Der Schmerz,2015, 29(1).60-72_s1

English version of „Opioide bei chronischem Kreuzschmerz. Systematische Übersicht und Metaanalyse der Wirksamkeit, Verträglichkeit und Sicherheit in randomisierten, placebokontrollierten Studien über mindestens 4 Wochen”DOI 10.1007/s0048201414498© Deutsche Schmerzgesellschaft e.V. Published by SpringerVerlag Berlin Heidelberg all rights reserved 2014

F. Petzke1 · P. Welsch2 · P. Klose3 · R. Schaefert4 · C. Sommer5 · W. Häuser6, 7

1 SchmerzTagesklinik und Ambulanz, Universitätsmedizin Göttingen, Göttingen2 Stichting Rugzorg Nederland, Ede3 Abteilung für Natuheilkunde und Integrative Medizin, Kliniken EssenMitte, Essen4 Allgemeine und Innere Medizin, Universitätsklinikum Heidelberg, Heidelberg5 Neurologische Klinik, Universitätsklinikum Würzburg, Würzburg6 Klinik und Poliklinik für Psychosomatische Medizin und Psychotherapie, Technische Universität München, München7 Innere Medizin I, Klinikum Saarbrücken gGmbH, Saarbrücken

Opioids in chronic low back painA systematic review and meta-analysis of efficacy, tolerability and safety in randomized placebo-controlled studies of at least 4 weeks duration

Introduction

Chronic low back pain (CLBP) is the main cause of disability-adjusted life years (DALYs) worldwide. The prevalence of CLBP-related disability in the general population is estimated at 11% [29]. Med-ications (nonsteroidal agents, muscle re-laxants, antidepressants) play an impor-tant role in the management of CLBP. The use of opioids remains a controver-sial issue in the management of chronic noncancer pain (CNCP) and of CLBP in particular [27]. The American College of Physicians and The American Pain Soci-ety consensus guidelines for the treatment of LBP recommend opioids for the short-term management of severe and disabling LBP that does not respond to anti-inflam-matories or acetaminophen. Notably, this guideline was published in 2007 and re-viewed in only a few trials [5]. The Ger-man National Patient-Centered guideline

on nonspecific LBP recommended the use of weak opioids (e.g. tilidine/naloxone and tramadol) in the case of a lack of re-sponse to paracetamol or nonsteroidal an-ti-inflammatory drugs (NSAIDs). Strong opioids were not specifically recommend-ed and their potential use was suggested within an overall multimodal therapeu-tic approach. Therapy >12 weeks was on-ly recommended if the desired pain relief or improvement in physical function was accomplished. The guideline recommen-dations were based on a qualitative review of the literature [3].

A recent systematic Cochrane review on opioids in CLBP [4] searched the lit-erature up until October 2012. The au-thors distinguished between short-term (4–12 weeks), intermediate-term (13–26 weeks) and long-term (>26 weeks) tri-als. They pooled results of trials with par-allel/cross-over and enriched enrolment randomized withdrawal (EERW) designs. The authors found evidence for short-term efficacy (moderate for pain and small for function) of opioids for treat-ing CLBP as compared to placebo. They concluded that the effectiveness and safe-

ty of long-term opioid therapy (LtOT) for treatment of CLBP remains unproven [4].

For the update of the German 2008 guidelines on the long-term administra-tion of opioids in CNCP (LONTS) [23], we updated the search of literature for a systematic review on opioids in CNCP. The objectives of this review were to de-termine the efficacy and harms of opioids compared to placebo in patients of any age with CLBP in short-term (4–12 weeks), in-termediate term (13–26 weeks) and long-term (>26 weeks) trials separated for par-allel/cross-over and ERRW designs.

Methods

The review was performed according to the Preferred Reporting Items for System-atic Reviews and Meta-Analyses (PRIS-MA) statement [15] and the recommenda-tions of the Cochrane Collaboration [13].

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Supplementary material online

This article contains supplementary evidence reports and tables. These are available at: dx.doi.org/10.1007/s0048201414262

The English fulltext version of this article is freely available at SpringerLink (under “Supplemental”).

1Der Schmerz 1 · 2015  | 

Criteria for considering studies for this review

Types of studiesWe included fully published double-blind randomized controlled trials (RCTs) that compared any opioid to placebo (pure or pseudo) for therapeutic purposes. We in-cluded studies with parallel and enriched enrolment withdrawal (EERW) designs. Studies with a cross-over design were in-cluded if (a), separated data from the two periods were reported or (b), data were presented which excluded a statistically significant carry-over effect or (c), statis-tical adjustments were carried out in the case of a significant carry-over effect.

Study duration should be at least 4 weeks (titration and maintenance phase for parallel and cross-over design; double-blind withdrawal phase for EERW). Stud-ies should include at least 10 patients per treatment arm.

We grouped outcome measures ac-cording to the timing of postrandomiza-tion follow-up: short-term (4–12 weeks), intermediate (12–26 weeks) and long-term (longer than 26 weeks) [4].

We placed no restriction on the lan-guage of the publication.

We excluded studies with duration of the titration/maintenance or withdrawal period of less than 4 weeks; with a paral-lel design that included only responders in the double-blind phase after complete tapering of opioids after the end of open-label run-in phase; with an experimental design (i.e. if the primary purpose was to study pain mechanisms and not pain re-lief) and studies which were only pub-lished as abstracts. We excluded studies in which different dosages of one opioid were compared without a control group.

Types of participantsWe included men and women of all ages and races or ethnicities with clinically di-agnosed CLBP. Trials exclusively includ-ing patients with inflammatory arthri-tis, such as rheumatoid arthritis, were not considered. We excluded studies in which participants with osteoarthritis and LBP were enrolled and responses of the two groups were not presented separately.

Types of interventionsWe included trials that examined the use of any opioid in an outpatient setting, for a period of at least 4 weeks (titration and maintenance). We considered trials with opioids given by oral and transdermal routes.

We included studies in which opioids were combined with abuse deterrent for-mulations (ADFs; e.g naltrexone).

We included studies with tramadol, a centrally acting, synthetic opioid analge-sic with two complementary mechanisms of action: binding of parent and M1 me-tabolite to μ-opioid receptors and inhibi-tion of reuptake of norepinephrine and se-rotonin. We included studies with tapen-tadol with its two mechanisms of action: μ-receptor agonism and norepinephrine reuptake inhibition. We included both drugs into this review because they are classified as opioids by German regulato-ry agencies.

We considered only trials comparing opioids to placebo. We excluded trials that examined opioids given by intrave-nous or spinal routes, including implant-able pumps due to the invasive nature of the therapy and its limited clinical rele-vance in the outpatient setting. We did not assess the effectiveness of opioids used in neuraxial implantable pumps as this has been discussed elsewhere [19]. We exclud-ed studies in which the primary aim of the study was to test the efficacy of opioids as rescue medication.

We excluded studies in which drugs other than opioid agonists were com-bined with opioids (e.g. tramadol with ac-etaminophen), because it is not possible to disentangle the effects of the opioids from those of the other analgesic.

We excluded studies in which a defined opioid was compared to the same opioid with ADFs (e.g. oxycodone with and with-out naloxone) without a placebo arm, or in which opioid combinations were com-pared to a single opioid.

We excluded studies in which opi-oids were compared to nonpharmaco-logical treatments. We excluded stud-ies with propoxyphene because the drug has been withdrawn from the market (US Food and Drug Agency NEWS RELEASE from 19.11.2010).

Types of outcome measuresThe selection of outcomes was based on the recommendations of the ACTINPAIN writing group of the International Asso-ciation for the Study of Pain (IASP) Spe-cial Interest Group (SIG) on Systemat-ic Reviews in Pain Relief and those of the Cochrane Pain, Palliative and Support-ive Care Systematic Review Group editors for reporting meta-analyses of RCTs in chronic pain [17]. We included pain inten-sity as additional outcome because most studies conducted before 2005 did not re-port responder analyses [4].

Outcomes

Efficacy1. Pain intensity ratings.2. Proportion of patients reporting 50%

pain relief.3. Global improvement: number of pa-

tient reports to be much or very much improved.

4. Function: examples of functional out-comes that could be extracted as fol-lows: Brief Pain Inventory; Multidi-mensional Pain Inventory (physical function); Neck Disability Index; Os-westry Disability Index; Pain Disabil-ity Index, Physical Disability; Roland Disability Questionnaire, Short Form (SF)-36 or SF-12 (physical function-ing scale). Where both generic and disease-specific instruments were used, we preferred disease-specific in-struments (e.g. Oswestry Disability Index over SF-36 physical functioning scale).

5. Proportion of patients who dropped out due to lack of efficacy.

Tolerability1. Proportion of patients who withdrew

because of adverse events.

Safety1. Proportion of patients who experi-

enced any serious adverse events.2. Proportion of patients who died dur-

ing the study

We excluded studies in which the primary outcome measure was not one of the five outcomes of efficacy defined above.

2 |  Der Schmerz 1 · 2015

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Search methods for identification of studies

Electronic searchesThe review updated and expanded the literature search of the first version of LONTS, which searched the literature up until October 2008 [23]. The updat-ed and expanded search included the Co-chrane Central Register of Controlled Tri-als (CENTRAL), MEDLINE and Scopus from October 2008 to October 2013 and all types of CNCP. The search was con-ducted by PK. Our search included all lan-guages.

Searching other resourcesThe search strategy has been detailed in another paper of this issue [25].

Data collection and analysis

Selection of studiesTwo authors (PW, WH) independent-ly screened titles, abstracts and keywords of trials identified by the search strate-gies to determine whether the referenc-es met the inclusion criteria. We obtained the full-text of trials that either appeared to meet the criteria or for which we con-sidered their inclusion was uncertain. We screened these articles for inclusion and resolved any disagreements through dis-cussion.

Data extractionUsing standardized forms, three pairs of authors (CS, WH; FP, WH; RS, WH) in-dependently extracted data on inclusion and exclusion criteria of studies, partici-pant characteristics, intervention group, clinical setting, interventions, country of study and study sponsorship. If data were not available in a format that was appro-priate for data extraction, we did not con-tact the authors of the trial for further clarification. We resolved any disagree-ments through discussion.

Dealing with missing dataIf both baseline observation carried for-ward (BOCF) and last observation carried forward (LOCF) data were reported for an intention-to-treat (ITT) analysis, we pre-ferred BOCF data [17].

Where means or standard deviations (SD) were missing, we calculated these from t-values, confidence intervals (CIs) or standard errors, where reported in ar-ticles [13]. Where missing SDs could not be calculated from t-values, the study was excluded from analysis.

Measures of treatment effectThe effect measures of choice were abso-lute risk difference (RD) for dichotomous data and standardized mean difference (SMD) for continuous data (pain inten-sity, physical functioning), calculated us-ing a random effects model (method in-verse variance). For subgroup analyses of

dichotomous outcomes, we calculated risk ratios (RR). We expressed uncertainty us-ing 95% CIs. The threshold for “apprecia-ble 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 catego-ries to evaluate the magnitude of the effect size, calculated by SMD, with Hedges’ g of 0.2= small, 0.5= medium and 0.8= large [5]. We labelled g<0.2 to be a “not sub-stantial” effect size. We assumed a min-imally important difference if Hedges’ g was ≥ 0.2 [9].

The numbers needed to treat for an ad-ditional beneficial outcome (NNTB) and

Abstract

Schmerz 2014 · [jvn]:[afp]–[alp] DOI 10.1007/s0048201414262© Deutsche Schmerzgesellschaft e.V. Published by SpringerVerlag Berlin Heidelberg all rights reserved 2014

F. Petzke · P. Welsch · P. Klose · R. Schaefert · C. Sommer · W. HäuserOpioids in chronic low back pain. A systematic review and meta-analysis of efficacy, tolerability and safety in randomized placebo-controlled studies of at least 4 weeks duration

AbstractBackground. The efficacy and safety of opioid therapy in chronic low back pain (CLBP) is under debate. We updated a recent systematic review on the efficacy and safety of opioids in CLBP.Methods. We screened MEDLINE, Scopus and the Cochrane Central Register of Controlled Trials (CENTRAL) up until October 2013, as well as reference sections of original studies and systematic reviews of randomized controlled trials (RCTs) of opioids in CLBP. We included doubleblind randomized placebocontrolled studies of at least 4 weeks duration. Using a random effects model, absolute risk differences (RD) were calculated for categorical data and standardized mean differences (SMD) for continuous variables.Results. We included 12 RCTs with 17 treatment arms and 4375 participants. Median study duration was 12 (4–16) weeks. Of the 17 treatment arms, seven (41.2%) used oxycodone; four (23.6%) tramadol; buprenorphine and oxymorphone were each used in two (11.8%) and hydromorphone and tapentadol each in one (5.8%). The results for studies with parallel/crossover design were as follows (with 95% confidence interval, CI): opioids were superior to placebo in reducing pain intensity (SMD −0.29 [−0.37, −0.21], p<0.0001; six studies with 2896 participants). Opioids were superior to placebo in 50% pain reduction (RD 0.05 [0.01, 0.10], p=0.01; two studies with 1492 participants; number needed to benefit (NNTB) 19 [95% CI 10–107]).

Opioids were not superior to placebo in reports of much or very much improved pain (RD 0.16 [−0.01, 0.34], p=0.07; two studies with 1153 participants). Opioids were superior to placebo in improving physical functioning (SMD −0.22 [−0.31, −0.12], p<0.0001; four studies with 1895 participants). Patients dropped out less frequently with opioids than with placebo due to lack of efficacy (RD −0.10 [−0.16, −0.04], p=0.001; five studies with 3168 participants; NNTB 10 [8–13]). Patients dropped out more frequently with opioids than with placebo due to adverse events (RD 0.12 [0.05, 0.19], p=0.0007; six studies with 2910 participants; number needed to harm (NNTH) 7 [95% CI 6–8]). There was no significant difference between opioids and placebo in terms of the frequency of serious adverse events or deaths.Conclusion. 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 during the study period. The conclusion on the safety of opioids compared to placebo is limited by the low number of serious adverse events and deaths. Shortterm and intermediate term opioid therapy may be considered in selected CLBP patients.

KeywordsSystematic review · Metaanalysis · Opioids · Chronic low back pain


the numbers needed to treat for an addi-tional harm (NNTH) were calculated for dichotomous variables (50% pain reduc-tion, PGIC, dropout due to adverse events, serious adverse events, death) with an ex-cel sheet provided by the Cochrane col-laboration (personal communication with the Cochrane Musculoskeletal Group).

Subgroup comparisons were per-formed by the test of interaction [1].

Unit of analysis issuesIn the case of multiple opioid arms com-pared to one placebo group, the number of participants in the placebo group was adjusted according to the number of par-ticipants in the different opioid arms for continuous outcomes.

Data synthesisWe pooled data from trials comparing opioids to controls by a random effects method of inverse variance. We used the I2 statistic to describe the percentage vari-

ability of effect estimates that is due to het-erogeneity. I2 values above 50% indicate high heterogeneity, between 25 and 50% moderate heterogeneity and below 25% low heterogeneity [13].

The risk of bias in each trial was as-sessed independently by three pairs of au-thors (CS, WH; FP; WH; RS, WH) using eight aspects of bias recommended by the Cochrane Collaboration [4]: selection bi-as, performance bias, detection bias, at-trition bias, reporting bias, selection bi-as, performance bias, detection bias and funding bias. We defined a high-quality study (study with a low risk of bias) as a study that fulfilled six to eight of the eight validity criteria; a moderate-quality study (study with a moderate risk of bias) ful-filled three to five and a low-quality study (study with high risk of bias) fulfilled ze-ro to two of the eight validity criteria. We used Grading of Recommendations As-sessment, Development and Evaluation (GRADE) to assess the overall quality of

the evidence [11], defined as the extent of confidence in the estimates of treatment benefits and harms. Quality ratings were made separately for each of the eight out-comes. The quality of evidence was down-graded by one level for each of the follow-ing factors that were encountered:FLimitations of study design: >50% of

participants from low-quality studies.FInconsistency of results: I2 of effect

size >50%.FIndirectness: we assessed whether the

question being addressed in this sys-tematic review was different from the available evidence regarding the pop-ulation in routine clinical care, if ex-clusion of patients with clinically rel-evant somatic disease and/or ma-jor mental disorders in the included studies resulted in >=50% of the to-tal patient collective of the systematic review coming from studies in which patients with relevant somatic disease and/or major mental disorders were excluded.

FImprecision: there was only one tri-al or when there was more than one trial, the total number of patients was <400 or when the pooled esti-mate of effect included no effect.

We categorized the quality of evidence as follows:FHigh (++++): we are very confident

that the true effect lies close to that of the estimate of the effect.

FModerate (+++): we are moderate-ly confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially dif-ferent.

FLow (++): our confidence in the effect estimate is limited; the true effect may be substantially different from the es-timate of the effect.

FVery low (+): we have very little con-fidence in the effect estimate; the true effect is likely to be substantially dif-ferent from the estimate of effect; any estimate of effect is very uncertain.

Assessment of reporting biasesFor analyses with at least 10 studies, we used the Egger intercept test and the Begg rank correlation test at the significance

Screen

ing

Includ

edEligibility

Iden

ti�catio

n

Records identi�ed throughdatabase searching

(n = 17591)

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

Additional records identi�edthrough hand searching

(n = 52)

Records after duplicates removed(n = 12601)

Records screened(n = 12601)

Records excluded(n = 12585)

Studies included inqualitative synthesis

(n = 12)

Full-text articles excluded, withreasons(n = 4)

Experimental study (n = 1)No separate outcomes for

chronic low back pain reported(n = 1)

Double publication (n = 2)

Studies included inquantitative synthesis

(meta-analysis)(n = 12)

Full-text articles assessedfor eligibility

(n = 16)

Fig. 1 8 Preferred Reporting Items for Systematic Reviews and MetaAnalyses (PRISMA) flow diagram


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Tab. 1 Overview of the randomized controlled trials in chronic low back pain included into the systematic review (grouped by type of opioid in alphabetical order)

Reference; year; countries of study centers

Study design Population type; no. of patients randomized

Interventiona and control group Duration of trial

Buprenorphine

Gordon et al. [34]2010USA, Canada

Crossover Low back pain79

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

Duration screening not reported4 weeks titration and maintenance each6 months openlabel

Steiner et al. [39]2011USA

Enriched enrollment randomized withdrawal

Low back pain539

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

6–10 days screeningUp to 4 weeks openlabel titration12 weeks doubleblind withdrawal

Hydromorphone

Hale et al. [36]2010USA

Enrichedenrollment randomized withdrawal

Low back pain268

Hydromorphone flexible 12–64 mg/d oralPlacebo oral

<2 weeks screening2–4 weeks openlabel titration12weeks doubleblind withdrawal

Oxycodone

Cloutier et al. [33]2013Canada

Crossover Low back pain83

Oxycodone/naloxone oral flexible 20/10 mg/d or 30/15 mg/d or 40/20 mg/dPlacebo oral

2–7 days washout4 weeks for each period6 months openlabel

Vondrackova et al. [41]2008Europe

Parallel Low back pain463

Oxycodone oral fixed 20 or 40 mg/dOxycodone/Naloxone oral 20/10 or 40/20 mg/d fixedPlacebo

≤7 days screening3 weeks tapering and titration12 weeks maintenance12 months openlabel extension

Webster et al. [43]2006USA


Oxycodone oral flexible 10–80 mg/dOxycodone/naltrexone oral flexible 10–80 mg/d two times/dOxycodone/naltrexone oral flexible 10–80 mg/d once/dPlacebo oral

4–10 days washout1–6 weeks titration12 weeks maintenance

Oxymorphone

Hale et al. [35]2007USA


Low back pain142

Oxymorphone flexible (no maximum dosage) oralPlacebo oral

Duration screening and washout not reportedDuration openlabel titration not reported12 weeks doubleblind withdrawal

Katz et al. [37]2007USA


Low back pain205

Oxymorphone flexible (no maximum dosage) oralPlacebo oral

Duration screening and washout not reportedOpenlabel titration up to 10 days12 weeks doubleblind withdrawal

Tapentadol

Buynak et al. [32]Australia, Canada, USA2010


Tapentadol flexible 200–500 mg/d oralOxycodon flexible 40–100 mg/d oralPlacebo

Duration of screening not reported3 weeks titration,12 weeks maintenanceDuration of followup not reported

Tramadol

Schnitzer et al. [38]USA2000


Low back pain254

Tramadol flexible 100–400 mg/d oralPlacebo

Up to 3 weeks washout3 weeks openlabel titration and maintenance4 weeks double blind withdrawal

Überall et al. [40]2012Germany


Tramadol 200 mg/d fixed oralPlacebo

1 week washout4 weeks maintenance1 week followup

Vorsanger et al. [42]2008USA


Tramadol 200 mg/d fixed oralTramadol 300 mg/d fixed oralPlacebo oral

2–7 days washout3 weeks openlabel12 weeks maintenance

aAll oral opioids were administered as extended release formulation.


level p<0.05. The Begg test examines the rank correlation between a standardized intervention effect and its standard error. An asymmetric funnel plot would give rise to such a correlation and may be in-dicative of publication bias [2]. In the Eg-ger test, the standard normal deviate is re-gressed on precision, defined as the in-verse of the standard error. The intercept of this regression corresponds to the slope in a weighted regression of the effect size on the standard error [8].

Subgroup analysisSubgroups were planned a priori to assess the variations in effect sizes (heterogene-ity) for all types of opioids pooled togeth-er compared to placebo groups pooled together for the outcomes (pain intensi-ty and dropout due to adverse events), for different types of opioids (opioids versus opioids with additional modes of action, i.e.tramadol, tapentadol), for studies with and without exclusion of neurological eti-ology of symptoms and for short-term,

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

Sensitivity analysisWe performed sensitivity analysis for all types of opioids pooled together com-pared to placebo groups pooled together for the outcomes in studies in which we extracted means and/or SDs from figures or calculated SDs from p-values.

Tab. 2 Inclusion and exclusion criteria of the studies analyzed with regard to prior analgesic therapy, duration and etiology of low back pain

Reference Prior analgesic regimen Duration of low back pain Exclusiona Specification for inclusion of low back pain etiology

Buynak et al. [32] Opioid (<160 mg ME) or nonopioid for 3 months and dissatisfied

>3 months Malignancy Nonmalignant

Cloutier et al. [33] Nonresponder to nonopioids or to opioids

>3 months None None

Gordon et al. [34] Treated with nonopioids >6 weeks None None

Hale et al. [35] At least 60 mg ME at screening

>3 months for several h/day Neurological etiology or signs/symptoms, infection, malignancy, surgery in the last 6 months

None

Hale et al. [36] At least 60 mg ME (but <320 mg ME) for 2 months

Not specified Neurological etiology or signs/symptoms, infection, malignancy, surgery in the last 6 months

Quebec classification of low back pain class 1–6Nonneuropathic

Katz et al. [37] Opioid naive for 2 weeks >3 months for several h/day Neurological etiology or signs/symptoms, infection, malignancy, surgery in the last 2 months

None

Schnitzer et al. [38] On daily medication (not further specified)

>3 months for several hours/day

Neurological deficits, malignancy, infection, surgical indication, spondylolisthesis, disk herniation, spinal stenosis, instability, no surgery for 5 years

None

Steiner et al. [39] Nonresponder to nonopioids

>3 months for several hours/day

Malignancy, radicular symptoms, neural compression, spondylarthtropathy, rhreumatological conditions, infection, no surgery the last 6 months

Nonmalignant, spinal stenosis, intervertebral disc disease, spondylolisthesis, osteoarthritis of the spine

Vondrackowa et al. [41] Daily opioid with adequate effect for at least 2 weeks

Not specified Malignancy, more than one back surgery

Mixed origin, osteoarthritis of the spine, spondylosis, disc herniation, sciatica, spinal stenosis

Vorsanger et al. [42] On daily medication (60 of 90 days), opioid or nonopioid

>6 months Malignancy, inflammatory, history of surgery or chemonucleolysis

None

Webster et al. [43] No information >6 months Malignancy, autoimmune etiology, infection, fracture, surgery in the last 4 months, spinal pump, SCS

None

Überall et al. [40] Adequate analgesics according to NVL, yet dissatisfied

>3 months Malignancy, neurological etiology, inflammatory, spinal fractures, spinal stenosis or disc problem with neurological impairment, anatomical abnormalities, history of surgery

None

ME Morphine equivalent dose in mg, SCS spinal cord stimulator, NVL Nationale Versorgungsleitlinie Kreuzschmerz (German National Patient-Centered Guideline Low Back Pain)aSurgery refers to spinal surgery.


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SoftwareComprehensive meta-analysis (Biostat, Englewood, NJ, USA) and the RevMan Analysis (RevMan 5.2; [24]) software of the Cochrane Collaboration software were used for statistical analyses.

Results

Search

After removing duplicates, the literature search produced unique 12,601 citations. Through screening, 12,585 records were excluded. Sixteen full-text articles were assessed for eligibility. Four studies were excluded after full-text review ([6, 10, 18, 31]). Twelve studies with 17 treatment arms were included in the meta-analysis ([32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43]; see .Fig. 1).

Characteristics of studies

Study designWe included twelve RCTs with 17 treat-ment arms and 4375 (79–981) partici-pants. Median study duration was 12 (4–16) weeks. Nine (75%) studies were of short-term (4-12 weeks) and three (25%) were of intermediate-term (13-26 weeks) duration. Five (41.7%) studies had an EERW design, five (41.7%) a parallel and two (16.6%) studies a cross-over de-sign. Nine (75.1%) studies were conduct-ed in North America, two studies (16.6%) in Europe and one (8.3%) in mixed con-tinents. All studies were funded by the manufacturer of one of the tested drugs (see .Tab. 1 and supplementary table 1).

ParticipantsOnly adults were included into the stud-ies. Nine (75%) studies specifically exclud-ed patients with current and/or a history of substance abuse and/or current major mental disorders. One study (8.3%) ex-cluded patients with psychiatric disease that put the subject at risk upon expo-sure to the study drug or would confound study results [41]. All studies excluded pa-tients with clinically relevant medical dis-eases. The range of the mean ages of par-ticipants in the studies was 46–62 years. The participants were predominantly white (see .Tab. 1 and supplementary

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

Fig. 2 8 Risk of bias graph

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+

?

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+

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Fund

ing

bias

–

–

–

–

–

–

–

–

–

–

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– Fig. 3 9 Risk of bias summary


table 1). Four (33.3%) studies excluded pa-tients with pending pain-related litigation.

Criteria for CLBP varied considerably between studies (see .Tab. 2), both for analgesic pretreatment and duration of CLBP (more than 6 weeks to more than 6 months).

Most studies required some form of regular medication (91.7%), ranging from daily nonopioids to an opioid dose equiv-alent to ≥60 mg of morphine. Half (50%) of the studies specifically excluded any neurological etiology, symptoms or signs. Inclusion criteria for specific CLBP enti-ties were only given in three studies (25%). Three of the studies (25%) reported a clin-ical CLBP diagnosis in the results section (one study recorded International Classi-fication of Diseases, ICD, 10 code M54 in 80% of subjects; two others described in-clusion of about 80% of subjects with os-teoarthritis or disc degeneration); two fur-ther studies (16.6%) differentiated neuro-pathic and nonneuropathic pain. Actual duration of CLBP was specified in three studies (25%); no study reported po-tential psychosocial risk factors for the maintenance of CLBP. Finally, five studies (43.4%) reported baseline functional sta-tus; available data indicated clinically rel-evant functional impairment.

InterventionsOxycodone and tramadol were primari-ly tested in three studies (25%) each; bu-prenorphine and oxymorphone in two each (16.7%) and hydromorphone and ta-pentadol were each tested in one study

(8.3%). With respect to treatment arms, seven of 17 (41.2%) used oxycodone, four (23.6%) tramadol; buprenorphine and oxymorphone were each used in two (11.8%) and hydromorphone and tapent-adol were each used in one (5.8%). Nine (75%) studies used a flexible dosage of the opioid; the remaining studies used fixed dosages. Four (33.3%) studies prohibited and the remaining eight studies (66.7%) allowed rescue medication for pain (ac-etaminophen, NSAIDs, short-acting opi-oids). Most studies did not detail wheth-er or not nonpharmacological therapies were allowed; the application of antide-pressants or anticonvulsants as comedica-tion was also rarely addressed (see supple-mentary table 1).

Quality of evidence

Risk of bias could not be properly assessed in all studies due to poor method report-ing. Nine studies (75%) had a moderate and three (25%) a low study quality (see .Fig. 2, 3 for risk of bias summary and graph). Detailed information regarding risk of bias assessments of every study are given in supplementary table 2.

Synthesis of results

Parallel and cross-over designResults are reported with 95% CIs

Six studies with 2869 participants were entered into an analysis of mean pain re-duction at the end of the study. Opioids were superior to placebo (SMD −0.29

[0.37, −0.21], p<0.00001, I2=0; moderate-quality evidence). According to Cohen’s categories the effect size was small (see supplementary figure 1). One study [41] reported that oxycodone was superior to placebo without giving means and SDs.

Two studies with 1492 participants were entered into an analysis of numbers of responders with at least 50% pain reduc-tion at the end of the study. Opioids were superior to placebo (RD 0.05 [0.01, 0.10], p=0.01, I2=0; moderate-quality evidence). In all, 196/748 (26.2%) patients in opioid groups and 156/744 (21.0%) patients in placebo groups reported pain reduction of at least 50% (NNTB 19 [10–107]; see sup-plementary figure 2). According to the predefined criteria, there was an appre-ciable additional benefit of opioid treat-ment (RRI 25% [4–50%]).

Two studies with 1153 participants were 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 0.16 [−0.01, 0.34], p=0.07, I2=92; low-quality evidence; see supple-mentary figure 3).

Four studies with 1895 participants were entered into an analysis of physi-cal function at the end of the study. Opi-oids were superior to placebo (SMD −0.22 [−0.31, −0.12], p<0.0001], I2=0; moderate-quality evidence; see supplementary fig-ure 4). According to Cohen’s categories, the effect size was small. One study with oxycodone [42] and one study with tra-madol [40] reported no significant differ-ence to placebo.

Five studies with 3168 participants were entered into an analysis of drop-ping out due to lack of efficacy. Pa-tients dropped out less frequently with opioids than with placebo (RD −0.10 [−0.16, −0.04], p=0.001, I2=89; low-qual-ity evidence; see supplementary figure 5). In all, 117/1933 (6.1%) patients dropped out in opioid groups and 201/1235 (16.3%) in placebo groups (NNTB 10 [8–13]). Ac-cording to the predefined criteria, there was an appreciable additional benefit of opioids (RRR 63% [54–70%]).

Six studies with 2910 participants were entered into an analysis of drop-ping out due to adverse events. Pa-tients dropped out more frequently with opioids than with placebo (RD 0.12

Tab. 3 Effect sizes of different types of opioids on selected outcome variables

Outcome title

Number of studies

Number of patients

Effect size [95% CI]

Test for overall effect p-value

Heterogene-ityI2 (%)

Pure opioids

Pain intensity 4 1660 SMD −0.30 [−0.41, −0.19)]

<0.0001 0

Dropout due to adverse events

4 1660 RR 3.98 [2.20, 7.18]

<0.0001 82

Opioids with an additional mode of action

Pain intensity 4 1240 SMD −0.26 [−0.40, −0.13]

0.0001 22

Dropout due to adverse events

4 1240 RR 1.58 [0.65, 3.97]

0.33 82

RR relative risk, SMD standardized mean difference, CI confidence interval.


Schwerpunkt

[0.05, 0.19], p=0.0007, I2=88; low-quality evidence; see supplementary figure 6). In all, 379/1784 (21.2%) patients dropped out due to adverse events in opioid groups and 67/1126 (6.0%) in placebo groups (NNH 7 [6–8]). According to the predefined cri-teria, there was an appreciable additional harm caused by opioids (RRI 257% [178–358%]).

Five studies with 2509 participants were entered into an analysis of serious adverse events. There was no significant difference between opioids and place-bo (RD −0.01 [−0.00, 0.02], p=0.08, I2=0; moderate-quality evidence); see supple-mentary figure 7).

Three studies with 1887 participants were entered into an analysis of deaths. There were no deaths in either group (moderate-quality evidence).

Enriched enrolment randomized withdrawal designFour studies with 1254 participants were entered into an analysis of mean pain re-duction from baseline to end of treat-

ment. Opioids were superior to place-bo (SMD −0.74 [−1.25, −0.22], p=0.005, I2=94; low-quality evidence). According to Cohen’s categories, the effect size was small (see supplementary figure 8).

Three studies with 925 partici-pants were entered into an analysis of 50% pain reduction at the end of the study. Opioids were superior to pla-cebo (RD 0.17 [0.05, 0.29], p=0.004, I2=69; very low-quality evidence). In all, 230/461 (49.9%) patients in opioid groups and 160/464 (34.5%) patients in place-bo groups reported 50% pain reduction (NNTB 6 [5–11]; see supplementary fig-ure 9). According to the predefined cri-teria, there was an appreciable addition-al benefit from treatment with opioids (RRI 45% [24–69%]).

One study with 498 participants was entered into an analysis of reports on much or very much improved pain at the end of the study. Opioid was superior to placebo (RD 0.10 [0.03, 0.17], p=0.008; low-quality evidence; see supplementary figure 10). In all, 61/237 (25.7%) patients in opioid the group and 42/261 (16.1%) patients in the placebo group reported pain to be much or very much improved (NNTB 10 [95% CI 6–40]). According to the predefined criteria, there was an ap-preciable additional benefit achieved by opioids (RRI 60% [13–127%]).

Two studies with 825 participants were entered into an analysis of physi-cal function at the end of the study. Opi-oids were superior to placebo (SMD −0.23 [−0.37, −0.10] p=0.0009], I2=0; low-quali-ty evidence; see supplementary figure 11). According to Cohen’s categories, the effect size was small.

Six studies with 1872 participants were entered into an analysis of dropping out due to lack of efficacy. Patients dropped out less frequently with opioids than with placebo (RD −0.22 [−0.36, −0.09], p=0.001, I2=90; low-quality evidence; see supplementary figure 12). In all, 83/692 (12.0%) patients dropped out in opioid groups and 211/717 (29.4%) in pla-cebo groups (NNTB 6 [5–7]). According to the predefined criteria, there was an appreciable additional benefit of opioids (RRR 59% [49–68%]).

Six studies with 1872 participants were entered into an analysis of dropping out

due to adverse events. There was no sig-nificant difference between opioids and placebo (RD 0.01 [−0.03, 0.04], p=0.69, I2=57; very low-quality evidence; see sup-plementary figure 13).

Six studies with 1875 participants were entered into an analysis of serious adverse events. There was no significant difference between opioids and placebo (RD −0.01 [−0.00, 0.02], p=0.64, I2=25; low-quali-ty evidence; see supplementary figure 14).

Two studies with 1006 participants ex-plicitly stated that were no deaths in either group (moderate-quality evidence).

Subgroup and sensitivity analyses

In parallel and cross-over studies, pure opioids and opioids with an additional mode of action (tapentadol, tramadol) did not differ in terms of mean pain reduc-tion (z=1.38, p=0.17). The dropout rates due to adverse events were lower in stud-ies with tapentadol and tramadol than in studies with buprenorphine or oxycodo-ne (z=2.29, p=0.02; see .Tab. 3). Short-term and intermediate-term studies did not differ significantly in terms of mean pain reduction or rates of dropout due to adverse events (data available on request). The remaining predefined subgroup anal-yses were not possible.

Removing two studies with means and SDs extracted from figures from analysis did not change the significance and the magnitude of effect of pain reduction and dropping out due to adverse events (de-tails available on request).

Publication bias

Since <10 studies were available for both parallel/cross-over and EERW designs, we did not perform the predefined tests.

Discussion

Summary of main results

Opioids were superior to placebo in terms of efficacy and inferior in terms of tol-erability. The effect sizes for efficacy of pain intensity and physical function were small. There was an appreciable additional beneficial outcome achieved by opioids in terms of at least 50% pain reduction and

Infobox 1: Excluded with reason

1. Chu LF, D’Arcy N, Brady C, Zamora AK, Young CA, Kim JE, Clemenson AM, Angst MS, Clark JD. Analgesic tolerance without demonstrable opioidinduced hyperalgesia: a doubleblinded, randomized, placebocontrolled trial of sustainedrelease morphine for treatment of chronic nonradicular lowback pain [6] (primary outcomes were experimental).

2. Gordon A, Rashiq S, Moulin DE, Clark AJ, Beaulieu AD, Eisenhoffer J, Piraino PS, Quigley P, Harsanyi Z, Darke AC. Buprenorphine transdermal system for opioid therapy in patients with chronic low back pain [10] (double publication; data of whole study sample published by Gordon 2010).

3. Moulin DE, Iezzi A, Amireh R, Sharpe WK, Boyd D, Merskey H. Randomised trial of oral morphine for chronic noncancer pain [18] (no separate outcomes for CLBP reported; outcomes not suited for metaanalysis: no SDs or pvalues reported).

4. Yarlas A, Miller K, Wen W, Dain B, Lynch SY, Pergolizzi JV, Raffa RB, Ripa SR. A randomized, placebocontrolled study of the impact of the 7day buprenorphine transdermal system on healthrelated quality of life in opioidnaïve patients with moderatetosevere chronic low back pain [31] (double publication).


global improvement. Opioids were inferi-or to placebo in terms of tolerability. Opi-oids and placebo did not differ in terms of safety.

Comparison with other systematic reviews

Our findings are in line with the findings on efficacy, tolerability and safety of a Co-chrane review on opioids in LBP, which searched the literature up until Octo-ber 2012 and included 15 studies ≥4 weeks duration [4]. Ten studies were includ-ed in both the Cochrane and in our re-view. In contrast to Chaparro and cowork-ers, we excluded two studies which com-bined tramadol and paracetamol; one study with morphine because we classi-fied the pain to be neuropathic (radicu-lar) [26]; one study with morphine be-cause we classified the study to be experi-mental ([32], .Infobox. 1) and one study which compared tramadol with celecox-ib [20]. In contrast, we included one new study which was published in 2013 [33]. We included one study which was exclud-ed by the Cochrane review because the design was not considered to represent a “true” placebo-controlled design [41]. We included only data on adverse events of this study into meta-analysis.

The Cochrane authors reported that tramadol (five trials, 1378 participants) was found to be better than placebo for pain (SMD −0.55 [−0.66, −0.44]; low-quali-ty evidence) and function (SMD −0.18 [−0.29, −0.07]; moderate-quality evi-dence). Strong opioids (morphine, hy-dromorphone, oxycodone, oxymorphone and tapentadol) examined in six trials (1887 participants) were better than pla-cebo for pain (SMD −0.43 [−0.52, −0.33]; moderate-quality evidence) and function (SMD −0.26 [−0.37, −0.15]; moderate-quality evidence). The authors empha-sized that the studies had limited inter-pretability of functional improvement [4].

The evidence of a superiority of opi-oids over placebo in physical function-ing in our review is likewise question-able, because data from two studies re-porting negative results for opioids were not suitable for entry into meta-analysis. While both systematic reviews highlight the rather high dropout rates (low toler-

ability) associated with opioids, they also stated that opioids were safe for the dura-tion of the studies.

In contrast, there is increasing evi-dence for relevant side effects of LtOP in clinical practice [14]. Most of these—such as addiction, hypogonadism and opioid-induced hyperalgesia—are unlikely to oc-cur or be detected in a clinical trial with a limited median duration of 12 weeks. Still, none of the trials reported any data rele-vant to such outcomes.

In addition, the reduced safety of LtOP observed in clinical practice can be par-tially explained by the fact that patients with a history of substance abuse or ma-jor medical disease were typically exclud-ed in the RCTs. However, in routine clini-cal care opioids are prescribed to these pa-tients [22].

The diagnostic label of CLBP used in the trials analyzed was very broad and provided little guidance for specific clin-ical situations and indications. All stud-ies allowed inclusion of patients with nonspecific CLBP; the majority of stud-ies even excluded potential specific con-ditions. Importantly, inclusion focused on the limited success of previous analgesic therapy alone. Accordingly, the ability of systematic reviews of placebo-controlled studies to guide patients and physicians in the choice of treatment options in CLBP is very limited. Head-to-head comparisons of opioids with other drugs have rarely been conducted. Celecoxib 200 mg/d was superior to tramadol 100 mg/d in terms of percentage of 30% pain reduction and dropout rates due to adverse events in two 6-week studies comprising a total of 1702 patients [20]. On the other hand, the long-term risks of treatment with drugs involving cyclo-oxygenase (COX)-related mechanisms are well established [12]. To the best of our knowledge, direct head-to-head comparisons of opioids with physi-cal or psychological therapy in CLBP have not been conducted. To provide a superior evidence base for future treatment guide-lines, additional RCTs must be conducted in which existing drugs are directly com-pared with each other and administered in various combinations. In addition, wheth-er other approaches for the management of patients with CLBP (e.g. physical thera-py and psychosocial interventions) should

be used before, in combination with, or af-ter pharmacological treatments must be tested in clinical trials. Traditional RCTs may not ultimately be the method of choice for answering all these questions; alternative approaches should be devel-oped and evaluated (e.g. systematic com-parative effectiveness studies of healthcare registry data).

Limitations

Only double-blind randomized placebo-controlled studies were included in this meta-analysis, representing a high lev-el in evidence-based medicine. However, the methodological quality of the includ-ed studies was predominantly moderate at most. The blinding of outcome assess-ment was mostly unclear, implying a high detection bias. Complete data reporting was often doubtful, leading to a high at-trition bias. There was a high risk of selec-tive reporting causing a relevant report-ing bias. All studies were funded by the manufacturers of the tested drugs, imply-ing a high funding bias. The external va-lidity of the study results for use in rou-tine clinical care is limited, because the di-agnostic label of CLBP used in the trials analyzed was very broad and mostly uni-dimensional. Negative study results may not have been published, which can lead to an overestimation of the true interven-tion effect. On the other hand, we might have underestimated the quality of stud-ies because we did not ask the authors for missing details. In summary, the method-ological quality of the studies and their re-porting should be improved in future re-search.

The conclusion on the safety of opi-oids compared to placebo is limited by the low number of serious adverse events and deaths.

There is uncertainty regarding unpub-lished studies with negative results.

Conclusion for clinical practice

Opioids may be considered in the short-term and intermediate-term treatment (4–26 weeks) of CLBP. Clinicians should keep in mind the heterogeneity be-hind the diagnostic label of CLBP and that no currently available evidence-

10 |  Der Schmerz 1 · 2015

Schwerpunkt

based guideline recommends opioids as a first-line treatment option for CLBP. Consistent therapeutic recommenda-tions in guidelines for CLBP were infor-mation, exercise therapy and combined physical and psychological interven-tions [21]. Monotherapy with opioids is discouraged. The German National Pa-tient-Centered guideline on nonspecif-ic LBP recommended a re-evaluation of opioid therapy at no later than 3 months. Opioid therapy should only be contin-ued if the goals of pain reduction and/or improvement of physical function, as defined by patient and physician be-fore the initiation of therapy, have been reached [3]. Long-term open-label stud-ies demonstrated that a minority of pa-tients with chronic noncancer pain (in-cluding patients with CLBP) treated with opioids will experience such a sus-tained (>1 year) response with no or tol-erable side effects [12, 30]. Long-term (≥26 weeks) opioid therapy may be of-fered to sustained responders to short-term and intermediate-term opioid ther-apy and/or to partial and nonresponders to exercise and/or psychological therapy. Careful monitoring of ongoing effect and of potential complications is advised.

Corresponding address

PD Dr. W. HäuserInnere Medizin I, Klinikum Saarbrücken gGmbHWinterberg 1, 66119 SaarbrückenGermanywhaeuser@klinikumsaarbruecken.de

Acknowledgements. We thank Professor Sorgatz (Essen) for reviewing our extractions of the dropout rates due to lack of efficacy. P Klose was supported by the Rut und KlausBahlsenStiftung.

Compliance with ethical guidelines

Conflict of interest. W. Häuser received honoraria for educational lectures from Abbott, JanssenCilag, MSD Sharp & Dohme and Pfizer, as well as one honorarium for consulting services (study design) from Daiichi Sankyo. C. Sommer has served on scientific advisory boards for Astellas Pharma Inc., Baxter Inc., Genzyme and Pfizer Inc.; she received speaker honoraria from Allergan, Baxter Inc., CSL Behring, Genzyme Corp., Grünenthal, GSK and Pfizer Inc., and she also received research support from Genzyme Corp., the German Research Foundation, the European Union and the Interdisciplinary Center for Clinical Research of the University of Würzburg. F. Petzke has served on scientific advi

sory boards for Grünenthal and JanssenCilag and has received speaker honoraria from JanssenCilag. P. Welsch, P. Klose and R. Schaefert state that there are no conflicts of interest. The accompanying manuscript does not include studies on humans or animals.

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Evidenzbericht: Forest Plots der standardisierten Mittelwertdifferenzen und Risikoreduktionen von Opioiden im

Vergleich zu Placebo für ausgewählte Endpunkte

Paralleles oder Cross-over-Design Abb. 1: Effektschätzer (standardisierte Mittelwertdifferenzen) der durchschnittlichen Reduktion der Schmerzintensität am Behandlungsende

Study or Subgroup

1.1.1 Buprenorphine

Gordon 2010Subtotal (95% CI)

Heterogeneity: Not applicable

Test for overall effect: Z = 1.31 (P = 0.19)

1.1.6 Oxycodone

Buynak 2010

Cloutier 2013

Webster 2006

Webster 2006

Webster 2006Subtotal (95% CI)

Heterogeneity: Tau² = 0.00; Chi² = 0.66, df = 4 (P = 0.96); I² = 0%

Test for overall effect: Z = 5.30 (P < 0.00001)

1.1.8 Tapentadol

Buynak 2010

Buynak 2010Subtotal (95% CI)



1.1.9 Tramadol

Vorsanger 2008

Vorsanger 2008

Überall 2012Subtotal (95% CI)



Total (95% CI)



Test for subgroup differences: Chi² = 0.85, df = 3 (P = 0.84), I² = 0%

Mean

39.2

-2.9

52.2

-42.6

-41.2

-46.2

0

-2.9

34.1

30.5

-2.1

SD

20.5

2.52

23

34.5

35.2

33.6

0

2.66

27.1

23

2

Total

7373

328

83

204

199

2051019

0

318318

129

127

107363

1773

Mean

43.9

-2.1

57.8

-32.2

-32.2

-32.2

0

-2.1

40.3

40.3

-2

SD

21.3

2.33

24.2

38

38

38

0

2.33

25.2

25.2

1.8

Total

6565

319

83

34

33

34503

0

319319

63

63

110236

1123

Weight

5.5%5.5%

25.9%

6.7%

4.7%

4.6%

4.7%46.6%

25.5%25.5%

6.8%

6.7%

8.8%22.3%

100.0%

IV, Random, 95% CI

-0.22 [-0.56, 0.11]-0.22 [-0.56, 0.11]

-0.33 [-0.48, -0.17]

-0.24 [-0.54, 0.07]

-0.30 [-0.66, 0.07]

-0.25 [-0.62, 0.12]

-0.41 [-0.77, -0.04]-0.31 [-0.43, -0.20]

Not estimable

-0.32 [-0.48, -0.16]-0.32 [-0.48, -0.16]

-0.23 [-0.54, 0.07]

-0.41 [-0.72, -0.11]

-0.05 [-0.32, 0.21]-0.22 [-0.43, -0.01]

-0.29 [-0.37, -0.21]

Opioids Placebo Std. Mean Difference Std. Mean Difference

IV, Random, 95% CI

-4 -2 0 2 4Favours opioids Favours placebo

Abb. 2: Effektschätzer (Risikodifferenzen) der 50%igen Schmerzreduktion am Behandlungsende

Study or Subgroup

1.2.1 Oxycodone


Total events



1.2.2 Tapentadol

Buynak 2010


Total events



1.2.3 Tramadol


Total events



Total (95% CI)

Total events




Events

76

76

85

0

85

35

35

196

Total

326326

315

0315

107107

748

Events

60

60

60

0

60

36

36

156

Total

317317

317

0317

110110

744

Weight

45.8%45.8%

42.6%

42.6%

11.6%11.6%

100.0%

IV, Random, 95% CI

0.04 [-0.02, 0.11]0.04 [-0.02, 0.11]

0.08 [0.02, 0.15]

Not estimable0.08 [0.02, 0.15]

-0.00 [-0.13, 0.12]-0.00 [-0.13, 0.12]

0.05 [0.01, 0.10]

Opioids Placebo Risk Difference Risk Difference

IV, Random, 95% CI

-0.5 -0.25 0 0.25 0.5Placebo Opioids

Abb. 3: Effektschätzer (Risikodifferenzen) von Berichten über eine starke oder sehr starke globale Besserung am Behandlungsende

Study or Subgroup

1.3.1 Oxycodone


Total events



1.3.2 Tapentadol

Buynak 2010


Total events



1.3.3 Tramadol


Total events



Total (95% CI)

Total events

Heterogeneity: Tau² = 0.02; Chi² = 24.53, df = 2 (P < 0.00001); I² = 92%


Test for subgroup differences: Chi² = 24.53, df = 2 (P < 0.00001), I² = 91.8%

Events

126

126

131

0

131

12

12

269

Total

210210

236

0236

107107

553

Events

80

80

80

0

80

14

14

174

Total

245245

245

0245

110110

600

Weight

33.2%33.2%

33.4%

33.4%

33.4%33.4%

100.0%

IV, Random, 95% CI

0.27 [0.18, 0.36]0.27 [0.18, 0.36]

0.23 [0.14, 0.31]


-0.02 [-0.10, 0.07]-0.02 [-0.10, 0.07]

0.16 [-0.01, 0.34]


IV, Random, 95% CI

-0.5 -0.25 0 0.25 0.5Placebo Opioids

Abb. 4: Effektschätzer (standardisierte Mittelwertdifferenzen) der Verbesserung der körperlichen Funktionsfähigkeit am Behandlungsende

Study or Subgroup

1.4.1 Buprenorphine




1.4.6 Oxycodone

Buynak 2010

Cloutier 2013Subtotal (95% CI)



1.4.8 Tapentadol

Buynak 2010




1.4.9 Tramadol

Vorsanger 2008

Vorsanger 2008Subtotal (95% CI)



Total (95% CI)




Mean

48.6

4.3

34.3

4.1

0

8.5

8.2

SD

20.7

2.76

15.6

2.77

0

5.9

5.5

Total

7373

323

54377

314

0314

129

127256

1020

Mean

51.6

4.8

37.5

4.8

0

9.8

9.8

SD

22.5

2.79

15.2

2.79

0

5.9

5.9

Total

6565

315

54369

315

0315

63

63126

875

Weight

7.5%7.5%

34.5%

5.8%40.4%

33.9%

33.9%

9.2%

9.1%18.2%

100.0%

IV, Random, 95% CI

-0.14 [-0.47, 0.20]-0.14 [-0.47, 0.20]

-0.18 [-0.34, -0.02]

-0.21 [-0.58, 0.17]-0.18 [-0.33, -0.04]

-0.25 [-0.41, -0.09]

Not estimable-0.25 [-0.41, -0.09]

-0.22 [-0.52, 0.08]

-0.28 [-0.59, 0.02]-0.25 [-0.47, -0.04]

-0.22 [-0.31, -0.12]


IV, Random, 95% CI

-4 -2 0 2 4Opioids Placebo

Abb. 5: Effektschätzer (Risikodifferenzen) der Abbruchraten wegen fehlender Wirksamkeit im Studienverlauf

Study or Subgroup

1.8.1 Oxycodone

Buynak 2010

Vondrackova 2008

Vondrackova 2008

Webster 2006

Webster 2006


Total events



1.8.2 Tapentadol


Total events



1.8.3 Tramadol

Vorsanger 2008

Vorsanger 2008


Total events



Total (95% CI)

Total events




Events

9

4

5

22

15

19

74

18

18

11

13

1

25

117

Total

328

154

151

206

206

2061251

318318

129

128

107364

1933

Events

66

3

3

13

13

14

112

66

66

11

10

2

23

201

Total

319

79

79

33

33

34577

319319

115

114

110339

1235

Weight

11.8%

11.8%

11.7%

6.4%

6.4%

6.4%54.5%

11.7%11.7%

10.8%

10.7%

12.3%33.9%

100.0%

IV, Random, 95% CI

-0.18 [-0.23, -0.13]

-0.01 [-0.06, 0.04]

-0.00 [-0.06, 0.05]

-0.29 [-0.46, -0.12]

-0.32 [-0.49, -0.15]

-0.32 [-0.49, -0.15]-0.16 [-0.27, -0.06]

-0.15 [-0.20, -0.10]-0.15 [-0.20, -0.10]

-0.01 [-0.08, 0.06]

0.01 [-0.06, 0.09]

-0.01 [-0.04, 0.02]-0.01 [-0.03, 0.02]

-0.10 [-0.16, -0.04]


IV, Random, 95% CI

-1 -0.5 0 0.5 1Favours placebo Favours opioid

Abb. 6: Effektschätzer (Risikodifferenzen) der Abbruchraten wegen unerwünschter Ereignisse im Studienverlauf

Study or Subgroup

1.5.1 Buprenorphine


Total events



1.5.5 Oxycodone

Buynak 2010

Cloutier 2013

Webster 2006

Webster 2006


Total events



1.5.7 Tapentadol

Buynak 2010


Total events



1.5.8 Tramadol

Vorsanger 2008

Vorsanger 2008


Total events



Total (95% CI)

Total events



Test for subgroup differences: Chi² = 6.95, df = 3 (P = 0.07), I² = 56.8%

Events

18

18

107

6

49

45

63

270

51

0

51

13

13

14

40

379

Total

7373

328

83

206

206

2061029

318

0318

128

129

107364

1784

Events

5

5

15

5

2

2

1

25

15

0

15

9

9

4

22

67

Total

6565

319

83

34

34

33503

319

0319

64

65

110239

1126

Weight

8.8%8.8%

10.9%

10.4%

9.6%

9.6%

10.0%50.5%

11.2%

11.2%

9.5%

9.6%

10.4%29.5%

100.0%

IV, Random, 95% CI

0.17 [0.05, 0.29]0.17 [0.05, 0.29]

0.28 [0.22, 0.33]

0.01 [-0.06, 0.09]

0.18 [0.08, 0.28]

0.16 [0.06, 0.26]

0.28 [0.19, 0.36]0.18 [0.08, 0.29]

0.11 [0.07, 0.16]


-0.04 [-0.14, 0.06]

-0.04 [-0.14, 0.06]

0.09 [0.02, 0.17]0.01 [-0.08, 0.11]

0.12 [0.05, 0.19]


IV, Random, 95% CI

-0.5-0.25 0 0.25 0.5Placebo Opioid

Abb. 7: Effektschätzer (Risikodifferenzen) schwerer unerwünschter Ereignisse im Studienverlauf

Study or Subgroup

1.6.1 Buprenorphine


Total events



1.6.4 Oxycodone

Buynak 2010

Cloutier 2013

Webster 2006

Webster 2006


Total events



1.6.5 Tapentadol

Buynak 2010


Total events



1.6.6 Tramadol


Total events



Total (95% CI)

Total events




Events

1

1

11

2

0

0

0

13

7

0

7

0

0

21

Total

7373

328

74

206

206

2061020

318

0318

107107

1518

Events

0

0

3

2

0

0

0

5

3

0

3

0

0

8

Total

6565

319

77

33

34

34497

319

0319

110110

991

Weight

6.3%6.3%

18.9%

3.5%

5.5%

5.8%

5.8%39.6%

24.9%

24.9%

29.1%29.1%

100.0%

M-H, Random, 95% CI

0.01 [-0.02, 0.05]0.01 [-0.02, 0.05]

0.02 [0.00, 0.05]

0.00 [-0.05, 0.05]

0.00 [-0.04, 0.04]

0.00 [-0.04, 0.04]

0.00 [-0.04, 0.04]0.01 [-0.00, 0.03]

0.01 [-0.01, 0.03]

Not estimable0.01 [-0.01, 0.03]

0.00 [-0.02, 0.02]0.00 [-0.02, 0.02]

0.01 [-0.00, 0.02]


M-H, Random, 95% CI

-0.5 -0.25 0 0.25 0.5Favours placebo Favours opioid

Forest Plots der standardisierten Mittelwertdifferenzen und Risikoreduktionen von Opioiden im Vergleich zu Placebo für

ausgewählte Endpunkte

"Enriched enrollment randomized withdrawal design" Abb. 8: Effektschätzer (standardisierte Mittelwertdifferenzen) der durchschnittlichen Reduktion der Schmerzintensität am Behandlungsende

Study or Subgroup

2.2.1 Buprenorphine

Steiner 2011Subtotal (95% CI)



2.2.2 Hydromorphone

Hale 2010Subtotal (95% CI)



2.2.5 Oxymorphone

Hale 2007

Katz 2007Subtotal (95% CI)



Total (95% CI)




Mean

3.81

3.2

8.7

29.5

SD

2.8

0.2

25.4

26.24

Total

356356

134134

70

105175

665

Mean

4.39

3.6

31.6

45.5

SD

2.8

0.4

24.6

26.91

Total

283283

134134

72

100172

589

Weight

26.2%26.2%

25.1%25.1%

23.9%

24.8%48.8%

100.0%

IV, Random, 95% CI

-0.21 [-0.36, -0.05]-0.21 [-0.36, -0.05]

-1.26 [-1.52, -1.00]-1.26 [-1.52, -1.00]

-0.91 [-1.26, -0.57]

-0.60 [-0.88, -0.32]-0.74 [-1.04, -0.44]

-0.74 [-1.25, -0.22]

Opioid Placebo Std. Mean Difference Std. Mean Difference

IV, Random, 95% CI

-4 -2 0 2 4Opioid Placebo

Abb. 9: Effektschätzer (Risikodifferenzen) der 50%igen Schmerzreduktion am Behandlungsende

Study or Subgroup

2.4.1 Buprenorphine


Total events



2.4.2 Hydromorphone


Total events



2.4.4 Oxymorphone


Total events



Total (95% CI)

Total events




Events

113

113

56

56

61

61

230

Total

256256

134134

7171

461

Events

102

102

32

32

26

26

160

Total

283283

134134

4747

464

Weight

39.9%39.9%

34.6%34.6%

25.5%25.5%

100.0%

IV, Random, 95% CI

0.08 [-0.00, 0.16]0.08 [-0.00, 0.16]

0.18 [0.07, 0.29]0.18 [0.07, 0.29]

0.31 [0.14, 0.47]0.31 [0.14, 0.47]

0.17 [0.05, 0.29]

Opioid Placebo Risk Difference Risk Difference

IV, Random, 95% CI


Abb. 10: Effektschätzer (Risikodifferenzen) von Berichten über eine starke oder sehr starke globale Besserung am Behandlungsende

Study or Subgroup

2.6.2 Buprenorphine


Total events



Total (95% CI)

Total events



Test for subgroup differences: Not applicable

Events

61

61

61

Total

237237

237

Events

42

42

42

Total

261261

261

Weight

100.0%100.0%

100.0%

IV, Random, 95% CI

0.10 [0.03, 0.17]0.10 [0.03, 0.17]

0.10 [0.03, 0.17]


IV, Random, 95% CI

-0.5 -0.25 0 0.25 0.5Placebo Opioid

Abb. 11: Effektschätzer (standardisierte Mittelwertdifferenzen) der Verbesserung der körperlichen Funktionsfähigkeit am Behandlungsende

Study or Subgroup

2.7.2 Tapentadol




2.7.3 Tramadol

Schnitzer 2000Subtotal (95% CI)



Total (95% CI)




Mean

-46

8.8

SD

16.9

6.2

Total

287287

127127

414

Mean

-42

10.2

SD

16.9

6.2

Total

284284

127127

411

Weight

69.2%69.2%

30.8%30.8%

100.0%

IV, Random, 95% CI

-0.24 [-0.40, -0.07]-0.24 [-0.40, -0.07]

-0.23 [-0.47, 0.02]-0.23 [-0.47, 0.02]

-0.23 [-0.37, -0.10]


IV, Random, 95% CI


Abb. 12: Effektschätzer (Risikodifferenzen) der Abbruchraten wegen fehlender Wirksamkeit im Studienverlauf

Study or Subgroup

2.5.1 Buprenorphine


Total events



2.5.2 Hydromorphone


Total events



2.5.3 Oxymorphone

Hale 2007


Total events



2.5.4 Tramadol


Total events



Total (95% CI)

Total events




Events

22

22

16

16

8

12

20

25

25

83

Total

256256

134134

70

105175

127127

692

Events

36

36

40

40

39

35

74

61

61

211

Total

283283

134134

73

100173

127127

717

Weight

22.0%22.0%

20.4%20.4%

18.4%

19.6%38.0%

19.6%19.6%

100.0%

IV, Random, 95% CI

-0.04 [-0.09, 0.01]-0.04 [-0.09, 0.01]

-0.18 [-0.27, -0.08]-0.18 [-0.27, -0.08]

-0.42 [-0.56, -0.28]

-0.24 [-0.35, -0.12]-0.32 [-0.50, -0.14]

-0.28 [-0.39, -0.17]-0.28 [-0.39, -0.17]

-0.22 [-0.36, -0.09]


IV, Random, 95% CI


Abb. 13: Effektschätzer (Risikodifferenzen) der Abbruchraten wegen unerwünschter Ereignisse im Studienverlauf

Study or Subgroup

2.8.1 Buprenorphine


Total events



2.8.2 Hydromorphone


Total events



2.8.4 Oxycodone

Vondrackova 2008

Vondrackova 2008Subtotal (95% CI)

Total events



2.8.5 Oxymorphone

Hale 2007


Total events



2.8.6 Tramadol


Total events



Total (95% CI)

Total events




Events

40

40

9

9

6

6

12

7

9

16

5

5

82

Total

256256

134134

154

151305

70

105175

127127

997

Events

20

20

4

4

7

6

13

8

8

16

6

6

59

Total

283283

134134

79

79158

73

100173

127127

875

Weight

16.7%16.7%

17.2%17.2%

13.4%

14.1%27.5%

8.8%

12.4%21.2%

17.5%17.5%

100.0%

IV, Random, 95% CI

0.09 [0.03, 0.14]0.09 [0.03, 0.14]

0.04 [-0.01, 0.09]0.04 [-0.01, 0.09]

-0.05 [-0.12, 0.02]

-0.04 [-0.10, 0.03]-0.04 [-0.09, 0.01]

-0.01 [-0.11, 0.09]

0.01 [-0.07, 0.08]0.00 [-0.06, 0.06]

-0.01 [-0.06, 0.04]-0.01 [-0.06, 0.04]

0.01 [-0.03, 0.04]


IV, Random, 95% CI

-0.5 -0.25 0 0.25 0.5Placebo Opioid

Abb. 14: Effektschätzer (Risikodifferenzen) schwerer unerwünschter Ereignisse im Studienverlauf

Study or Subgroup

2.9.1 Buprenorphine


Total events



2.9.2 Hydromorphone


Total events



2.9.4 Oxycodone

Vondrackova 2008


Total events



2.9.5 Oxymorphone

Hale 2007


Total events



2.9.7 Tramadol


Total events



Total (95% CI)

Total events




Events

3

3

6

6

0

1

1

2

2

4

4

4

18

Total

256256

134134

151

158309

70

105175

127127

1001

Events

2

2

4

4

2

2

4

0

3

3

0

0

13

Total

283283

134134

79

79158

72

100172

127127

874

Weight

34.0%34.0%

9.0%9.0%

11.4%

12.6%24.0%

8.5%

10.0%18.5%

14.5%14.5%

100.0%

IV, Random, 95% CI

0.00 [-0.01, 0.02]0.00 [-0.01, 0.02]

0.01 [-0.03, 0.06]0.01 [-0.03, 0.06]

-0.03 [-0.06, 0.01]

-0.02 [-0.06, 0.02]-0.02 [-0.05, 0.00]

0.03 [-0.02, 0.08]

-0.01 [-0.05, 0.03]0.01 [-0.03, 0.05]

0.03 [-0.00, 0.07]0.03 [-0.00, 0.07]

0.00 [-0.01, 0.02]


IV, Random, 95% CI

-0.5 -0.25 0 0.25 0.5Placebo Opioid

Evidence report: forest plots of standardized mean differences and risk differences for opioids compared to placebo for selected

outcomes

Parallel or cross-over design Supplementary figure 1: Effect estimates (standardized mean differences) of mean pain intensity reduction at end of treatment

Study or Subgroup

1.1.1 Buprenorphine




1.1.6 Oxycodone

Buynak 2010

Cloutier 2013

Webster 2006

Webster 2006




1.1.8 Tapentadol

Buynak 2010




1.1.9 Tramadol

Vorsanger 2008

Vorsanger 2008




Total (95% CI)




Mean

39.2

-2.9

52.2

-42.6

-41.2

-46.2

0

-2.9

34.1

30.5

-2.1

SD

20.5

2.52

23

34.5

35.2

33.6

0

2.66

27.1

23

2

Total

7373

328

83

204

199

2051019

0

318318

129

127

107363

1773

Mean

43.9

-2.1

57.8

-32.2

-32.2

-32.2

0

-2.1

40.3

40.3

-2

SD

21.3

2.33

24.2

38

38

38

0

2.33

25.2

25.2

1.8

Total

6565

319

83

34

33

34503

0

319319

63

63

110236

1123

Weight

5.5%5.5%

25.9%

6.7%

4.7%

4.6%

4.7%46.6%

25.5%25.5%

6.8%

6.7%

8.8%22.3%

100.0%

IV, Random, 95% CI

-0.22 [-0.56, 0.11]-0.22 [-0.56, 0.11]

-0.33 [-0.48, -0.17]

-0.24 [-0.54, 0.07]

-0.30 [-0.66, 0.07]

-0.25 [-0.62, 0.12]

-0.41 [-0.77, -0.04]-0.31 [-0.43, -0.20]

Not estimable

-0.32 [-0.48, -0.16]-0.32 [-0.48, -0.16]

-0.23 [-0.54, 0.07]

-0.41 [-0.72, -0.11]

-0.05 [-0.32, 0.21]-0.22 [-0.43, -0.01]

-0.29 [-0.37, -0.21]


IV, Random, 95% CI

-4 -2 0 2 4Favours opioids Favours placebo

Supplementary figure 2: Effect estimates (risk differences) of 50% pain reduction at end of treatment

Study or Subgroup

1.2.1 Oxycodone


Total events



1.2.2 Tapentadol

Buynak 2010


Total events



1.2.3 Tramadol


Total events



Total (95% CI)

Total events




Events

76

76

85

0

85

35

35

196

Total

326326

315

0315

107107

748

Events

60

60

60

0

60

36

36

156

Total

317317

317

0317

110110

744

Weight

45.8%45.8%

42.6%

42.6%

11.6%11.6%

100.0%

IV, Random, 95% CI

0.04 [-0.02, 0.11]0.04 [-0.02, 0.11]

0.08 [0.02, 0.15]


-0.00 [-0.13, 0.12]-0.00 [-0.13, 0.12]

0.05 [0.01, 0.10]


IV, Random, 95% CI

-0.5 -0.25 0 0.25 0.5Placebo Opioids

Supplementary figure 3: Effect estimates (risk differences) of reports to be much or very much improved at end of treatment

Study or Subgroup

1.3.1 Oxycodone


Total events



1.3.2 Tapentadol

Buynak 2010


Total events



1.3.3 Tramadol


Total events



Total (95% CI)

Total events




Events

126

126

131

0

131

12

12

269

Total

210210

236

0236

107107

553

Events

80

80

80

0

80

14

14

174

Total

245245

245

0245

110110

600

Weight

33.2%33.2%

33.4%

33.4%

33.4%33.4%

100.0%

IV, Random, 95% CI

0.27 [0.18, 0.36]0.27 [0.18, 0.36]

0.23 [0.14, 0.31]


-0.02 [-0.10, 0.07]-0.02 [-0.10, 0.07]

0.16 [-0.01, 0.34]


IV, Random, 95% CI

-0.5 -0.25 0 0.25 0.5Placebo Opioids

Supplementary figure 4: Effect estimates (standardized mean differences) of physical function improvement at end of treatment

Study or Subgroup

1.4.1 Buprenorphine




1.4.6 Oxycodone

Buynak 2010

Cloutier 2013Subtotal (95% CI)



1.4.8 Tapentadol

Buynak 2010




1.4.9 Tramadol

Vorsanger 2008

Vorsanger 2008Subtotal (95% CI)



Total (95% CI)




Mean

48.6

4.3

34.3

4.1

0

8.5

8.2

SD

20.7

2.76

15.6

2.77

0

5.9

5.5

Total

7373

323

54377

314

0314

129

127256

1020

Mean

51.6

4.8

37.5

4.8

0

9.8

9.8

SD

22.5

2.79

15.2

2.79

0

5.9

5.9

Total

6565

315

54369

315

0315

63

63126

875

Weight

7.5%7.5%

34.5%

5.8%40.4%

33.9%

33.9%

9.2%

9.1%18.2%

100.0%

IV, Random, 95% CI

-0.14 [-0.47, 0.20]-0.14 [-0.47, 0.20]

-0.18 [-0.34, -0.02]

-0.21 [-0.58, 0.17]-0.18 [-0.33, -0.04]

-0.25 [-0.41, -0.09]

Not estimable-0.25 [-0.41, -0.09]

-0.22 [-0.52, 0.08]

-0.28 [-0.59, 0.02]-0.25 [-0.47, -0.04]

-0.22 [-0.31, -0.12]


IV, Random, 95% CI

-4 -2 0 2 4Opioids Placebo

Supplementary figure 5: Effect estimates (risk differences) of dropping out due to lack of efficacy during study

Study or Subgroup

1.8.1 Oxycodone

Buynak 2010

Vondrackova 2008

Vondrackova 2008

Webster 2006

Webster 2006


Total events



1.8.2 Tapentadol


Total events



1.8.3 Tramadol

Vorsanger 2008

Vorsanger 2008


Total events



Total (95% CI)

Total events




Events

9

4

5

22

15

19

74

18

18

11

13

1

25

117

Total

328

154

151

206

206

2061251

318318

129

128

107364

1933

Events

66

3

3

13

13

14

112

66

66

11

10

2

23

201

Total

319

79

79

33

33

34577

319319

115

114

110339

1235

Weight

11.8%

11.8%

11.7%

6.4%

6.4%

6.4%54.5%

11.7%11.7%

10.8%

10.7%

12.3%33.9%

100.0%

IV, Random, 95% CI

-0.18 [-0.23, -0.13]

-0.01 [-0.06, 0.04]

-0.00 [-0.06, 0.05]

-0.29 [-0.46, -0.12]

-0.32 [-0.49, -0.15]

-0.32 [-0.49, -0.15]-0.16 [-0.27, -0.06]

-0.15 [-0.20, -0.10]-0.15 [-0.20, -0.10]

-0.01 [-0.08, 0.06]

0.01 [-0.06, 0.09]

-0.01 [-0.04, 0.02]-0.01 [-0.03, 0.02]

-0.10 [-0.16, -0.04]


IV, Random, 95% CI


Supplementary figure 6: Effect estimates (risk differences) of dropping out due to adverse events during study

Study or Subgroup

1.5.1 Buprenorphine


Total events



1.5.5 Oxycodone

Buynak 2010

Cloutier 2013

Webster 2006

Webster 2006


Total events



1.5.7 Tapentadol

Buynak 2010


Total events



1.5.8 Tramadol

Vorsanger 2008

Vorsanger 2008


Total events



Total (95% CI)

Total events




Events

18

18

107

6

49

45

63

270

51

0

51

13

13

14

40

379

Total

7373

328

83

206

206

2061029

318

0318

128

129

107364

1784

Events

5

5

15

5

2

2

1

25

15

0

15

9

9

4

22

67

Total

6565

319

83

34

34

33503

319

0319

64

65

110239

1126

Weight

8.8%8.8%

10.9%

10.4%

9.6%

9.6%

10.0%50.5%

11.2%

11.2%

9.5%

9.6%

10.4%29.5%

100.0%

IV, Random, 95% CI

0.17 [0.05, 0.29]0.17 [0.05, 0.29]

0.28 [0.22, 0.33]

0.01 [-0.06, 0.09]

0.18 [0.08, 0.28]

0.16 [0.06, 0.26]

0.28 [0.19, 0.36]0.18 [0.08, 0.29]

0.11 [0.07, 0.16]


-0.04 [-0.14, 0.06]

-0.04 [-0.14, 0.06]

0.09 [0.02, 0.17]0.01 [-0.08, 0.11]

0.12 [0.05, 0.19]


IV, Random, 95% CI

-0.5-0.25 0 0.25 0.5Placebo Opioid

Supplementary figure 7: Effect estimates (risk differences) of serious adverse events during study

Study or Subgroup

1.6.1 Buprenorphine


Total events



1.6.4 Oxycodone

Buynak 2010

Cloutier 2013

Webster 2006

Webster 2006


Total events



1.6.5 Tapentadol

Buynak 2010


Total events



1.6.6 Tramadol


Total events



Total (95% CI)

Total events




Events

1

1

11

2

0

0

0

13

7

0

7

0

0

21

Total

7373

328

74

206

206

2061020

318

0318

107107

1518

Events

0

0

3

2

0

0

0

5

3

0

3

0

0

8

Total

6565

319

77

33

34

34497

319

0319

110110

991

Weight

6.3%6.3%

18.9%

3.5%

5.5%

5.8%

5.8%39.6%

24.9%

24.9%

29.1%29.1%

100.0%

M-H, Random, 95% CI

0.01 [-0.02, 0.05]0.01 [-0.02, 0.05]

0.02 [0.00, 0.05]

0.00 [-0.05, 0.05]

0.00 [-0.04, 0.04]

0.00 [-0.04, 0.04]

0.00 [-0.04, 0.04]0.01 [-0.00, 0.03]

0.01 [-0.01, 0.03]

Not estimable0.01 [-0.01, 0.03]

0.00 [-0.02, 0.02]0.00 [-0.02, 0.02]

0.01 [-0.00, 0.02]


M-H, Random, 95% CI


Forest plots of standardized mean differences and risk differences for opioids compared to placebo for selected outcomes

Enriched enrolment randomized withdrawal design

Supplementary figure 8: Effect estimates (standardized mean differences) of mean pain intensity reduction at end of treatment

Study or Subgroup

2.2.1 Buprenorphine




2.2.2 Hydromorphone




2.2.5 Oxymorphone

Hale 2007




Total (95% CI)




Mean

3.81

3.2

8.7

29.5

SD

2.8

0.2

25.4

26.24

Total

356356

134134

70

105175

665

Mean

4.39

3.6

31.6

45.5

SD

2.8

0.4

24.6

26.91

Total

283283

134134

72

100172

589

Weight

26.2%26.2%

25.1%25.1%

23.9%

24.8%48.8%

100.0%

IV, Random, 95% CI

-0.21 [-0.36, -0.05]-0.21 [-0.36, -0.05]

-1.26 [-1.52, -1.00]-1.26 [-1.52, -1.00]

-0.91 [-1.26, -0.57]

-0.60 [-0.88, -0.32]-0.74 [-1.04, -0.44]

-0.74 [-1.25, -0.22]


IV, Random, 95% CI


Supplementary figure 9: Effect estimates (risk differences) of 50% pain reduction at end of treatment

Study or Subgroup

2.4.1 Buprenorphine


Total events



2.4.2 Hydromorphone


Total events



2.4.4 Oxymorphone


Total events



Total (95% CI)

Total events




Events

113

113

56

56

61

61

230

Total

256256

134134

7171

461

Events

102

102

32

32

26

26

160

Total

283283

134134

4747

464

Weight

39.9%39.9%

34.6%34.6%

25.5%25.5%

100.0%

IV, Random, 95% CI

0.08 [-0.00, 0.16]0.08 [-0.00, 0.16]

0.18 [0.07, 0.29]0.18 [0.07, 0.29]

0.31 [0.14, 0.47]0.31 [0.14, 0.47]

0.17 [0.05, 0.29]


IV, Random, 95% CI


Supplementary figure 10: Effect estimates (risk differences) of reports of pain to be much or very much improved at end of treatment

Study or Subgroup

2.6.2 Buprenorphine


Total events



Total (95% CI)

Total events



Test for subgroup differences: Not applicable

Events

61

61

61

Total

237237

237

Events

42

42

42

Total

261261

261

Weight

100.0%100.0%

100.0%

IV, Random, 95% CI

0.10 [0.03, 0.17]0.10 [0.03, 0.17]

0.10 [0.03, 0.17]


IV, Random, 95% CI

-0.5 -0.25 0 0.25 0.5Placebo Opioid

Supplementary figure 11: Effect estimates (standardized mean differences) of physical function improvement at end of treatment

Study or Subgroup

2.7.2 Tapentadol




2.7.3 Tramadol




Total (95% CI)




Mean

-46

8.8

SD

16.9

6.2

Total

287287

127127

414

Mean

-42

10.2

SD

16.9

6.2

Total

284284

127127

411

Weight

69.2%69.2%

30.8%30.8%

100.0%

IV, Random, 95% CI

-0.24 [-0.40, -0.07]-0.24 [-0.40, -0.07]

-0.23 [-0.47, 0.02]-0.23 [-0.47, 0.02]

-0.23 [-0.37, -0.10]


IV, Random, 95% CI


Supplementary figure 12: Effect estimates (risk differences) of dropping out due to lack of efficacy during study

Study or Subgroup

2.5.1 Buprenorphine


Total events



2.5.2 Hydromorphone


Total events



2.5.3 Oxymorphone

Hale 2007


Total events



2.5.4 Tramadol


Total events



Total (95% CI)

Total events




Events

22

22

16

16

8

12

20

25

25

83

Total

256256

134134

70

105175

127127

692

Events

36

36

40

40

39

35

74

61

61

211

Total

283283

134134

73

100173

127127

717

Weight

22.0%22.0%

20.4%20.4%

18.4%

19.6%38.0%

19.6%19.6%

100.0%

IV, Random, 95% CI

-0.04 [-0.09, 0.01]-0.04 [-0.09, 0.01]

-0.18 [-0.27, -0.08]-0.18 [-0.27, -0.08]

-0.42 [-0.56, -0.28]

-0.24 [-0.35, -0.12]-0.32 [-0.50, -0.14]

-0.28 [-0.39, -0.17]-0.28 [-0.39, -0.17]

-0.22 [-0.36, -0.09]


IV, Random, 95% CI


Supplementary figure 13: Effect estimates (risk differences) of dropping out due to adverse events during study

Study or Subgroup

2.8.1 Buprenorphine


Total events



2.8.2 Hydromorphone


Total events



2.8.4 Oxycodone

Vondrackova 2008


Total events



2.8.5 Oxymorphone

Hale 2007


Total events



2.8.6 Tramadol


Total events



Total (95% CI)

Total events




Events

40

40

9

9

6

6

12

7

9

16

5

5

82

Total

256256

134134

154

151305

70

105175

127127

997

Events

20

20

4

4

7

6

13

8

8

16

6

6

59

Total

283283

134134

79

79158

73

100173

127127

875

Weight

16.7%16.7%

17.2%17.2%

13.4%

14.1%27.5%

8.8%

12.4%21.2%

17.5%17.5%

100.0%

IV, Random, 95% CI

0.09 [0.03, 0.14]0.09 [0.03, 0.14]

0.04 [-0.01, 0.09]0.04 [-0.01, 0.09]

-0.05 [-0.12, 0.02]

-0.04 [-0.10, 0.03]-0.04 [-0.09, 0.01]

-0.01 [-0.11, 0.09]

0.01 [-0.07, 0.08]0.00 [-0.06, 0.06]

-0.01 [-0.06, 0.04]-0.01 [-0.06, 0.04]

0.01 [-0.03, 0.04]


IV, Random, 95% CI

-0.5 -0.25 0 0.25 0.5Placebo Opioid

Supplementary figure 14: Effect estimates (risk differences) of serious adverse events during study

Study or Subgroup

2.9.1 Buprenorphine


Total events



2.9.2 Hydromorphone


Total events



2.9.4 Oxycodone

Vondrackova 2008


Total events



2.9.5 Oxymorphone

Hale 2007


Total events



2.9.7 Tramadol


Total events



Total (95% CI)

Total events




Events

3

3

6

6

0

1

1

2

2

4

4

4

18

Total

256256

134134

151

158309

70

105175

127127

1001

Events

2

2

4

4

2

2

4

0

3

3

0

0

13

Total

283283

134134

79

79158

72

100172

127127

874

Weight

34.0%34.0%

9.0%9.0%

11.4%

12.6%24.0%

8.5%

10.0%18.5%

14.5%14.5%

100.0%

IV, Random, 95% CI

0.00 [-0.01, 0.02]0.00 [-0.01, 0.02]

0.01 [-0.03, 0.06]0.01 [-0.03, 0.06]

-0.03 [-0.06, 0.01]

-0.02 [-0.06, 0.02]-0.02 [-0.05, 0.00]

0.03 [-0.02, 0.08]

-0.01 [-0.05, 0.03]0.01 [-0.03, 0.05]

0.03 [-0.00, 0.07]0.03 [-0.00, 0.07]

0.00 [-0.01, 0.02]


IV, Random, 95% CI

-0.5 -0.25 0 0.25 0.5Placebo Opioid

Electronic Supplementary Material, Tabelle 1: Eigenschaften der eingeschlossenen

Studien

Buynak 2010

Methoden Erkrankung: Kreuzschmerz

Studienorte: 85 Zentren in den USA, 15 in Kanada, 3 in Australien

Studiendesign: Parallel

Studiendauer: 3-wöchige Titration, 12-wöchige Erhaltung

Teilnehmer Einschlusskriterien: Alter ≥18 Jahre; Männer und nichtschwangere, nichtstillende Frauen mit diagnostiziertem, mindestens 3 Monate bestehendem Kreuzschmerz nichtmaligner Ursache; Patienten, die vor dem Screening seit mindestens 3 Monaten Analgetika eingenommen hatten und mit der aktuellen Therapie unzufrieden waren; Patienten mit erforderlicher Opioidtherapie mussten opioidbasierte Analgetika in Tagesdosen äquivalent zu <160 mg oralem Morphin einnehmen; Ausgangswert von ≥5 auf einer 11-stufigen numerischen Rating-Skala (NRS), berechnet als durchschnittliche Schmerzintensität während der letzten 3 Tage vor Randomisierung

Ausschlusskriterien: Alkohol- und/oder Drogenabusus in der Anamnese nach Ermessen des Untersuchers; relevante Leberinsuffizienz in der Anamnese; chronische Hepatitis B/C oder HIV, aktive Hepatitis B/C innerhalb der vorausgegangenen 3 Monate; Anfallsleiden oder Epilepsie in der lebenslangen Anamnese; unkontrollierte Hypertonie; stark eingeschränkte Nierenfunktion; mäßig bis schwer eingeschränkte Leberfunktion oder mit Laborwerten, die eine ungenügende Leberfunktion anzeigen; klinisch relevante psychiatrische Erkrankung; Behandlung mit Neuroleptika, Monoaminoxidase(MAO)-Hemmern, Serotonin-Noradrenalin-Wiederaufnahmehemmern (SNRI), trizyklischen Antidepressiva (TCA), Antikonvulsiva oder Anti-Parkinson-Mitteln; jegliche analgetische Therapie, die nicht der untersuchten Medikation oder Bedarfsmedikation während der Studie

entsprach

Gesamtstichprobe: n=987; Durchschnittsalter 62,1 Jahre; 60,4% weiblich; 99,3% weiß; Schmerzausgangswert, Tapentadol 7,6±1,33; Schmerzausgangswert Oxycodon 7,5±1,21; Schmerzausgangswert Tapentadol 7,6±1,33

Interventionen Studienmedikation: Tapentadol, 200–500 mg/Tag (Durchschnittsdosis 393±117 mg/Tag); Oxycodon, 40–100 mg/Tag (Durchschnittsdosis 53±23 mg/Tag); Placebo

Bedarfsmedikation: Paracetamol (bis zu 1 g/Tag an 3 aufeinanderfolgenden Tagen)

Zulässige Kotherapien: Transkutane elektrische Nervenstimulation (TENS), Akupunktur, physikalische Therapie, Packungen, Massagen und andere interventionelle Begleittherapien waren während der Studie erlaubt, soweit die Patienten die Behandlungen ≥14 Tage vor Studieneinschluss begonnen hatten und während der Studie nach demselben Regime fortführten. Selektive Serotoninwiederaufnahmehemmer (SSRI) oder andere Antidepressiva (nicht NSRI, MAO-Hemmer oder TCA), soweit seit >3 Wochen konstant

Endpunkte Schmerz: Durchschnittliche Schmerzintensität während der vorausgegangenen 12 h (NRS 0–10)

Responder: 50%ige Schmerzreduktion auf NRS (0–10)

PGIC: Stark oder sehr stark verbessert

Funktion: SF-36, körperliche Funktionsfähigkeit, nur Angaben zu LSMD vs. Placebo (Daten für Metaanalyse extrahiert aus Arbeit von Chaparro)

Behandlungsabbruch wegen fehlender Wirksamkeit: Angegeben

Behandlungsabbruch wegen unerwünschter Ereignisse: Angegeben

Schwere unerwünschte Ereignisse: Angegeben

Todesfälle: Angegeben

PGIC Patient Global Impression of Change

Cloutier 2013


Studienorte: 6 Zentren in Kanada

Studiendesign: Cross-over

Studiendauer: 2- bis 7-tägige Auswaschung, 4 Wochen in jeder Phase

Teilnehmer Einschlusskriterien: Erwachsene Patienten (>18 Jahre) mit Kreuzschmerz von mäßiger oder starker Intensität in den zurückliegenden 3 Monaten oder länger

Ausschlusskriterien: Andere kürzlich erfolgte oder bald beginnende Behandlung (Physiotherapie, Kortikosteroidinjektion, operativer Eingriff); Bedarf von >12 Tabletten 300/30 mg Paracetamol/Codein; Schmerz mit erwartbarer Resistenz gegenüber einer kontinuierlichen Opioidtherapie; neben Kreuzschmerz relevante andere Schmerzquelle; Erhöhung der Leberenzyme auf mehr als das 2-Fache des oberen Grenzwerts oder beeinträchtigte Nierenfunktion; korrigiertes QT-Intervall >450 ms; bekannte schwere Organdysfunktion; chronisch-obstruktive Lungenerkrankung; Magengeschwür; chronisch-entzündliche Darmerkrankung; psychische Abhängigkeit von Narkotika; schwere psychiatrische Störung, z. B. schwere Depression; somatoformer Schmerz; Rechtsstreit im Zusammenhang mit Schmerz

Gesamtstichprobe: n=54 (nach Protokoll); Durchschnittsalter 50,6 Jahre; 50% weiblich; 94,4% weiß; Schmerzausgangswert 61,4±10,3

Interventionen Studienmedikation: Oxycodon/Naloxon flexibel 40/20 mg/Tag, 60/30 mg/Tag oder 80/40 mg/Tag (Durchschnittsdosis 73/36 mg/Tag); Placebo

Bedarfsmedikation: Paracetamol/Codein 300/30 mg bis zu 6-mal pro Tag

Zulässige Kotherapien: Antidepressiva oder Antikonvulsiva in konstanten Dosen

Endpunkte Schmerz: Durchschnittliche Schmerzintensität

auf visueller Analogskala (VAS; 0–100)

Responder: Für 50%ige Schmerzreduktion keine Raten angegeben

PGIC: Durchschnittswerte, aber keine Zahl der Patienten mit starker oder sehr starker Verbesserung angegeben

Funktion: Pain Disability Index (0–70)

Behandlungsabbruch wegen fehlender Wirksamkeit: Nicht angegeben


Schwere unerwünschte Ereignisse: Keine Angaben

Todesfälle: Nicht explizit angegeben

Anmerkungen "Weder in der Per-protocol- noch in der Intention-to-treat(ITT)-Population gab es Anzeichen für einen Überhangeffekt (p=0,70 und p=0,62)."

Gordon 2010


Studienorte: USA und Kanada, Zahl der Zentren nicht angegeben

Studiendesign: Cross-over

Studiendauer: 2- bis 7-tägige Auswaschung; jeweils 4 Wochen Die Initialdosis von Buprenorphin (10 μg/h) wurde mit 10- und 20-μg/h-Pflastern wöchentlich titriert auf 20 μg/h und ein Maximum von 40 μg/h, basierend auf der Schmerzlinderung und unerwünschten Ereignissen.

Teilnehmer Einschlusskriterien: Eingeschlossen wurden Männer und nichtschwangere Frauen >18 Jahre mit zumindest mäßig starkem Kreuzschmerz (Wert 2 auf einer ordinalen 5-Punkte-Skala) seit >6 Wochen, der mit Nichtopioiden unzureichend behandelt war.

Ausschlusskriterien: Ein erwarteter Analgetikabedarf, der die maximale Dosis von transdermalem Buprenorphin überstieg, Refraktärität auf Opioidtherapie oder eine Allergie auf Paracetamol bzw. Opioide führten zum Auschluss. Patienten, die einer Prozedur oder Behandlung mit wahrscheinlichem Einfluss auf den Schmerz unterzogen wurden (z. B. Physiotherapie oder operativer Eingriff), und Patienten mit relevanter anderer Schmerzquelle wurden ebenso ausgeschlossen wie solche, die den Gebrauch externer Wärmequellen benötigen würden. Zu den weiteren Ausschlusskriterien zählten erhöhte Werte in Leberfunktionstests, schwere Organfunktionsstörungen, Kopfverletzungen oder Anfälle, chronisch-obstruktive Lungenerkrankung, Asthma, Atemdepression, Cor pulmonale, Herzinsuffizienz, Magengeschwüre und Entzündung des Magen-Darm-Trakts. Ausgeschlossen wurden auch Patienten mit vermuteter psychischer Abhängigkeit von Narkotika oder Alkohol oder mit schweren psychiatrischen Erkrankungen in der Anamnese.

Gesamt: n=79; Durchschnittsalter 54,5 Jahre;

47% weiblich; keine Angaben zur ethnischen Herkunft; Schmerzausgangswert 61,4±16,4

Interventionen Studienmedikation: Titration auf individuelle optimale Dosis von Buprenorphin, 5, 10 oder 20 μg/h (durchschnittliche Tagesdosis 14,3±6,3 μg/h); Placebo

Bedarfsmedikation: Codein 30 mg/Paracetamol 300 mg, 1–2 Tabletten alle 4–6 h nach Bedarf

Zulässige Kotherapien: Acetylsalicylsäure zur antithrombotischen Therapie in einer Dosis von ≥325 mg/Tag erlaubt

Endpunkte Schmerz: Durchschnittliche Schmerzintensität auf NRS (0–100), Tagebuch


PGIC: Nicht ermittelt

Funktion: Pain Disability Index (Daten in Abbildungen angegeben; Mittelwerte und Standardabweichungen wie von Chaparro berichtet)

Behandlungsabbruch wegen fehlender Wirksamkeit: Nicht angegeben




Anmerkungen In keiner Population gab es Hinweise auf einen Überhangeffekt (p=0,81 für ITT-Population).

Hale 2007


Studienorte: 30 Zentren in den USA

Studiendesign: "Enriched enrollment randomized withdrawal design"

Studiendauer: Dauer des Screenings und der Auswaschung nicht angegeben, Dauer der offenen Titration nicht angegeben.

12-wöchige doppelblinde Absetzphase

Teilnehmer Einschlusskriterien: Patienten ≥18 Jahre mit mäßigem bis schwerem chronischem Kreuzschmerz, täglich zumindest mehrere Stunden über mindestens 3 Monate. Die Patienten mussten in den 2 Wochen vor dem Screening zur Behandlung des Kreuzschmerzes eine konstante 24-h-Opioidmedikation erhalten haben, äquivalent zu ≥60 mg/Tag oralem Morphin. Prämenopausale Frauen mussten eine angemessene Verhütungsmethode einsetzen.

Ausschlusskriterien: Schwangere oder stillende Frauen waren nicht für die Teilnahme geeignet. Ausgeschlossen wurden auch Patienten mit Radikulopathie, Fibromyalgie, sympathischer Reflexdystrophie oder Kausalgie, akuter Rückenmarkkompression, Cauda-equina-Kompression, akuter Nervenwurzelkompression, ausgeprägter Schwäche oder Taubheit in den unteren Extremitäten, sekundärer Darm- oder Blasenfunktionsstörung wegen Cauda-equina-Kompression, diabetischer Amyotrophie, Meningitis, Diszitis oder mit Rückenschmerz, der durch eine sekundäre Infektion oder einen Tumor hervorgerufen wurde. Weitere Ausschlusskriterien waren ein chirurgischer Eingriff zur Therapie des Rückenschmerzes innerhalb von 6 Monaten vor dem Screening, Schmerzen aufgrund eines bestätigten oder vermuteten Tumors, Dysphagie oder Schwierigkeiten beim Schlucken von Tabletten, eine frühere Einnahme von Oxymorphon, Überempfindlichkeit gegenüber Opioidanalgetika, Anfälle in der Anamnese sowie Ileo- oder

Kolostomie.

Placebo: n=72; Durchschnittsalter 46 Jahre; 33,3% weiblich; 88,9% weiß; Schmerzausgangswert 71,9±15,4

Oxymorphon n=70; Durchschnittsalter 48,2 Jahre; 72% weiblich; 84,3% weiß; Schmerzausgangswert 67,6±16,8

Interventionen Studienmedikation: Oxymorphon flexibel vs. Placebo. Die Patienten erhielten zu Beginn 2-mal täglich Oxymorphon, ungefähr äquivalent zur Opioidanalgetikadosis, die sie zum Zeitpunkt des Screenings eingenommen hatten. Auf der Grundlage vordefinierter Relationen und klinischer Erfahrung stellten die Untersucher die Patienten von der vorherigen Opioidtherapie auf OPANA ER um. Bewirkte die Initialdosis keine ausreichende Schmerzlinderung, wurde mit Erhöhungen von 10 mg (2-mal täglich) alle 3–7 Tage auftitriert, bis eine konstante Dosis erreicht war. Die konstante Tagesdosis war definiert durch ihre Verträglichkeit und eine Verringerung der durchschnittlichen Schmerzintensität auf 40 mm (100-mm-VAS; 0= kein Schmerz bis 100= schwerster vorstellbarer Schmerz) an 3 von 5 aufeinanderfolgenden Tagen mit ≤2 Dosen Oxymorphon pro Tag als ergänzende Analgesie. In der Titrationsphase stand den Patienten Oxymorphon (5 mg alle 4–6 h nach Bedarf) für die Behandlung von Durchbruchschmerzen zur Verfügung. Alle stabilisierten Patienten wurden in eine Gruppe mit Fortsetzung der konstanten Dosierung (durchschnittliche Dosis 87 mg/Tag) oder in eine Placebogruppe randomisiert.

Bedarfsmedikation: Kurz wirksame nichtsteroidale Antirheumatika (NSAR) oder andere ergänzende Analgetika durften nicht zur Therapie von Schmerzen eingesetzt werden, die Behandlung anderer Symptome war aber erlaubt (z. B. kardiovaskuläre Prophylaxe oder Fieber).

Zulässige Kotherapien: Die Patienten mussten zustimmen, während der Studie zusätzliche Therapien unverändert fortzuführen (z. B. physikalische Therapie, Biofeedback, Akupunktur, pflanzliche Heilmittel) und auf jegliche lokal-regionalen Schmerzbehandlungen zu verzichten, die sie vor Studieneinschluss

wegen des Kreuzschmerzes erhalten hatten.

Endpunkte Schmerz: Änderung der durchschnittlichen Schmerzintensität in der letzten Studienvisite gegenüber dem Ausgangswert (VAS 0–100)



Funktion: Nicht ermittelt





Anmerkungen

Hale 2010




Studiendauer: 2–4 Wochen offen, 12 Wochen doppelblinde Absetzphase

Teilnehmer Einschlusskriterien:

1. Die Patienten mussten vor Beginn der Studienbehandlung schriftlich in die Teilnahme eingewilligt haben und wissen, dass sie die Studie jederzeit abbrechen konnten.

2. Patienten, die sprechen, lesen und schreiben konnten und Englisch verstanden. Sie mussten die Einwilligungserklärung lesen und verstehen, mit der Studie zusammenhängende Prozeduren durchführen und mit dem Studienpersonal kommunizieren können.

3. Patientinnen und Patienten in einem Alter von 18 bis 75 Jahren, einschließlich:

4. Dokumentierte Diagnose von bestehendem mäßigem bis schwerem chronischem Kreuzschmerz

5. Patienten, deren Kreuzschmerz nach der Quebec Task Force Classification of Spinal Disorders nichtneuropathisch (Klasse 1 und 2) oder neuropathisch waren (Klasse 3–6), wurden eingeschlossen.

6. Patienten, die vor der Screening-Visite mindestens 2 Monate eine tägliche Einnahme von Opioidanalgetika wegen Kreuzschmerz benötigten

7. Patienten mit Tagesbedarf an Opioiden von ≥60 mg oralem Morphinäquivalent (≥12 mg Hydromorphon), aber ≤320 mg Morphin (≤64 mg Hydromorphon) in den 2 Monaten vor der Screening-Visite

8. Patienten, die nach Ansicht des Untersuchers alle zuvor eingenommenen Analgetika (sowohl Opioide als auch

Nichtopioide) vor der Screening-Visite in konstanter Dosis einnahmen (≥2 Wochen)

9. Gebärfähige Frauen einschließlich Frauen, bei denen eine Tubenligatur durchgeführt worden war, aber ausgenommen Frauen, die seit mindestens 2 Jahren keine Menstruationsblutung gehabt hatten, mussten in der Screening-Visite einen negativen Schwangerschaftstest haben. Sie mussten einwilligen, im gesamten Studienzeitraum einschließlich Auswaschphase und eine Woche nach Studienabschluss eine medizinisch akzeptable Verhütungsmethode anzuwenden.

Ausschlusskriterien:

1. Patienten mit Diagnose einer Fibromyalgie, eines komplexen regionalen Schmerzsyndroms (einschließlich sympathische Reflexdystrophie oder Kausalgie), akuter Rückenmarkkompression, ausgeprägter oder fortschreitender Schwäche oder Taubheit in den unteren Extremitäten, Darm- oder Blasenfunktionsstörung wegen Cauda-equina-Kompression, diabetischer Amyotrophie, Meningitis, Diszitis, Rückenschmerz wegen sekundärer Infektion oder Tumor oder Schmerzen aufgrund eines bestätigten oder vermuteten Tumors

2. Chirurgischer Eingriff zur Therapie des Rückenschmerzes innerhalb von 6 Monaten vor dem Screening

3. Nerven- oder Plexusblockade, einschließlich epiduraler Steroidinjektionen oder Facettenblockade, innerhalb von einem Monat vor der Screening-Visite

4. Patienten mit anderer chronischer Schmerzstörung, die nach Ansicht des Untersuchers die Einschätzung des Kreuzschmerzes beeinträchtigen würde (z. B. Arthrose, rheumatoide Arthritis, Postzosterneuralgie, mit diabetischer Neuropathie assoziierter Schmerz, Migränekopfschmerz mit Opioidbedarf)

5. Patienten, die nach Arbeitsunfall

Entschädigungszahlungen erhalten, mit Anspruch auf Versicherungsgelder/Invalidenrente oder Rechtsstreit im Zusammenhang mit Rückenschmerz

6. Patienten mit anamnestischem Missbrauch illegaler Drogen, Opioidabusus oder Beschaffungsverhalten innerhalb der letzten 5 Jahre vor der Screening-Visite

7. Patienten, die innerhalb der letzten 5 Jahre vor der Screening-Visite verschriebene Medikamente oder Alkohol missbraucht haben (s. Anhang 11 der DSM-IV-Kriterien für Substanzabusus)

8. Positiver Test auf Alkohol oder Drogen 9. Schwangerschaft (belegt durch das

positive Ergebnis eines Serum-Schwangerschaftstests in der Screening-Visite), Laktation oder Absicht, in den 30 Tagen vor der Screening-Visite zu stillen

10. Allergische Reaktion oder Überempfindlichkeit gegenüber Opioiden

11. Patienten ohne Darmentleerung innerhalb von 3 Tagen oder mit Darmverschluss innerhalb von 60 Tagen vor der Screening-Visite

12. Vorbestehend sekundäre starke Verengung des Magen-Darm-Trakts wegen gastrointestinaler Operation (z. B. Vagotomie, Antrektomie, Pyloroplastik, Gastroplastik, Gastrojejunostomie) oder Erkrankung, die zu einer Funktionsstörung des Magen-Darm-Trakts führt (z. B. paralytischer Ileus, Gastroparese, entzündliche Darmerkrankung, "Kurzdarmsyndrom" aufgrund von Adhäsionen oder verkürzter Passagezeit, in Anamnese Peritonitis, zystische Fibrose, chronische intestinale Pseudoobstruktion oder Meckel-Divertikel)

13. Schwere psychiatrische Störung (z. B. Schizophrenie, schwere Depression) oder klinisch relevante Angst oder Depression, definiert durch einen HADS-Score>10

14. Patienten, die in den 14 Tagen vor der Screening-Visite MAO-Inhibitoren erhalten haben

15. Patienten mit klinisch relevanten abnormen Laborergebnissen der

klinischen Chemie, Hämatologie oder Urinanalyse nach Definition in Anhang 9, einschließlich Serumwerten der Glutamat-Oxalacetat-Transaminase/Aspartat-Aminotransferase (AST) oder Glutamat-Pyruvat-Transaminase/Alanin-Aminotransferase (ALT) über/gleich dem 3,0-fachen oberen Grenzwert des Referenzbereichs oder Serumkreatinin ≥2,0 mg/dl im Screening

16. Schwere oder instabile zwischenzeitlich eingetretene Erkrankung

17. Unkontrolliertes Anfallsleiden in der Anamnese

18. Erhöhter Hirndruck, Benommenheit mit unbekannter Ätiologie, Koma oder Hypotonie

19. Schweres Asthma, schwere chronisch-obstruktive Lungenerkrankung oder eine andere Erkrankung, die den Patienten zur Kohlendioxidretention oder Atemdepression neigen lassen

20. Einnahme eines Medikaments, das sich noch in der Entwicklung befindet, in den 30 Tagen vor der Screening-Visite oder aktuelle Teilnahme an einer Studie zu einem solchen Medikament

Placebo: n=133; Durchschnittsalter 49,4 Jahre; 54,9% weiblich; 88,0% weiß; Schmerzausgangswert 6,5±1,88

Hydromorphon: n=133; Durchschnittsalter 47,8 Jahre; 45,9% weiblich; 88,0% weiß; Schmerzausgangswert 6,3±1,94

Interventionen Studienmedikation: In der offenen Konversions-/Titrationsphase erhielten die Patienten retardiertes Hydromorphon in Dosen von 12, 16, 24, 32, 40, 48 oder 64 mg/Tag. Die Konversion wurde unter Annahme eines Morphinäquivalent/Hydromorphon-Potenzverhältnisses von 5:1 erreicht. In die doppelblinde Phase wurden Patienten eingeschlossen, die die folgenden Stabilitätskriterien erfüllten: ≥12 mg und ≤64 mg Hydromorphon/Tag; gleiche Hydromorphon-Dosis an zumindest 7 aufeinanderfolgenden Tagen; Schmerzscore ≥4 in der Periode mit konstanter Dosis; Bejahung der Frage "Hat Ihnen diese Medikation so weit geholfen, dass Sie sie weiterhin einnehmen würden? Keine intolerablen

Nebenwirkungen."

Bedarfsmedikation: Sofort freisetzendes Hydromorphon, 2, 4 und 8 mg, in allen Studienphasen

Zulässige Kotherapien: Keine Angaben

Endpunkte Schmerz: Mittlere Schmerzintensität, Schmerztagebuch, NRS (0–10); Mittelwerte und Standardabweichungen aus Abbildung extrahiert

Responder: ≥50%ige Reduktion der Schmerzintensität von Screening bis Studienende





Schwere unerwünschte Ereignisse: Angegeben*


Anmerkungen *Alle schweren unerwünschten Ereignisse wurden als "nicht tödlich" eingestuft.

Katz 2007




Studiendauer: Dauer des Screenings und der Auswaschung nicht angegeben, bis zu 10-tägige offene Titration, 12-wöchige doppelblinde Absetzphase

Teilnehmer Einschlusskriterien: Die Patienten durften keine Opioide eingenommen haben (definiert als Einnahme von <5 mg/Tag Oxycodon oder eines Äquivalents in den 14 Tagen vor dem Screening), mussten ≥18 Jahre alt sein und eine initiale Schmerzintensität von ≥50 mm (VAS 0–100 mm) aufweisen. Des Weiteren mussten sie im Screening berichtet haben, dass sie seit ≥3 Monaten zumindest mehrere Stunden täglich mäßige bis schwere Kreuzschmerzen hatten.

Ausschlusskriterien: Ausgeschlossen wurden Patienten mit sympathischer Reflexdystrophie oder Kausalgie (komplexes regionales Schmerzsyndrom), akuter Rückenmarkkompression, Cauda-equina-Kompression, akuter Nervenwurzelkompression, Meningitis und Diszitis. Nicht geeignet waren auch Patienten mit schwerer organisch-psychiatrischer Störung, schwerer oder instabiler zwischenzeitlich eingetretener Erkrankung, einer organischen Erkrankung, die die Medikamentenabsorption beeinflusst, unkontrollierten Anfallsleiden in der Anamnese, Drogen- oder Alkoholabhängigkeit in der Vorgeschichte oder Überempfindlichkeit gegenüber Opioiden. Ebenfalls ausgeschlossen wurden Patienten, die innerhalb von 2 Monaten vor dem Screening einem operativen Eingriff wegen des Rückenschmerzes unterzogen worden waren oder die in den 4 Wochen vor Beginn der Dosistitration eine Nerven- bzw. Plexusblockade erhalten hatten. Auch ein laufender oder anhängiger Rechtsstreit im Zusammenhang mit dem Rückenschmerz war ein

Ausschlusskriterium.

Placebo: n=100; Durchschnittsalter 48,1 Jahre; 50% weiblich; 91% weiß; Schmerz vor Randomisierung 2,6±1,2

Oxymorphon n=105; Durchschnittsalter 51,3 Jahre; 56,2% weiblich; 88,6% weiß; Schmerz vor Randomisierung 2,8±1,3

Interventionen Studienmedikation: Oxymorphon flexibel vs. Placebo. Die aktuelle Schmerzmedikation wurde am Vorabend der Screening-Visite beendet. Die Patienten erhielten retardiertes Oxymorphon 5 mg p.o. alle 12 h für 2 Tage; dann wurde die Medikation durch Erhöhungen von 5–10 mg alle 12 h alle 3–7 Tage titriert, bis eine Dosisstabilisierung erreicht war. Als stabil galt die Dosis, wenn an 3 von 5 aufeinanderfolgenden Tagen sowohl Verträglichkeit als auch Wirksamkeit (Schmerz ≤40 mm auf VAS) gegeben war. Eine ergänzende Bedarfsmedikation war in der Phase der Dosistitration nicht erlaubt. Patienten mit stabilisierter Dosis wurden in eine 12-wöchige doppelblinde Therapiephase randomisiert, in der sie ihre konstante Dosis von retardiertem Oxymorphon oder Placebo alle 12 h erhielten. Allen Patienten war die Einnahme von sofort freisetzendem Oxymorphon als Bedarfsmedikation bei Durchbruchschmerzen gestattet. An den ersten 4 Tagen durften die Patienten nach Bedarf alle 4–6 h bis zu 5 mg sofort freisetzendes Oxymorphon einnehmen; danach war die Einnahme auf maximal 2 Dosen pro Tag beschränkt. Mittlere Tagesdosis 40,05±25,8 mg

Bedarfsmedikation: Kurz wirksame NSAR oder andere ergänzende Analgetika durften nicht zur Therapie von Schmerzen eingesetzt werden, die Behandlung anderer Symptome war aber erlaubt (z. B. kardiovaskuläre Prophylaxe oder Fieber).

Zulässige Kotherapien: Physikalisches Biofeedback, Akupunktur und pflanzliche Heilmittel wurden während der Studie unverändert eingesetzt.

Endpunkte

Schmerz: Änderung der durchschnittlichen Schmerzintensität in der letzten Studienvisite gegenüber dem Ausgangswert (VAS 0–100)

Responder: 50%ige Schmerzreduktion in der letzten Studienvisite gegenüber Ausgangswert (VAS 0–100)







Anmerkungen

Schnitzer 2000


Studienorte: USA, Anzahl der Zentren nicht angegeben

Studiendesign: "Enriched enrollment randomized withdrawal"

Studiendauer: Bis zu 3-wöchige Auswaschung, 3-wöchige offene Titration und 4-wöchige doppelblinde Absetzphase

Teilnehmer Einschlusskriterien: 25–75 Jahre; chronischer Kreuzschmerz mit einer Intensität, die seit mindestens 3 Monaten eine tägliche Medikation erforderte; ansonsten guter Gesundheitszustand; kein oder lang zurückliegender operativer Eingriff am Rücken in der Anamnese. Das Protokoll wurde später ergänzt: Es wurde der Einschluss von Patienten erlaubt, die sich >5 Jahre zuvor einem einmaligen Eingriff am Rücken unterzogen hatten, der zu einer kompletten Schmerzlinderung führte.

Ausschlusskriterien: Neurologische Störungen in den unteren Extremitäten, Tumoren oder Infektionen der Meningen oder des Rückenmarks, Rückenschmerz durch eine Läsion, die chirurgisch behandelbar war, anderer stärkerer Schmerz nicht im Bereich des Kreuzes; Fibromyalgie, Bandscheibenvorfall, Spondylolisthesis, Spinalkanalstenose, Instabilität lumbaler Wirbel in Anamnese, Wirbelfrakturen, Tumoren, Infektionen, entzündliche Erkrankung; relevante Leber- oder Nierenerkrankungen; morbide Adipositas; Borderline-Persönlichkeitsstörung; Narkotika- oder Alkoholabusus in der Vorgeschichte; Einsatz der TENS; Kortikosteroidtherapie (lokal oder systemisch in den vorausgegangenen 3 Monaten); Punktwert im Waddell-Test mindestens 3 von 5

Gesamtstichprobe: n=254; Durchschnittsalter 47,1 Jahre; 50% weiblich; 92,9% weiß; Schmerzausgangswert oder Wert bei Randomisierung nicht angegeben

Interventionen Studienmedikation: Tramadol flexibel, 100–400 mg/Tag. Die Patienten wurden in die doppelblinde Phase eingeschlossen, wenn sie die folgende Frage bejahten: Hat Ihnen diese Medikation in Bezug auf den Schmerz so geholfen, dass Sie sie weiterhin einnehmen möchten? Über die gesamte doppelblinde Phase lag die durchschnittliche Tramadol-Tagesdosis bei 242 mg.

Bedarfsmedikation: Nicht erlaubt

Zulässige Kotherapien: Fortsetzung einer Physiotherapie erlaubt. Physiotherapien durften nicht in der offenen oder randomisierten Phase begonnen werden.

Endpunkte Schmerz: Durchschnittliche Schmerzintensität in den vorausgegangenen 24 h (VAS 0–10) bei Studienvisite am Ende der doppelblinden Phase



Funktion: Roland Disability Questionnaire



Schwere unerwünschte Ereignisse: Keine Angaben


Anmerkungen

Steiner 2011




Studiendauer: Bis zu 4 Wochen offen, 12 Wochen doppelblinde Absetzphase

Teilnehmer Einschlusskriterien: Alter ≥18 Jahre; mäßiger bis schwerer Kreuzschmerz mit einer Dauer von mindestens 3 Monaten vor Studieneinschluss. Kreuzschmerz musste die dominierende Schmerzstörung sein und täglich mehrere Stunden bestehen. Geeignete Patienten hatten keine Opioide eingenommen (Einnahme von <5 mg/Tag Oxycodon oder eines Äquivalents in den 14 Tagen vor dem Screening, keine tägliche Opioideinnahme von ≥5 mg Oxycodon oder eines Äquivalents in den 3 Monaten vor dem Screening und, nach Einschätzung des Untersuchers, keine Opioidabhängigkeit zum Zeitpunkt des Studieneinschlusses), sie hatten nicht von einer Nichtopioidtherapie profitiert oder diese nicht vertragen. Eingeschlossen wurden Patienten mit Kreuzschmerz, der mit nichtmalignen Störungen zusammenhing (z. B. bandscheibenbedingte Erkrankung, Spinalkanalstenose, Spondylolyse, Spondylolisthesis, und Arthrose). Der QTc-Wert musste <480 ms liegen, die Patienten mussten eukaliämisch sein.

Ausschlusskriterien: Ausgeschlossen wurden Patienten mit radikulärer Symptomatik, akuter Rückenmarkkompression, akuter Kompressionsfraktur, seronegativer Spondylarthropathie, akuter Nervenwurzelkompression, Cauda-equina-Kompression, Fibromyalgie, sympathischer Reflexdystrophie oder Kausalgie (komplexes regionales Schmerzsyndrom), diabetischer Amyotrophie, Meningitis, Diszitis, Gicht, Pseudogicht, Psoriasisarthritis, aktiver Lyme-Borreliose, rheumatoider Arthritis oder anderer entzündlicher Gelenkerkrankung, Bursitis trochanterica, Bursitis am Sitzbeinhöcker, neuropathischer Störung oder mit

Rückenschmerz, der durch eine sekundäre Infektion, einen Tumor oder eine Postzosterneuralgie hervorgerufen wurde. Zum Ausschluss führte auch ein chirurgischer Eingriff zur Behandlung des Rückenschmerzes innerhalb von 6 Monaten vor dem Screening oder ein geplanter chirurgischer Eingriff im Studienzeitraum. Patienten, die eine Behandlung mit Klasse-IA- oder Klasse-III-Antiarrhythmika benötigten, durften ebenfalls nicht teilnehmen.

Placebo: n=284; Durchschnittsalter 50,0 Jahre; 58% weiblich; 69% weiß; Schmerzausgangswert 7,2±1,2

Buprenorphin: n=257; Durchschnittsalter 48,8 Jahre; 52% weiblich; 72% weiß; Schmerzausgangswert 7,2±1,3

Interventionen Studienmedikation: Titration auf das individuell optimale transdermale Buprenorphin-System 10–20 mg/h; Patienten mit Reduktion des "durchschnittlichen Schmerzes innerhalb der letzten 24 h" um ≥2 Punkte und einem "durchschnittlichen Schmerz innerhalb der letzten 24 h" für Kreuzschmerz von ≤4 wurden 1:1 randomisiert und erhielten die optimale feste Dosierung des transdermalen Buprenorphins oder Placebo.

Bedarfsmedikation: 5-mg-Oxycodon-Kapseln, bis zu 10 mg/Tag als ergänzende Bedarfsmedikation in den ersten 6 Tagen der doppelblinden Phase. Zusätzlich wurden Paracetamol und Ibuprofen als Bedarfsmedikation für die Wochen 2–12 der doppelblinden Phase zur Verfügung gestellt.

Zulässige Kotherapien: Paracetamol und Ibuprofen waren in der doppelblinden Phase zur Behandlung von anderen Erkrankungen als chronischem Schmerz zugelassen, soweit die gesamte Tagesdosis (vom Sponsor und aus anderen Quellen) 2 g bzw. 800 mg nicht überstieg. NSAR, Aspirin und Cyclooxygenase(COX)-2-Hemmer waren erlaubt, wenn sie nicht zur Behandlung chronischer Schmerzen, sondern für andere Störungen eingesetzt wurden (u. a. Kopfschmerz, Fieber und kardiovaskuläre Prophylaxe). Muskelrelaxanzien durften gegen Muskelspasmen eingesetzt werden. Konstante

Einnahmeregime von Antidepressiva und Antikonvulsiva waren erlaubt, soweit sie nicht schmerztherapeutisch eingesetzt wurden. Orale Kortikosteroide, Glukosamin, Chondroitinsulfat, TENS, Biofeedback, physikalische Therapie und Entspannungstherapie waren zulässig, wenn der Untersucher die Behandlung als stabil betrachtete.

Endpunkte Schmerz: Durchschnittlicher Schmerz in den vorausgegangenen 24 h auf NRS (0–10)

Responder: 50%ige Schmerzreduktion im Vergleich zur Screening-Visite (NRS 0–10)

PGIC: Erhaltung der starken oder sehr starken Verbesserung im Vergleich zur Baseline

Funktion: Oswestry Disability Index; SF-36, körperliche Funktionsfähigkeit*





Anmerkungen "Mittelwerte des Oswestry Disability Index angegeben, aber keine p-Werte und Standardabweichungen (Daten nicht in Metaanalyse einbezogen); SF-36, körperliche Funktionsfähigkeit bei Yarlas (2013) angegeben; Mittelwerte und Standardfehler aus Abbildungen extrahiert

Vondrackova 2008

Methoden Erkrankung: Kreuzschmerz verschiedener Ursache

Studienorte: 4 europäische Länder (Tschechien, Deutschland, Ungarn), Zahl der Zentren nicht angegeben


Studiendauer: ≤7 Tage Screening, 3-wöchige Aufdosierung und Titration, 12-wöchige Erhaltung von Oxycodon und Absetzung von Placebo, 12 Monate offene Erweiterung

Teilnehmer Einschlusskriterien: Frauen und Männer ≥18 Jahre wurden eingeschlossen, wenn sie dokumentierte mäßige bis starke chronische, nichtmaligne Kreuzschmerzen hatten (z. B. wegen Arthrose/Arthritis der Wirbelsäule, Spondylosis deformans, Spondylolisthesis, Bandscheibenvorfall/Ischias, Spinalkanalstenose), die vor Studieneinschluss mit Opioidanalgetika mindestens 2 Wochen ausreichend behandelt waren, wenn sie täglich Opioidanalgetika einnahmen und wahrscheinlich von einer dauerhaften Opioidtherapie im Studienzeitraum profitieren würden.

Ausschlusskriterien: Überempfindlichkeit gegenüber Oxycodon, Naloxon oder einem verwandten Produkt in der Anamnese; Patienten, die aktuell ein Äquivalent von 10 mg oder 40 mg/Tag Oxycodon einnahmen; aktiver Alkohol- oder Drogenabusus; abnorme Ergebnisse in Leberfunktionstests; Patienten mit 2 chirurgischen Eingriffen am Kreuz in der Vorgeschichte. Ausgeschlossen wurden auch Patienten mit Hinweisen auf eine klinisch relevante Herz-Kreislauf-, Nieren-, Leber-, Magen-Darm- (paralytischer Ileus) oder psychiatrische Erkrankung, die bei Einnahme der Studienmedikation ein Risiko bedeutet bzw. die Analyse und/oder Interpretation der Studienergebnisse verfälscht hätte.

Oxycodon: n=151; Durchschnittsalter 56,7 Jahre; 59,6% weiblich; keine Angaben zu ethnischer Abstammung; Schmerzausgangswert

nicht angegeben

Oxycodon/Naloxon: n=154; Durchschnittsalter 55,8 Jahre; 53,9% weiblich; keine Angaben zu ethnischer Abstammung; Schmerzausgangswert nicht angegeben

Placebo: n=158; Durchschnittsalter 56,7 Jahre; 70,9% weiblich; keine Angaben zur ethnischen Herkunft

Interventionen Studienmedikation: Oxycodon: In der Screening-Phase ("opioid taper") konnten die Patienten als Bedarfsmedikation alle 4–6 h Oxycodon erhalten (ein Viertel der zuvor eingenommenen Gesamttagesdosis an Opioiden). In der Vorbereitungsphase (Opioidtitration) wurde die OxyIR-Dosis nach der Wirkung titriert; die Zieldosis betrug 20 oder 40 mg/Tag. Zu Beginn der doppelblinden Phase wurde die Medikation aller randomisierten Patienten von OxyIR auf eine äquivalente Dosis der Studienmedikation umgestellt. Patienten, die in die Oxycodon-PR/Naloxon-PR-Therapiegruppe randomisiert wurden, erhielten Dosen von 10/5 mg oder 20/10 mg Oxycodon PR/Naloxon PR alle 12 h. Patienten in der Oxycodon-PR-Therapiegruppe erhielten 10 mg oder 20 mg Oxycodon PR alle 12 h. In der Placebogruppe wurde alle 12 h angepasstes Placebo verabreicht. Die Dosierung war fest und äquivalent zur wirksamen OxyIR-Dosis, die in der Vorbereitungsphase (Opioidtitration) bestimmt worden war.

Bedarfsmedikation: Oxycodon alle 4–6 h als Bedarfsmedikation durfte nur bei Schmerzen von ≥5 auf NRS eingenommen werden (ein Viertel der Gesamttagesdosis an Opioiden).


Endpunkte Schmerz: Durchschnittliche Schmerzintensität in den vorausgegangenen 24 h auf NRS (0–10)*




Behandlungsabbruch wegen fehlender

Wirksamkeit: Angegeben




Anmerkungen *Keine Mittelwerte und Standardabweichungen angegeben. "In der doppelblinden Phase zeigten die Patienten in der Oxycodon-PR/Naloxon-PR- (p=0,0396) und der Oxycodon-PR-Therapiegruppe (p=0,0080) einen statistisch signifikant niedrigeren 'durchschnittlichen Schmerz in den zurückliegenden 24 h' im Vergleich zu Placebo. Die Placebogruppe hatten signifikant höhere BPI-SF-Schmerz-Subscores als die Oxycodon-PR- (p=0,0012) und Oxycodon-PR/Naloxon-PR-Gruppe (p=0,0158)."

Vorsanger 2008

Methoden Erkrankung: Chronischer Kreuzschmerz



Studiendauer: 1) 2- bis 7-tägige Auswaschungs-/Screeningphase; 2) 3-wöchige offene Vorbereitungsphase; 3) 12-wöchige doppelblinde, placebokontrollierte Erhaltung; 1-wöchiges Follow-up

Teilnehmer Einschlusskriterien: Chronischer Kreuzschmerz seit ≥6 Monaten und täglicher Therapiebedarf mit NSAR, Paracetamol, Opioidanalgetika, selektiven COX-2-Hemmern und/oder Muskelrelaxanzien an mindestens 60 von 90 Tagen vor der Screening-Visite. Schmerzintensitäts-Score ≥40 auf einer 100-mm-VAS nach 2- bis 7-tägiger Auswaschung

Ausschlusskriterien: Jede Erkrankung außer Kreuzschmerz, die nicht gut kontrolliert war; komplexes regionales Schmerzsyndrom; relevanter Entzündungsschmerz oder Fibromyalgie; chirugischer Eingriff an lumbaler Wirbelsäule oder Chemonukleolyse in der Vorgeschichte; Behandlung mit TENS oder Manipulation der Wirbelsäule; Gewicht ≤45,4 kg; Dysphagie oder Probleme beim Schlucken von Tabletten; anhaltende Übelkeit oder Erbrechen; Opioidüberempfindlichkeit in der Anamnese; Erhöhung der Leberenzyme auf das >2-Fache der Obergrenze des Normbereichs, Kreatinin >1,9 mg/dl; Substanzabusus innerhalb von 6 Monaten vor Screening; Tumorerkrankung innerhalb der letzten 3 Jahre; Schmerz mit fehlendem Ansprechen auf angemessene Dosisanpassungen oder inakzeptable Nebenwirkungen in offener Phase; intraartikuläre Viskosupplementation in den vorausgegangenen 3 Monaten

Placebo: n=129; Durchschnittsalter 47,6 Jahre; 50,0% weiblich; 87% weiß; aktuelle Schmerzintensität bei Randomisierung 30,7±25,9

Tramadol 200 mg/Tag: n=129; Durchschnittsalter 47,4±13,8 Jahre; 53%

weiblich; 83% weiß; Schmerzausgangswert nicht angegeben; aktuelle Schmerzintensität bei Randomisierung 29,5±26,0

Tramadol 300 mg/Tag: n=128; Durchschnittsalter 48,5 Jahre; 47% weiblich; 84% weiß; aktuelle Schmerzintensität bei Randomisierung 26,8±23,7

Interventionen Studienmedikation: Feste Dosen von 200 oder 300 mg Tramadol ER pro Tag oral, 1-mal täglich; Placebo oral

Bedarfsmedikation: Acetylsalicylsäure und Paracetamol in niedriger Dosis. Die Patienten durften in den vorausgegangenen 15 Tagen keinen MAO-Inhibitor oder ein TCA erhalten haben. Die Einnahme von NSAR, Kortikosteroiden, Opioiden oder anderen Analgetika während der Studie war mit Ausnahme von Acetylsalicylsäure und Paracetamol in niedriger Dosis nicht gestattet. Zu den weiteren ausgeschlossenen Medikationen gehörten u. a. Neuroleptika, SSRI, SNRI, Carbamazepin (Induktor des Tramadol-Metabolismus) und Chinidin (Inhibitor des Tramadol-Metabolismus).


Endpunkte Schmerz: VAS (0–100)



Funktion: Roland Disability Index (0–24)



Schwere unerwünschte Ereignisse: Angegeben*


Anmerkungen *Neun schwere unerwünschte Ereignisse; nicht angegeben, in welcher Gruppe.

Webster 2006




Studiendauer: 4- bis 10-tägige Auswaschung; 1- bis 6-wöchige Titration, 12-wöchige Erhaltung

Teilnehmer Einschlusskriterien: Alter 18–70 Jahre, anhaltender Kreuzschmerz seit mindestens 6 Monaten, Ausgangswert der Schmerzintensität von 5 in der Screening-Visite; durchschnittliche tägliche Schmerzintensität von 5 gemäß Tagebuch an den letzten 3 Tagen einer 4- bis 10-tägigen Auswaschphase, während alle Analgetika außer Paracetamol abgesetzt waren; bestätigender Wert der Schmerzintensität von 5 bei der Ausgangsvisite am Ende der Auswaschphase. Bei Patienten, die Tagesopioiddosen äquivalent zu 20 mg Oxycodon einnahmen, war eine Aufdosierung notwendig. Eine 72-stündige Phase ohne Opioidmedikation vor dem Screening wurde von allen Patienten verlangt.

Ausschlusskriterien: Sekundärer Kreuzschmerz bedingt durch maligne Erkrankung, Autoimmunerkrankung, Fibromyalgie, Fraktur in der jüngeren Vergangenheit oder Infektion. Zum Ausschluss führten auch Urinproben zu Studienbeginn, die positiv auf illegale Substanzen waren, ein Substanzabusus in den vergangenen 5 Jahren in der Anamnese und die Verwicklung in einen Rechtsstreit wegen des Kreuzschmerzes. Zu den weiteren Ausschlusskriterien zählten: Schwangerschaft; bekannte Überempfindlichkeit gegenüber einem der Studienmedikamente; schwere Leber-, Lungen- oder Nierenfunktionsstörung; instabile Herzerkrankung; aktuelle maligne Erkrankung oder Leukämie, Lymphom bzw. metastasierter Tumor in der Vorgeschichte; Einnahme von Medikamenten, die sich noch in der Entwicklung befinden; Kortikosteroidtherapie; intraspinale Analgetikainfusion oder Rückenmarkstimulation im Vormonat; größerer chirurgischer Eingriff in den vorausgegangenen 3 Monaten; perkutaner

oder offener Eingriff an der lumbosakralen Wirbelsäule in den vorausgegangenen 4 Monaten; hohe Dosen von ZNS-Depressiva oder Phenothiazinen

Oxycodon 2-mal täglich: n=206; Durchschnittsalter 47,9 Jahre; 61,2% weiblich; keine Angaben zur ethnischen Herkunft; Schmerzausgangswert 7,6±1,36

Oxycodon/Naltrexon 2-mal täglich: n=206; Durchschnittsalter 47,8 Jahre; 61,7% weiblich; keine Angaben zur ethnischen Herkunft; Schmerzausgangswert 7,3±1,36

Oxycodon/Naltrexon 1-mal täglich: n=206; Durchschnittsalter 47,9 Jahre; 61,7% weiblich; keine Angaben zur ethnischen Herkunft; Schmerzausgangswert 7,6±1,33

Placebo: n=101; Durchschnittsalter 48,7 Jahre; 61,4% weiblich; keine Angaben zur ethnischen Herkunft; Schmerzausgangswert 7,7±1,44

Interventionen Studienmedikation: Oxycodon mit und ohne Naltrexon flexibel, 20–80 mg/Tag (durchschnittliche Tagesdosis nicht angegeben); Placebo

Bedarfsmedikation: In der Behandlungsphase waren keine anderen Analgetika erlaubt. Paracetamol während der Auswaschung

Zulässige Kotherapien: TCA, SSRI, Glukosamin/Chondroitin und Johanniskraut waren erlaubt, wenn die Dosierung vor Studieneinschluss 4 Wochen stabil gewesen war.

Endpunkte Schmerz: Durchschnittliche tägliche Schmerzintensität in Tagebuch auf NRS (0–10)*



Funktion: Oswestry Disability Index**


Behandlungsabbruch wegen unerwünschter

Ereignisse: Angegeben



Anmerkungen *Prozentuale Schmerzreduktion als Endpunkt berichtet.

**Keine Mittelwerte und Standardabweichungen angegeben. "In Bezug auf den Oswestry Disability Index bestanden keine signifikanten Unterschieden zwischen den Behandlungsgruppen."

Uberall 2012


Studienorte: 31 Zentren in Deutschland


Studiendauer: 1-wöchige Auswaschung, 4-wöchige Erhaltung, 1-wöchiges Follow-up

Teilnehmer Einschlusskriterien: Frauen und Männer im Alter von 18–75 Jahren; nichtmaligner Kreuzschmerz mit einer Dauer von ≥3 Monaten; Einnahme von Analgetika, die nach nationalen Leitlinien zur Behandlung von Kreuzschmerz geeignet sind; Unzufriedenheit mit der aktuellen Therapie; Bericht eines Ausgangswerts der Schmerzintensität von ≥4 auf einer 11-stufigen NRS

Ausschlusskriterien: Kreuzschmerz mit neurologischer Ätiologie, bedingt durch ein schwereres Trauma in der jüngeren Vergangenheit oder eine viszerale Erkrankung: Klinisch relevante organische oder psychiatrische Erkrankungen; entzündliche rheumatische oder andere Erkrankung mit Wirbelsäulenbeteiligung; metabolische Knochenerkrankung; Spinalkanalstenose mit neurologischer Schädigung; Wirbelsäulenfrakturen; anatomische Anomalien; maligne Erkrankungen; Fibromyalgie; Infektionen des zentralen oder peripheren Nervensystems; Bandscheibenvorfall verbunden mit neurologischer Schädigung; Anfallsleiden; Alkohol-/Analgetika-/Narkotikamissbrauch oder anderer Substanzabusus in den zurückliegenden 2 Jahren; chirurgische Eingriffe an der Wirbelsäule in der Anamnese; Nieren- oder Leberfunktionsstörung

Tramadol: n=116; Durchschnittsalter 57,6 Jahre; 61,2% weiblich; 95,8% weiß; durchschnittlicher Schmerzausgangswert 6,0±1,2

Placebo: n=120; Durchschnittsalter 59,2 Jahre; 55,8% weiblich; 98,3% weiß; durchschnittlicher Schmerzausgangswert 6,1±1,4

Interventionen Studienmedikation: Flupirtin fest, 400 mg/Tag; Tramadol fest, 200 mg/Tag; Placebo

Bedarfsmedikation: Diclofenac bis zu einer Dosis von 150 mg/Tag. Die Patienten wurden dringend dazu angehalten, die Bedarfsmedikation mindestens 24 h vor einer klinischen Visite abzusetzen.

Zulässige Kotherapien: Keine anderen Medikamente oder pharmakologischen Behandlungen zugelassen

Endpunkte Schmerz: Durchschnittliche Intensität des Kreuzschmerzes in den vergangenen 24 h, NRS (0–10)

Responder: 50%ige Schmerzreduktion

PGIC: Stark oder sehr stark verbessert

Funktion: SF-12 und Quality of Life Impairment by Pain Inventory; Ergebnisse nicht im Detail publiziert*





Anmerkungen *SF-12 und Quality of Life Impairment by Pain Inventory verbesserten sich in allen 3 Studiengruppen signifikant gegenüber dem Ausgangswert (p<0,001). Nur geringfügige, statistisch nicht signifikante Unterschiede fanden sich dagegen in Bezug auf behandlungsbedingte Unterschiede zwischen den Gruppen.

Electronic Supplementary Material, Tabelle 2: Einschätzung des Risikos

systematischer Fehler

Buynak 2010

Bias Einschätzung

der Autoren Gründe für die Einschätzung

Randomisierung (Selektionsbias) Low risk "Die Randomisierung basierte auf einer computergenerierten Randomisierungsliste, balanciert durch zufällig permutierte Blöcke und stratifiziert nach Studienzentrum. (2.2 Studiendesign)"

Verdeckte Zuteilung

(Selektionsbias)

Low risk ”Die Randomisierung wurde mit einem Interactive-voice-response-System realisiert."

Verblindung von Teilnehmern und

Personal (Interventionsbias)

Low risk ”Double-dummy-Design"

Verblindung der Ergebnismessung

(Messungsbias)

Unclear risk Es ist unklar, ob die Untersucher versuchten, die Kliniker zu verblinden, die die Opioidtitration überwachten.

Unvollständige Ergebnisse

(Verschleißbias)

High risk "ITT-Analyse nach Last-observation-carried-forward(LOCF)-Verfahren; die Zahl der in der ITT-Population verbleibenden Patienten nahm allerdings im Studienverlauf ab (Abb. 3)"

Selektive Veröffentlichung von

Daten (Publikationsbias)

Low risk Die Studie wurde auf clinicaltrials.gov registriert (NCT00449176); die primären und sekundären Endpunkte im Protokoll und in der Publikation stimmten überein.

Selektionsbias Low risk Keine signifikanten Unterschiede in demografischen und klinischen Merkmalen zwischen den drei Gruppen bei Studienbeginn

Finanzierungsbias High risk Finanzierung und statistische Auswertung durch den

Hersteller eines Medikaments. Acht von 9 Autoren mit Verbindungen zum Hersteller des Medikaments.

Cloutier 2013

Bias Einschätzung


Randomisierung (Selektionsbias) Low risk "Computergenerierte Randomisierungsliste der Patientennummern wurde von einem Biostatistiker erstellt"

Verdeckte Zuteilung

(Selektionsbias)

Low risk "In die Studie aufgenommene Patienten wurden zentral zugeteilt."



Low risk Double-dummy-Verfahren


(Messungsbias)

Unclear risk "Patienten, Untersucher und das gesamte klinische Studienpersonal wurden verblindet." Die Untersucher könnten aufgrund des Nebenwirkungsprofils von Oxycodon einem Bias unterlegen haben.


(Verschleißbias)

High risk Für den Endpunkt Beeinträchtigung nur Responder-Analyse publiziert



High risk Die Studie war registriert (ISRCTN 35931095); die primären und sekundären Endpunkte im Protokoll und in der Publikation stimmten überein. Keine Angaben zu schweren unerwünschten Ereignissen

Selektionsbias Unclear risk Keine signifikanten Unterschiede in demografischen und klinischen Merkmalen zwischen den drei Gruppen bei Studienbeginn

Finanzierungsbias High risk Finanzierung durch Pharmafirma. Drei von 12 Autoren (einschließlich Seniorautor) mit Verbindungen zur Pharmafirma.

Gordon 2010

Bias Einschätzung


Randomisierung (Selektionsbias) Low risk “Der Randomisierungscode wurde mithilfe von PROC PLAN in SAS, Version 6.12 (SAS Institute Inc., Cary, North Carolina) generiert."

Verdeckte Zuteilung

(Selektionsbias)

Low risk "Die Behandlungszuteilungen wurden mithilfe eines Blockrandomisierungsverfahrens generiert: Von jeweils 4 aufeinanderfolgenden Patienten erhielten 2 BTDS in der ersten Phase und 2 in der zweiten Phase. Studienkontrolleure, Untersucher, Koordinatoren, Apotheker, Patienten und das klinische Studienpersonal des Sponsors blieben während der Studiendurchführung bezüglich der Behandlungszuteilung verblindet."



Low risk In der Studie wurden angepasste Placebopflaster verwendet.


(Messungsbias)

Unclear risk Das klinische Personal blieb in Bezug auf die Behandlungszuteilung verblindet. Die Untersucher könnten aufgrund des Nebenwirkungsprofils von Buprenorphin einem Bias unterlegen haben.


(Verschleißbias)

Unclear risk ITT-Analyse, Methode nicht publiziert



Low risk Die Studie war auf Current Controlled Trials registriert (ISRCTN 06013881); die primären und sekundären Endpunkte im Protokoll und in der Publikation stimmten überein.

Selektionsbias Low risk Nicht anwendbar (Cross-over-Design)

Finanzierungsbias High risk 4 von 8 Autoren mit Verbindungen zu Pharmabranche

Hale 2007

Bias Einschätzung


Randomisierung (Selektionsbias) Low risk "Computergenerierte Randomisierung"

Verdeckte Zuteilung

(Selektionsbias)

Unclear risk Keine Dokumentation des Verfahrens zur Maskierung der Zuteilung



Unclear risk Keine Angaben zu den physischen Eigenschaften der Placebos


(Messungsbias)

Unclear risk Die vorliegenden Daten reichten für eine Einschätzung nicht aus. Die Untersucher könnten aufgrund der Nebenwirkungen von Oxymorphon einem Bias unterlegen haben.


(Verschleißbias)

Unclear risk Keine ITT-Analyse: "Es wurde kein Imputationsverfahren auf fehlende Schmerzintensitätswerte angewendet."





Finanzierungsbias High risk 4 von 5 Autoren gehörten dem Pharmaunternehmen an, das die Studie finanzierte.

Hale 2010

Bias Einschätzung


Randomisierung (Selektionsbias) Low risk "Computergenerierte Randomisierung"

Verdeckte Zuteilung

(Selektionsbias)

Low risk "Interactive-voice-response-System für die Codierung der Patientenzuweisung zu einer der zwei Behandlungsgruppen"



Low risk "Passendes Placebo"


(Messungsbias)

Unclear risk "Das gesamte an der doppelblinden Phase beteiligte Personal war bezüglich der Medikationscodes verblindet." Die Untersucher könnten aufgrund des Nebenwirkungsprofils von Buprenorphin einem Bias unterlegen haben.


(Verschleißbias)

Unclear risk LOCF oder "baseline observation carried forward" (BOCF) je nach Endpunkt





Finanzierungsbias High risk Einer von 4 Autoren (Seniorautor) gehörte dem Pharmaunternehmen an, das die Studie finanzierte.

Katz 2007

Bias Einschätzung der Autoren

Gründe für die Einschätzung

Randomisierung (Selektionsbias) Unclear risk "Der Sponsor generierte einen Randomisierungscode, um sicherzustellen, dass jeder Behandlungsgruppe nach dem Zufallsprinzip eine angemessene Zahl an Patienten zugeteilt wurde." Keine weiteren Angaben

Verdeckte Zuteilung (Selektionsbias)

Unclear risk Die vorliegenden Daten reichten für eine Einschätzung nicht aus.

Verblindung von Teilnehmern und Personal (Interventionsbias)

Low risk "Die Tabletten mit retardiertem Oxymorphon und Placebo waren mit Gelatine verkapselt, um die Patienten, Untersucher, das Studienpersonal und das Personal des Sponsors bezüglich der Behandlung verblindet zu halten."

Verblindung der Ergebnismessung (Messungsbias)

Unclear risk Die Untersucher waren möglicherweise wegen der Nebenwirkungen von Oxymorphon entblindet.

Unvollständige Ergebnisse (Verschleißbias)


Selektive Veröffentlichung von Daten (Publikationsbias)

Low risk NCT00225797. Alle im Protokoll aufgeführten Endpunkte wurden im Volltextbeitrag berichtet.

Selektionsbias Low risk Keine signifikanten Unterschiede zwischen den Gruppen in demografischen und klinischen Eigenschaften bei Studienbeginn

Finanzierungsbias High risk Finanzierung durch den Hersteller des Medikaments. Zwei der 6 Autoren mit Verbindungen zum Hersteller des Medikaments

Schnitzer 2000



Randomisierung (Selektionsbias) Low risk "Computergenerierte Zufallsnummern"




Low risk "Tramadol- und Placebokapseln mit identischem Aussehen"


Unclear risk Die vorliegenden Daten reichten für eine Einschätzung nicht aus. Die Untersucher könnten aufgrund des Nebenwirkungsprofils von Tramadol einem Bias unterlegen haben.


Unclear risk ITT-Analyse, Methode nicht genauer erläutert


Unclear risk Kein Protokoll verfügbar

Selektionsbias Unclear risk Daten zu Patienten mit Tramadol und Placebo nicht separat aufgeführt

Finanzierungsbias High risk Finanzierung durch den Hersteller des Medikaments

Steiner 2011



Randomisierung (Selektionsbias) Unclear risk Die vorliegenden Daten reichten für eine Einschätzung nicht aus.






Unclear risk Keine Angaben Die Untersucher könnten aufgrund des Nebenwirkungsprofils von Buprenorphin einem Bias unterlegen haben.


Low risk ITT-Analyse nach LOCF- und BOCF-Verfahren


High risk NCT00490919; die primären und sekundären Endpunkte im Protokoll und in der Publikation stimmten überein. Allerdings waren die Standardabweichungen und p-Werte der sekundären Endpunkte Funktion und Lebensqualität nicht angegeben.

Selektionsbias Unclear risk Keine signifikanten Unterschiede zwischen den Gruppen in demografischen und klinischen Eigenschaften bei Studienbeginn

Finanzierungsbias High risk Finanzierung durch Pharmaunternehmen; alle Autoren mit Verbindung zur Pharmabranche

Vondrackova 2011









Unclear risk Keine Angaben Die Untersucher könnten aufgrund des Nebenwirkungsprofils von Oxycodon einem Bias unterlegen haben.


Unclear risk ITT-Analyse; keine weiteren Angaben


High risk Kein Protokoll verfügbar; Schmerzergebnisse unvollständig publiziert und nicht für Metaanalyse geeignet

Selektionsbias Unclear risk Schmerzausgangswert nicht angegeben

Finanzierungsbias High risk Finanzierung durch Pharmaunternehmen; 6 von 11 Autoren mit Verbindungen zum Hersteller des Medikaments

Vorsanger 2011



Randomisierung (Selektionsbias) Low risk Computergenerierter Randomisierungsplan


Unclear risk Keine Angaben


Low risk In der Studien wurden lediglich retardierte 100-mg-Tramadol- und Placebotabletten verwendet. Sie waren in Optik und Struktur identisch, sodass die doppelte Verblindung aufrechterhalten wurde.


Unclear risk Die Untersucher waren möglicherweise wegen des Nebenwirkungsprofils von Tramadol befangen.




High risk Kein Protokoll verfügbar. In welcher Gruppe schwere unerwünschte Ereignisse auftraten, nicht angegeben

Selektionsbias Low risk Keine signifikanten Unterschiede in demografischen und klinischen Eigenschaften bei Studienbeginn

Finanzierungsbias High risk Erstautor mit Verbindungen zu Hersteller des Medikaments

Webster 2011





Low risk "Alle Studienmedikamente waren optisch identisch."


Low risk "Patienten, das Personal vor Ort und die Studienkontrolleure waren bezüglich der Behandlungszuteilung verblindet."


Unclear risk Keine Angaben Die Untersucher könnten aufgrund des Nebenwirkungsprofils von Oxycodon einem Bias unterlegen haben.


Unclear risk ITT-Analyse nach LOCF-Verfahren


High risk Kein Protokoll verfügbar; Daten zum Endpunkt Funktion waren unvollständig publiziert und konnten nicht in die Metaanalyse einbezogen werden.

Selektionsbias Low risk Keine signifikanten Unterschiede zwischen den Gruppen in demografischen und klinischen Eigenschaften bei Studienbeginn

Finanzierungsbias High risk Finanzierung durch Pharmaunternehmen

Uberall 2012



Randomisierung (Selektionsbias) Low risk "Computergenerierte Randomisierungsliste"




Low risk "Alle Studienmedikamente waren optisch identisch."


Unclear risk Die vorliegenden Daten reichten für eine Einschätzung nicht aus. Die Untersucher waren möglicherweise wegen der Nebenwirkungen von Tramadol und Flupirtin befangen.


Unclear risk ITT-Analyse nach LOCF-Verfahren


High risk EudraCT 2009-013268-38. Sekundäre Endpunkte unvollständig publiziert

Selektionsbias Low risk Keine signifikanten Unterschiede zwischen den beiden Gruppen in demografischen und klinischen Eigenschaften bei Studienbeginn.

Finanzierungsbias High risk Finanzierung durch den Hersteller des Medikaments. Einer der 3 Autoren mit Verbindungen zum Hersteller des Medikaments

Supplementary table 1: Characteristics of included studies

Buynak 2010

Methods Disease: Low back pain

Study setting: 85 sites in the US, 15 sites in Canada, 3 sites in Australia

Study design: Parallel

Study duration: 3 weeks titration, 12 weeks maintenance

Participants Inclusion criteria: Age ≥ 18 years; Men and non-pregnant, non-lactating women having a diagnosis of Lower Back Pain (LBP) of non-malignant origin present 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 in investigator's judgment; History of significant liver insufficiency; Chronic hepatitis B or C, or HIV, presence of active hepatitis B or C within the past 3 months; Life-long history of seizure disorder or epilepsy; Uncontrolled hypertension; Severely impaired renal function; Moderate to severely impaired hepatic function or with laboratory values reflecting inadequate hepatic function; Clinically significant psychiatric disease; Treatment with neuroleptics, monoamine oxidase inhibitors, serotonin norepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants, anticonvulsants, or anti-parkinsonian drugs, treatment with any other analgesic therapy than investigational medication or rescue medication during the trial

Total sample: N=987; mean age 62.1 years; 60.4% female; 99.3% white. Pain baseline tapentadol 7.6 (±1.33), Pain baseline oxycodone 7.5 (±1.21), Pain baseline tapentadol 7.6 (±1.33)

Interventions Study medication: Tapentadol 200 - 500 mg/d (mean daily dosage 393 ± 117 mg/d); Oxycodon 40 - 100 mg/d (mean daily dosage 53 ± 23 mg/d); Placebo

Rescue medication: Paracetamol up to 1g for 3 consecutive days

Allowed cotherapies: TENS, acupuncture, physical therapy, packs, massages and other interventional adjunctive therapies were permitted during the study if the patients started the therapies ≥ 14 days before enrollment and continued on the same regimen during the study. SSRI or other antidepressants (non NSRI or MAO or TCA), if stable > 3 weeks

Outcomes Pain: Average pain intensity in the previous 12 hours NRS 0 - 10

Responder: 50% pain reduction NRS 0 - 10

PGIC: Much or very much improved

Function: SF-36 physical functioning; Only LSMD vs placebo reported (data for meta-analysis extracted from Chaparro)

Withdrawal due to lack of efficacy: Reported

Withdrawal due to adverse events: Reported

Serious adverse events: Reported

Deaths: Reported

Cloutier 2013


Study setting: 6 sites in Canada

Study design: Cross-over

Study duration: 2 - 7 days wash out, 4 weeks for each period

Participants Inclusion criteria: Adult patients (> 18 years) with low back pain of moderate or greater intensity for the previous three months or longer

Exclusion criteria: Recently undergone or ware to commence any other treatment (physiotherapy, corticosteroid injection, surgery); Required more than 12 tablets of 300/30 mg acetaminophen/codeine; Had pain that was expected to be refractory to continuous opioid therapy; Had a significant source of pain other than low back; Elevated liver enzymes higher than two times the upper limit or compromised kidney function; Corrected QT interval > 450 msec; known severe organ dysfunction; Chronic obstructive pulmonary diseases; Peptic ulcer; Inflammatory bowel disease; Psychological dependence on narcotics; Major psychiatric disorders such as major depression; Psychogenic pain; Involved in litigation that was related to pain

Total sample: N=54 (per protocol); mean age 50.6 years; 50% female; 94.4% white. Pain baseline 61.4 (±10.3)

Interventions Study medication: Oxycodone/naloxone flexible 40/20 mg/d or 60/30 mg/d or 80/40 mg/d (mean dosage 73/36 mg/d) placebo

Rescue medication: Acetaminophen/codeine 300/30 mg/ up to 6 times a day

Allowed cotherapies: Stable dosages of antidepressants or anticonvulsants

Outcomes Pain: Average pain intensity VAS 0-100

Responder: No 50% pain reduction rates reported

PGIC: Average values, but not number of patients reported who improved much or very

much

Function: Pain Disability Index 0-70

Withdrawal due to lack of efficacy: Not reported


Serious adverse events: Not reported

Deaths: Not explicitly stated

Notes "There was no indication for a carry over effect for both the per-protocol and ITT populations (p=0.70 and p=0.62)".

Gordon 2010


Study setting: Number of sites in the US and Canada not reported

Study design: Cross-over

Study duration: 2 - 7 days washout; 4 weeks each. The initial dose of buprenorphine 10 ug/h was titrated weekly to 20 mcg/h and a maximum of 40 mcg/ h using 10- and 20-mcg/h patches based on pain relief and adverse events

Participants Inclusion criteria: Men and nonpregnant women older than 18 years of age with low back pain of at least moderate severity (2 on a five-point ordinal scale) for more than six weeks duration that was inadequately treated with nonopioids were enrolled

Exclusion criteria: Patients whose analgesic requirement was expected to exceed the maximum BTDS dose, or who were refractory to opioid therapy or had an allergy to acetaminophen or opioids were excluded from the study. Patients who were undergoing any procedures or treatments (such as physiotherapy or surgery) that were likely to affect their pain, or those with a significant alternative source of pain, were also excluded, as were patients who would require the use of external heat sources. Other exclusion criteria included elevated liver function tests, severe organ dysfunction, head injury or seizures, chronic obstructive pulmonary disease, asthma, respiratory depression, cor pulmonale, heart failure, peptic ulcer disease or gastrointestinal tract inflammation. Patients with suspected psychological dependence on narcotic drugs or alcohol, or with a history of major psychiatric disorders were also excluded

Total: N=79; mean age 54.5 years; 47% female; race not reported. Pain baseline 61.4 (±16.4)

Interventions Study medication: Titration to individually optimal dosage buprenorphine 5, 10 or 20 ug/h (mean daily dosage 14.3 ± 6.3 μg/h); Placebo

Rescue medication: Codein 30 mg/acetaminophen 300 mg one to two tablets

every 4 to 6 h as required

Allowed cotherapies: Aspirin as antithrombotic ≥ 325 mg/d allowed

Outcomes Pain: Average pain intensity score NRS 0-100 daily diary


PGIC: Not assessed

Function: Pain Disability Index (data reported in figures; means and SD as reported by Chaparro)

Withdrawal due to lack of efficacy: Not reported




Notes There was no evidence for a carry over effect in either population (p=0.81 for ITT-population)

Hale 2007


Study setting: 30 sites in the US

Study design: Enriched enrollment randomized withdrawal

Study duration: Duration screening and washout not reported, duration open label titration not reported

12 weeks double-blind withdrawal

Participants Inclusion criteria: Patients ≥ 18 years with moderate to severe, chronic LBP that had been present for at least several hours each day for a minimum of 3 months. Patients were required to have been receiving stable ATC opioid pain medication equivalent to at least 60 mg/d of oral morphine for the management of their LBP for the 2 weeks before screening. Premenopausal women had to take appropriate birth control measures

Exclusion criteria: Pregnant or lactating women were not eligible for entry. In addition, patients with radiculopathy, fibromyalgia, reflex sympathetic dystrophy or causalgia, acute spinal cord compression, cauda equina compression, acute nerve root compression, severe lower extremity weakness or numbness, bowel or bladder dysfunction secondary to cauda equina compression, diabetic amyotrophy, meningitis, diskitis, or back pain caused by secondary infection or tumor were excluded from entry. Other exclusion criteria included having undergone a surgical procedure to resolve back pain within 6 months of screening, having pain as a result of a confirmed or suspected neoplasm, dysphagia or difficulty swallowing tablets, previous exposure to oxymorphone, hypersensitivity to opioid analgesics, history of seizure, or an ileostomy or colostomy

Placebo: N=72; mean age 46 years; 33.3% female; 88.9% white. Pain baseline 71.9 (±15.4)

Oxymorphone: N=70; mean age 48.2 years; 72% female; 84.3% white. Pain baseline 67.6

(±16.8)

Interventions Study medication: Oxymorphone flexible vs. placebo. Patients were to be initiated on a twice daily dose of oxymorphine that was approximately equivalent to the dosage of opioid analgesic that they were receiving at screening. Investigators converted patients from previous opioid therapy to OPANA ER on the basis of predefined ratios and their clinical experience. If the starting dose did not provide adequate pain relief, patients were to be titrated up by 10 mg (twice daily) increments every 3 to 7 days until a stabilized dose was reached. The stabilized daily dose was defined as one that was tolerated and reduced the average pain intensity score to 40 mm on a 100 mm visual analogue scale (VAS 0 = no pain to 100 = worst pain imaginable) for 3 of 5 consecutive days with no more than 2 doses of oxymorphone per day as a supplemental analgesic. During the titration period, patients were provided with oxymorphone (5 mg every 4 to 6 hours as needed) to be used as rescue for any breakthrough pain. All stabilized patients were randomized to either continue their fixed dose of (mean dosage 87 mg/d) or receive placebo

Rescue medication: Short-acting nonsteroidal anti-inflammatory drugs or other adjuvant analgesics were not permitted except for the treatment of nonpain symptoms (e.g., cardiovascular prophylaxis or fever)

Allowed cotherapies: For the duration of the study, patients had to agree to continue without change any adjunct therapy (e.g., physical therapy, biofeedback therapy, acupuncture therapy, or herbal remedies) and to forgo any local regional pain treatment that they were receiving for LBP before entry

Outcomes Pain: Change in average pain intensity from baseline VAS 0 - 100 at final study visit


PGIC: Not assessed

Function: Not assessed




Deaths: Reported

Notes

Hale 2010




Study duration: 2 to 4 weeks open label, 12 weeks double-blind withdrawal

Participants Inclusion criteria:

1. Patients must have been provided with written consent to participate in the study prior to any study procedures, and must understand that they are free to withdraw from the study at any time

2. Patients who can speak, read, write, and understand English and must be able to read and understand the consent form, complete study-related procedures, and communicate with the study staff.

3. Male and female patients aged 18 - 75 years, inclusive

4. Documented diagnosis of moderate to severe chronic low back pain that must have been present

5. Patients who are classified as non-neuropathic (class 1 and 2) or neuropathic (class 3, 4, 5 and 6) of LBP based on the Quebec Task Force Classification of Spinal Disorders will be enrolled for this study

6. Patients who require daily scheduled opioid analgesics for low back pain for at least 2 months prior to the screening visit

7. Patients with a daily opioid requirement of ≥ 60 mg oral morphine equivalent (≥ 12 mg hydromorphone), but ≤ 320 mg morphine (≤ 64 mg hydromorphone) per day within the 2 months prior to the screening visit

8. Patients who, in the investigator's opinion, are on a stable dose (≥ 2 weeks) of all prior analgesics (both opioid and non-opioid) prior to the screening visit

9. Female subjects of childbearing potential including those who have had a tubal ligation surgery but excluding those who have not experienced a menstrual period

for a minimum of 2 years, must have a negative serum pregnancy test at screening visit, and must consent to utilize a medically acceptable method of contraception throughout the entire study period including the washout period and for 1 week after the study is completed

Exclusion criteria:

1. Patients with an active diagnosis of fibromyalgia, complex regional pain syndrome (including reflex sympathetic dystrophy or causalgia), acute spinal cord compression, severe or progressive lower extremity weakness or numbness, bowel or bladder dysfunction as a result of cauda equina compression, diabetic amyotrophy, meningitis, diskitis, back pain because of secondary infection or tumor, or pain caused by a confirmed or suspected neoplasm

2. Patients who have undergone a surgical procedure for back pain within 6 months prior to the screening visit

3. Patients who have had nerve or plexus block, including epidural steroid injections or facet blocks, within 1 month prior to the screening visit

4. Patients with any other chronic pain condition that, in the investigator's opinion, would interfere with the assessment of low back pain (e.g., osteoarthritis, rheumatoid arthritis, postzoster neuralgia, pain associated with diabetic neuropathy, migraine headaches requiring opioid therapy)

5. Patients who are involved in an active workman's compensation or insurance claim or disability claim or litigation related to back pain

6. Patients who have by history used any illicit drugs of abuse, abused opioids or exhibited drug seeking behavior within 5 years prior to the screening visit.

7. Patients who have abused prescription medication or alcohol within 5 years prior to the screening visit. (See appendix 11 for the DSM-IV criteria for substance abuse)

8. Patients with a positive alcohol or drugs of abuse test

9. Women who are pregnant (as indicated by a positive result in a serum pregnancy test administered at screening visit), or breast feeding, or planning to breast feed within 30 days prior to the screening visit

10. Patients who have demonstrated allergic reactions or hypersensitivity to opioids

11. Patients who have had no bowel movement within three days, or bowel obstruction within 60 days, prior to the screening visit

12. Patients with pre-existing severe narrowing of the gastrointestinal tract secondary to: prior gastrointestinal surgery (e.g., vagotomy, antrectomy, pyroloplasty, gastroplasty, gastrojejunostomy) or gastrointestinal disease resulting in impaired gastrointestinal function (e.g., paralytic ileus, gastroparesis, inflammatory bowel disease, "short gut" syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudobstruction, or Meckel diverticulum)

13. Patients who have a major psychiatric condition (e.g., schizophrenia, major depression) or who have clinically significant anxiety or depression as defined by a HADS score greater than 10

14. Patients who have received monoamine oxidase (MAO) inhibitors within 14 days prior to the screening visit

15. Patients with clinically significant abnormal laboratory results in clinical chemistry, hematology or urinalysis as defined by appendix 9, including serum glutamic-oxaloacetic transaminase/aspartate aminotransferase (AST) or serum glutamic-pyruvic transaminase/alanine aminotransferase (ALT) ≥ 3.0 times the upper limit of the reference range or a serum creatinine ≥ 2.0 mg/dl at screening

16. Patients with a serious or unstable intercurrent illness

17. Patients with a history of uncontrolled seizure disorder

18. Patients with increased intracranial pressure, mental clouding of unknown etiology, coma, or hypotension

19. Patients who have severe asthma, severe chronic obstructive pulmonary disease, or

any other disorder that predisposes the patient to CO2 retention or respiratory depression

20. Patients who have taken any investigational drug within 30 days prior to the screening visit or are currently enrolled in another investigational drug study

Placebo: N=133; mean age 49.4 years; 54.9% female; 88.0% white. Pain baseline 6.5 (±1.88)

Hydromorphone: N=133; mean age 47.8 years; 45.9% female; 88.0% white. Pain baseline 6.3 (±1.94)

Interventions Study medication: In open-label-dose conversion/titration phase patients received hydromorphone extended release to provide doses of 12,16, 24, 32, 40, 48 or 64 mg/d. The conversion was accomplished by assuming a morphine equivalent hydromorphone potency ratio of 5:1. Patients meeting the following predefined stability criteria were included into double-blind phase: ≥ 12 mg and ≤ 64 mg hydromorphone/d; same dose of hydromorphone for at least 7 consecutive days; pain score ≥ 4 during stable dose period; ”Yes” to the question "Has this medication helped you enough so that you would continue to take the medication? No intolerable side effects"

Rescue medication: Hydromorphone immediate release 2, 4 and 8 mg during all phases of the study

Allowed cotherapies: No information provided

Outcomes Pain: Pain intensity on mean patient diary NRS 0-10; mean and SD extracted from figure

Responder: ≥ 50% reduction in pain intensity from screening to endpoint

PGIC: Not assessed




Serious adverse events: Reported*


Notes *All serious adverse events were labelled "non-fatal"

Katz 2007




Study duration: Duration screening and washout not reported, up to 10 days open label titration, 12 weeks double-blind withdrawal

Participants Inclusion criteria: Patients had to be opioid-naive (defined as taking less than 5 mg/day of oxycodone, or equivalent, for the 14 days before screening), 18 years of age or older, and have an initial pain intensity score of ≥ 50 mm (0 - 100-mm Visual Analog Scale). In addition, patients had to have reported at screening that they experienced moderate to severe CLBP that had been present daily for at least several hours per day for ≥ 3 months.

Exclusion criteria: Patients with reflex sympathetic dystrophy or causalgia (complex regional pain syndrome), acute spinal cord compression, cauda equina compression, acute nerve root compression, meningitis, and discitis were excluded. Patients were ineligible if they had a major organic psychiatric condition, serious or unstable intercurrent illness, medical conditions affecting drug absorption, history of uncontrolled seizure disorders, history of drug or alcohol dependence, or hypersensitivity to opioids. Patients who had undergone a surgical procedure for back pain within 2 months of screening or had nerve/plexus block within 4 weeks of beginning dose titration were also excluded. Patients with active or pending litigation involving back pain were excluded

Placebo: N=100; mean age 48.1 years; 50% female; 91% white. Pain before randomization 2.6 (±1.2)

Oxymorphone: N=105; mean age 51.3 years; 56.2% female; 88.6% white. Pain before randomization 2.8 (±1.3)

Interventions Study medication: Oxymorphone flexible vs. placebo. Current pain medications were

terminated the evening before the screening visit. Patients received oxymorphone ER 5 mg PO every 12 h for 2 days; thereafter, patients were to be titrated at increments of 5–10 mg every 12 h every 3 – 7 days until dose stabilization was achieved. A stable dose was one that provided both tolerability and efficacy (pain ≤ 40 mm on the VAS) for three of five consecutive days. Supplemental rescue medication was not permitted during the dose-titration period. Dose-stabilized patients were randomized into a 12-week double-blind treatment period in which they received their stabilized dose of oxymorphone ER or placebo every 12 h. All patients were allowed oxymorphone immediate release (IR) as rescue medication for breakthrough pain. During the first 4 days, patients were allowed up to 5 mg of oxymorphone IR every 4 – 6 h as needed; thereafter, rescue medication was restricted to a maximum of two doses each day. Mean daily dosage 40.05 ± 25.8 mg

Rescue medication: Short-acting nonsteroidal anti-inflammatory drugs or other adjuvant analgesics were not permitted except for the treatment of non-pain symptoms (eg, cardiovascular prophylaxis or fever)

Allowed cotherapies: Any physical biofeedback therapy, acupuncture therapy, or herbal remedies remained unchanged during the study

Outcomes

Pain: Change in average pain intensity from baseline VAS 0 - 100 at final study visit

Responder: 50% pain reduction baseline VAS 0–100 at final study visit

PGIC: Not assessed






Notes

Schnitzer 2000


Study setting: Number of sites in US not reported

Study design: Enriched-enrollment randomized withdrawal

Study duration: Up to 3 weeks washout, 3 week open label titration and 4 weeks double-blind withdrawal

Participants Inclusion criteria: 25 - 75 years with chronic low back pain severe enough to require daily medication for at least 3 months and in otherwise good health state: no or a distant history of back surgery: The protocol was later amended to allow inclusion of patients who had a single back surgery more than 5 years in the past that resulted in complete pain relief

Exclusion criteria: Neurological deficits in the lower extremities, tumors or infections of the meninges or spinal cord, back pain caused by a lesion manageable to surgery, other more severe pain in a location other than the low than back pain; fibromyalgia, disk herniation, spondylolisthesis, spinal stenosis, history of instability of lumbar vertebrae, vertebral fractures, tumors, infections, inflammatory disease; Significant hepatic or renal diseases; Morbid obesity; Borderline personality disorder; History of narcotic or alcohol abuse; Use of TENS; Corticosteroid therapy (local or systemical in the last 3 months); Score of at least 3 out of 5 on Waddell's test

Total randomised sample: N=254; mean age 47.1years; 50% female; 92.9% white. Pain baseline or randomisation not reported

Interventions Study medication: Tramadol flexible 100 - 400 mg/d. Patients were included into double-blind phase if they answered yes to the following question: Has this treatment helped your pain enough so that you would wish to continue to take this medication? Over the entire double-blind phase, the average daily dose of tramadol was 242 mg

Rescue medication: Not allowed

Allowed cotherapies: Continuation of physiotherapy allowed. Physiotherapy could not be initiated during open label or randomized phase

Outcomes Pain: Average pain intensity during last 24 hours VAS 0-10 at study visit at the end of double-blind phase


PGIC: Not assessed

Function: Roland Disability Questionnaire



Serious adverse events: Not reported


Notes

Steiner 2011


Study setting: 86 sites in US


Study duration: Up to 4 weeks open label, 12 weeks double-blind withdrawal

Participants Inclusion criteria: Age ≥ 18 years; moderate to severe low back pain persisting for a minimum of three months prior to study entry. Low back pain must have been the predominant pain condition and must have lasted several hours daily. Eligible patients were opioid naive (defined as patients who were receiving less than 5 mg of oxycodone or the equivalent in the 14 days prior to screening, and who did not have a history of daily opioid use of 5 mg or more of oxycodone or the equivalent for three months prior to screening, and who, in the opinion of the investigator, were not opioid dependent at time of entry to the study), had not benefited from or had not tolerated nonopioid therapy. Patients with low back pain that was related to nonmalignant conditions (e.g., intervertebral disc disease, spinal stenosis, spondylolysis, spondylolisthesis, and osteoarthritis) were eligible for inclusion. Patients must have had a QTc value of < 480 milliseconds and must have been eukalemic

Exclusion criteria: Patients were excluded if they presented with radicular symptoms, acute spinal cord compression, acute compression fracture, seronegative spondyloarthropathy, acute nerve root compression, cauda equina compression, fibromyalgia, reflex sympathetic dystrophy or causalgia (complex regional pain syndrome), diabetic amyotrophy, meningitis, discitis, gout, pseudogout, psoriatic arthritis, active Lyme disease, rheumatoid arthritis or other inflammatory arthritis, trochanteric bursitis, ischial tuberosity bursitis, neuropathic conditions, or back pain caused by secondary infection, tumor,or postherpetic neuralgia. Patients also were excluded if they had had surgery to treat their back pain within six months of screening or had planned to have such surgery during the study conduct period. The study also excluded

patients who required treatment with Class IA or Class III antiarrhythmic medications

Placebo: N=284; mean age 50.0 years; 58% female; 69% white. Pain baseline 7.2 (±1.2)

Buprenorphine: N=257; mean age 48.8 years; 52% female; 72% white. Pain baseline 7.2 (±1.3)

Interventions Study medication: Titration to individually optimal buprenorphine transdermal system 10 - 20 mg/h; patients with a two-point or more reduction from screening in ‘‘average pain over the last 24 hours’’ scores, and an ‘‘average pain over the last 24 hours’’ score for low back pain of 4 or less were randomised 1:1 to receive optimal fixed dose of buprenorphine transdermal system or placebo

Rescue medication: Oxycodon 5 mg capsules, up to 10 mg/day to be used as supplemental rescue medication during the first six days of the double-blind phase. Additionally, acetaminophen and ibuprofen were provided as supplemental rescue medication for weeks 2 to12 of the double-blind phase.

Allowed cotherapies: Acetaminophen and ibuprofen used for conditions other than chronic pain were permitted during the double-blind phase provided that the total daily doses (sponsor provided plus other sources) did not exceed 2 g or 800 mg, respectively. Nonsteroidal anti-inflammatory drugs, aspirin, and COX-2 inhibitors were permitted only for conditions other than chronic pain, including headache, fever, and cardiovascular disease prophylaxis. Muscle relaxants were allowed for the treatment of muscle spasms. Patients on stable regimens of antidepressants and anticonvulsants for uses other than pain treatment were allowed. Treatment with oral corticosteroids, glucosamine, chondroitin sulfate, transcutaneous electrical nerve stimulation, biofeedback, physical therapy, and relaxation therapy were allowed, provided treatment was considered stable by the investigator

Outcomes Pain: Average pain NRS 0 - 10 over the last 24 hours.

Responder: 50% pain reduction NRS 0 - 10

compared to screening

PGIC: Maintenance of much or very much improved compared to baseline

Function: Oswestry Disability Index; SF 36 physical functioning*;




Deaths: Reported

Notes *means, but no p-values and SDs of Oswestry Disability Index reported (data not used for meta-analysis); SF 36 physical functioning reported in Yarlas (2013); mean and SE extracted from figures

Vondrackova 2008

Methods Disease: Low back of mixed origin

Study setting: Number of sites in four European countries (Czech Republic, Germany, Hungary) not reported

Study design: Parallel design

Study duration: ≤ 7 days screening, 3 weeks tapering and titration, 12 weeks maintenance for oxycodone and withdrawal for placebo, 12 months open-label extension

Participants Inclusion criteria: Males and females ≥ 18 years of age were enrolled into the study if they had a documented history of moderate to severe chronic nonmalignant lower back pain (e.g., osteoarthrosis / osteoarthritis of spine, deforming spondylosis, spondylolisthesis, disc herniation/sciatica, spinal stenosis) adequately managed by an opioid analgesic for at least 2 weeks before study enrolment, and if they received daily opioid analgesic treatment and were likely to benefit from chronic opioid therapy for the duration of the study

Exclusion criteria: Any history of hypersensitivity to oxycodone, naloxone or related products; patients currently taking the equivalent of 10 mg or 40 mg/d oxycodone; patients diagnosed with cancer (not including basal cell carcinoma); active alcohol or drug abuse; abnormal liver function tests; and patients with a history of 2 lower back surgeries. Patients were also excluded if they had evidence of clinically significant cardiovascular, renal, hepatic, gastrointestinal (paralytic ileus), or psychiatric disease that would have placed the subject at risk upon exposure to the study medication or that could confound the analysis and/or interpretation of the study results

Oxycodone: N=151; mean age 56.7 years; 59.6% female; race and pain baseline not reported

Oxycodone/naloxone: N=154; mean age 55.8 years; 53.9% female; race and pain baseline not reported

Placebo: N=158; mean age 56.7 years; 70.9% female; race not reported

Interventions Study medication: Oxycodone. During the screening period (opioid taper), patients could receive oxycodone every 4 to 6 hours when necessary as rescue medication at a quarter of the dose of their previous total daily opioid medication. During the run-in period (opioid titration), the OxyIR dose was titrated to effect; the target dose was 20 or 40 mg/d. At the start of the double-blind phase, all randomized patients were converted from OxyIR to an equivalent study medication dose. Patients randomized to the oxycodone PR/naloxone PR treatment group received a dose of 10/5 mg or 20/10 mg of oxycodone PR/naloxone PR every 12 hours. Patients randomized to the oxycodone PR treatment group received 10 mg or 20 mg oxycodone PR every 12 hours. Patients randomized to the placebo group received matched placebo every 12 hours. Dosing was fixed and equivalent to the effective OxyIR dose identified during the run-in period (opioid titration)

Rescue medication: Oxycodone every 4 to 6 hours as required as rescue medication at a quarter of the dose of their total daily opioid medication, to be taken only if NRS ≥ 5


Outcomes Pain: Average pain intensity past 24 hours NRS 0 - 10*


PGIC: Not assessed





Deaths: Reported

Notes *No means and SDs reported; "Throughout the double-blind phase, patients in the oxycodone PR/naloxone PR (P 0.0396) and the oxycodone

PR (P 0.0080) treatment groups showed statistically significantly lower “Average pain over the last 24 hours” scores compared with placebo. Subjects in the placebo group had significantly higher BPI-SF pain subscores compared with subjects in the oxycodone PR group (P 0.0012) and oxycodone PR/naloxone PR group (P 0.0158).

Vorsanger 2008

Methods Disease: Chronic Low back pain

Study setting: 30 centers in the US


Study duration: (1) 2 - 7 days washout/ screening phase; (2) 3-week open-label run-in phase; (3) 12 weeks double-blind, placebo-controlled maintenance; 1 week follow-up

Participants Inclusion criteria: Chronic low back pain ≥ 6 months requiring daily treatment with NSAID, acetaminophen, opioid analgesic, COX-2 selective inhibitor, and/or muscle relaxant for at least 60 of 90 days preceding the screening visit. Pain intensity score ≥ 40 on a 100 mm VAS after 2 to 7 days washout

Exclusion criteria: Any medical condition other than low back pain which was not well controlled; Complex regional pain syndrome, significant inflammatory pain or fibromyalgia, history of lumbar spine surgery or chemonucleolysis, undergoing TENS or spinal manipulation, weight ≤ 45.4 kg, dysphagia or problems swallowing tablets; Intractable nausea or vomiting, previous intolerance to opioids; Elevated liver enzymes > two times the upper limits of normal, creatinine > 1.9 mg/dl; History of substance abuse within six months prior to screening; History of cancer in the previous three years; Pain unresponsive to appropriate dose adjustments or unacceptable side effects during open-label; Intra-articular viscosupplementation in the prior three months;

Placebo: N=129; mean age 47.6 years; 50.0% female; 87% white. Current pain intensity randomization 30.7 (±25.9)

Tramadol 200 mg/d: N=129; mean age 47.4 (± 13.8) years; 53% female; 83% white. Pain baseline not reportedCurrent pain intensity randomization 29.5 (±26.0)

Tramadol 300 mg/d: N=128; mean age 48.5 years; 47% female; 84% white. Current pain intensity randomization 26.8 (±23.7)

Interventions Study medication: Fixed dosage of 200 or 300

mg tramadol ER/d oral once daily; Placebo oral

Rescue medication: Low dose aspirin and acetaminophen. Patients were not permitted ot have received a monomamine oxydase (MAO) inhibitor or a tricyclic antidepressant in the prior 15 days. Patients were not permitted to use an NSAID, corticosteroid, opioid, or other analgesic during the study, with the exception of low-dose aspirin or acetaminophen. Other medications excluded during the study included neuroleptic medication, a selective serotonin reuptake inhibitor, a serotonin/norepinephrine reuptake inhibitor, carbamazepin (an inducer of tramadol metabolism), or quinidine (an inhibitor of tramadol metabolism)


Outcomes Pain: VAS 0 - 100


PGIC: Not assessed

Function: Roland Disability Index (0-24)



Serious adverse events: Reported*

Deaths: Reported

Notes *Nine serious adverse events; no data provided in which group

Webster 2006


Study setting: 45 sites in US


Study duration: 4 - 10 days washout,1 - 6 weeks titration, 12 weeks maintenance

Participants Inclusion criteria: Ages between 18 and 70 with persistent low back pain for at least 6 months, baseline pain intensity (PI) score 5 at the screening visit, a mean daily PI score 5 recorded in a diary over the last 3 days of a 4 - 10 day washout period while off all analgesics except acetaminophen, and a confirmatory PI score 5 at the baseline visit at the conclusion of the washout period. Patients taking a daily opioid dose equivalent to 20 mg of oxycodone required a taper, and a 72-h period of no opioid medication before screening was required of all patients

Exclusion criteria: Low back pain that was secondary to malignancy, autoimmune disease, fibromyalgia, recent fracture, or infection. Patients were also excluded for positive urine drug screens for any illicit substance at baseline, a history of substance abuse within 5 years, or involvement in litigation regarding their lower back condition. Further exclusion criteria included: Pregnancy; Known hypersensitivity to any of study medications; Severe hepatic, pulmonary, or renal impairment; Unstable cardiac disease, active malignancy, or history of leukemia, lymphoma, or metastatic cancer; Investigational drug use; Corticosteroid therapy; Intraspinal analgesic infusion or spinal cord stimulator in the preceding month; Major surgery in the preceding 3 months; Percutaneous or open procedure of the lumbosacral spine in the preceding 4 months; or high doses of central nervous system depressants or phenothiazines

Oxycodone twice/day: N= 206; mean age 47.9 years; 61.2% female; race not reported. Pain baseline 7.6 (1.36)

Oxycodone/Naltrexone twice/day: N=206; mean age 47.8 years; 61.7% female; race not

reported. Pain baseline 7.3 (±1.36)

Oxycodone/Naltrexone once/day: N=206; mean age 47.9 years; 61.7% female; race not reported. Pain baseline 7.6 (±1.33)

Placebo: N=101; mean age 48.7 years; 61.4% female; race not reported. Pain baseline 7.7 (±1.44)

Interventions Study medication: Oxycodone with and without naltrexone flexible 20-80 mg/d (mean daily dosage not reported), placebo

Rescue medication: No other analgesics were allowed during the treatment period. acetaminophen during washout

Allowed cotherapies: Tricyclic antidepressants, selective serotonin reuptake inhibitors, glucosamine/chrondroitin, or St. John’s wort were allowed if doses were stable for 4 weeks before study entry

Outcomes Pain: Average daily pain intensity diary NRS 0 - 10*


PGIC: Not assessed

Function: Owestry disability index**





Notes *Percentage pain reduction reported as outcome

**No means and SDs reported; "For the ODI, there were no significant differences between any of the treatment groups."

Überall 2012


Study setting: 31 sites in Germany


Study duration: 1 week washout, 4 weeks maintenance, 1 week follow-up

Participants Inclusion criteria: Men and women 18 - 75 years, a history of non-malignant low back pain ≥ 3 months; have been taken adequate analgesics for low back pain according to national LBP guideline; were dissatisfied with their current treatment, reported a baseline pain intensity ≥ 4 on a 11-point NRS scale

Exclusion criteria: LBP neurological in etiology, due to recent major trauma or visceral disorder: Clinically significant medical or psychiatric diseases; Inflammatory rheumatic or other disease with involvement of the spinal column; Metabolic bone disease; Spinal stenosis with neurological impairment; Spinal fractures; Anatomical abnormalities; Malignancy, Fibromyalgia; Infections of the central or peripheral nervous system; Herniated disc with neurological impairment; Seizure disorder; alcohol/analgesic/narcotic or other substance abuse within the past two years; history of spinal surgeries; renal or hepatic impairment;

Tramadol: N=116; Mean age 57.6 years; 61.2% female; 95.8% white; average pain baseline: 6.0 (±1.2)

Placebo: N=120; Mean age 59.2 years; 55.8% female; 98.3% white; average pain baseline: 6.1 (±1.4)

Interventions Study medication: Flupirtine 400 mg/d fixed, tramadol 200 mg/d fixed, placebo

Rescue medication: Diclofenac up to 150 mg/d. Patients were urged to discontinue rescue medication at least 24 h before any clinical visit

Allowed cotherapies: No other drug or pharmacological therapy allowed.

Outcomes Pain: Average low pain intensity last 24 hours NRS 0 - 10

Responder: 50% pain reduction

PGIC: Much or very much improved

Function: SF-12 and Quality of life impairment by pain inventory; detailed results not reported*




Deaths: Reported

Notes *SF-12 and Quality of life impairment by pain inventory improved significantly within all three study groups vs. baseline (p<0.001) each, but only minor and statistically insignificant differences were found with respect to treatment-related between group differences"

Supplementary table 2: Risk of bias assessment

Buynak 2010

Bias Authors'

judgment Support for judgment

Random sequence generation

(selection bias) "randomization was based on a computer generated randomization list, balanced by randomly permuted blocks and stratified by study site. (2.2. study design)"

Allocation concealment (selection

bias) ”Randomization was implemented through an interactive voice response system"

Blinding of participants and

personnel (performance bias) ”double dummy design"

Blinding of outcome assessment

(detection bias) Unclear whether the researchers took any approach to blind the clinicians who monitored the opioid titration

Incomplete outcome data (attrition

bias) ITT analysis by LOCF reported: however, the number of patients remaining in the ITT population decreased with time of the study (see figure 3)

Selective reporting (reporting bias) The trial was registered at clinicaltrials.gov (NCT00449176); the primary and the secondary outcomes were consistent in the protocol compared with the publication

Selection bias No significant baseline differences in demographic and clinical variables between the three groups

Funding bias Study sponsored and statistical analysis performed by the manufacturer of one drug. Eight of nine authors affiliated with manufacturer of the drug

Low risk

Low risk

Low risk

Unclear risk

High risk

Low risk

Low risk

High risk

Cloutier 2013

Bias Authors'



(selection bias) "Computer-generated random list of patient numbers was generated by biostatistician"


bias) "Patients entering the study were centrally allocated"


personnel (performance bias) Double dummy technique


(detection bias) "Patients, investigator and all clinical research stuff were blinded". Outcomes assessors could be biased on the side effects profile of oxycodone


bias) Only responder analysis published for disability outcome

Selective reporting (reporting bias) The trial was registered ISRCTN35931095); the primary and the secondary outcomes were consistent in the protocol compared with the publication; SAE not reported


Funding bias Study funded by pharmaceutical company; 3/12 authors (including senior author) affiliated with pharmaceutical company

Low risk

Low risk

Low risk

Unclear risk

High risk

High risk

Unclear risk

High risk

Gordon 2010

Bias Authors'



(selection bias) “The randomization code was generated using PROC PLAN in SAS version 6.12 (SAS Institute Inc., Cary, North Carolina)"


bias) “A block-randomization procedure was used to generate the treatment allocations: for every 4 successive patients, 2 received BTDS in the first phase and 2 received BTDS in the second phase. Study monitors, investigators, coordinators, pharmacists, patients, and sponsor clinical research personnel remained blinded to treatment allocation throughout the conduct of the study”


personnel (performance bias) The study used matching placebo patches


(detection bias) Clinical personnel remained blinded to treatment allocation. Outcomes assessors could be biased by the side effects profile of buprenorphine


bias) ITT analysis, method not reported

Selective reporting (reporting bias) The trial was registered at Current Controlled Trials: ISRCTN 06013881; the primary and the secondary outcomes were consistent in the protocol compared with the publication

Selection bias Not applicable (cross-over design)

Funding bias 4 of 8 authors affiliated with pharmaceutical industry

Low risk

Low risk

Low risk

Unclear risk

Unclear risk

Low risk

Low risk

High risk

Hale 2007

Bias Authors'



(selection bias) "Computer-generated randomization"


bias) The authors did not document the method for concealment of allocation.


personnel (performance bias) The authors did not report the physical characteristics of the placebos


(detection bias) We had insufficient information to permit judgment. Outcome assessors could be biased by side effects of oxymorphone


bias) No ITT analysis: "An imputation method was not applied to missing pain intensity values."



Funding bias The affiliation of 4 of 5 study authors was the pharmaceutical company which sponsored the study

Low risk

Unclear risk

Unclear risk

Unclear risk

Unclear risk

Low risk

Low risk

High risk

Hale 2010

Bias Authors'



(selection bias) "Computer-generated randomization"


bias) "Interactive voice response system to encode patient's assignment to one of the two treatment groups"


personnel (performance bias) "matching placebo"


(detection bias) "All personnel involved in the double-blind phase were blinded to medication codes". Outcomes assessors could be biased by the side effects profile of buprenorphine


bias) LOCF or BOCF depending on type of outcome



Funding bias The affiliation of 1 of 4 study author (senior author) was the pharmaceutical company which sponsored the study

Low risk

Low risk

Low risk

Unclear risk

Unclear risk

Low risk

Low risk

High risk

Katz 2007

Bias Authors' judgment

Support for judgment


"A randomization code was generated by the sponsor to ensure the appropriate number of patients was allocated to each treatment group at random". No additional information provided


We had insufficient information to permit judgment


"The tablets of oxymorphone ER and placebo were over-encapsulated with gelatin to ensure that patients, investigator/study staff, and sponsor staff remained blind to study treatment."


Outcome assessors could be unblinded by the side effects of oxymorphone


ITT analysis, method not reported

Selective reporting (reporting bias) NCT00225797. All outcomes of protocol were reported in the full text publication

Selection bias No significant baseline differences in demographic and clinical variables between the groups

Funding bias The study was sponsored by the manufacturer of the drug. 2 of 6 authors were affiliated with the manufacturer of the drug

Unclear risk

Unclear risk

Low risk

Unclear risk

Unclear risk

Low risk

Low risk

High risk

Schnitzer 2000




"Computer-generated random numbers"




"Identical appearing capsules of tramadol and placebo"


We had insufficient information to permit judgment. Outcomes assessors could be bias based on the side effects profile of tramadol


ITT analysis, method not detailed

Selective reporting (reporting bias) No protocol available

Selection bias No separated data of patients with tramadol and placebo provided

Funding bias Study funded by manufacturer of the drug

Low risk

Unclear risk

Low risk

Unclear risk

Unclear risk

Unclear risk

Unclear risk

High risk

Steiner 2011




We had insufficient information to permit judgment.


We had insufficient information to permit judgment.


The authors did not report the physical characteristics of the placebos.


No information provided. Outcomes assessors could be bias based by the side effects profile of buprenorphine


ITT analysis according to LOCF and BOCF

Selective reporting (reporting bias) NCT00490919; 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


Funding bias Funding by pharmaceutical industry; all authors affiliated with industry

Unclear risk

Unclear risk

Unclear risk

Unclear risk

Low risk

High risk

Unclear risk

High risk

Vondrackova 2011








The authors did not report the physical characteristics of the placebos


No information provided. Outcomes assessors could be biased by the side effects profile of oxycodone


ITT analysis, No further information provided

Selective reporting (reporting bias) No protocol reported by the authors; pain outcomes incompletely reported and not suited for meta-analysis

Selection bias Pain baseline not reported

Funding bias Funding by pharmaceutical industry; 6 of 11 authors affiliated with manufacturer of the drug

Unclear risk

Unclear risk

Unclear risk

Unclear risk

Unclear risk

High risk

Unclear risk

High risk

Vorsanger 2011




Computer-generated randomization schedule


No information provided


Only tramadol ER 100 mg and placebo tablets were used in the study and they were identical in appearance and texture to maintain the double-blind


Outcome assessors could be biased by the side effects profile of tramadol


ITT analysis, method not reported

Selective reporting (reporting bias) No protocol reported by the authors; no information provided in which group serious adverse occurred

Selection bias No significant baseline differences in demographic and clinical variables

Funding bias First author affiliated with manufacturer of the drug

Low risk

Unclear risk

Low risk

Unclear risk

Unclear risk

High risk

Low risk

High risk

Webster 2011






"All study medications were identical in appearance,"


"Patients, site personnel, and study monitors were blinded to treatment assignments"


No information provided. Outcomes assessors could be bias based on the side effects profile of oxycodone


ITT analysis by LOCF

Selective reporting (reporting bias) No protocol reported by the authors; data of outcome function were incompletely reported and could not be used for meta-analysis


Funding bias Funding by pharmaceutical industry

Unclear risk

Low risk

Low risk

Unclear risk

Unclear risk

High risk

Low risk

High risk

Überall 2012




"Computer-generated allocation list"




"All study medications were identical in appearance"


We had insufficient information to permit judgment. Outcome assessors could be blinded by the side effects of tramadol and flupirtine


ITT by LOCF

Selective reporting (reporting bias) EudraCT 2009-013268-38. Secondary outcomes incompletely reported

Selection bias No significant baseline differences in demographic and clinical variables between the two groups

Funding bias Study sponsored by manufacturer of the drug. 1 of 3 authors affiliated with manufacturer of the drug

Low risk

Unclear risk

Low risk

Unclear risk

Unclear risk

High risk

Low risk

High risk

Documents

Der Schmerz,2015, 29(1).60-72_s1