Introduction
Low-back pain (LBP) is related to disability and work absence and accounts for high economical costs in Western societies [
1]. The management of LBP comprises a range of different intervention strategies including surgery, non-medical interventions such as exercise, behavioral therapy, and alternative therapies. Pharmacological interventions are the most frequently recommended intervention for back pain [
2,
3]. Over the last years, a substantial number of randomized clinical trials and systematic reviews have been published. Based on this literature, this overview presents the current evidence on pharmacological interventions for non-specific chronic low back pain.
Objectives
The objective of this review was to determine the effectiveness of pharmacological interventions [i.e., non-steroid anti-inflammatory drugs (NSAIDs), muscle relaxants, antidepressants, and opioids] for non-specific chronic LBP.
Criteria for considering studies for this review
Types of studies
Only randomized controlled trials with at least 1 day of follow-up were considered in this systematic review.
Types of participants
In order to be included in this review, participants of the RCTs must fulfill the following inclusion criteria: adult subjects (≥18 years of age) with chronic (>12 weeks) non-specific LBP (including discopathy or any other non-specific degenerative pathology such as osteoarthritis).
The exclusion criteria were: (1) trials including subjects with specific LBP caused by pathologies such as vertebral spinal stenosis, ankylosing spondylitis, scoliosis, and coccydynia the diagnosis of which had to be confirmed by an MRI or another diagnostic imaging tool; (2) post-partum LBP or pelvic pain due to pregnancy; (3) post-operative studies;
1 (4) prevention studies; and (5) abstracts or non-published studies.
Types of interventions
The RCTs studying the following interventions were included in this overview: NSAIDs, muscle relaxants, antidepressants, and opioids. All types of NSAIDs (including COX-2), antidepressants (i.e., tricyclic and heterocyclic antidepressants, selective serotonin reuptake inhibitors, mono-amine oxidase inhibitors and ‘atypical’ antidepressants), muscle relaxants and opioids [given by oral, transdermal, mucosal (nasal or rectal), or intramuscular routes] were included.
Additional interventions were allowed in all studies if there was a contrast for the pharmacological intervention in the study.
Types of outcome measures
For inclusion, at least one of the following outcome measures should have been measured in the RCT: pain intensity [e.g., visual analog scale (VAS), numerical rating scale (NRS), McGill pain questionnaire], back-specific functional status (e.g., Roland–Morris Disability Questionnaire, Oswestry Disability Index), perceived recovery (e.g., overall improvement), and return to work (e.g., return to work status, sick leave days). The primary outcomes for this review were pain and functional status.
Search methods for identification of studies
Existing Cochrane reviews for the four interventions were screened for studies fulfilling the inclusion criteria [
4‐
7]. Then, the literature searches were updated from the last date onward for each of the interventions.
The search was conducted in MEDLINE, EMBASE, CINAHL, CENTRAL, and PEDro up to December 22, 2008. References of relevant studies were screened, and experts were approached in order to identify additional primary studies not identified in the previous steps. The language was limited to English, Dutch, and German, because these are the languages that the authors are able to read and understand. The search strategy outlined by the Cochrane Back Review Group (CBRG) was followed and is available upon request from the primary author [
8].
Methods of the review
Study selection
Three authors (TK, SMR, and MM) independently screened the abstracts and titles retrieved by the search strategy and applied the inclusion criteria to all these abstracts. The first author screened all abstracts (TK), the others both half of the references. Full text of the article was obtained if the title and the abstract seemed to fulfill the inclusion criteria or if eligibility of the study was unclear. All full text articles from the existing Cochrane reviews were compiled and screened on inclusion criteria by the authors, independently. Any disagreements between the authors were resolved by discussion and consensus.
Risk-of-bias assessment
Two reviewers (TK and SMR) assessed the risk of bias (RoB) independently, using the criteria list advised by the CBRG, which consists of 11 items [
8]. Items were scored as ‘positive’ if they fulfilled the criteria, as ‘negative’ when there was a clear RoB, and as ‘inconclusive’ if there was insufficient information. Differences in assessment were discussed during a consensus meeting. A total score was computed by adding the number of positive scores, and high quality was defined as fulfilling 6 or more (more than 50%) of the 11 internal validity criteria [
9].
A standardized form was used for data extraction consisting of both descriptive data on the study population, the type of intervention examined, and quantitative data regarding the outcome measures. Data on the characteristics of the study population (gender, age), type and dose of medication, control treatment, and study results were also described.
Data analysis
If studies were clinically homogeneous regarding study population, types of treatment, reference treatment, outcomes, and measurement instruments, a meta-analysis was performed. If possible, we calculated the weighted mean difference (WMD) because this improves the interpretability of the results. If a WMD was not possible the standardized mean difference (SMD) was calculated. If trials reported outcomes as graphs, the mean scores and standard deviations (SDs) were estimated from these graphs. If SDs were not reported, they were calculated using the reported values of the confidence intervals, if possible. If the SD of the baseline score was reported, we used the ratio between the baseline score and SD to calculate the SD for other follow-up moments. Finally, if none of these data were reported, an estimation of the SD was based on study data (population and score) of other studies. In order to correct for error introduced by “double-counting” of subjects of “shared” interventions (i.e., two comparisons within one study that used the same control group as contrast) in the meta-analyses, the number of subjects in similar contrasts was divided by the number of comparisons that this one study added in the meta-analyses. For the comparisons where studies were clinically too heterogeneous, no meta-analysis was performed. We chose for random effect model when inspection of the forest plots showed heterogeneity represented by different directions of the effects or if I
2 > 20% (arbitrary cutoff point). When no new studies were added to the results of the original reviews we followed the presentation of the original results. Heterogeneity was tested with Chi-square and I
2. For the statistical analyses the software package ‘Review Manager 5’ was used.
Quality of the evidence
Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) was used to evaluate the overall quality of the evidence and the strength of the recommendations [
10]. Quality of the evidence for a specific outcome was based upon five principal factors: (1) limitations (e.g., due to study design), (2) inconsistency of results, (3) indirectness (e.g., generalizability of the findings), (4) imprecision (e.g., sufficient data), and (5) other considerations, such as reporting bias. The overall quality was considered to be high when multiple RCTs with a low RoB provide consistent, generalizable, precise data for a particular outcome. The quality of the evidence was downgraded by one level when one of the factors described above was not met [
10]. Single studies were considered imprecise (i.e., sparse data) and provide “low quality evidence”, which could be further downgraded to “very low quality evidence” if there were also limitations in design or indirectness. The following grades of quality of the evidence were applied:
High quality
Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality
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 quality
We are very uncertain about the estimate.
To improve the readability of this review, a GRADE table was only completed when we completed a meta-analysis. If only one study was present for a given comparison, the results are described in the text and in the table with characteristics of included studies.
Adverse events were reported using relative risk (RR) for the total number of any adverse event.
Discussion
In this review, 17 RCTs were included that evaluated the effectiveness of pharmacological interventions for non-specific chronic low back pain.
The effectiveness of the different pharmacological interventions
No studies were found for muscle relaxants. In this review we found low quality evidence for effects on pain intensity for NSAIDs and opioids, and a small effect on function for opioids compared to placebo on the short term (<3 months) for patients with chronic low back pain. No effects were found for the use of antidepressants compared to placebo on any of the primary outcomes. NSAIDS and opioids seem to be associated with more adverse effects compared with placebo.
Methodological considerations
Despite the fact that the RoB of the studies was generally low, many studies showed flaws regarding concealment of treatment allocation, compliance, and drop-out rates. We feel the quality of future RCTs in the field of low back pain regarding these issues could be improved to reduce bias in future systematic reviews and overviews.
In three of the four studies assessing NSAIDs for chronic LBP and five of the eight studies on opioids, a so called “flare design” was used, in which patients who were already responding well to NSAIDs or opioids were only included when they showed a large worsening in LBP complaints during a wash-out period. This may have caused favourable results of the investigated NSAIDs and opioids, expressed in an overestimation of the effects and an underestimation of the adverse effects due to the selection of the study population, and certainly decreases the external validity for daily practice. It is uncertain if the results also apply to other patients with low back pain (who have not yet received NSAIDs or opioids for their LBP episode).
Adverse effects
In the studies presented in this review adverse effects were reported, although we would like to emphasize the need for a complete and better report of adverse effects in clinical trials. Clearly, smaller randomised trials are unlikely to detect rare adverse events. Better reporting of adverse events in larger trials or prospective cohort sties is required.
According to the authors of the studies on NSAIDs, most adverse effects, including abdominal pain, diarrhea, edema, dry mouth, rash, dizziness, headache, and tiredness, were considered to be mild to moderately severe. However, the sample sizes of most of the studies were relatively small, and therefore no clear conclusion can be drawn from these studies regarding the risks of gastrointestinal and other adverse effects of NSAIDs. The statistical pooling of all adverse effects of NSAIDs compared to placebo for acute LBP indeed showed an increased RR, indicating the additional risk of using NSAIDs.
For antidepressants adverse effects, such as dry mouth, constipation, tachycardia, sedation, orthostatic hypotension, and tremor, were commonly reported, but no serious adverse effects were documented. However, the trials were also very small and not designed to evaluate adverse effects.
For opioids adverse effects were reported extensively and seemed to occur more in the opioid group compared to placebo, although here as well the numbers are small.
Overall it is difficult to draw firm conclusions regarding the risks for adverse effects of NSAIDs, antidepressants and opioids. Prospective studies with larger sample sizes are necessary to evaluate the incidence of both minor and major adverse effects.
Strengths and limitations
Several biases can be introduced in systematic reviews by literature search and selection procedure. We might have missed relevant unpublished trials, which are more likely to be small studies without positive results, leading to publication bias. Screening references of identified trials and systematic reviews may result in an over representation of positive studies in the review, because trials with a positive result are more likely to be referred to in other publications, leasing to reference bias. Studies not published in English, Dutch or German were not included in this review. It is not clear whether a language restriction is associated with bias [
30].
Another important limitation was the poor reporting of co-interventions, especially in the studies regarding NSAIDs and antidepressants, which hampered the study of the potential bias caused by this issue.
Implications for research
To conclude, we identified 17 RCTs that evaluated pharmacological treatment effects for patients with chronic non-specific LBP. Most of the studies included in this review had a low RoB, although there were methodological weaknesses, especially regarding concealment of allocation, compliance, and drop-out rates. There is a need for future high-quality RCTs with special emphasis on these subjects.
Implications for practice
NSAIDs and opioids might be useful for short-term pain relief in patients with chronic LBP, who responded with an exacerbation of their symptoms after stopping their medication. However, possible adverse effects should be weighed in deciding which medication to prescribe.