Opioids in chronic low back pain

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Schwerpunkt English version of „Opioide bei chronischem Kreuzschmerz. Systematische Übersicht und Metaanalyse der Wirksamkeit, Verträglichkeit und Sicherheit in randomisierten, placebo­ kontrollierten Studien über mindestens 4 Wochen” DOI 10.1007/s00482-014-1449-8 © Deutsche Schmerzgesellschaft e.V. Published by Springer-Verlag Berlin Heidelberg - all rights reserved 2014

F. Petzke1 · P. Welsch2 · P. Klose3 · R. Schaefert4 · C. Sommer5 · W. Häuser6, 7 1 Schmerz-Tagesklinik und -Ambulanz, Universitätsmedizin Göttingen, Göttingen 2 Stichting Rugzorg Nederland, Ede 3 Abteilung für Natuheilkunde und Integrative Medizin, Kliniken Essen-Mitte, Essen 4 Allgemeine und Innere Medizin, Universitätsklinikum Heidelberg, Heidelberg 5 Neurologische Klinik, Universitätsklinikum Würzburg, Würzburg 6 Klinik und Poliklinik für Psychosomatische Medizin und Psychotherapie,

Technische Universität München, München 7 Innere Medizin I, Klinikum Saarbrücken gGmbH, Saarbrücken

Opioids 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

Supplementary material online This article contains supplementary evidence reports and tables. These are available at: dx.doi.org/10.1007/s00482-014-1426-2

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]. Medications (nonsteroidal agents, muscle relaxants, antidepressants) play an important role in the management of CLBP. The use of opioids remains a controversial issue in the management of chronic noncancer pain (CNCP) and of CLBP in particular [27]. The American College of Physicians and The American Pain Society consensus guidelines for the treatment of LBP recommend opioids for the shortterm management of severe and disabling LBP that does not respond to anti-inflammatories or acetaminophen. Notably, this guideline was published in 2007 and reviewed in only a few trials [5]. The German 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 response to paracetamol or nonsteroidal anti-inflammatory drugs (NSAIDs). Strong opioids were not specifically recommended and their potential use was suggested within an overall multimodal therapeutic approach. Therapy >12 weeks was only recommended if the desired pain relief or improvement in physical function was accomplished. The guideline recommendations were based on a qualitative review of the literature [3]. A recent systematic Cochrane review on opioids in CLBP [4] searched the literature up until October 2012. The authors distinguished between short-term (4–12 weeks), intermediate-term (13– 26 weeks) and long-term (>26 weeks) trials. They pooled results of trials with parallel/cross-over and enriched enrolment randomized withdrawal (EERW) designs. The authors found evidence for shortterm efficacy (moderate for pain and small for function) of opioids for treating 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 administration 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 determine the efficacy and harms of opioids compared to placebo in patients of any age with CLBP in short-term (4–12 weeks), intermediate term (13–26 weeks) and longterm (>26 weeks) trials separated for parallel/cross-over and ERRW designs.

Methods The review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [15] and the recommendations of the Cochrane Collaboration [13].

The English full-text version of this article is free­ ly available at SpringerLink (under “Supplemen­ tal”). Der Schmerz 1 · 2015 

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Schwerpunkt

Criteria for considering studies for this review Types of studies

We included fully published double-blind randomized controlled trials (RCTs) that compared any opioid to placebo (pure or pseudo) for therapeutic purposes. We included studies with parallel and enriched enrolment withdrawal (EERW) designs. Studies with a cross-over design were included 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), statistical 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; doubleblind withdrawal phase for EERW). Studies should include at least 10 patients per treatment arm. We grouped outcome measures according to the timing of postrandomization follow-up: short-term (4–12 weeks), intermediate (12–26 weeks) and longterm (longer than 26 weeks) [4]. We placed no restriction on the language of the publication. We excluded studies with duration of the titration/maintenance or withdrawal period of less than 4 weeks; with a parallel design that included only responders in the double-blind phase after complete tapering of opioids after the end of openlabel run-in phase; with an experimental design (i.e. if the primary purpose was to study pain mechanisms and not pain relief) and studies which were only published as abstracts. We excluded studies in which different dosages of one opioid were compared without a control group.

Types of participants

We included men and women of all ages and races or ethnicities with clinically diagnosed CLBP. Trials exclusively including patients with inflammatory arthritis, 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.

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Der Schmerz 1 · 2015

Types of interventions

We 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 formulations (ADFs; e.g naltrexone). We included studies with tramadol, a centrally acting, synthetic opioid analgesic with two complementary mechanisms of action: binding of parent and M1 metabolite to μ-opioid receptors and inhibition of reuptake of norepinephrine and serotonin. We included studies with tapentadol 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 regulatory agencies. We considered only trials comparing opioids to placebo. We excluded trials that examined opioids given by intravenous or spinal routes, including implantable pumps due to the invasive nature of the therapy and its limited clinical relevance in the outpatient setting. We did not assess the effectiveness of opioids used in neuraxial implantable pumps as this has been discussed elsewhere [19]. We excluded 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 combined with opioids (e.g. tramadol with acetaminophen), 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 without naloxone) without a placebo arm, or in which opioid combinations were compared to a single opioid. We excluded studies in which opioids were compared to nonpharmacological treatments. We excluded studies 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 measures

The selection of outcomes was based on the recommendations of the ACTINPAIN writing group of the International Association for the Study of Pain (IASP) Special Interest Group (SIG) on Systematic Reviews in Pain Relief and those of the Cochrane Pain, Palliative and Supportive Care Systematic Review Group editors for reporting meta-analyses of RCTs in chronic pain [17]. We included pain intensity as additional outcome because most studies conducted before 2005 did not report responder analyses [4].

Outcomes Efficacy

1. Pain intensity ratings. 2. Proportion of patients reporting 50% pain relief. 3. Global improvement: number of patient reports to be much or very much improved. 4. Function: examples of functional outcomes that could be extracted as follows: Brief Pain Inventory; Multidimensional Pain Inventory (physical function); Neck Disability Index; Oswestry Disability Index; Pain Disability Index, Physical Disability; Roland Disability Questionnaire, Short Form (SF)-36 or SF-12 (physical functioning scale). Where both generic and disease-specific instruments were used, we preferred disease-specific instruments (e.g. Oswestry Disability Index over SF-36 physical functioning scale). 5. Proportion of patients who dropped out due to lack of efficacy.

Tolerability

1. Proportion of patients who withdrew because of adverse events.

Safety

1. Proportion of patients who experienced any serious adverse events. 2. Proportion of patients who died during the study We excluded studies in which the primary outcome measure was not one of the five outcomes of efficacy defined above.

Abstract

Search methods for identification of studies Electronic searches

The review updated and expanded the literature search of the first version of LONTS, which searched the literature up until October 2008 [23]. The updated and expanded search included the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Scopus from October 2008 to October 2013 and all types of CNCP. The search was conducted by PK. Our search included all languages.

Searching other resources

The search strategy has been detailed in another paper of this issue [25].

Data collection and analysis Selection of studies

Two authors (PW, WH) independently screened titles, abstracts and keywords of trials identified by the search strategies to determine whether the references met the inclusion criteria. We obtained the full-text of trials that either appeared to meet the criteria or for which we considered their inclusion was uncertain. We screened these articles for inclusion and resolved any disagreements through discussion.

Data extraction

Using standardized forms, three pairs of authors (CS, WH; FP, WH; RS, WH) independently extracted data on inclusion and exclusion criteria of studies, participant characteristics, intervention group, clinical setting, interventions, country of study and study sponsorship. If data were not available in a format that was appropriate for data extraction, we did not contact the authors of the trial for further clarification. We resolved any disagreements through discussion.

Dealing with missing data

If both baseline observation carried forward (BOCF) and last observation carried forward (LOCF) data were reported for an intention-to-treat (ITT) analysis, we preferred BOCF data [17].

Schmerz 2014 · [jvn]:[afp]–[alp]  DOI 10.1007/s00482-014-1426-2 © Deutsche Schmerzgesellschaft e.V. Published by Springer-Verlag Berlin Heidelberg - all rights reserved 2014 F. Petzke · P. Welsch · P. Klose · R. Schaefert · C. Sommer · W. Häuser

Opioids 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 Abstract Background.  The efficacy and safety of opi­ oid therapy in chronic low back pain (CLBP) is under debate. We updated a recent system­ atic review on the efficacy and safety of opi­ oids in CLBP. Methods.  We screened MEDLINE, Scopus and the Cochrane Central Register of Con­ trolled Trials (CENTRAL) up until October 2013, as well as reference sections of original studies and systematic reviews of random­ ized controlled trials (RCTs) of opioids in CLBP. We included double-blind randomized place­ bo-controlled studies of at least 4 weeks du­ ration. Using a random effects model, abso­ lute risk differences (RD) were calculated for categorical data and standardized mean dif­ ferences (SMD) for continuous variables. Results.  We included 12 RCTs with 17 treat­ ment arms and 4375 participants. Median study duration was 12 (4–16) weeks. Of the 17 treatment arms, seven (41.2%) used oxy­ codone; four (23.6%) tramadol; buprenor­ phine and oxymorphone were each used in two (11.8%) and hydromorphone and tapen­ tadol each in one (5.8%). The results for stud­ ies with parallel/cross-over design were as follows (with 95% confidence interval, CI): opioids were superior to placebo in reduc­ ing pain intensity (SMD −0.29 [−0.37, −0.21], p=50% of the total patient collective of the systematic review coming from studies in which patients with relevant somatic disease and/or major mental disorders were excluded. F Imprecision: there was only one trial or when there was more than one trial, the total number of patients was 6 weeks >3 months for several h/day

None None

Hale et al. [36]

At least 60 mg ME (but 3 months for several h/day

Schnitzer et al. [38]

On daily medication (not further specified)

>3 months for several hours/day

Steiner et al. [39]

Nonresponder to nono­ pioids

>3 months for several hours/day

Vondrackowa et al. [41]

Daily opioid with adequate effect for at least 2 weeks

Not specified

None Neurological etiology or signs/ symptoms, infection, malignan­ cy, surgery in the last 6 months Neurological etiology or signs/ symptoms, infection, malignan­ cy, surgery in the last 6 months Neurological etiology or signs/ symptoms, infection, malignan­ cy, surgery in the last 2 months Neurological deficits, malignan­ cy, infection, surgical indication, spondylolisthesis, disk hernia­ tion, spinal stenosis, instability, no surgery for 5 years Malignancy, radicular symptoms, neural compression, spondy­ larthtropathy, rhreumatological conditions, infection, no surgery the last 6 months Malignancy, more than one back surgery

Vorsanger et al. [42]

On daily medication (60 of 90 days), opioid or nono­ pioid No information

>6 months

Cloutier et al. [33] Gordon et al. [34] Hale et al. [35]

Webster et al. [43]

Überall et al. [40]

>6 months

Adequate analgesics accord­ >3 months ing to NVL, yet dissatisfied

Malignancy, inflammatory, his­ tory of surgery or chemonucle­ olysis Malignancy, autoimmune etiol­ ogy, infection, fracture, surgery in the last 4 months, spinal pump, SCS Malignancy, neurological etiology, inflammatory, spinal fractures, spinal stenosis or disc problem with neurological impairment, anatomical abnor­ malities, history of surgery

Quebec classification of low back pain class 1–6 Nonneuropathic None

None

Nonmalignant, spinal stenosis, intervertebral disc disease, spondylolisthesis, osteoarthritis of the spine Mixed origin, osteoarthritis of the spine, spondylosis, disc herniation, sciatica, spi­ nal stenosis None

None

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.

level p