Plain language summary
Opioids for the treatment of chronic low-back pain
We reviewed the evidence about the effect of opioids on pain and function among people with chronic low-back pain (CLBP).
Opioids are pain relievers that act on the central nervous system. People with low-back pain (LBP) use these drugs to relieve pain. We examined whether the use of opioids for at least four weeks was better or worse than other treatments of CLBP.
We searched for trials, both published and unpublished, up to October 2012. We included fifteen trials which included 5540 participants and compared opioids against a placebo (fake medication) or other drugs that have been used for LBP. Most people included in the trials were aged 40 to 50 years and all reported at least moderate pain across the low-back area. The trials included a slightly higher proportion of women. Most of the trials followed the patients during three months and were supported by the pharmaceutical industry.
In general, people that received opioids reported more pain relief and had less difficulty performing their daily activities in the short-term than those who received a placebo. However, there is little data about the benefits of opioids based on objective measures of physical functioning. We have no information from randomized controlled trials supporting the efficacy and safety of opioids used for more than four months. Furthermore, the current literature does not support that opioids are more effective than other groups of analgesics for LBP such as anti-inflammatories or antidepressants.
This review partially supports the effectiveness of several opioids for CLBP relief and function in the short-term. However, the effectiveness of prescribing of these medications for long-term use is unknown and should take into consideration the potential for serious adverse effects, complications, and increased risk of misuse, abuse, addiction, overdose, and deaths.
As expected, side effects are more common with opioids but non-life-threatening with short-term use. Insufficient data prevented making conclusions about the side-effect profile of opioids versus other type of analgesics (for example, antidepressants or anti-inflammatories).
Quality of the evidence
The quality of evidence in this review ranged between "very low" and "moderate". The review results should be interpreted with caution and may not be appropriate in all clinical settings. High quality randomized trials are needed to address the long-term (months to years) risks and benefits of opioid use in CLBP, their relative effectiveness compared with other treatments, and to better understand which people may benefit most from this type of intervention.
Opioidi u usporedbi s placebom ili drugim terapijama za kroničnu križobolju
U ovom Cochrane sustavnom pregledu analizirani su dokazi iz literature o učinku opioida na bol i funkciju među ljudima s kroničnom križoboljom.
Opioidi su lijekovi za ublažavanje boli koji djeluju na središnji živčani sustav. Osobe koje pate od križobolje ponekad uzimaju te lijekove za ublažavanje boli. U ovom je sustavnom pregledu istraženo je li uporaba opioida kroz najmanje 4 tjedna bolja ili lošija u usporedbi s drugim terapijama za kroničnu (dugotrajnu) križobolju.
Autori sustavnog pregleda tražili su klinička ispitivanja, i objavljena i neobjavljena, dostupna do listopada 2012. Uključeno je 15 studija s ukupno 5540 ispitanika te su u njima uspoređeni opioidi s placebom (lažni lijek) ili drugim lijekovima koji su korišteni za liječenje kronične križobolje. Većina ispitanika koji su sudjelovali u studijama imali su 40-50 godina te su svi opisali da pate barem od umjerene boli u području donjeg dijela leđa. Ispitivanja su uključila nešto veći broj žena nego muškaraca. Većina ispitivanja pratila je pacijente kroz 3 mjeseca i financirala ih je farmaceutska industrija.
Općenito, osobe koje su primili opioide opisale su bolje ublažavanje boli i manje problema s obavljanjem dnevnih aktivnosti kroz kratko vrijeme praćenja nego osobe koje su primile placebo. Međutim, malo je podataka o korisnom učinku opioida koji se temelje na objektivnim mjerama tjelesnog funkcioniranja. Nisu pronađene inforamacije iz randomiziranih kontroliranih studija koje su istražile djelotvornost i sigurnost opioda za kroničnu križobolju za trajanje terapije dulje od 4 mjeseca. Nadalje, trenutno dostupna literatura ne podržava stav da su opioidi djelotvorniji nego druge skupine lijekova protiv bolova za kroničnu križobolju, kao što su protuupalni lijekovi ili antidepresivi.
Ovaj sustavni pregled djelomično podržava djelotvornost nekolicine opioida za ublažavanje boli i popravljanje funkcije kod osoba koje pate od kronične križobolje, kroz kratko vrijeme. međutim, djelotvornost tih lijekova pri dugoročnom uzimanju nije poznata, i pri tom bi svakako trebalo uzeti u obzir potencijalno ozbiljne nuspojave opioida, njihove komplikacije i povećani rizik od zlouporabe tih lijekova, ovisnosti, predoziranja i smrti.
Kao što se i moglo očekivati, nupojave opioida bile su česte ako se uzimaju tijekom kratkog vremena kao u analiziranim studijama, ali nisu ugrožavale život. Trenutno imamo nedovoljno podataka za donošenje zaključaka o nuspojavama opioida u odnosu na druge tipove analgetika (kao što su protuupalni lijekovi ili antidepresivi) zbog manjkavosti tih podataka u pronađenim studijama.
Kvaliteta dokaza je bila u rasponu od vrlo niske do umjerene. Rezultati ovog sustavnog pregleda trebaju se razmotriti sa zadrškom jer možda nisu primjereni za sve kliničke uvjete i ne odnose se nužno na sve pacijente. Potrebna su daljnja kvalitetna randomizirana istraživanja kako bi se otkrile kratkoročne i dugoročne koristi od uporabe opioida kod kronične križobolje, njihove učinkovitosti u usporedbi s drugim terapijama, te za bolje razumijevanje koji pacijenti mogu imati najviše koristi od te vrste intervencije.
Prevela: Livia Puljak
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: firstname.lastname@example.org
Resumo para leigos
Opioides para o tratamentos de dor lombar crônica
Questões de revisão
Foi revisada as evidência sobre os efeitos de opioides na dor e função entre pessoas com dor lombar crônica (DLC).
Os opióides são analgésicos que atuam sobre o sistema nervoso central. Pessoas com dor lombar crônica (DLC) usam esses medicamentos para alívio da dor. Foi avaliado se o uso de opioides por pelo menos quatro semanas era melhor ou pior do que outros tratamentos para DLC.
Características do estudo
Foi pesquisado ensaios clínicos, publicados ou não, até Outubro de 2012. Foram incluídos 15 ensaios clínicos com 5540 participantes que comparavam opioides versus placebo (substância inerte) ou outros fármacos que tem sido utilizados para DLC. A maioria das pessoas incluídas nos ensaios clínicos tinham entre 40 a 50 anos e todos relataram pelo menos uma dor moderada ao redor da área lombar. Os ensaios incluíram uma pequena proporção de mulheres. A maioria dos ensaios acompanharam os pacientes durante três meses e eram apoiados por indústrias farmacêuticas.
Em geral, pessoas que utilizaram opioides relataram mais alívio da dor e tiveram menos dificuldades na realização de atividades diárias em curto prazo do que aqueles que receberam um placebo. No entanto, há poucos dados sobre os benefícios dos opióides baseado nos objetivos medidos da função física. Não há informação de ensaios clínicos controlados e randomizados que apoiam a eficácia e segurança do uso de opioides por mais de quatro meses. Além disso, a literatura atual não suporta que opioides são mais efetivos do que outros grupos de analgésicos para DLC, tais como anti-inflamatórios ou antidepressivos.
Esta revisão parcialmente corrobora com a efetividade de vários opioides para alívio da DLC e função em curto prazo. No entanto, a eficácia da prescrição destes medicamentos para uso a longo prazo é desconhecido e deve levar em consideração o potencial para efeitos adversos graves, complicações e aumento do risco de mau uso, abuso, dependência, overdose, e mortes.
Como esperado, os efeitos colaterais são mais comuns com opióides, mas não ameaçam a vida com o uso a curto prazo. Dados insuficientes impediram tirar conclusões sobre o perfil de efeitos colaterais dos opióides versus outro tipo de analgésicos (por exemplo, antidepressivos ou anti-inflamatórios).
Qualidade da evidência
A qualidade da evidência nesta revisão variou entre "muito baixo" e "moderado". Os resultados da revisão devem ser interpretados com cautela e podem não ser apropriados em todos os casos clínicos. Ensaios clínicos randomizados de alta qualidade são necessários para abordar riscos e benefícios a longo prazo (meses ou anos) do uso de opióides na DLC, a sua eficácia relativa em comparação com outros tratamentos, e para compreender melhor quais pessoas podem se beneficiar mais com este tipo de intervenção.
Notas de tradução
Notas de tradução CD004959.pub4
쉬운 말 요약
만성 요통 치료를 위한 아편 유사제
우리는 만성 요통 환자의 통증과 기능에 대한 아편 유사제의 효과에 관한 근거를 조사했다.
아편 유사제는 중추 신경계에 작용하는 통증완화제이다. 요통 환자는 이 약으로 통증을 줄인다. 우리는 아편 유사제를 최소 4주 사용하면 다른 만성 요통 치료제보다 효과가 있는지를 조사했다.
우리는 2012년 10월 까지의 발표 및 미 발표 시험들을 검색했다. 우리는 5,540명을 대상으로 하여 아편 유사제를 위약(가짜 약) 또는 만성 요통 약과 비교한 15건의 시험을 확인했다. 시험 참가자의 대부분은 40세 - 50세였고, 모두 허리 아래 부위에 최소 중간 정도의 통증이 있었다. 여성 참가자가 조금 더 많았다. 대부분의 시험은 환자를 3개월 간 사후 관리했고, 제약업계로부터 지원을 받았다.
대체로, 아편 유사제 치료를 받은 사람들은 위약 그룹보다 단기적으로 통증이 많이 경감되었고 일상생활의 어려움이 적다고 보고했다. 그러나, 신체적 기능을 객관적으로 측정한 자료를 기반으로 한 아편 유사제의 편익에 관한 데이터는 거의 없다. 아편 유사제를 4개월 이상 사용하는 방법의 효과와 안전성을 지지하는 무작위배정 비교임상시험연구에서 나온 정보가 없다. 또, 현재의 문헌들은 아편 유사제가 항염증제 또는 항우울제와 같은 다른 진통제보다 효과적이라는 점을 지지하지 않는다.
본 연구에서는 일부 아편 유사제가 단기적으로 만성 요통 완화와 기능에 효과적이라는 점을 부분적으로 지지한다. 그러나, 아편 유사제를 오래 사용하도록 처방하는 효과는 알려진 바 없으며, 심각한 부작용, 합병증과 오용, 남용, 중독, 과용 및 사망 위험이 상승할 가능성을 고려해야 한다.
예상대로, 아편 유사제의 부작용은 매우 자주 발생하나, 단기간 사용한다면 치명적이지는 않다. 데이터가 충분치 않아서 아편 유사제와 기타 진통제(예: 항우울제 또는 항염증제)의 부작용 양상에 대해 결론을 내릴 수 없었다.
본 연구의 근거의 질은 “매우 낮음”에서 “중간 정도”에 걸쳐 있다. 본 연구 결과는 신중히 해석되어야 하며, 모든 임상적 세팅에 적합하지 않을 수도 있다. 질 높은 무작위 시험으로 만성 요통 치료를 위한 아편 유사제 사용에 따른 장기적(몇 개월 - 몇 년간) 위험과 편익, 다른 치료법과 비교한 아편 유사제의 상대적 효과를 밝히고, 이러한 중재로 어떤 사람들에게 가장 많은 편익이 있는지에 관해 보다 더 이해해야한다.
코크란연합 한국지부에서 번역하였다.
Description of the condition
Low back pain (LBP) is the main cause of pain, disability, social and financial cost throughout the world (Volinn 1997; Vos 2012). Approximately 80% of people will experience at least one episode of acute back pain during their lifetime (Cassidy 1998). Almost one quarter of North Americans are estimated to have experienced an episode of LBP within the previous three months (Deyo 2006). Although an early review concluded that 80% to 90% of people with chronic low back pain (CLBP) improve by 12 weeks (Shekelle 1995), a proportion continue to report symptoms over several months and even years. In one study, one-third of people with CLBP continued to be symptomatic after 12 months (Thomas 1999). More recent reviews suggest that the prevalence of LBP is around 23% (Vos 2012). Moreover, a substantial proportion of people with back pain will have recurrences even after the resolution of initial symptoms (Von Korff 1996).
CLBP and functionality
LBP is the main cause of disability-adjusted life years (DALYs) worldwide (Vos 2012) and the prevalence of CLBP-related disability is estimated at 11% (Vos 2012). Individuals with CLBP not only experience personal distress, but also present with significant sleep disorders and disability (Gore 2012). According to an early study (Spitzer 1987), fewer than 50% of individuals with CLBP who missed work for more than 12 weeks actually returned to work. An absence of two years from employment was associated with almost no chance of returning to work.
Description of the intervention
The vast majority of CLBP treatments are directed towards symptomatic and functional improvement rather than cure. Patients may be offered a variety of treatment regimens as either monotherapy or a combination of therapies. Treatments may include medications and physical modalities (for example, transcutaneous electrical nerve stimulation (TENS), massage therapy, work hardening), rehabilitation, or injection therapy (such as, epidurals, facet joint blocks, and trigger point injections) that are directed specifically at potential anatomic causes for CLBP. A proportion of individuals with CLBP will undergo surgery to alleviate their symptoms. Despite general acceptance of lumbar discectomy, with or without decompression, and lumbar fusion (with or without instrumentation), the actual success rates for symptomatic and functional improvement have been variable, with surgical 'failure' rates estimated between 10% and 40% (Fritsch 1996; Ostelo 2003). Furthermore, the results are similar with surgery or pharmacological therapy (Peul 2007). These individuals often return to the pool of patients with CLBP, and they often experience poor outcomes regardless of future treatment. Medications play an important role in the management of CLBP and generally fall into four broad categories: non-steroidal anti-inflammatory drugs (NSAIDs), antidepressants, muscle relaxants, and analgesics including opioids.
Opioids are generally classified as either weak or strong. These terms refer to relative efficacy rather than potency; weak opioids exhibit a ceiling to their analgesic effect, limited principally by increased adverse reactions. The use of opioids remains a controversial issue in the management of chronic non-cancer pain (CNCP) (Furlan 2010), and CLBP in particular (Turk 2011). The American College of Physicians & The American Pain Society consensus guidelines for the treatment of LBP recommend opioids for the short-term management of severe and disabling LBP that has had no response with anti-inflammatories or acetaminophen. Notably, this guideline was published in 2007 and includes only a few trials (Chou 2007). In contrast, the American Geriatrics Society Guidelines have suggested that given the problems of NSAIDs and cyclooxygenase-2 (COX-2) inhibitors, opioids should be considered first line treatment for moderate-to-severe pain in older adults (Ferrell 2009). However, recent evidence links the abuse of opioids to negative social consequences (Bohnert 2011).
Controversies with use of opioids
Although many clinicians believe that opioids offer a valuable tool in the management of CNCP, there is still a large group of practitioners who remain hesitant, or even opposed to, the use of these medications. A survey of Canadian physicians exploring attitudes towards opioid use for chronic pain confirmed that 35% of general practitioners and 23% of palliative care physicians would never use opioids for the management of severe CNCP (Morley-Foster 2003). A recent study of opioid prescribing stratified across the United States by region and by medical specialty found that 41.5% of respondents prescribed long-term opioids in fewer than 20% of their CNCP patients (Wilson 2013). Clinicians reluctant to prescribe opioids to treat people with CNCP believe that side-effects (Wilson 2013), somnolence resulting in poor function, the risk of abuse (Von Korff 2004), and general ineffectiveness of opioids may outweigh any potential benefit. Several trials have demonstrated that rather than underlying pathology, characteristics such as age, depression, personality disorder, and substance abuse, distinguished patients with CLBP who were on opioids from those who were receiving non-opioid treatments (Turk 1997; Breckenridge 2003; Edlund 2007). These trials continue to contribute to the confusion and uncertainty regarding the indications and actual benefits of opioids in CLBP. A recent survey among Canadian primary care physicians revealed that the most common fears for opioid prescription were abuse, overdose, and early prescription renewals (Wenghofer 2011).
How the intervention might work
Current evidence suggests that opioids are effective for the treatment of CNCP in the short-term (Furlan 2010), irrespective of somatic or neuropathic etiology. The diverse mechanisms of action of opioids across the central and peripheral nervous system can be the reason for unpredictable responses to these medications. More importantly, they can lead to the potential development of adverse effects, including development of addictive behaviour.
Why it is important to do this review
This is an update of a Cochrane review that was published in 2007 (Deshpande 2007). The original review included only four RCTs. Three of the trials included tramadol and a fourth trial evaluated morphine and oxycodone in an open-label fashion.
Our primary objective was to determine whether opioids were effective in improving pain, or function, or both, in individuals with CLBP.
Our secondary objectives were to determine the effectiveness of opioids in:
Patients with CLBP with or without prior spinal surgery;
Patients with CLBP with or without radicular symptoms (patients with symptoms radiating into the buttock or leg irrespective of radiological or electrophysiological evidence);
Patients with CLBP managed with tramadol;
Patients with CLBP managed with transdermal buprenorphine;
Patients with CLBP managed with strong opioids.
Criteria for considering studies for this review
Types of studies
We included published RCTs with a blinded assessment of outcomes that compared any opioid to placebo or any other drug with analgesic properties. We had no restriction on the language of the publication.
Types of participants
We included male and female participants, aged 18 years or older, that had persistent pain in the low-back for at least 12 weeks, with or without radiating symptoms to the legs or prior low-back surgery (failed back surgery syndrome).
We defined LBP as pain occurring below the lower ribs and above the gluteal folds, including the buttocks. We defined failed back surgery syndrome as back pain, leg pain, or both, lasting longer than six months from the date of surgical intervention, or pain that began prior to one year from the date of intervention, after the individual had achieved symptomatic relief.
We excluded patients with cancer, infections, inflammatory arthritic conditions (including osteoarthritis [OA]) or compression fractures. We also excluded trials where < 50% of participants had CLBP or study authors failed to report results separately for this specific cohort
Types of interventions
We included trials that examined the use of any opioid prescribed in an outpatient setting, for a period of one month or longer. We considered trials with opioids given by oral, transdermal, mucosal (nasal or rectal), or intramuscular routes, administered either alone or in combination with other interventions, such as: pharmacological therapy (for example, anti-inflammatories, antidepressants, sedatives), physical modalities (for example, TENS, chiropractic), exercise, or alternative pain management techniques (for example, acupuncture).
We required opioids to be prescribed for a period of one month or longer to provide relevant feedback to the clinician and identify trials that may simulate actual clinical practice patterns. We excluded trials that examined opioids given by intravenous route, including implantable pumps, due to the invasive nature of the therapy and its limited clinical relevance in the outpatient setting. We did not assess the effectiveness of opioids used in neuraxial implantable pumps as this has been discussed elsewhere (Noble 2008).
We considered trials with the following comparisons:
Opioids compared to placebo;
Opioids compared to no treatment;
Opioids compared to non-pharmacological treatments;
Opioids compared to other pharmacological agents, alone or in combination (for example, NSAIDs, muscle relaxants, anti-depressants);
Opioids given in combination with other pharmacological agents (for example, NSAIDs, muscle relaxants, anti-depressants) or non-pharmacological treatments compared to other pharmacological or non-pharmacological treatments, either alone or in combination.
We excluded trials where comparisons were made between opioids.
Types of outcome measures
Trials must have reported on at least one of four primary outcome measures for efficacy:
Pain ratings: verbal rating scale, visual analog scale or final visit pain score.
Function: Oswestry Disability Index (ODI), Roland-Morris Disability Questionnaire (RMDQ) or Quebec Back Pain Disability Scale (QBPDS).
Global improvement: patient satisfaction or quality of life improvements.
Proportion of patients reporting 30% or 50% pain relief.
Work-related disability: time on compensation, return-to-work, or productivity.
Treatment-related adverse effects.
Others: healthcare usage, non-opioid medication consumption, addiction, or overdose-related events.
We grouped outcome measures according to the timing of post-randomization follow-up: very short-term (less than one month), short-term (between one and three months), intermediate (greater than three but less than six months) and long-term (longer than six months).
Search methods for identification of studies
We searched the following databases for relevant trials: MEDLINE (OVID) 1966 to Oct 2012; EMBASE (OVID) 1980 to Oct 2012; Cochrane Library, Central Register of Controlled Trials (Wiley) 2012, Issue 10; PsycINFO (OVID) 1967 to Oct 2012; and CINAHL (Ebsco) 1982 to Oct 2012. We performed electronic searches with the assistance of an experienced librarian, using the sensitive searches recommended by the Cochrane Back Review Group (Furlan 2009). We have presented the search strategy for MEDLINE in Appendix 1. We adapted this search strategy as indicated to search the other databases (see Appendix 2). We examined references provided in the trials we identified from the database search and relevant systematic reviews for further trials. We also tracked the citations of identified relevant trials.
Data collection and analysis
We followed the methods recommended by the Cochrane Back Review Group (Furlan 2009).
Selection of studies
Two teams of two authors each (AF and LEC; LEC and AD) independently screened titles, abstracts, and keywords of trials that we identified by the search strategies to determine if the references met the inclusion criteria. We obtained the full text of trials that either appeared to meet criteria or for which we considered their inclusion was uncertain. We screened these articles for inclusion and we resolved any disagreements through discussion.
Data extraction and management
Three authors (LEC, AD, AF) independently extracted data, using the standardized forms developed by the Cochrane Back Review Group, on characteristics of participants, intervention group, clinical setting, method of recruitment, interventions, primary and secondary outcomes, opioid abuse or addiction, side effects, country of study, and sponsorship of study. If data were not available in a format that was appropriate for data extraction, we contacted the authors of the trial for further clarification. We resolved any disagreements through discussion.
Given the similarities in populations, methodology, interventions and outcomes, we pooled data from trials comparing opioids to placebo (using Review Manager (RevMan)). We performed meta-analyses (both fixed-effect and random-effects methods) on the outcomes of pain, function, and side effects. If we noted a significant statistical discrepancy between methods, we reported the more conservative result. We reported the results of pain and function from the pooled data as standardized mean difference (SMD) with a 95% confidence interval (CI). We reported side effects using absolute risk differences (RD) with a 95% CI.
We used the GRADE approach, as recommended by the Cochrane Collaboration (Higgins 2011) and by the updated Cochrane Back Review Group method guidelines (Furlan 2009). Following GRADE guidelines, we categorized the quality of evidence as follows:
· High: further research is very unlikely to change the confidence in the estimate of effect.
· Moderate: further research is likely to have an important impact in the confidence in the estimate of effect.
· Low: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
· Very low: any estimate of effect is very uncertain.
We graded the evidence available on specific domains as follows:
1. Study design
In this review we only included randomized, controlled, double-blinded trials.
2. Risk of bias
Three authors (LC, AD and AF) independently evaluated the risk of bias of the selected articles, based on criteria described in the Cochrane Back Review Group's updated methods guidelines (Furlan 2009). We scored each criterion as "low risk", "high risk", or "unclear". We have presented the description of this evaluation in Appendix 3. We examined all trials for five types of bias:
Selection (random sequence generation, allocation concealment, group similarities at baseline)
Performance (blinding of participants, blinding of healthcare providers, co-interventions, and compliance with intervention)
Attrition (dropouts and intention-to-treat (ITT) analysis)
Measurement (blinding of the outcome assessors and timing of outcome assessment)
Reporting bias (selective reporting)
We used the overall risk of bias for each trial in the GRADE synthesis. When all trials were judged as "low risk of bias" for all five categories, we did not downgrade the evidence. We downgraded the evidence by one point when less than three categories were judged "high or unclear". We downgraded the evidence by 2 points when four or more categories were judged "high or unclear".
Inconsistency refers to an unexplained heterogeneity of results. Widely differing estimates of the treatment effect (such as, heterogeneity or variability in results) across trials suggest true differences in underlying treatment effect. Inconsistency may arise from differences in: populations (for example, drugs may have larger relative effects in sicker populations), interventions (for example, larger effects with higher drug doses), or outcomes (for example, diminishing treatment effect with time). This item does not apply when there is only one trial. We downgraded the quality of evidence by one point when the heterogeneity or variability in results was large (for example: I2 > 80%). We downgraded by two points when the heterogeneity or variability in results was large and there was inconsistency arising from populations, interventions, or outcomes.
We assessed whether the question being addressed in this systematic review was different from the available evidence regarding the population, intervention, comparator, or an outcome. We downgraded the quality of evidence by one point when there was indirectness in only one area; and by two levels when there was indirectness in two or more areas.
Results are imprecise when trials include relatively few patients and few events and thus have wide CIs around the estimate of the effect.
For dichotomous outcomes, we considered imprecision for either of the following two reasons:
(1) There was only one trial. When there was more than one trial, the total number of events was < 300 (a threshold rule-of-thumb value) (Mueller 2007).
(2) 95% CI around the pooled or best estimate of effect included both (1) no effect and (2) appreciable benefit or appreciable harm. The threshold for "appreciable benefit" or "appreciable harm" is a relative risk reduction (RRR) or relative risk increase (RRI) > 25%. We downgraded the quality of the evidence by one point when there was imprecision due to (1) or (2); or by two levels when there was imprecision due to (1) and (2).
For continuous outcomes, we considered imprecision for either of the following two reasons:
(1) There was only one trial. When there was more than one trial, the total population size was < 400 (a threshold rule-of-thumb value; using the usual α and β, and an effect size of 0.2 SD, representing a small effect).
(2) 95% CI included no effect and the upper or lower CI crosses an effect size (standardized mean difference) of 0.5 in either direction. We downgraded the quality of the evidence by one point when there was imprecision due to (1) or (2); or by two points when there was imprecision due to (1) and (2).
6. Publication bias
Publication bias is a systematic underestimate or an overestimate of the underlying beneficial or harmful effect due to the selective publication of trials. We downgraded the quality of the evidence by one point when the funnel plot suggested publication bias.
7. Magnitude of the effect
We did not assess this in the review.
8. Dose response gradient
We did not assess this in the review.
9. Influence of all plausible residual confounding
We did not assess this in the review.
We prepared the summary of findings tables following published guidelines from the Cochrane Collaboration (Higgins 2011).
We used GRADEprofiler 3.6 to prepare the GRADE tables and Summary of Findings Tables.
We included 15 RCTs in this review that assessed the use of opioids for longer than four weeks in the management of CLBP. Overall, the quality of the evidence ranged from very low to moderate regarding use of opioids compared to placebo for pain and functional outcomes. The magnitude of the effect sizes were small to medium. All trials suffered from attrition bias with a large number of drop-outs. Many trials employed an enriched enrolment design which is known to under-report adverse events (Furlan 2011). The duration of the included RCTs was longer than four weeks but shorter than 15 weeks. Also, there was poor generalizability to populations at high risk for complications. We identified very few active-controlled (non placebo-controlled) trials. We identified an insufficient number of trials that examined use of tramadol compared to NSAIDS (such as celecoxib) or compared use of opioids with use of antidepressants to treat people with CLBP.
1) Strict inclusion criteria and duration of treatment
In the included trials, CLBP was well-defined. However, these trials imposed limitations by excluding patients who presented with pain outside this area (even those with radicular symptoms), had previous unsuccessful lumbar surgery or a history of substance abuse. Given the heterogeneous nature of the CLBP population, narrowly defined criteria prevent extrapolation of results to a more diverse group commonly seen in clinical settings. Importantly, exclusion of failed back surgery syndrome is also significant since it may occur in 10% to 40% of lumbar spine operations and contributes to CLBP (Oaklander 2001).
Our review excluded trials of opioid use in CLBP that were shorter than four weeks. Only two trials followed the participants for more than three months (15 weeks) (Buynak 2010; Steiner 2011). While these trials lasted substantially longer than most involving opioids and CLBP, we consider these articles to have a 'short-term' time frame. This limited treatment duration, when in reality patients are often treated for years, leaves important unanswered questions including long-term efficacy, safety, tolerance and pain sensitivity (Ballantyne 2003). Only one study focused on the potential development of opioid tolerance (Chu 2012), but the participants were followed for only one month. The high drop-out rate in the included studies demonstrates the huge challenge of developing double-blinded and placebo-controlled studies for long-term follow-up. We recommend that future studies should compare opioids to other analgesics with the goal of obtaining long-term data on relative effectiveness and safety. These studies should also enroll patients commonly presenting with CLBP, including those with prior spine surgery and at variable risk for opioid misuse or abuse (for example, explicitly identifying risk using valid questionnaires).
2) Poorly-defined study population
In the included RCTs that compared opioids with placebo, the study authors did not report sufficient information regarding the history of study populations. Although study authors documented demographic data well, many studies neglected to report other parameters affecting outcomes, such as duration of pain prior to enrolment, employment or compensation status or poor response to previous treatment, including opioids (Sanders 1986; Greenough 1993; Andersson 1999). Thus we were unable to compare intervention and placebo arms based on potentially relevant factors other than age, sex and race. Finally, all studies permitted physiotherapy under certain circumstances, but none of the trials reported the number of patients who may have received concurrent treatment or the types of therapy these patients obtained.
3) Limited interpretation of functional improvement
Most of the studies used validated questionnaires to assess functional outcomes. As noted by our results, the pooled SMD favoured in a moderate grade the use of tramadol or strong opioids for improvement of the functional outcomes. Further information is required for any recommendation for transdermal buprenorphine.
An additional limitation regarding functional outcomes is the difficulty associated with the interpretation of these data in meaningful economic or social activities, such as return-to-work or improvement in ADLs. This issue is not specific to these trials, but highlights a problem present in the pain literature when attempting to interpret improvement registered in research-based tools alone.
4) High drop-out rates and ITT analysis
Most studies had significant drop-out rates (> 20%). Although the reasons were clearly documented, the implications on final outcomes could be significant. Experimental mortality (loss of patients during the trial) with greater loss in the control arm could enhance the effect seen in favour of treatment. In addition, substantial drop-outs reduce the power of the study, compromising the ability to detect a significant difference. Overall, interpretation of the study outcomes with any level of confidence is questionable, given the significant number of drop-outs.
Several studies stated that efficacy analysis was performed on the ITT population. However, some of them failed to perform a proper ITT. The method of handling absent data for patients lost to follow-up was documented through the use of LOCF. This method has been criticized given the potential overestimation of the effect (Moore 2012).
5) Comparison to other reviews on opioids in CNCP and CLBP
Two recently published systematic reviews have addressed the issue of opioids in the pharmacological management of CNCP (Furlan 2011) and CLBP (Kuijpers 2011). Furlan 2011 concluded that opioids were more effective than placebo for improving both pain and function in the management of CNCP. The results were significant for both neuropathic and nociceptive pain. Subgroup analyses revealed that only strong opioids (oxycodone and morphine) were statistically more effective in reducing pain but not function when compared to naproxen and nortriptyline. Kuijpers 2011 evaluated opioids, antidepressants and NSAIDs for CLBP; however, they excluded patients with sciatica. Several studies that we included in our review were not considered in Kuijpers 2011 due to timing of publication. Their conclusion regarding the effectiveness of opioids does not differ from our conclusion.
Our review confirms the effectiveness of tramadol, buprenorphine and strong opioids in the management of CLBP in the short-term. Other systematic reviews on opioids in people with CNCP have included people with multiple pathologies. This factor and the predominance of short-term studies could limit any meaningful interpretation when considering opioids for the long-term management of CLBP.
The results of our review differ from another published systematic review (Martell 2007). The review (Martell 2007) included 15 studies in the literature assessing the efficacy of opioids in CLBP. Nine of the studies considered comparisons among different opioids, while another six compared opioids with placebo or other analgesics. Meta-analysis of this latter group was completed with four of the six studies. The review authors found that opioids were ineffective in the management of CLBP when compared to the pooled sample of placebo and other analgesics.
The existence of discordant reviews has been previously described in the literature (Jadad 1997; Furlan 2001). The only common clinical query between our review and that of Martell 2007 related to the efficacy of opioids in CLBP. Notably, the two reviews used different outcomes to define the efficacy of opioids. Our review considered pain and function as outcome measures. Also, there were differences between inclusion and exclusion criteria. Our review restricted original articles to opioid treatment that was longer than one month in duration to provide more meaningful clinical interpretation in the management of CLBP. We excluded comparisons among opioids to avoid issues with head-to-head trials or equivalency determinations. We also considered only articles published in peer-review journals. Taking these criteria into account, we excluded nine trials (all opioid comparators) found in Martell 2007 from our review. From the six trials comparing the efficacy of opioids to placebo or another analgesic, we excluded five from our review for the following reasons: two trials were published in abstract form (Tennant 1993; Richards 2002), two trials had a treatment duration of less than 30 days (Kuntz 1996; Muller 1998) and one trial had a lack of randomization when comparing opioids to placebo (Hale 2005; Characteristics of excluded studies). The three trials (all involving tramadol) we used to derive our meta-analyses were absent from the Martell 2007 review. Although not specifically stated in their inclusion and exclusion criteria, the review authors may have excluded tramadol as an opioid, given its atypical status. Finally, Martell 2007 combined studies involving placebo and other comparators to determine efficacy. In this case, conceptual homogeneity may not have existed due to differences in patient response to an active control compared with placebo. Statistical pooling of these studies may lead to questionable results.
Many people experience recurring episodes of LBP or never fully recover from their initial episode (Abenhaim 1988; Von Korff 1996). With direct and indirect costs estimated to exceed $100 billion annually in the United States alone, LBP continues to inflict a huge economic toll on society (Hashemi 1997; Katz 2006). Opioids have become a popular tool to help manage patients with CLBP. The prevalence of opioid prescribing in CLBP varies by treatment setting but has been found to be as low as 3% or as high as 66% (Martell 2007). Moreover, the same review (Martell 2007) identified prescription of opioids to be more common to patients with impaired functional status. Despite significant concerns surrounding the use of opioids, there is still little evidence in the literature for their efficacy and effectiveness in long-term treatment of CLBP. Although few systematic reviews suggest that opioids are effective in the management of CNCP in general, the extrapolation of this evidence to CLBP is cautioned. Further, the few original studies that do exist focusing on opioids for the management of CLBP are of limited value in clinical practice given their lack of long-term follow-up and description of long-term safety profile. As the pendulum has swung from an 'opiophobic' to an 'opiophilic' society, physicians should question whether the current trend is based on evidence or simply the outcries of well-intentioned patient advocates and aggressive marketing efforts by the pharmaceutical industry (Chinellato 2003).
We are grateful to Rachel Couban (Cochrane Back Review Group Trials Coordinator) for assisting with literature searches and Ute Bültmann for helping to translate the non-English language study. We would like to gratefully and sincerely thank Teresa Marin (Managing Editor, Cochrane Back Review Group) for her invaluable assistance on the manuscript preparation.
Appendix 1. MEDLINE search strategy
1 randomized controlled trial.pt.
2 controlled clinical trial.pt.
3 Randomized Controlled Trials/
4 Random Allocation/
5 Double-Blind Method/
6 Single-Blind Method/
8 Animal/ not Human/
9 7 not 8
10 clinical trial.pt.
11 explode Clinical Trials/
12 (clinical$ adj 25 trial$).tw.
13 ((singl$ or doubl$ or trebl$ or tripl$) adj(mask$ or blind$)).tw.
17 Research Design/
18 (latin adj square).tw.
20 19 not 8
21 20 not 9
22 Comparative Study/
23 explode Evaluation Studies/
24 Follow-Up Studies/
25 Prospective Studies/
26 (control$ or prospective$ or volunteer$).tw.
27 Cross-Over Studies/
29 28 not 8
30 29 not (9 or 21)
31 9 or 21 or 30
32 PAIN/pc, dt, rh, th [Prevention & Control, Drug Therapy, Rehabilitation, Therapy]
33 Chronic Disease/dt, pc, rh, th [Drug Therapy, Prevention & Control, Rehabilitation, Therapy]
34 (chronic adj3 pain).mp
35 Low Back Pain/
36 (low adj back adj pain).mp
37 or/ 32-36
38 exp Analgesics, opioid/
52 or/ 38-51
53 31 and 37 and 52
Appendix 2. Other search strategies
1 exp Clinical Trial/
2 exp randomization/
3 Double Blind Procedure/
4 Single Blind Procedure/
6 exp animal/
8 6 or 7
9 exp human/
10 8 not 9
11 5 not 10
12 (clinical$ adj25 trial$).tw.
13 ((singl$ or doubl$ or trebl$ or tripl$) adj (mask$ or blind$)).tw.
14 exp Placebo/
17 methodology/ or latin square design/
18 (latin adj square).tw.
20 19 not 10
21 20 not 11
22 comparative study/
24 Follow Up/
25 Prospective Study/
26 (control$ or prospective$ or volunteer$).tw.
27 Crossover Procedure/
29 28 not 10
30 29 not (11 or 21)
31 30 or 21 or 11
32 exp Chronic Pain/
33 exp PAIN/pc, rh, dt, th [Prevention, Rehabilitation, Drug Therapy, Therapy]
34 exp Chronic Disease/pc, rh, dt, th [Prevention, Rehabilitation, Drug Therapy, Therapy]
35 33 and 34
36 32 or 35
37 (chronic adj3 pain$).tw.
38 exp Low Back Pain/
39 (low adj back adj pain$).tw.
41 exp Narcotic Analgesic Agent/
56 31 and 40 and 55
S69 S53 and S68
S68 S54 or S55 or S56 or S57 or S58 or S59 or S60 or S61 or S62 or S63 or S64 or S65 or S66 or S67
S67 (MH "Tramadol") OR "tramadol"
S66 (MH "Sufentanil") OR "sufentanil"
S65 (MH "Propoxyphene") OR "propoxyphene"
S64 (MH "Pentazocine") OR "pentazocine"
S62 (MH "Oxycodone") OR "oxycodone"
S61 (MH "Morphine+") OR "morphine"
S60 (MH "Meperidine") OR "meperidine"
S56 (MH "Fentanyl+") OR "fentanyl"
S55 (MH "Codeine+") OR "codeine"
S54 (MH "Analgesics, Opioid+")
S53 S28 and S52
S52 S48 or S51
S51 S49 or S50
S50 (MM "Chronic Disease/DT/PC/RH/TH")
S49 (MM "Pain/PC/DT/RH/TH")
S48 S35 or S43 or S47
S47 S44 or S45 or S46
S45 (MH "Spondylolisthesis") OR (MH "Spondylolysis")
S44 (MH "Thoracic Vertebrae")
S43 S36 or S37 or S38 or S39 or S40 or S41 or S42
S42 lumbar N2 vertebra
S41 (MH "Lumbar Vertebrae")
S37 (MH "Sciatica")
S36 (MH "Coccyx")
S35 S29 or S30 or S31 or S32 or S33 or S34
S34 lumbar N5 pain
S33 lumbar W1 pain
S31 (MH "Low Back Pain")
S30 (MH "Back Pain+")
S28 S26 NOT S27
S27 (MH "Animals")
S26 S7 or S12 or S19 or S25
S25 S20 or S21 or S22 or S23 or S24
S21 followup stud*
S20 follow-up stud*
S19 S13 or S14 or S15 or S16 or S17 or S18
S18 (MH "Prospective Studies+")
S17 (MH "Evaluation Research+")
S16 (MH "Comparative Studies")
S15 latin square
S14 (MH "Study Design+")
S13 (MH "Random Sample")
S12 S8 or S9 or S10 or S11
S9 (MH "Placebos")
S8 (MH "Placebo Effect")
S7 S1 or S2 or S3 or S4 or S5 or S6
S3 clinical W3 trial
S2 "randomi?ed controlled trial*"
S1 (MH "Clinical Trials+")
#1 MeSH descriptor: [Back Pain] explode all trees
#4 MeSH descriptor: [Low Back Pain] explode all trees
#5 lumbar next pain OR coccyx OR coccydynia OR sciatica OR spondylosis
#6 MeSH descriptor: [Spine] explode all trees
#7 MeSH descriptor: [Spinal Diseases] explode all trees
#8 lumbago OR discitis OR disc near degeneration OR disc near prolapse OR disc near herniation
#9 spinal fusion
#10 spinal neoplasms
#11 facet near joints
#12 MeSH descriptor: [Intervertebral Disk] explode all trees
#15 failed near back
#16 MeSH descriptor: [Cauda Equina] explode all trees
#17 lumbar near vertebra*
#18 spinal near stenosis
#19 slipped near (disc* or disk*)
#20 degenerat* near (disc* or disk*)
#21 stenosis near (spine or root or spinal)
#22 displace* near (disc* or disk*)
#23 prolap* near (disc* or disk*)
#24 MeSH descriptor: [Sciatic Neuropathy] explode all trees
#26 back disorder*
#27 back near pain
#28 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27
#29 MeSH descriptor: [Analgesics, Opioid] explode all trees
#46 #29 or #30 or #31 or #32 or #33 or #34 or #35 or #36 or #37 or #38 or #39 or #40 or #41 or #42 or #43 or #44 or #45
#47 #28 and #46 in Trials
1 clinical trials/
2 controlled trial.mp.
4 (Random* adj3 trial).mp.
5 (clin* adj3 trial).mp
6 (sing* adj2 blind*).mp.
7 (doub* adj2 blind*).mp.
8 placebo.mp. or exp Placebo/
9 latin square.mp.
10 (random* adj2 assign*).mp.
11 prospective studies/
12 (prospective adj stud*).mp.
13 (comparative adj stud*).mp.
14 treatment effectiveness evaluation/
15 treatment effectiveness evaluation/
16 (evaluation adj stud*).mp.
17 exp Posttreatment Followup/
18 follow?up stud*.mp.
20 back pain/
21 lumbar spinal cord/
22 (low adj back adj pain).mp.
23 (back adj pain).mp.
24 spinal column/
25 (lumbar adj2 vertebra*).mp.
30 back disorder*.mp.
31 "back (anatomy)"/
32 ((disc or disk) adj degenerat*).mp.
33 ((disc or disk) adj herniat*).mp.
34 ((disc or disk) adj prolapse*).mp.
35 (failed adj back).mp.
37 exp opiates/
38 exp analgesic drugs/
39 codeine.mp. or exp Codeine/
40 fentanyl.mp. or exp Fentanyl/
44 exp Meperidine/ or meperidine.mp.
45 morphine.mp. or exp Morphine/
48 pentazocine.mp. or exp Pentazocine/
50 tramadol.mp. or exp Tramadol/
54 36 and 53
55 19 and 54
Appendix 3. Criteria for risk of bias assessment for RCTs
Random sequence generation (selection bias)
Selection bias (biased allocation to interventions) due to inadequate generation of a randomized sequence
There is a low risk of selection bias if the investigators describe a random component in the sequence generation process such as: referring to a random number table, using a computer random number generator, coin tossing, shuffling cards or envelopes, throwing dice, drawing of lots or minimization (minimization may be implemented without a random element, and this is considered to be equivalent to being random).
There is a high risk of selection bias if the investigators describe a non-random component in the sequence generation process such as: sequence generated by odd or even date of birth, date (or day) of admission, hospital or clinic record number; or allocation by judgement of the clinician, preference of the participant, results of a laboratory test or a series of tests, or availability of the intervention.
Allocation concealment (selection bias)
Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment
There is a low risk of selection bias if the participants and investigators enrolling participants could not foresee assignment because one of the following, or an equivalent method, was used to conceal allocation: central allocation (including telephone, web-based and pharmacy-controlled randomization); sequentially numbered drug containers of identical appearance; or sequentially numbered, opaque, sealed envelopes.
There is a high risk of bias if participants or investigators enrolling participants could possibly foresee assignments and thus introduce selection bias, such as allocation based on: using an open random allocation schedule (for example, a list of random numbers); assignment envelopes were used without appropriate safeguards (for example, if envelopes were unsealed or non-opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; or other explicitly unconcealed procedures.
Blinding of participants
Performance bias due to knowledge of the allocated interventions by participants during the study
There is a low risk of performance bias if blinding of participants was ensured and it was unlikely that the blinding could have been broken; or if there was no blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding.
Blinding of personnel/ care providers (performance bias)
Performance bias due to knowledge of the allocated interventions by personnel/care providers during the study
There is a low risk of performance bias if blinding of personnel was ensured and it was unlikely that the blinding could have been broken; or if there was no blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding.
Blinding of outcome assessor (detection bias)
Detection bias due to knowledge of the allocated interventions by outcome assessors
There is low risk of detection bias if the blinding of the outcome assessment was ensured and it was unlikely that the blinding could have been broken; or if there was no blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding, or:
for patient-reported outcomes in which the patient was the outcome assessor (for example, pain, disability): there is a low risk of bias for outcome assessors if there is a low risk of bias for participant blinding (Boutron 2005)
for outcome criteria that are clinical or therapeutic events that will be determined by the interaction between patients and care providers (for example, co-interventions, length of hospitalisation, treatment failure), in which the care provider is the outcome assessor: there is a low risk of bias for outcome assessors if there is a low risk of bias for care providers (Boutron 2005)
for outcome criteria that are assessed from data from medical forms: there is a low risk of bias if the treatment or adverse effects of the treatment could not be noticed in the extracted data (Boutron 2005)
Incomplete outcome data (attrition bias)
Attrition bias due to amount, nature or handling of incomplete outcome data
There is a low risk of attrition bias if there were no missing outcome data; reasons for missing outcome data were unlikely to be related to the true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data were balanced in numbers, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with the observed event risk was not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, the plausible effect size (difference in means or standardised difference in means) among missing outcomes was not enough to have a clinically relevant impact on observed effect size, or missing data were imputed using appropriate methods (if drop-outs are very large, imputation using even "acceptable" methods may still suggest a high risk of bias) (van Tulder 2003). The percentage of withdrawals and drop-outs should not exceed 20% for short-term follow-up and 30% for long-term follow-up and should not lead to substantial bias (these percentages are commonly used but arbitrary, not supported by literature) (van Tulder 2003).
Selective reporting (reporting bias)
Reporting bias due to selective outcome reporting
There is low risk of reporting bias if the study protocol is available and all of the study's pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way, or if the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified (convincing text of this nature may be uncommon).
There is a high risk of reporting bias if not all of the study's pre-specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (for example, subscales) that were not pre-specified; one or more reported primary outcomes were not pre-specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta-analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study.
Group similarity at baseline (selection bias)
Bias due to dissimilarity at baseline for the most important prognostic indicators.
There is low risk of bias if groups are similar at baseline for demographic factors, value of main outcome measure(s), and important prognostic factors (examples in the field of back and neck pain are duration and severity of complaints, vocational status, percentage of patients with neurological symptoms) (van Tulder 2003).
Co-interventions (performance bias)
Bias because co-interventions were different across groups
There is low risk of bias if there were no co-interventions or they were similar between the index and control groups (van Tulder 2003).
Compliance (performance bias)
Bias due to inappropriate compliance with interventions across groups
There is low risk of bias if compliance with the interventions was acceptable, based on the reported intensity/dosage, duration, number and frequency for both the index and control intervention(s). For single-session interventions (for example surgery), this item is irrelevant (van Tulder 2003).
There is low risk of bias if all randomized patients were reported or analysed in the group to which they were allocated by randomization.
Timing of outcome assessments (detection bias)
Bias because important outcomes were not measured at the same time across groups
There is low risk of bias if all important outcome assessments for all intervention groups were measured at the same time (van Tulder 2003).
Bias due to problems not covered elsewhere in the table
There is a low risk of bias if the study appears to be free of other sources of bias not addressed elsewhere (for example, study funding).
Appendix 4. Questions for clinical relevance assessment
1. Are the patients described in detail so that you can decide whether they are comparable to those that you see in your practice?
2. Are the interventions and treatment settings described well enough so that you can provide the same for your patients?
3. Were all clinically relevant outcomes measured and reported?
4. Is the size of the effect clinically important?
5. Are the likely treatment benefits worth the potential harms?
Contributions of authors
S Atlas contributed to study selection, reviewed and edited the protocol and review.
LE Chaparro contributed to study selection, risk of bias assessment, data extraction, data analysis and drafting of the review.
A Deshpande contributed to study selection, risk of bias assessment, data extraction, data analysis and drafted both the protocol and review.
A Furlan - contributed to study selection, risk of bias assessment, data extraction, data analysis, assisted with writing and editing the protocol and review.
A Mailis-Gagnon reviewed and edited the protocol and review.
D Turk reviewed and edited the protocol and review.