versus 34% of those
receiving placebo. The overall risk difference was 0.25 (95% CI 0.13 to 0.37, P <
0.0001), translating to a number needed to treat for an additional beneficial outcome
(NNTB) of 4.0 (95% CI 2.7, 7.7). When the number of participants achieving at least
50% pain relief was analyzed, the overall point estimate of risk difference between
opioids (47%) and placebo (30%) was 0.17 (95% CI 0.02, 0.33, P = 0.03), translating
to an NNTB of 5.9 (3.0, 50.0). The authors did not find improvement in physical
functioning. More participants withdrew from opioid treatment due to adverse events
(13%) than from placebo (4%) (NNTH 12.5; 95% CI 8.3, 25.0). The authors
concluded that the studies demonstrated significant efficacy of opioids over placebo
in pain reduction in CNP (14).
16
In contrast to the Cochrane review, we found a moderate effect size of opioids on
physical function. However, two studies which did not find a significant difference
between opioids and placebo could not be included into meta-analysis. In conclusion,
despite of efficacy in terms of pain reduction, the overall efficay to improve clinical
status in neuropathic pain is subject to considerable uncertainty (14).
In addition, RCTs of up to six weeks duration do not necessarily provide information
about long-term use, which is important in treatment of a chronic condition. In
particular, concern has been raised about the lack of evidence on potential problems
with long-term use of opioids in the treatment of neuropathic pain (such as safety
issues, addiction and misuse) (21,23).
The presently available systematic reviews of placebo-controlled studies on CNP are
not very helpful in guiding patients and physicians in the choice of first- and second-
line treatment. Head-to-head comparisons of opioids with other drugs have been
rarely conducted. Morphine was compared with antidepressants (two studies), an
anticonvulsant (one study) and an antiarrhythmic (one study) in different CNP
syndromes. There was no difference between the opioids, antidepressants and
anticonvulsants tested in terms of efficacy and tolerability (24. Therefore, evidence-
based recommendations of first- or second-line drug therapies in CNP are not
possible. To provide a superior evidence base for future treatment guidelines,
additional studies must be conducted in which existing drugs are directly compared
with each other and administered in various combinations. Traditional RCTs may
ultimately not be the method of choice to answer all these questions; alternative
approaches should be developed and evaluated, e.g. systematic comparative
effectiveness studies of health care registry data (7).
Limitations
Only double-blind randomized placebo-controlled studies were included in this meta-
analysis, representing a high level in evidence based medicine. However, the
methodological quality of the majority of included studies was only moderate. There
was a high risk of selective reporting causing a relevant reporting bias.
We may have missed published studies by our search strategy. Since clinical trial
registries were searched, this statement is mainly valid for studies conducted before
the establishment of these registries. In addition, we may have underestimated the
quality of studies because we did not ask the authors for missing details.
17
The conclusion on the safety of opioids compared to placebo is limited by the low
number of serious adverse events and deaths.
Conclusions for clinical practice
Opioids may be considered in the short-term treatment (4 - 12 weeks) of CNP
syndromes. There are no RCTs with opioids available for some neuropathic
conditions like, poststroke pain, multiple sclerosis-related and non-diabetic PNP pain
(e.g. HIV, alcoholic). Diverse pharmacological treatments of CNP have become
available, and interpreting the data on their efficacy and safety involves substantial
complexity and ambiguities (7). Recent guidelines (update of the NeuPSIG
pharmacological guidelines for management of neuropathic pain; European
Federation of Neurological Societies Task Force) did not recommend first- and
second-line drug treatment options, but a multifactorial evaluation that carefully
considers the clinical importance of the improvements shown by patients and the
benefits and risks of each treatment in view of the other available treatments (2,7).
The German National Patient-Centered Guideline on neuropathy in type 2 diabetes
recommended morphine, oxycodone and tramadol if opioid therapy is considered in
painful diabetic neuropathy (4).
Long-term open-label studies demonstrated that a minority of patients with chronic
non-cancer pain (including CNP) treated with opioids experienced a sustained (> 1
year) response with no or tolerable side effects (12,24). These data support the
notion that long-term ( 26 months) opioid therapy may be offered to sustained
responders to short-term opioid therapy, especially when alternative treatment
options fail, show only partial efficacy, or have significant side effects. However, the
potential benefits must be carefully balanced against potential risks of long-term
opioid therapy (12).
Acknowledgements: We thank Professor Sorgatz (Essen) for reviewing our data on
drop outs due to lack of efficacy
18
Table 1: Overview of the randomized controlled trials in chronic neuropathic pain
included into the systematic review (grouped by type of opioid in alphabetical order)
Morphine
Reference Year Countries of study centers
Study design Population type Number of patients randomized
Interventions and control group
Duration of trial (titration and maintenance)
Gilron 2005 Canada
Cross over Postherpetic neuralgia and painful diabetic neuropathy
57
Morphine up to 120 mg/d flexible oral Active placebo (lorazepam) flexible
No reports on wash-out periods 4 weeks each
Khoromi 2007 USA
Cross over Lumbar root pain 56
Morphine flexible 15 - 90 mg/d oral Nortriptyline flexible 25 - 100 mg/d oral Benztropine flexible (0.25 -1 mg/d) (active placebo)
Duration screening and wash-out not reported 3 weeks titration 2 weeks maintenance 2 weeks tapering
Raja 2002 USA
Cross over Postherpetic neuralgia 50
Morphine flexible 15 - 240 mg/d oral or methadone 5 - 75 mg/d or placebo oral flexible
Duration wash-out: 1 week
Approximately 8 weeks titration, maintenance and dose tapering for each period
1 week drug-free wash-out
Wu 2008 USA
Cross over Postamputation (stump and phantom pain) 60
Morphine 15 - 180 mg/d flexible oral vs. flexible oral placebo
4 weeks titration
2 weeks,
19
maintenance
2 weeks dose tapering for each period
1 week drug-free wash-out
Oxycodone
Reference Year Countries of study centers
Study design
Population type Number of patients randomized
Interventions and control group
Duration of trial (titration and maintenance)
Gimbel 2003 USA
Parallel Painful diabetic neuropathy 159
Oxycodone oral flexible up to 20 mg/d oral Placebo
Screening 7 days 6 weeks titration and maintenance 1-week tapering optional
Watson 1998 USA
Cross over Postherpetic neuralgia 38
Oxycodone oral flexible 20 - 160 mg/d Placebo
Duration wash out and screening not reported 4 weeks each No wash out between periods
Watson 2003 USA
Cross over Painful diabetic polyneuropathy 45
Oxycodone oral flexible 20 - 80 mg/d Active placebo flexible 0,5 – 2mg mg/d
2 - 7 days wash out 4 weeks each No wash out between periods Up to one year open label
20
Tapentadol
Reference Year Countries of study centers
Study design Population type Number of patients randomized
Interventions and control group
Duration of trial (weeks)
Schwartz Canada, USA 2011
Enriched-enrollment randomized withdrawal
Painful diabetic polyneuropathy 395
Tapentadol 200 - 500 mg/d flexible oral Placebo
Duration screening not reported 3 weeks open-label titration phase 12 week double blind withdrawal
Tramadol
Reference Year Countries of study centers
Study design
Population type Number of patients randomized
Interventions and control group
Duration of trial (weeks)
Boureau France 2003
Parallel Postherpetic neuralgia pain 125
Tramadol flexible 100 - 400 mg/d oral Placebo
Duration of screening not reported 6 weeks titration and maintenance
Harati 1998 USA
Parallel Painful diabetic polyneuropathy 131
Tramadol flexible 100 - 400 mg/d oral Placebo
Duration of wash-out not reported
6 weeks titration and maintenance
6 months open label
Norrbrink 2009 Sweden
Parellel Neuropathic pain after spinal cord injury 35
Tramadol flexible 100 - 400 mg/d oral Placebo
Duration of wash-out not reported
6 weeks titration and maintenance
Sindrup 1999 Denmark
Cross-over Polyneuropathy of different etiologies
Tramadol flexible 100 - 400 mg/d oral
Up to 1 week wash-out
21
45
Placebo 4 weeks each period
1 week wash-out
22
Table 2: Effect sizes of opioids on selected outcome variables (parallel and cross-over
design) in different types of chronic neuropathic pain
Outcome
title
Number
of
studies
Number
of
patients
Effect size
[95% CI])
Test for
overall
effect
p-value
Heteroge
neity
I² [%]
Painful diabetic neuropathy
01 Pain 3 380 SMD -0.74 (-1.06, -0.43)
<
0.0001
55
02 Drop out
due to
adverse
events
3 380 RD 0.07 [0.01, 0.13]
0.01 10
Postherpetic neuralgia
01 Pain 3 323 SMD -0.58 [-0.85, -0.31]
<
0.0001
29
02 Function 1 122 SMD -0.13 [-0.49, 0.22]
0.47
03 Drop out
due to
adverse
events
3 323 RD 0.09 [0.03, 0.14]
0.001 0
Mixed polyneuropathy and postherpetic neuralgia
01 Pain 2 177 SMD -0.54 [-1.03, -0.06]
0.03 62
02 Drop out
due to
adverse
events
2 170 RD 0.10 [0.02, 0.18]
0.002 0
23
Abbreviations: CI: Confidence interval; PNP= Polyneuropathy; RD = Risk
difference; SMD: Standardized mean difference;
24
Table 3: Effect sizes of opioids on selected outcome variables (parallel and cross-over
design) in studies with and without industry sponsoring
Outcome
title
Number
of
studies
Number
of
patients
Effect size
[95% CI])
Test for
overall
effect
p-value
Heteroge
neity
I² [%]
Without industry sponsoring
01 Pain 5 391 SMD -0.59 (-0.92, -0.26)
0.0004 58
02 Drop out
due to
adverse
events
5 354 RR 3.41 (1.64, 7.06)
0.001 0
With industry sponsoring
01 Pain 6 649 SMD -0.67(-0.88, -0.46]
<
0.0001
40
02 Drop out
due to
adverse
events
6 664 RR 2.23 (1.16, 4.27)
0.02 0
Abbreviations: CI: Confidence interval; RR = Relative Risk; SMD: Standardized
mean difference;
25
Figure 1: PRISMA Flow Diagram
Records identified through
database searching (n = 17 591)
CENTRAL: (n=3688) Medline: (n=6944) Scopus: (n=6959)
Scre
enin
g
Incl
ud
ed
Elig
ibili
ty
Iden
tifi
cati
on
Additional records identified through hand searching
(n = 52)
Records after duplicates removed (n = 12 601 )
Records screened (n = 12601 )
Records excluded (n =12 589)
Full-text articles assessed for eligibility
(n = 12 )
Full-text articles excluded, with reasons (n = 0)
Studies included in qualitative synthesis
(n = 12)
Studies included in quantitative synthesis
(meta-analysis) (n =12)
26
Figure 2: Risk of bias graph
Random sequence generation (selection bias)
Allocation concealment (selection bias)
Blinding of participants and personnel (performance bias)
Blinding of outcome assessment (detection bias)
Incomplete outcome data (attrition bias)
Selective reporting (reporting bias)
Selection bias
Funding bias
0% 25% 50% 75% 100%
Low risk of bias Unclear risk of bias High risk of bias
27
Figure 3: Risk of bias summary
Ran
do
m s
equ
en
ce
gen
era
tion
(sele
ction
bia
s)
Boureau 2003 +
Gilron 2005 ?
Gimbel 2003 +
Harati 1998 +
Khoromi 2007 +
Norrbrink 2007 ?
Raja 2002 +
Schwartz 2011 ?
Sindrup 1999 +
Watson 1998 +
Watson 2003 +
Wu 2008 +
Allo
cation c
oncealm
ent (s
ele
ction b
ias)
?
+
+
+
+
+
+
+
+
?
+
+
Blin
din
g o
f part
icip
ants
and p
ers
onnel (p
erf
orm
ance b
ias)
+
?
+
+
+
+
+
?
?
?
?
+
Blin
din
g o
f outc
om
e a
ssessm
ent (d
ete
ction b
ias)
?
?
?
?
+
?
?
?
?
?
?
?
Incom
ple
te o
utc
om
e d
ata
(a
ttrition
bia
s)
?
–
?
+
?
?
?
?
–
–
?
–
Sele
ctive r
eport
ing (
report
ing b
ias)
–
–
?
+
–
–
–
–
–
–
?
–
Sele
ction b
ias
+
+
+
+
+
–
+
+
+
+
+
+
Fu
nd
ing b
ias
–
+
–
–
+
+
+
–
–
–
–
+
28
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gabapentin, or their combination for neuropathic pain. NEJM 2005;352:1324–34.
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Cornblath D, Sachdeo R, Siu CO, Kamin M. Double-blind randomized trial of
tramadol for the treatment of the pain of diabetic neuropathy. Neurology 1998;50:
1842-1846.
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combination vs. placebo in patients with chronic lumbar root pain. Pain 2007;130:66–
75.
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randomized, double-blind, placebo- controlled trial. Clin J Pain 2009;25:177-184.
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Rauschkolb C. Safety and efficacy of tapentadol ER in patients with painful diabetic
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32
Electronic supplementary material tables Table 1: Characteristics of included studies Boureau 2013
Methods Disease: Postherpetic neuralgia
Study setting: 77 general practitioners in France
Study design: Parallel
Study duration: Duration of screening not reported, 1 week titration and 5 weeks maintenance
Participants Inclusion criteria: Aged 18 – 85 years, had to suffer from PHN for at least 3 months and for a maximum of 1 year, and to present with spontaneous pain rated at least 40 mm on a standard 100 mm Visual Analogue Scale (VAS)
Exclusion criteria: Symptoms or past history of depression, immune-depression, seizures, illicit drug abuse or central nervous system depressant drug abuse, cerebral tumour or recent cranial traumatism, severe hepatic, renal, cardiac or respiratory pathology, hypersensitivity to tramadol or to opioids. Pregnant or breast-feeding women, and women who risked becoming pregnant during the study period could not be included. Other exclusion criteria concerned patients treated with monoamine oxidase inhibitors within 15 days prior to the inclusion visit and patients treated with antidepressants, anticonvulsants, opioid analgesics or local/general anaesthetics within 7 days prior to the inclusion visit. Patients could not be included if they were likely to receive any treatment known to interfere with the studied drug or to be able to interfere with the study design (neurological surgery, anaesthetic blocks, local treatments of pain, antidepressants, anticonvulsants, anti-vitamin K, enzymatic inductors, psychoactive agents with the exception of clonazepam, if prescribed for insomnia for more than 15 days and at a constant dose, central and peripheral analgesics
Tramadol: N=53 (per protocol); mean age 65.7 years; 62.3% female; race not reported. Pain baseline 60.8 (±12.1)
33
Placebo: N=55 (per protocol); mean age 67.9 years; 80 % female; race not reported. Pain baseline 60.0 (±13.6)
Interventions Study medication: Upward titration up to tramadol 400mg/d (mean dosage 275 (±90) mg/d
Rescue medication: Acetaminophen if given at the maximal daily dose of 3 g
Allowed co-therapies: Concomitant treatments other than those defined in the exclusion criteria were authorized. During the study all patients took at least one concomitant medication differing from acetaminophen.
Outcomes Pain: Average daily pain intensity during the past 24 h VAS 0-100
Responder: No 50% pain reduction rates reported
PGIC: Not assessed
Function: Nottingham scale *
Withdrawal due to lack of efficacy: Not reported
Withdrawal due to adverse events: Reported
Serious adverse events: Reported **
Death: Not explicitly stated
Notes * Mean (SD) scores on the Nottingham scale decreased in both groups from day 1 (10.6 (7.2) in the tramadol group and 12.4 (7.0) in the placebo group) to day 43 (5.7 (6.0) in the tramadol group and 6.7 (7.0) in the placebo group) with no significant difference between groups
** Serious adverse events occurred in 3 patients; no information provided in which group the SAE occurred
34
Gilron 2005
Methods Disease: Postherpetic neuralgia and painful diabetic neuropathy
Study setting: 1 site in Canada
Study design: Cross over
Study duration: 4 weeks in each period
Participants Inclusion criteria: Patients with diabetic neuropathy had distal, symmetric, sensory diabetic polyneuropathy as determined on the basis of their medical history and either an unequivocal decrease in response to pinprick, temperature, or vibration in both feet or bilaterally decreased or absent ankle-jerk reflexes. Patients with postherpetic neuralgia had had an eruption of herpes zoster rash not more recently than six months before enrollment. General criteria for inclusion were daily moderate pain for three months or more, an age of 18 to 89 years, a serum alanine aminotransferase or aspartate aminotransferase level less than 1.2 times the normal level, a creatinine level less than 1.5 times the upper limit of the normal range, and sufficient language skills to communicate with research staff
Exclusion criteria: Hypersensitivity to study medications, another painful condition as severe as the diabetic neuropathy or postherpetic neuralgia, a recent myocardial infarction, unstable angina or congestive heart failure, any central neurologic disorder (including seizures), a serious mood disorder, a history of serious drug or alcohol abuse, pregnancy, lactation, and lack of a primary care physician
Total sample: N=57; median 60 years; 49 % female; 97% white (demographics of N=35 patients with diabetic neuropathy). Pain baseline 5.7 (±1.7)
Interventions Study medication: Morphine up to 120 mg/d flexible (mean 45 mg/d) vs. placebo
Rescue medication: No information provided
Allowed co-therapies: NSAIDS,
35
acetaminophen, antidepressants, anticonvulsants
Outcomes Pain: Average pain intensity last 24 hours NRS 0-10
Responder: No 50% pain reduction rates reported
PGIC: Not assessed
Function: SF-36 physical functioning
Withdrawal due to lack of efficacy: Not reported
Withdrawal due to adverse events: Reported
Serious adverse events: Not reported
Death: Not explicitly stated
Notes "The primary analysis showed no significant main effects of either sequence or treatment period, but the effects of drug treatment (P<0.001) and carryover (P=0.04) were statistically significant. An exploratory analysis of all differences in pairwise carryover effects showed a difference only between morphine and placebo (P=0.005); the effect of morphine is more likely to carry over to the next treatment period than that of placebo. In the linear mixed model, all treatment contrasts were adjusted for all observed carry-over effects
36
Gimbel 2003
Methods Disease: Painful diabetic neuropathy
Study setting: 18 sites in US
Study design: Parallel
Study duration: Up to 6 weeks titration, 1-week taper optional
Participants Inclusion criteria: History of pain in both feet defined as an average pain intensity ≥ 5 on an 11-point NRS the three days prior to randomisation, absence of any opioid therapy for 3 days prior randomisation
Exclusion criteria: Unstable or poorly controlled diabetes, chronic pain unrelated to diabetic polyneuropathy, history of substance or alcohol abuse, elevated serum creatinine and liver enzymes, history of cancer, hypersensitivity to oxycodone, rapidly increasing pain or neurology deficits within the previous 3 months, autonomic neuropathy or gastrointestinal dysfunction, a need for selective surgery in the study period, treatment with longacting opioids or >3 doses short acting opioids prior two weeks
Oxycodone: N=82; mean age 58.8 years; 51.6% female; 80.5% white. Pain baseline 4.9 (±2.1)
Placebo: N=77; mean age 59.0 years; 45.1% female; 87.8 % white. Pain baseline 5.9 (±2.0)
Interventions Study medication: Upward titration up to 120 mg oxycodone/d (overall daily dosage 37 ± 11 mg/d)
Rescue medication: No opioid rescue was allowed
Allowed co-therapies: Stable dosages of acetaminophen and NSAIDs allowed as well as analgesic co-medications
Outcomes Pain: Average daily pain intensity during the past 24 h NRS 0-10
Responder: No 50% pain reduction rates reported
37
PGIC: Not assessed
Function: Brief Pain Inventory physical functioning score
Withdrawal due to lack of efficacy: Reported
Withdrawal due to adverse events: Reported
Serious adverse events: Reported
Death: Reported
Notes
38
Harati 1998
Methods Disease: Painful diabetic neuropathy
Study setting: 6 sites US
Study design: Parallel
Study duration: Wash out phase of 7 - 21 days before randomization, 6 weeks tapering and maintenance
Participants Inclusion criteria: Patients with diabetes mellitus and acceptable glycemic control (total glycosylated hemoglobin of <14% in an assay where the upper limit for nondiabetic individuals is <6.1%). All patients had distal symmetric diabetic neuropathy documented by clinical, electrophysiologic, or quantitative sensory testing and were required to have pain on a daily basis in the lower extremities due to diabetic neuropathy for the previous 3 months. Before entering the double-blind treatment phase of the study, patients were required to have moderate pain, as assessed using a Likert pain rating scale, in the absence of any analgesic therapy. All patients were 18 years of age or older and required to sign an informed consent before participation in the study. At least moderate pain on a daily basis in the lower extremities due to diabetic polyneuropathy for at least 3 previous months
Exclusion criteria: Patients were excluded from participation for any of the following reasons: (1) known contraindication to or prior use of tramadol; (2) peripheral neuropathy attributable to other causes such as alcoholism, connective tissue disease, or toxic exposure; (3) pain more severe than the neuropathic pain; (4) severe depression; (5) estimated creatinine clearance <30 mL/ min; (6) clinically significant medical conditions, profound autonomic dysfunction, or brittle diabetes; (7) history of narcotic or alcohol abuse; (8) use of multiple daily doses of narcotic analgesics or mexiletine on a regular basis; (9) evidence of amputations (including toes), open ulcers, or Charcot joint
Tramadol: N=65 mean age 59 years; 40% female; race not reported; pain intensity baseline
39
2.5 (±0.1)
Placebo: N=66; mean age 59 years; 41 % female; race not reported; pain intensity baseline 2.6 (± 0.1)
Interventions Study medication: Tramadol flexible 100-400 mg/d (average dosage 210 ± 113 mg/day); Placebo
Rescue medication: No rescue medication allowed
Allowed co-therapies: No information provided. Anticonvulsants and antidepressants were washed out.
Outcomes Pain: Average pain intensity NRS 0-4 at clinical visit
Responder: No 50% pain reduction rates reported
PGIC: Much or very much improved
Withdrawal due to lack of efficacy: Reported
Function: Subscale physcial functioning of the SF-36
Withdrawal due to adverse events: Reported
Serious adverse events: Not reported
Death: Not explicitly stated
Notes
40
Khoromi 2007
Methods Disease: Chronic lumbar root pain
Study setting: 1 site in US
Study design: Cross over
Study duration: 4 weeks titration, 2 weeks maintenance, 2 weeks dose tapering for each period
Participants Inclusion criteria: 1.) Evidence of lumbar radiculopathy, including pain in one or both buttocks or legs for 3 months or greater for at least 5 days a week and at least one of the following features on the side corresponding to leg pain: a. Sharp and shooting pain below the knee; b. Pain evoked by straight leg raising to 60 degrees or less; c. Decreased or absent ankle reflex; d. Weakness of muscles below the knee. e. Sensory loss in L5/S1 distribution; f. Electromyographic evidence for L4, L5, or S1 root denervation; g. Imaging (MRI, CT/myelogram) evidence of nerve root compression in the lower lumbar region; 2.) Average leg pain of at least 4/10 for the past month on a numerical scale of 0 to 10 where 0 represents no pain and 10 represents the worst possible pain; 3.) Willingness to refrain from making changes in non-study medications taken for sciatica, and 4.) Age between 18 and 65 years at the start of the study
Exclusion criteria: 1.) Serious medical illness involving other organ systems such as unstable angina disease, advanced diabetes, and cancer; 2.) Prostatic disease requiring usage of urological medications; 3.) Pregnancy or lactation; 4.) History of depression requiring treatment with antidepressants within the 6 months preceding study participation or a score of 20 or greater on the Beck Depression Inventory at the screening visit; 5.) History of narcotic or alcohol abuse; 6.) Narrow angle glaucoma; 7.) Seizure disorder; 8.) Fibromyalgia; 9.) Pain of greater intensity in any other location than the low back or leg; 10.) Polyneuropathy and peripheral vascular disease associated with symptoms of numbness, or burning pain in the lower extremities; 11.) Allergy
41
to morphine, nortriptyline or benztropine; 12.) Evidence for multisomatoform disorder as assessed by a 15 item questionnaire, the PHQ-15; 13.) Unwillingness to be tapered off of opioids and then maintained drug free for two weeks prior to randomization to study medications for participants on maintenance opioid regimen at the time of study enrollment
Total study sample: N=56; Completers: Mean age 52.5 years; 100% Female; Race nor reported. Pain baseline 5.0 (± 2.25)
Interventions Study medication: Morphine flexible 15-90 mg/d (average 62 ± 29 mg/d); active placebo (benztopine) 0.25-1 mg/d
Rescue medication: Anti-inflammatory medications and acetaminophen
Allowed co-therapies: Patients also were asked to refrain from making changes in their analgesic medication regimen, or taking any opioids, SSRIs and tricylic medications outside of the protocol during the study
Outcomes Pain: Average overall pain intensity NRS 0-10
Responder: No 50% pain reduction rates reported
PGIC: Not assessed
Function: Oswestry disability index
Withdrawal due to lack of efficacy: Reported
Withdrawal due to adverse events: Reported
Serious adverse events: Not reported
Death: Not explicitly stated
Notes "The primary analysis for the 28 study completers showed no significant period or carry over effect between any two possible sequences of treatment."
42
Norrbrink 2007
Methods Disease: Neuropathic pain after spinal cord injury
Study setting: 4 sites Sweden
Study design: Parallel
Study duration: Duration wash out not reported, 4 weeks tapering and maintenance
Participants Inclusion criteria: Traumatic or nontraumatic injury and pain diagnosed in a previous annual health control as being of at or below level neuropathic pain in origin were selected from the database. Patients between 18 and 70 years of age with no known cognitive dysfunction and currently not using tramadol; SCI for more than 12 months, pain classified as neuropathic pain at or below the level of lesion14 and of a duration of more than 6 months, fluency in Swedish, and no known cognitive impairment. Pain intensity ratings of either the general or the worst pain intensity in the last week were required to be equivalent to or more than 3 on Borg’s Category Ratio (CR-10) scale, a combined numerical and verbal rating scale. The patients had to be naive to treatment with tramadol and have had no signs of intolerance to treatment with opioids in the past. If patients were currently using opioids or antidepressants, inclusion was decided on an individual basis. The patients had to be naive to treatment with tramadol and have had no signs of intolerance to treatment with opioids in the past
Exclusion criteria: Patients who were pregnant or lactating were excluded
Tramadol: N=23; mean age 51.4 years; 82.6% female; race not reported. Pain baseline median 3
Placebo: N=12; mean age 51.2 years; 75% % female; race not reported. Pain baseline median 5
Interventions Study medication: Tramadol flexible 100-400 mg/d (Median maximum dose 250 mg/d); Placebo
Rescue medication: Other analgesics (no
43
detailed infromation provided) allowed
Allowed co-therapies: No information provided
Outcomes Pain: Present pain intensity NRS 0-4 at clinical visit *
Responder: No 50% pain reduction rates reported
PGIC: Much or very much improved
Function: Multidimensional Pain Inventory Subscale pain interference *
Withdrawal due to lack of efficacy: Reported
Withdrawal due to adverse events: Reported
Serious adverse events: Not reported
Death: Not explicitly stated
Notes * No SDs and precise p-values reported; differences between tramadol and placebo were reported to be "significant" (p<0.05). p=0.05 chosen for calculating SD
44
Raja 2002
Methods Disease: Chronic postherpetic neuralgia
Study setting: 1 site in US
Study design: Cross over
Study duration: Approximately 8 weeks titration, maintenance and dose tapering for each period, 1 week drug-free wash-out
Participants Inclusion criteria: Age 18 years, pain persisting for 3 months after the resolution of the cutaneous lesions, and typical pain intensity of 4/10 (numerical rating scale) during the previous week
Exclusion criteria: History of substance abuse or an allergic reaction to an opioid or a TCA, a myocardial infarction in the previous 3 months, cardiac conduction defects, severe pulmonary disease, angle-closure glaucoma, pregnancy, dementia, or encephalopathy were excluded, as were HIV-positive patients and those with life expectancy of 6 months. In addition, patients on monoamine oxidase inhibitors or with severe depression precluding withdrawal from antidepressants were excluded
Total study sample: N=76; Mean age 71 years; 55.3% Female; 88.2% white. Pain baseline opioids 6.5 (±1.9); Pain baseline placebo 6 (±2)
Interventions Study medication: Morphine 15-240 mg/d (average 91 mg/d) or or methadone flexible (average15 mg) or placebo
Rescue medication: Anti-inflammatory medications and acetaminophen (no maximum dosage reported)
Allowed co-therapies: No information provided
Outcomes Pain: Average overall pain intensity during the previous 24 hours NRS 0-10
Responder: No 50% pain reduction rates reported
PGIC: Not assessed
Function: Interference and general activity
45
subscale of the Multidimensional Pain Inventory
Withdrawal due to lack of efficacy: Not reported
Withdrawal due to adverse events: Reported
Serious adverse events: Not reported
Death:Not explicitly stated
Notes "Analysis of the treatment sequence did not reveal significant carry-over or order effects"
46
Schwartz 2011
Methods Disease: Painful diabetic neuropathy
Study setting: 87 sites in US, 16 sites in Canada
Study design: Enriched enrollment randomized withdrawal
Study duration: 3 weeks open label, 12 weeks double-blind withdrawal
Participants Inclusion criteria: Age ≥ 18 years; type 1 or 2 diabetes mellitus; HbA1c no more than 11% for at least 3 months; Patients taking analgesic medications for at least 3 months prior to screening and dissatisfied with their current therapy; Patients requiring opioid treatment must be taking daily doses of opioid-based analgesic, equivalent to <160 mg of oral morphine; Baseline score of ≥ 5 on an 11-point numeric rating scale, calculated as the average pain intensity during the last 3 days prior to randomization
Exclusion criteria: History of alcohol and/or drug abuse; other chronic pain condition; significant disorder (e.g. pulmonary, psychiatric); moderate to severe hepatic impairment, severely impaired renal function; seizure disorder or epilepsy; uncontrolled hypertension; severely impaired renal 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
Placebo: N=196; mean age 60.6 years; 39.9% female; 69.9% white. Severe pain baseline 11.2%
Tapentadol: N=199; mean age 59.9 years; 39.3% female; 69.9% white. Severe pain baseline 12.4%
Interventions Study medication: Titration to individually optimal dosage tapentadol 200-500 mg/d, patients with at least 1-point pain reduction were randomised 1:1 to receive optimal fixed dose of tapentadol or placebo
47
Rescue medication: Tapentadol
Allowed co-therapies: Use of selective serotonine reuptake inhibitors allowed of patients were on stable dose for at least 30 days prior to screening
Outcomes Pain: Change from baseline in average pain intensity NRS 0-10
Responder: Maintenance of 50% pain reduction NRS 0-10
PGIC: Maintenance of much or very much improved
Function: Not assessed
Withdrawal due to lack of efficacy: Reported
Withdrawal due to adverse events: Reported
Serious adverse events: Reported
Death: Reported
Notes
48
Sindrup 1999
Methods Diasease: Polyneuropathic pain of various etiology (no details on etiology provided)
Study setting: 2 sites in Denmark
Study design: Cross over
Study duration: (1) Up to 1 week wash-out; (2) cross-over treatment sequence for 4 plus 4 weeks with tramadol and placebo 4 weeks each period; (3) a washout period of at least one week seperated the two treatment periods
Participants Inclusion criteria: More than 6 months, polyneuropathy diagnosis confirmed by electrophysiological tests (slowing of nerve conduction or reduction of amplitude of sensory action potential), a pain rating off-medication of at least 4 on a 11-point NRS, and age 20±80 years
Exclusion criteria: Causes of pain other than polyneuropathy, previous allergic reactions towards tramadol, intolerance to tramadol or other opioids, treatment with MAO inhibitors, pregnancy or breast-feeding period, epilepsy and severe terminal illness
Total sample: N=34; mean age 58 years; 44.1% female; race and pain baseline not reported
Interventions Study medication: Tramadol flexible 100-400 mg/d; Average dosage not reported: The final tramadol dose was 400 mg/day in 23 patients, 300 mg/day in four patients and 200 mg/day in seven patients. Placebo
Rescue medication: Acetaminophen up to 3g/d
Allowed co-therapies: No information provided
Outcomes Pain: Average pain intensity last 24 hours NRS 0-10 *
Responder: 50% pain reduction **
PGIC: Not assessed
Function: Not reported
49
Withdrawal due to lack of efficacy: Reported
Withdrawal due to adverse events: Reported
Serious adverse events: Not reported
Death: Not explicitly stated
Notes * Mean and SDs calculated from raw data presented in table 2
** Only NNT, but no absolute values for both groups reported
*** Period and hang-over effects were not present for pain (p=0.40 and 0.38)
50
Watson 1998
Methods Diasease: Postherpetic neuralgia
Study setting: 1 site in US
Study design: Cross over
Study duration: Duration screening and wash-out not reported, 4 weeks each, no wash-out between cross over periods
Participants Inclusion criteria: History of postherpetic neuralgia ≥ 3months and pain of at least moderate intensity for at least half of the days
Exclusion criteria: Intolerance to oxycodone, a history of drug or alcohol abuse, or significant pain of alternate etiology
Total sample: N=54; evaluable N=36; mean age 63.0 years; 47.2% female; race and pain intensity baseline not reported
Interventions Study medication: Oxycodone flexible 20-160 mg/d (mean daily dosage 45 mg/d), Placebo
Rescue medication: Not reported
Allowed co-therapies: Stable doses of antidepressants, NSAIDs and acetaminophen
Outcomes Pain: Average daily pain intensity diary VAS 0-100
Responder: No 50% pain reduction rates reported
PGIC: Not assessed
Function: Disability as rated by the investigator (none, mild, moderate and severe disability)*
Withdrawal due to lack of efficacy: Reported
Withdrawal due to adverse events: Reported
Serious adverse events: Not reported
Death: Not explicitly stated
Notes * Not used for meta-analysis, because no patient-
51
reported outcome
"Analysis of treatment sequence revealed no significant carryover effect for the primary variables."
52
Watson 2003
Methods Disease: Painful diabetic neuropathy
Study setting: 2 sites in Canada
Study design: Cross over
Study duration: 2-7 days wash out, 4 weeks each, no wash-out between cross over periods, up to one year open label
Participants Inclusion criteria: Stable glycemic control suffering painful symmetrical distal sensory neuropathy were enrolled in the study. Patients had at least moderate pain in the lower extremities assessed at the screening visit on a 5-point categorical scale (0, none; 1, mild; 2, moderate; 3, severe; 4, excruciating), a medical history of moderate daily pain based on the patient’s recall over the previous 3 months, one or more symptoms of diabetic neuropathy (including paresthesia, dysesthesia, hyperesthesia, hyperalgesia, and allodynia) and signs of reduced sensation, strength or tendon reflexes not attributable to any other cause.
Exclusion criteria: Intolerance to oxycodone, a history of drug or alcohol abuse, or significant pain of alternate etiology
Total sample: N=54; evaluable N= 36; mean age 63.0 years; 47.2% female; race not reported. Pain baseline 67.0 ± 14.9
Interventions Study medication: Oxycodone flexible 20-80 mg/d (mean daily dosage 40 mg/d), Active placebo flexible 0,5 – 2mg mg/d Benztropine
Rescue medication: Acetaminophen, 325–650 mg 4 to 6 times/d
Allowed co-therapies: Stable doses of antidepressants, anticonvulsants, or non-opioid analgesics
Outcomes Pain: Average daily pain intensity diary VAS 0-100
Responder: No 50% pain reduction rates reported
53
PGIC: Not assessed
Function: Pain Disability Index
Withdrawal due to lack of efficacy: Reported
Withdrawal due to adverse events: Reported
Serious adverse events: Reported
Death: Not explicitly stated
Notes "Analysis of treatment sequence revealed no significant carryover effect for the primary variables."
54
Wu 2008
Methods Disease: Postamputation pain
Study setting: 1 site in US
Study design: Cross over
Study duration: 4 weeks titration, 2 weeks maintenance, 2 weeks dose tapering for each period, 1 week drug-free wash-out
Participants Inclusion criteria: Adults (aged 18 yrs) and presence of persistent postamputation pain rated as greater than 3 on a 0–10 numerical rating scale for a period of 6 months or longer
Exclusion criteria: History of allergic reaction to any of the study drugs (i.e., morphine and mexiletine), cardiac conduction defects (e.g., second-degree or complete heart block), myocardial infarction within 3 months of evaluation, severe pulmonary disease, current history of alcohol or substance abuse, seizures, dementia, encephalopathy, current pregnancy or breast-feeding, chronic hepatic disease, hepatic or renal failure, any hematologic disease associated with leukopenia or thrombocytopenia, or the presence of any terminal disease with a life expectancy of less than 6 months
Total sample: N=60; mean age 63.4 years; 21.7% female; 85% white. Pain baseline 6.8 (extracted from figure)
Interventions Study medication: Morphine 15-180 mg/d flexible (mean 112 mg/d) vs. placebo
Rescue medication: NSAIDS (no information on maximum dosage provided
Allowed co-therapies: No information provided.
Outcomes Pain: Average pain intensity NRS 0-10
Responder: 50% pain reduction
PGIC: Not assessed
Function: Multidimensional PIan Inventory interference subscale; detailed results not
55
reported *
Withdrawal due to lack of efficacy: Reported
Withdrawal due to adverse events: Not reported (only total drop out rate reported)
Serious adverse events: Moderate or severe side effects reported (data not used for analysis)
Death: Not explicitly stated
Notes "we concluded that no significant drug carry-over effects, independent of a time effect, occurred."
* "There were no differences between groups with regard to the effects of study drug on self-reported levels of overall functional activity and pain-related interference in daily activities as assessed by the Multidimensional Pain Inventory
56
Table 2: Support for risk of bias judgement Boureau 2003
Bias Authors'
judgement Support for judgement
Random sequence generation (selection bias)
Low risk
"computer-generated four-block centralized randomization list"
Allocation concealment (selection bias)
Unclear risk
We had insufficient information to permit judgement
Blinding of participants and personnel (performance bias)
Low risk
"Both treatments were identical with regard to appearance"
Blinding of outcome assessment (detection bias)
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)
Unclear risk ITT, method not reported
Selective reporting (reporting bias) High risk
No protocol reported by the authors; means and SDs of Nottingham subscales not available for meta-analysis; SAE not reported
Selection bias Low risk
No significant baseline differences in demographic and clinical variables between the groups
Funding bias High risk
No information on study sponsoring provided; 2 of 3 study authors affiliated with pharmaceutical company
57
Gilron 2005
Bias Authors'
judgement Support for judgement
Random sequence generation (selection bias)
Unclear risk
We had insufficient information to permit judgement
Allocation concealment (selection bias)
Low risk
"At the commencement of the trial, a pharmacist at the Kingston General Hospital in Kingston, Ontario, Canada, prepared a concealed allocation schedule randomly”
Blinding of participants and personnel (performance bias)
Unclear risk
We had insufficient information to permit judgement
Blinding of outcome assessment (detection bias)
Unclear risk
We had insufficient information to permit judgement. Outcome assessors could be unblinded by the side effects of morphine and gabapentin
Incomplete outcome data (attrition bias)
High risk No ITT
Selective reporting (reporting bias) High risk
No study protocol provided by authors; SAE not reported
Selection bias Low risk
Cross over design
Funding bias Low risk
Study funded by Canadian Institutes of Helath Research. No author affiliated with manufacturer of the drug
58
Gimbel 2003
Bias Authors'
judgement Support for judgement
Random sequence generation (selection bias)
Low risk
“A computer generated randomization schedule with permuted blocks of size 4 was used to assign subjects to study treatment”
Allocation concealment (selection bias)
Low risk
Randomized information sealed at sponsor site
Blinding of participants and personnel (performance bias)
Low risk
Placebo described as being identical to opioid
Blinding of outcome assessment (detection bias)
Unclear risk
We had insufficient information to permit judgement. Outcomes assessors could be biased by the side effects profile of oxycodone
Incomplete outcome data (attrition bias)
Unclear risk ITT by LOCF
Selective reporting (reporting bias) Unclear risk
No protocol reported by the authors
Selection bias Low risk
No significant baseline differences in demographic and clinical variables between the groups
Funding bias High risk
Stuy funded by pharmaceutical company
59
Harati 1998
Bias Authors'
judgement Support for judgement
Random sequence generation (selection bias)
Low risk
"Computer random number generator"
Allocation concealment (selection bias)
Low risk
"The randomization code was not revealed to patients, investigators and clinical stuff or study monitors"
Blinding of participants and personnel (performance bias)
Low risk
"Tramadol and placebo were administered as identical capsules"
Blinding of outcome assessment (detection bias)
Unclear risk
Outcome assessors could be unblinded by the side effects of tramadol
Incomplete outcome data (attrition bias)
Low risk ITT by LOCF
Selective reporting (reporting bias) Low risk
Protocol reported by the authors
Selection bias Low risk
The demographic and baseline characteristics of the two treatment groups were similar
Funding bias High risk
The study was sponsored by the manufacturer of the drug. 2 of 9 authors were affiliated with the manufacturer of the drug
60
Khoromi 2007
Bias Authors'
judgement Support for judgement
Random sequence generation (selection bias)
Low risk
“Patients were assigned by random numbers within blocks of four to one of four treatment sequences specified by a Latin square”
Allocation concealment (selection bias)
Low risk
“Randomization was performed by the NIH Pharmaceutical Development Service”
Blinding of participants and personnel (performance bias)
Low risk
“During the MS Contin treatment period, each blue pill containedMS Contin 15 mg and each pink pill contained inert placebo”
Blinding of outcome assessment (detection bias)
Low risk
"The rate of guessing by the nurses was above the rate for chance only (> 25%), but did not reach a high percentage. “Patients and research staff were blinded to the randomization order”
Incomplete outcome data (attrition bias)
Unclear risk
ITT-analysis, method not reported
Selective reporting (reporting bias) High risk
The trial was registered at clinicaltrials.gov (NCT00009672); the primary and the secondary outcomes were consistent in the protocol compared with the publication. SAE not reported
Selection bias Low risk
Cross over design
Funding bias Low risk
No funding by pharmaceutical industry: the study was sponsored by the National Institute of Dental and Craniofacial Health
61
Norrbrink 2007
Bias Authors'
judgement Support for judgement
Random sequence generation (selection bias)
Unclear risk
We had insufficient information to permit judgement
Allocation concealment (selection bias)
Low risk "Sealed and coded envelopes"
Blinding of participants and personnel (performance bias)
Low risk
" The active and placebo drug were identical in appearance"
Blinding of outcome assessment (detection bias)
Unclear risk
No details provided. Outcomes assessors could be biased by the side effects profile of tramadol
Incomplete outcome data (attrition bias)
Unclear risk ITT-analysis, LOCF
Selective reporting (reporting bias) High risk
No protocol reported by the authors; imputation method used to calculate SDs
Selection bias High risk
Baseline pain values higher in placebo than in tramadol group
Funding bias Low risk
Public funding; no authors affiliated with industry
62
Raja 2002
Bias Authors'
judgement Support for judgement
Random sequence generation (selection bias)
Low risk
"The randomization sequence was computer generated by the biostatistician"
Allocation concealment (selection bias)
Low risk
" After meeting eligibility criteria, patients were assigned identification numbers by the investigator, and the pharmacy was informed. Study medications were mailed directly to the patients by the pharmacy in a box marked Study Drug A, B, or C, depending on the treatment period
Blinding of participants and personnel (performance bias)
Low risk
"The pharmacist formulated the study drugs in identical gel capsules to maintain the blinding."
Blinding of outcome assessment (detection bias)
Unclear risk
"All investigators were blinded to the drug treatments during the study." Outcomes assessors could be biased by the side effects profile of morphine
Incomplete outcome data (attrition bias)
Unclear risk ITT-analysis according to LCOF
Selective reporting (reporting bias) High risk
No protocol reported by the authors. SAE not reported
Selection bias Low risk
Cross over design
Funding bias Low risk
No funding by pharmaceutical industry reported; no authors affiliated with industry. Study supported by NIH
63
Schwartz 2011
Bias Authors'
judgement Support for judgement
Random sequence generation (selection bias)
Unclear risk
We had insufficient information to permit judgement
Allocation concealment (selection bias)
Low risk
Randomization was implemented by interactive voice response system
Blinding of participants and personnel (performance bias)
Unclear risk
We had insufficient information to permit judgement
Blinding of outcome assessment (detection bias)
Unclear risk
We had insufficient information to permit judgement. Outcomes assessors could be bias based on the side effects profile of tapentadol
Incomplete outcome data (attrition bias)
Unclear risk
ITT-analysis according to LOCF; BOCF analysis performed, but data not reported
Selective reporting (reporting bias) High risk
NCT00455520; EuroQol-5 (EQ-5D) Health Status Index and sleep questionnaire data as reported in the protocol were not published
Selection bias Low risk
No significant baseline differences in demographic and clinical variables between the three groups
Funding bias High risk
Funding by pharmaceutical industry; 3 of 4 authors affiliated with industry
64
Sindrup 1999
Bias Authors'
judgement Support for judgement
Random sequence generation (selection bias)
Low risk
"Treatment sequence was random via computer generated randomisation code"
Allocation concealment (selection bias)
Low risk
"Sealed envelopes with treatment sequence for each patient"
Blinding of participants and personnel (performance bias)
Unclear risk
We had insufficient information to permit judgement.
Blinding of outcome assessment (detection bias)
Unclear risk
We had insufficient information to permit judgement. Outcomes assessors could be bias based on the side effects profile of tramadol
Incomplete outcome data (attrition bias)
High risk No ITT-analysis
Selective reporting (reporting bias) High risk
No protocol published by the authors; some data for meta-analysis extracted from figures
Selection bias Low risk
Cross-over design
Funding bias High risk
Study sponsored by manufacturer of the drug
65
Watson 1998
Bias Authors'
judgement Support for judgement
Random sequence generation (selection bias)
Low risk
Treatment assignment was retained in an opaque envelope
Allocation concealment (selection bias)
Unclear risk
We had insufficient information to permit judgement
Blinding of participants and personnel (performance bias)
Unclear risk
We had insufficient information to permit judgement
Blinding of outcome assessment (detection bias)
Unclear risk
No information provided. Outcomes assessors could be bias based on the side effects profile of oxycodone
Incomplete outcome data (attrition bias)
High risk No ITT-analysis
Selective reporting (reporting bias) High risk
No protocol reported by the authors; SAE not reported
Selection bias Low risk
Cross over
Funding bias High risk
Funding by pharmaceutical industry; 1 of 2 authors affiliated with manufacturer of the drug
66
Watson 2003
Bias Authors'
judgement Support for judgement
Random sequence generation (selection bias)
Low risk
We had insufficient information to permit judgement
Allocation concealment (selection bias)
Low risk
"Patient's treatment assignment was retained in an opaque envelope"
Blinding of participants and personnel (performance bias)
Unclear risk
We had insufficient information to permit judgement
Blinding of outcome assessment (detection bias)
Unclear risk
No information provided. Outcomes assessors could be bias based on the side effects profile of oxycodone
Incomplete outcome data (attrition bias)
Unclear risk
ITT-analysis, method not reported
Selective reporting (reporting bias) Unclear risk
No protocol reported by the authors
Selection bias Low risk
Cross-over design
Funding bias High risk
Funding by pharmaceutical industry
67
Wu 2008
Bias Authors'
judgement Support for judgement
Random sequence generation (selection bias)
Low risk
"The randomization sequence was computer generated by a biostatistician"
Allocation concealment (selection bias)
Low risk
"The sequence of drug and placebo treatment periods for each subject was provided in sealed envelopes to the investigational pharmacy and the monitoring committee"
Blinding of participants and personnel (performance bias)
Low risk
"Mexiletine and placebo were similarly packaged in sealed capsules that were identical in appearance"
Blinding of outcome assessment (detection bias)
Unclear risk
No information provided. Outcomes assessors could be bias based on the side effects profile of morphine and mexitilene
Incomplete outcome data (attrition bias)
High risk
ITT-analysis, method not reported; Only completer data for 50% pain reduction reported
Selective reporting (reporting bias) High risk
NCT00383682; the primary and the secondary outcomes were consistent in the protocol compared with the publication. However, the standard deviations and p-values of the secondary outcomes function and quality of life not reported. SAE not reported
Selection bias Low risk
No significant baseline differences in demographic and clinical variables between the two groups
Funding bias Low risk
No funding by pharmaceutical industry; grant by NIH
68
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
Study or Subgroup
1.1.5 Morphine
Gilron 2005
Khoromi 2007
Raja 2002
Wu 2008Subtotal (95% CI)
Heterogeneity: Tau² = 0.02; Chi² = 4.47, df = 3 (P = 0.21); I² = 33%
Test for overall effect: Z = 3.68 (P = 0.0002)
1.1.6 Oxycodone
Gimbel 2003
Watson 1998
Watson 2003Subtotal (95% CI)
Heterogeneity: Tau² = 0.00; Chi² = 1.56, df = 2 (P = 0.46); I² = 0%
Test for overall effect: Z = 5.50 (P < 0.00001)
1.1.9 Tramadol
Boureau 2003
Harati 1998
Norrbrink 2007
Sindrup 1999Subtotal (95% CI)
Heterogeneity: Tau² = 0.12; Chi² = 9.86, df = 3 (P = 0.02); I² = 70%
Test for overall effect: Z = 3.84 (P = 0.0001)
Total (95% CI)
Heterogeneity: Tau² = 0.04; Chi² = 18.20, df = 10 (P = 0.05); I² = 45%
Test for overall effect: Z = 7.18 (P < 0.00001)
Test for subgroup differences: Chi² = 1.79, df = 2 (P = 0.41), I² = 0%
Mean
3.3
3.8
4.4
-2.8
-2
35
26.3
25.3
1.4
3
4.24
SD
1.3
2.5
2.4
2
2.1
25
24.7
23
0.8
1.7
2.49
Total
44
28
64
50186
82
38
45165
63
65
23
34185
536
Mean
3.9
3.9
6
-1.4
-1
54
46.7
33.6
2.2
5.5
6.16
SD
1.3
2.4
2
2.7
2
25
26.9
25.4
0.8
1.7
2.3
Total
43
28
56
43170
77
38
45160
62
66
12
34174
504
Weight
9.2%
7.2%
10.7%
9.4%36.5%
12.3%
8.3%
9.1%29.8%
11.2%
10.9%
4.0%
7.7%33.7%
100.0%
IV, Random, 95% CI
-0.46 [-0.88, -0.03]
-0.04 [-0.56, 0.48]
-0.72 [-1.09, -0.35]
-0.59 [-1.01, -0.17]-0.49 [-0.75, -0.23]
-0.48 [-0.80, -0.17]
-0.75 [-1.22, -0.29]
-0.78 [-1.21, -0.35]-0.63 [-0.85, -0.40]
-0.34 [-0.69, 0.01]
-0.99 [-1.36, -0.63]
-1.44 [-2.22, -0.65]
-0.79 [-1.29, -0.30]-0.82 [-1.24, -0.40]
-0.64 [-0.81, -0.46]
Opioids Placebo Std. Mean Difference Std. Mean Difference
IV, Random, 95% CI
-2 -1 0 1 2Favours opioids Favours placebo
69
Figure 2 (Electronic Supplementary Material): Effect estimates (risk difference) of at least
50% pain reduction at end of treatment
Study or Subgroup
1.2.1 Morphine
Wu 2008Subtotal (95% CI)
Total events
Heterogeneity: Not applicable
Test for overall effect: Z = 1.59 (P = 0.11)
Total (95% CI)
Total events
Heterogeneity: Not applicable
Test for overall effect: Z = 1.59 (P = 0.11)
Test for subgroup differences: Not applicable
Events
23
23
23
Total
5050
50
Events
13
13
13
Total
4343
43
Weight
100.0%100.0%
100.0%
IV, Random, 95% CI
0.16 [-0.04, 0.35]0.16 [-0.04, 0.35]
0.16 [-0.04, 0.35]
Opioids Placebo Risk Difference Risk Difference
IV, Random, 95% CI
-0.5 -0.25 0 0.25 0.5Opioids Placebo
70
Figure 3 (Electronic Supplementary Material): Effect estimates (risk difference) of reports to
be much or very much improved at end of treatment
Study or Subgroup
1.3.3 Tramadol
Norrbrink 2007Subtotal (95% CI)
Total events
Heterogeneity: Not applicable
Test for overall effect: Z = 1.81 (P = 0.07)
Total (95% CI)
Total events
Heterogeneity: Not applicable
Test for overall effect: Z = 1.81 (P = 0.07)
Test for subgroup differences: Not applicable
Events
4
4
4
Total
2323
23
Events
0
0
0
Total
1212
12
Weight
100.0%100.0%
100.0%
IV, Random, 95% CI
0.17 [-0.01, 0.36]0.17 [-0.01, 0.36]
0.17 [-0.01, 0.36]
Opioids Placebo Risk Difference Risk Difference
IV, Random, 95% CI
-0.5 -0.25 0 0.25 0.5Placebo Opioids
71
Figure 4 (Electronic Supplementary Material): Effect estimates (standardised mean
differences) of physical function improvement at end of treatment
Study or Subgroup
1.4.5 Morphine
Gilron 2005
Khoromi 2007
Raja 2002Subtotal (95% CI)
Heterogeneity: Tau² = 0.00; Chi² = 0.30, df = 2 (P = 0.86); I² = 0%
Test for overall effect: Z = 1.64 (P = 0.10)
1.4.6 Oxycodone
Gimbel 2003
Watson 2003Subtotal (95% CI)
Heterogeneity: Tau² = 0.01; Chi² = 1.40, df = 1 (P = 0.24); I² = 29%
Test for overall effect: Z = 2.10 (P = 0.04)
1.4.9 Tramadol
Harati 1998
Norrbrink 2007Subtotal (95% CI)
Heterogeneity: Tau² = 0.00; Chi² = 0.94, df = 1 (P = 0.33); I² = 0%
Test for overall effect: Z = 2.29 (P = 0.02)
Total (95% CI)
Heterogeneity: Tau² = 0.00; Chi² = 3.37, df = 6 (P = 0.76); I² = 0%
Test for overall effect: Z = 3.63 (P = 0.0003)
Test for subgroup differences: Chi² = 0.75, df = 2 (P = 0.69), I² = 0%
Mean
-57.8
25.7
2.3
-2.4
16.8
-64.3
2.45
SD
26.5
16.5
1.5
2.5
15.6
30.6
1.7
Total
44
28
66138
82
45127
65
2388
353
Mean
-51.7
30.5
2.5
-1.9
25.2
-55.1
3.64
SD
23
15.9
1.5
2.5
16.7
32.5
1.7
Total
43
28
56127
77
45122
66
1278
327
Weight
12.9%
8.3%
18.1%39.4%
23.7%
13.0%36.7%
19.4%
4.5%23.9%
100.0%
IV, Random, 95% CI
-0.24 [-0.67, 0.18]
-0.29 [-0.82, 0.23]
-0.13 [-0.49, 0.22]-0.20 [-0.44, 0.04]
-0.20 [-0.51, 0.11]
-0.52 [-0.94, -0.10]-0.32 [-0.63, -0.02]
-0.29 [-0.63, 0.05]
-0.68 [-1.40, 0.03]-0.36 [-0.67, -0.05]
-0.28 [-0.43, -0.13]
Opioids Placebo Std. Mean Difference Std. Mean Difference
IV, Random, 95% CI
-4 -2 0 2 4Opioids Placebo
72
Figure 5 (Electronic Supplementary Material): Effect estimates (risk difference) of dropping
out due to lack of efficacy during study
Study or Subgroup
1.8.1 Morphine
Khoromi 2007Subtotal (95% CI)
Total events
Heterogeneity: Not applicable
Test for overall effect: Z = 1.57 (P = 0.12)
1.8.2 Oxycodone
Gimbel 2003
Watson 1998
Watson 2003Subtotal (95% CI)
Total events
Heterogeneity: Tau² = 0.00; Chi² = 4.57, df = 2 (P = 0.10); I² = 56%
Test for overall effect: Z = 2.33 (P = 0.02)
1.8.4 Tramadol
Harati 1998
Sindrup 1999Subtotal (95% CI)
Total events
Heterogeneity: Tau² = 0.02; Chi² = 6.70, df = 1 (P = 0.010); I² = 85%
Test for overall effect: Z = 0.88 (P = 0.38)
Total (95% CI)
Total events
Heterogeneity: Tau² = 0.00; Chi² = 15.52, df = 5 (P = 0.008); I² = 68%
Test for overall effect: Z = 2.58 (P = 0.010)
Test for subgroup differences: Chi² = 0.49, df = 2 (P = 0.78), I² = 0%
Events
0
0
1
0
1
2
9
0
9
11
Total
5555
82
38
45165
65
45110
330
Events
3
3
11
1
7
19
22
0
22
44
Total
5555
77
38
45160
66
45111
326
Weight
19.0%19.0%
16.9%
18.7%
12.5%48.1%
9.8%
23.1%32.8%
100.0%
IV, Random, 95% CI
-0.05 [-0.12, 0.01]-0.05 [-0.12, 0.01]
-0.13 [-0.21, -0.05]
-0.03 [-0.10, 0.04]
-0.13 [-0.25, -0.02]-0.09 [-0.17, -0.01]
-0.19 [-0.34, -0.05]
0.00 [-0.04, 0.04]-0.09 [-0.27, 0.10]
-0.07 [-0.13, -0.02]
Opioids Placebo Risk Difference Risk Difference
IV, Random, 95% CI
-1 -0.5 0 0.5 1Favours placebo Favours opioid
73
Figure 6 (Electronic Supplementary Material): Effect estimates (risk difference) of dropping
out due to adverse events during study
Study or Subgroup
1.5.4 Morphine
Gilron 2005
Khoromi 2007
Raja 2002Subtotal (95% CI)
Total events
Heterogeneity: Tau² = 0.00; Chi² = 0.09, df = 2 (P = 0.95); I² = 0%
Test for overall effect: Z = 3.19 (P = 0.001)
1.5.5 Oxycodone
Gimbel 2003
Watson 1998
Watson 2003Subtotal (95% CI)
Total events
Heterogeneity: Tau² = 0.00; Chi² = 0.19, df = 2 (P = 0.91); I² = 0%
Test for overall effect: Z = 1.42 (P = 0.16)
1.5.8 Tramadol
Boureau 2003
Harati 1998
Norrbrink 2007
Sindrup 1999Subtotal (95% CI)
Total events
Heterogeneity: Tau² = 0.00; Chi² = 2.01, df = 3 (P = 0.57); I² = 0%
Test for overall effect: Z = 4.23 (P < 0.0001)
Total (95% CI)
Total events
Heterogeneity: Tau² = 0.00; Chi² = 5.24, df = 9 (P = 0.81); I² = 0%
Test for overall effect: Z = 5.21 (P < 0.00001)
Test for subgroup differences: Chi² = 2.95, df = 2 (P = 0.23), I² = 32.1%
Events
5
5
7
17
7
5
7
19
6
9
11
8
34
70
Total
44
55
66165
82
38
45165
63
65
23
43194
524
Events
1
1
1
3
4
3
4
11
0
1
2
3
6
20
Total
43
55
56154
77
38
45160
62
66
12
40180
494
Weight
9.1%
14.1%
14.7%38.0%
16.2%
5.2%
5.5%26.9%
16.6%
12.5%
1.1%
4.9%35.2%
100.0%
IV, Random, 95% CI
0.09 [-0.01, 0.19]
0.07 [-0.01, 0.16]
0.09 [0.01, 0.17]0.08 [0.03, 0.13]
0.03 [-0.04, 0.11]
0.05 [-0.08, 0.19]
0.07 [-0.07, 0.20]0.04 [-0.02, 0.10]
0.10 [0.02, 0.17]
0.12 [0.03, 0.21]
0.31 [0.02, 0.61]
0.11 [-0.03, 0.25]0.11 [0.06, 0.17]
0.08 [0.05, 0.12]
Opioids Placebo Risk Difference Risk Difference
IV, Random, 95% CI
-0.5 0 0.25 0.5Placebo Opioid
74
Figure 7 (Electronic Supplementary Material): Effect estimates (risk difference) of serious
adverse events during study
Study or Subgroup
1.6.4 Oxycodone
Gimbel 2003
Watson 2003Subtotal (95% CI)
Total events
Heterogeneity: Tau² = 0.00; Chi² = 0.04, df = 1 (P = 0.85); I² = 0%
Test for overall effect: Z = 1.60 (P = 0.11)
1.6.6 Tramadol
Boureau 2003Subtotal (95% CI)
Total events
Heterogeneity: Not applicable
Test for overall effect: Z = 1.58 (P = 0.11)
Total (95% CI)
Total events
Heterogeneity: Tau² = 0.00; Chi² = 5.48, df = 2 (P = 0.06); I² = 63%
Test for overall effect: Z = 0.28 (P = 0.78)
Test for subgroup differences: Chi² = 5.03, df = 1 (P = 0.02), I² = 80.1%
Events
5
1
6
3
3
9
Total
82
45127
5353
180
Events
9
3
12
0
0
12
Total
77
45122
5555
177
Weight
31.1%
32.2%63.3%
36.7%36.7%
100.0%
M-H, Random, 95% CI
-0.06 [-0.14, 0.03]
-0.04 [-0.13, 0.04]-0.05 [-0.11, 0.01]
0.06 [-0.01, 0.13]0.06 [-0.01, 0.13]
-0.01 [-0.09, 0.07]
Opioids Placebo Risk Difference Risk Difference
M-H, Random, 95% CI
-0.5 -0.25 0 0.25 0.5Favours placebo Favours opioid
75
Forest Plots of standardised mean differences and risk differences of opioids compared to placebo on selected outcomes
EERW design
Figure 8 (Electronic Supplementary Material): Effect estimates (standardised mean
differences) of at least 50% pain reduction maintenance
Study or Subgroup
2.3.1 Tapentadol
Schwartz 2011Subtotal (95% CI)
Total events
Heterogeneity: Not applicable
Test for overall effect: Z = 3.29 (P = 0.001)
Total (95% CI)
Total events
Heterogeneity: Not applicable
Test for overall effect: Z = 3.29 (P = 0.001)
Test for subgroup differences: Not applicable
Events
55
55
55
Total
9393
93
Events
39
39
39
Total
107107
107
Weight
100.0%100.0%
100.0%
IV, Random, 95% CI
0.23 [0.09, 0.36]0.23 [0.09, 0.36]
0.23 [0.09, 0.36]
Opioid Placebo Risk Difference Risk Difference
IV, Random, 95% CI
-4 -2 0 2 4Favours placebo Favours opioid
76
Figure 9 (Electronic Supplementary Material): Effect estimates (risk difference) of reports to
be much or very much improved at end of treatment
Study or Subgroup
2.6.1 Tapentadol
Schwartz 2011Subtotal (95% CI)
Total events
Heterogeneity: Not applicable
Test for overall effect: Z = 5.09 (P < 0.00001)
Total (95% CI)
Total events
Heterogeneity: Not applicable
Test for overall effect: Z = 5.09 (P < 0.00001)
Test for subgroup differences: Not applicable
Events
116
116
116
Total
180180
180
Events
68
68
68
Total
177177
177
Weight
100.0%100.0%
100.0%
IV, Random, 95% CI
0.26 [0.16, 0.36]0.26 [0.16, 0.36]
0.26 [0.16, 0.36]
Opioid Placebo Risk Difference Risk Difference
IV, Random, 95% CI
-0.5 -0.25 0 0.25 0.5Placebo Opioid
77
Figure 10 (Electronic Supplementary Material): Effect estimates (risk difference) of dropping
out due to adverse events during study
Study or Subgroup
2.8.7 Tapentadol
Schwartz 2011Subtotal (95% CI)
Total events
Heterogeneity: Not applicable
Test for overall effect: Z = 2.21 (P = 0.03)
Total (95% CI)
Total events
Heterogeneity: Not applicable
Test for overall effect: Z = 2.21 (P = 0.03)
Test for subgroup differences: Not applicable
Events
29
29
29
Total
196196
196
Events
15
15
15
Total
193193
193
Weight
100.0%100.0%
100.0%
IV, Random, 95% CI
0.07 [0.01, 0.13]0.07 [0.01, 0.13]
0.07 [0.01, 0.13]
Opioid Placebo Risk Difference Risk Difference
IV, Random, 95% CI
-0.5 -0.25 0 0.25 0.5Placebo Opioid
78
Figure 11 (Electronic Supplementary Material): Effect estimates (risk difference) of serious
adverse events during study
Study or Subgroup
2.9.6 Tapentadol
Schwartz 2011Subtotal (95% CI)
Total events
Heterogeneity: Not applicable
Test for overall effect: Z = 1.96 (P = 0.05)
Total (95% CI)
Total events
Heterogeneity: Not applicable
Test for overall effect: Z = 1.96 (P = 0.05)
Test for subgroup differences: Not applicable
Events
10
10
10
Total
196196
196
Events
3
3
3
Total
193193
193
Weight
100.0%100.0%
100.0%
IV, Random, 95% CI
0.04 [0.00, 0.07]0.04 [0.00, 0.07]
0.04 [0.00, 0.07]
Opioid Placebo Risk Difference Risk Difference
IV, Random, 95% CI
-0.5 -0.25 0 0.25 0.5Placebo Opioid