BACKGROUND: Antidepressants are commonly used to treat low back pain and spine-related leg pain. However, their benefits and harms are uncertain. This is an update of a 2008 Cochrane review of antidepressants for non-specific low back pain.
OBJECTIVES: To assess the benefits and harms of antidepressants for non-specific low back pain and spine-related leg pain.
SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform, and EU Clinical Trials Register from inception to 14 November 2024.
SELECTION CRITERIA: We included randomised controlled trials that compared antidepressants with placebo, usual care, or no treatment/waiting list. Participants were 18 years of age or older with non-specific low back pain or spine-related leg pain of any duration. We excluded participants with low back pain due to spinal fracture, inflammatory disease, aortic dissection, malignancy, or infection. Primary outcomes were pain intensity and disability, measured at short-term follow-up (> 4 to 14 weeks post-randomisation), and total adverse events. Secondary outcomes were serious adverse events, withdrawals due to adverse events, depressive symptoms, and health-related quality of life.
DATA COLLECTION AND ANALYSIS: Two review authors independently screened records to determine study inclusion, extracted data, and evaluated risk of bias using RoB 1 tool. Where possible, we conducted meta-analyses. We used GRADE to assess the certainty of evidence.
MAIN RESULTS: We included 26 randomised controlled trials. Eighteen studies included 2535 participants with non-specific low back pain, seven studies included 329 participants with spine-related leg pain, and one study included 68 participants with either condition. Most participants had pain lasting more than three months, with a mean duration between 18 months and 20 years. Mean ages ranged from 27 to 59 years. Studies evaluated serotonin and norepinephrine reuptake inhibitors (SNRIs; eight studies), selective serotonin reuptake inhibitors (SSRIs; two studies), tricyclic antidepressants (TCAs; 14 studies), tetracyclic antidepressants (TeCAs; two studies), or 'other antidepressants' (two studies). All studies were placebo-controlled. Outcomes were measured at short-term follow-up in 73% of studies. All included studies had at least one domain judged at high risk of bias, with 69% at high risk of attrition bias. Non-specific low back pain (benefits) Moderate-certainty evidence demonstrated that SNRIs probably have a small effect on pain intensity (mean difference (MD) (0 to 100 scale) -5.25, 95% confidence interval (CI) -7.17 to -3.34; I2 = 0; 4 studies, 1415 participants) and a trivial effect on disability (MD (0 to 24 scale) -0.91, 95% CI -1.30 to -0.51; I2 = 0; 4 studies, 1348 participants) at short-term follow-up. Low-certainty evidence showed that SSRIs may have little to no effect on pain intensity (MD 1.20, 95% CI -4.90 to 7.30; I2 = 0; 3 studies, 199 participants) and disability (MD -2.20 (0 to 100 scale), 95% CI -8.11 to 3.71; 1 study, 92 participants) at short-term follow-up. Moderate-certainty evidence demonstrated that TCAs probably have little to no effect on pain intensity (MD -2.00, 95% CI -7.25 to 3.24; I² = 31%; 4 studies, 417 participants), but probably have a small effect on disability (MD (0 to 24 scale) -1.76, 95% CI -2.70 to -0.82; I2 = 0; 3 studies, 330 participants) at short-term follow-up. The effects of TeCAs (MD -4.50, 95% CI -17.59 to 8.59; 1 study, 52 participants) and other antidepressants (MD -5.40, 95% CI -23.08 to 12.28; 1 study, 39 participants) on pain intensity at short-term follow-up are unclear (very low-certainty evidence). No studies assessed the effects of TeCAs or other antidepressants on disability. Spine-related leg pain (benefits) The effects of SNRIs on pain intensity (MD -46.10, 95% CI -89.29 to -2.91; 1 study, 11 participants) and disability (MD (0 to 100 scale) -4.40, 95% CI -20.25 to 11.45; 1 study, 11 participants) at short-term follow-up are very uncertain (very low-certainty evidence). Low-certainty evidence showed TCAs may have a large effect on pain intensity at short-term follow-up (MD -23.00, 95% CI -32.12 to -13.88; 1 study, 60 participants), and a moderate effect on disability (MD (0 to 100 scale) -13.00, 95% CI -19.42 to -6.58; 1 study, 60 participants). There were no studies that assessed the effects of SSRIs, TeCAs, or other antidepressants in people with spine-related leg pain. Non-specific low back pain and spine-related leg pain (harms) Moderate-certainty evidence demonstrated that SNRIs probably increase the risk of adverse events (risk ratio (RR) 1.17, 95% CI 1.07 to 1.27; I2 = 0%; 5 studies, 1510 participants), but it is unclear whether they increase the risk of serious adverse events (Peto odds ratio (OR) 1.75, 95% CI 0.79 to 3.89; 5 studies, 1510 participants; very low-certainty evidence). It is unclear whether TCAs increase the risk of adverse events (RR 1.76, 95% CI 0.79 to 3.90; 7 studies, 474 participants; low-certainty evidence) or serious adverse events (Peto OR 6.64, 95% CI 0.41 to 106.72; I² = 0%; 1 study, 142 participants; very low-certainty evidence). It is unclear whether SSRIs (RR 1.83, 95% CI 0.14 to 24.19; I² = 95%; 2 studies, 107 participants; very low-certainty evidence) or TeCAs increase the risk of adverse events (RR 0.93, 95% CI 0.79 to 1.09; 1 study, 52 participants; very low-certainty evidence). No studies assessed the risk of serious adverse events for these classes. No studies measured total adverse events for other antidepressants. It is unclear whether other antidepressants increase the risk of serious adverse events (Peto OR 0.90, 95% CI 0.16 to 4.96; 1 study, 42 participants; very low-certainty evidence).
AUTHORS' CONCLUSIONS: We found that in people with non-specific low back pain, SNRIs probably have small effects on pain intensity, trivial effects on disability, and are probably associated with adverse effects. TCAs probably do not reduce low back pain intensity, but may have a small effect on disability. The effects of antidepressants on spine-related leg pain are uncertain, though SNRIs and TCAs might be prioritised over other classes for future investigations. Evidence for the safety of SSRIs, TCAs, TeCAs, and other antidepressants in non-specific low back pain and spine-related leg pain remains unclear.
BACKGROUND: Chronic pain is common in adults, and often has a detrimental impact upon physical ability, well-being, and quality of life. Previous reviews have shown that certain antidepressants may be effective in reducing pain with some benefit in improving patients' global impression of change for certain chronic pain conditions. However, there has not been a network meta-analysis (NMA) examining all antidepressants across all chronic pain conditions.
OBJECTIVES: To assess the comparative efficacy and safety of antidepressants for adults with chronic pain (except headache).
SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, LILACS, AMED and PsycINFO databases, and clinical trials registries, for randomised controlled trials (RCTs) of antidepressants for chronic pain conditions in January 2022.
SELECTION CRITERIA: We included RCTs that examined antidepressants for chronic pain against any comparator. If the comparator was placebo, another medication, another antidepressant, or the same antidepressant at different doses, then we required the study to be double-blind. We included RCTs with active comparators that were unable to be double-blinded (e.g. psychotherapy) but rated them as high risk of bias. We excluded RCTs where the follow-up was less than two weeks and those with fewer than 10 participants in each arm. DATA COLLECTION AND ANALYSIS: Two review authors separately screened, data extracted, and judged risk of bias. We synthesised the data using Bayesian NMA and pairwise meta-analyses for each outcome and ranked the antidepressants in terms of their effectiveness using the surface under the cumulative ranking curve (SUCRA). We primarily used Confidence in Meta-Analysis (CINeMA) and Risk of Bias due to Missing Evidence in Network meta-analysis (ROB-MEN) to assess the certainty of the evidence. Where it was not possible to use CINeMA and ROB-MEN due to the complexity of the networks, we used GRADE to assess the certainty of the evidence. Our primary outcomes were substantial (50%) pain relief, pain intensity, mood, and adverse events. Our secondary outcomes were moderate pain relief (30%), physical function, sleep, quality of life, Patient Global Impression of Change (PGIC), serious adverse events, and withdrawal.
MAIN RESULTS: This review and NMA included 176 studies with a total of 28,664 participants. The majority of studies were placebo-controlled (83), and parallel-armed (141). The most common pain conditions examined were fibromyalgia (59 studies); neuropathic pain (49 studies) and musculoskeletal pain (40 studies). The average length of RCTs was 10 weeks. Seven studies provided no useable data and were omitted from the NMA. The majority of studies measured short-term outcomes only and excluded people with low mood and other mental health conditions. Across efficacy outcomes, duloxetine was consistently the highest-ranked antidepressant with moderate- to high-certainty evidence. In duloxetine studies, standard dose was equally efficacious as high dose for the majority of outcomes. Milnacipran was often ranked as the next most efficacious antidepressant, although the certainty of evidence was lower than that of duloxetine. There was insufficient evidence to draw robust conclusions for the efficacy and safety of any other antidepressant for chronic pain. Primary efficacy outcomes Duloxetine standard dose (60 mg) showed a small to moderate effect for substantial pain relief (odds ratio (OR) 1.91, 95% confidence interval (CI) 1.69 to 2.17; 16 studies, 4490 participants; moderate-certainty evidence) and continuous pain intensity (standardised mean difference (SMD) -0.31, 95% CI -0.39 to -0.24; 18 studies, 4959 participants; moderate-certainty evidence). For pain intensity, milnacipran standard dose (100 mg) also showed a small effect (SMD -0.22, 95% CI -0.39 to 0.06; 4 studies, 1866 participants; moderate-certainty evidence). Mirtazapine (30 mg) had a moderate effect on mood (SMD -0.5, 95% CI -0.78 to -0.22; 1 study, 406 participants; low-certainty evidence), while duloxetine showed a small effect (SMD -0.16, 95% CI -0.22 to -0.1; 26 studies, 7952 participants; moderate-certainty evidence); however it is important to note that most studies excluded participants with mental health conditions, and so average anxiety and depression scores tended to be in the 'normal' or 'subclinical' ranges at baseline already. Secondary efficacy outcomes Across all secondary efficacy outcomes (moderate pain relief, physical function, sleep, quality of life, and PGIC), duloxetine and milnacipran were the highest-ranked antidepressants with moderate-certainty evidence, although effects were small. For both duloxetine and milnacipran, standard doses were as efficacious as high doses. Safety There was very low-certainty evidence for all safety outcomes (adverse events, serious adverse events, and withdrawal) across all antidepressants. We cannot draw any reliable conclusions from the NMAs for these outcomes.
AUTHORS' CONCLUSIONS: Our review and NMAs show that despite studies investigating 25 different antidepressants, the only antidepressant we are certain about for the treatment of chronic pain is duloxetine. Duloxetine was moderately efficacious across all outcomes at standard dose. There is also promising evidence for milnacipran, although further high-quality research is needed to be confident in these conclusions. Evidence for all other antidepressants was low certainty. As RCTs excluded people with low mood, we were unable to establish the effects of antidepressants for people with chronic pain and depression. There is currently no reliable evidence for the long-term efficacy of any antidepressant, and no reliable evidence for the safety of antidepressants for chronic pain at any time point.
OBJECTIVE: To assess the effectiveness and safety of different preparations and doses of non-steroidal anti-inflammatory drugs (NSAIDs), opioids, and paracetamol for knee and hip osteoarthritis pain and physical function to enable effective and safe use of these drugs at their lowest possible dose.
DESIGN: Systematic review and network meta-analysis of randomised trials.
DATA SOURCES: Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, regulatory agency websites, and ClinicalTrials.gov from inception to 28 June 2021.
ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised trials published in English with ≥100 patients per group that evaluated NSAIDs, opioids, or paracetamol (acetaminophen) to treat osteoarthritis.
OUTCOMES AND MEASURES: The prespecified primary outcome was pain. Physical function and safety outcomes were also assessed.
REVIEW METHODS: Two reviewers independently extracted outcomes data and evaluated the risk of bias of included trials. Bayesian random effects models were used for network meta-analysis of all analyses. Effect estimates are comparisons between active treatments and oral placebo.
RESULTS: 192 trials comprising 102 829 participants examined 90 different active preparations or doses (68 for NSAIDs, 19 for opioids, and three for paracetamol). Five oral preparations (diclofenac 150 mg/day, etoricoxib 60 and 90 mg/day, and rofecoxib 25 and 50 mg/day) had ≥99% probability of more pronounced treatment effects than the minimal clinically relevant reduction in pain. Topical diclofenac (70-81 and 140-160 mg/day) had ≥92.3% probability, and all opioids had ≤53% probability of more pronounced treatment effects than the minimal clinically relevant reduction in pain. 18.5%, 0%, and 83.3% of the oral NSAIDs, topical NSAIDs, and opioids, respectively, had an increased risk of dropouts due to adverse events. 29.8%, 0%, and 89.5% of oral NSAIDs, topical NSAIDs, and opioids, respectively, had an increased risk of any adverse event. Oxymorphone 80 mg/day had the highest risk of dropouts due to adverse events (51%) and any adverse event (88%).
CONCLUSIONS: Etoricoxib 60 mg/day and diclofenac 150 mg/day seem to be the most effective oral NSAIDs for pain and function in patients with osteoarthritis. However, these treatments are probably not appropriate for patients with comorbidities or for long term use because of the slight increase in the risk of adverse events. Additionally, an increased risk of dropping out due to adverse events was found for diclofenac 150 mg/day. Topical diclofenac 70-81 mg/day seems to be effective and generally safer because of reduced systemic exposure and lower dose, and should be considered as first line pharmacological treatment for knee osteoarthritis. The clinical benefit of opioid treatment, regardless of preparation or dose, does not outweigh the harm it might cause in patients with osteoarthritis.
SYSTEMATIC REVIEW REGISTRATION: PROSPERO number CRD42020213656.
BACKGROUND: A 2007 American College of Physicians guideline addressed pharmacologic options for low back pain. New evidence and medications have now become available.
PURPOSE: To review the current evidence on systemic pharmacologic therapies for acute or chronic nonradicular or radicular low back pain.
DATA SOURCES: Ovid MEDLINE (January 2008 through November 2016), Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and reference lists.
STUDY SELECTION: Randomized trials that reported pain, function, or harms of systemic medications versus placebo or another intervention.
DATA EXTRACTION: One investigator abstracted data, and a second verified accuracy; 2 investigators independently assessed study quality.
DATA SYNTHESIS: The number of trials ranged from 9 (benzodiazepines) to 70 (nonsteroidal anti-inflammatory drugs). New evidence found that acetaminophen was ineffective for acute low back pain, nonsteroidal anti-inflammatory drugs had smaller benefits for chronic low back pain than previously observed, duloxetine was effective for chronic low back pain, and benzodiazepines were ineffective for radiculopathy. For opioids, evidence remains limited to short-term trials showing modest effects for chronic low back pain; trials were not designed to assess serious harms. Skeletal muscle relaxants are effective for short-term pain relief in acute low back pain but caused sedation. Systemic corticosteroids do not seem to be effective. For effective interventions, pain relief was small to moderate and generally short-term; improvements in function were generally smaller. Evidence is insufficient to determine the effects of antiseizure medications.
LIMITATIONS: Qualitatively synthesized new trials with prior meta-analyses. Only English-language studies were included, many of which had methodological shortcomings. Medications injected for local effects were not addressed.
CONCLUSION: Several systemic medications for low back pain are associated with small to moderate, primarily short-term effects on pain. New evidence suggests that acetaminophen is ineffective for acute low back pain, and duloxetine is associated with modest effects for chronic low back pain.
PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. (PROSPERO: CRD42014014735).
Muscle relaxants are commonly prescribed for low back pain (LBP); however, there is limited evidence of their clinical efficacy and tolerability. This review evaluated the efficacy and tolerability of muscle relaxants in people with LBP. We searched online databases including Medline, EMBASE, CENTRAL and PsycINFO (inception to end October 2015) and performed citation tracking for eligible randomized controlled trials (RCTs). Two authors independently extracted data and assessed risk of bias of randomized controlled trials of muscle relaxants. Pain outcomes were converted to a common 0–100 scale. Data were pooled using a random effects model with strength of evidence assessed using GRADE. Fifteen trials (3362 participants) were evaluated in this review. A total of five trials (496 participants) provide high quality evidence that muscle relaxants provide clinically significant pain relief in the short term for acute LBP; MD −21.3, [−29.0, −13.5]. There was no information on long‐term outcomes. The median adverse event rate in clinical trials for muscle relaxants was similar to placebo 14.1% IQR (7.0–28.7%) and 16.0% (4.1–31.2%); <i>p</i> = 0.5, respectively. There is no evidence for the efficacy of benzodiazepines in LBP. For people with acute LBP, muscle relaxants provide clinically significant short‐term pain relief. For chronic LBP, the efficacy of muscle relaxants is largely unknown. There was no eligible RCT evidence to support the efficacy of benzodiazepines in LBP. Prolonged use of these medicines in LBP cannot be guided by trial evidence. What does this review add?: Muscle relaxants provide clinically significant pain relief for acute low back pain. Caution must be taken with the interpretation of the findings as the evidence comes from specific muscle relaxant medicines. (PsycInfo Database Record (c) 2022 APA, all rights reserved)
BACKGROUND: Analgesic medication is the most frequently prescribed treatment for low back pain (LBP), of which paracetamol (acetaminophen) is recommended as the first choice medication. However, there is uncertainty about the efficacy of paracetamol for LBP.
OBJECTIVES: To investigate the efficacy and safety of paracetamol for non-specific LBP.
SEARCH METHODS: We conducted searches on the Cochrane Central Register of Controlled Trials (CENTRAL, which includes the Back and Neck Review Group trials register), MEDLINE, EMBASE, CINAHL, AMED, Web of Science, LILACS, and IPA from their inception to 7 August 2015. We also searched the reference lists of eligible papers and trial registry websites (WHO ICTRP and ClinicalTrials.gov).
SELECTION CRITERIA: We only considered randomised trials comparing the efficacy of paracetamol with placebo for non-specific LBP. The primary outcomes were pain and disability. We also investigated quality of life, function, adverse effects, global impression of recovery, sleep quality, patient adherence, and use of rescue medication as secondary outcomes.
DATA COLLECTION AND ANALYSIS: Two review authors independently performed the data extraction and assessed risk of bias in the included studies. We also evaluated the quality of evidence using the GRADE approach. We converted scales for pain intensity to a common 0 to 100 scale. We quantified treatment effects using mean difference for continuous outcomes and risk ratios for dichotomous outcomes. We used effect sizes and 95% confidence intervals as a measure of treatment effect for the primary outcomes. When the treatment effects were smaller than 9 points on a 0 to 100 scale, we considered the effect as small and not clinically important.
MAIN RESULTS: Our searches retrieved 4449 records, of which three trials were included in the review (n = 1825 participants), and two trials were included in the meta-analysis. For acute LBP, there is high-quality evidence for no difference between paracetamol (4 g per day) and placebo at 1 week (immediate term), 2 weeks, 4 weeks, and 12 weeks (short term) for the primary outcomes. There is high-quality evidence that paracetamol has no effect on quality of life, function, global impression of recovery, and sleep quality for all included time periods. There were also no significant differences between paracetamol and placebo for adverse events, patient adherence, or use of rescue medication. For chronic LBP, there is very low-quality evidence (based on a trial that has been retracted) for no effect of paracetamol (1 g single intravenous dose) on immediate pain reduction. Finally, no trials were identified evaluating patients with subacute LBP.
AUTHORS' CONCLUSIONS: We found that paracetamol does not produce better outcomes than placebo for people with acute LBP, and it is uncertain if it has any effect on chronic LBP.
IMPORTANCE: Opioid analgesics are commonly used for low back pain, however, to our knowledge there has been no systematic evaluation of the effect of opioid dose and use of enrichment study design on estimates of treatment effect.
OBJECTIVE: To evaluate efficacy and tolerability of opioids in the management of back pain; and investigate the effect of opioid dose and use of an enrichment study design on treatment effect.
DATA SOURCES: Medline, EMBASE, CENTRAL, CINAHL, and PsycINFO (inception to September 2015) with citation tracking from eligible randomized clinical trials (RCTs).
STUDY SELECTION: Placebo-controlled RCTs in any language.
DATA EXTRACTION AND SYNTHESIS: Two authors independently extracted data and assessed risk of bias. Data were pooled using a random effects model with strength of evidence assessed using the grading of recommendations assessment, development, and evaluation (GRADE).
MAIN OUTCOMES AND MEASURES: The primary outcome measure was pain. Pain and disability outcomes were converted to a common 0 to 100 scale, with effects greater than 20 points considered clinically important.
RESULTS: Of 20 included RCTs of opioid analgesics (with a total of 7925 participants), 13 trials (3419 participants) evaluated short-term effects on chronic low back pain, and no placebo-controlled trials enrolled patients with acute low back pain. In half of these 13 trials, at least 50% of participants withdrew owing to adverse events or lack of efficacy. There was moderate-quality evidence that opioid analgesics reduce pain in the short term; mean difference (MD), -10.1 (95% CI, -12.8 to -7.4). Meta-regression revealed a 12.0 point greater pain relief for every 1 log unit increase in morphine equivalent dose (P = .046). Clinically important pain relief was not observed within the dose range evaluated (40.0-240.0-mg morphine equivalents per day). There was no significant effect of enrichment study design.
CONCLUSIONS AND RELEVANCE: For people with chronic low back pain who tolerate the medicine, opioid analgesics provide modest short-term pain relief but the effect is not likely to be clinically important within guideline recommended doses. Evidence on long-term efficacy is lacking. The efficacy of opioid analgesics in acute low back pain is unknown.
BACKGROUND: Chronic back pain is an important health problem. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat people with low back pain, especially people with acute back pain. Short term NSAID use is also recommended for pain relief in people with chronic back pain. Two types of NSAIDs are available and used to treat back pain: non-selective NSAIDs and selective COX-2 NSAIDs. In 2008, a Cochrane review identified a small but significant effect from NSAIDs compared to placebo in people with chronic back pain. This is an update of the Cochrane review published in 2008 and focuses on people with chronic low back pain.
OBJECTIVES: To determine if NSAIDs are more efficacious than various comparison treatments for non-specific chronic low back pain and if so, which type of NSAID is most efficacious.
SEARCH METHODS: We searched CENTRAL, MEDLINE, EMBASE, PubMed and two clinical trials registry databases up to 24 June 2015 for randomized controlled trials (RCTs) published in English, German or Dutch. We also screened references cited in relevant reviews.
SELECTION CRITERIA: We included RCTs (double-blind and single-blind) of NSAIDs used to treat people with chronic low back pain.
DATA COLLECTION AND ANALYSIS: Two review authors independently screened trials for inclusion in this Cochrane review according to the inclusion criteria. One review author extracted the data, and a second review author checked the data. Two review authors independently evaluated the risk of bias of all included trials. If data were clinically homogeneous, we performed a meta-analysis and assessed the quality of evidence using the GRADE approach.
MAIN RESULTS: We included 13 trials in this Cochrane review. Ten studies were at 'low' risk of bias. Six studies compared NSAIDs with placebo, and included 1354 participants in total. There is low quality evidence that NSAIDs are more effective than placebo, with a mean difference in pain intensity score from baseline of -3.30 (95% CI −5.33 to −1.27) on a 0 to 100 visual analogue scale (VAS) with a median follow-up of 56 days (interquartile range (IQR) 13 to 91 days). Four studies measured disability using the Roland Morris Disability Questionnaire. There is low quality evidence that NSAIDs are more effective than placebo on disability, with a mean difference from baseline of −0.85 (95% CI −1.30 to −0.40) on a scale from 0 to 24 with a median follow-up of 84 days (IQR 42 to 105 days). All six placebo controlled studies also reported adverse events, and suggested that adverse events are not statistically significant more frequent in participants using NSAIDs compared to placebo (RR 1.04, 95% CI 0.92 to 1.17). Due to the relatively small sample size and relatively short follow-up in most included trials, it is likely that the proportion of patients experiencing an adverse event is underestimated.Two studies compared different types of non-selective NSAIDs, namely ibuprofen versus diclofenac and piroxicam versus indomethacin. The trials did not find any differences between these NSAID types, but both trials had small sample sizes. One trial reported no differences in pain intensity between treatment groups that used selective or non-selective NSAIDs. One other trial compared diflunisal with paracetamol and showed no difference in improvement from baseline on pain intensity score. One trial showed a better global improvement in favour of celecoxib versus tramadol.One included trial compared NSAIDs with 'home-based exercise'. Disability improved more in participants who did exercises versus participants receiving NSAIDs, but pain scores were similar.
AUTHORS' CONCLUSIONS: Six of the 13 included RCTs showed that NSAIDs are more effective than placebo regarding pain intensity. NSAIDs are slightly more effective than placebo regarding disability. However, the magnitude of the effects is small, and the level of evidence was low. When we only included RCTs at low risk of bias, differences in effect between NSAIDs and placebo were reduced. We identified no difference in efficacy between different NSAID types, including selective versus non-selective NSAIDs. Due to inclusion of RCTs only, the relatively small sample sizes and relatively short follow-up in most included trials, we cannot make firm statements about the occurrence of adverse events or whether NSAIDs are safe for long-term use.
OBJECTIVE: To investigate the efficacy and safety of paracetamol (acetaminophen) in the management of spinal pain and osteoarthritis of the hip or knee.
DESIGN: Systematic review and meta-analysis.
DATA SOURCES: Medline, Embase, AMED, CINAHL, Web of Science, LILACS, International Pharmaceutical Abstracts, and Cochrane Central Register of Controlled Trials from inception to December 2014.
ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials comparing the efficacy and safety of paracetamol with placebo for spinal pain (neck or low back pain) and osteoarthritis of the hip or knee.
DATA EXTRACTION: Two independent reviewers extracted data on pain, disability, and quality of life. Secondary outcomes were adverse effects, patient adherence, and use of rescue medication. Pain and disability scores were converted to a scale of 0 (no pain or disability) to 100 (worst possible pain or disability). We calculated weighted mean differences or risk ratios and 95% confidence intervals using a random effects model. The Cochrane Collaboration's tool was used for assessing risk of bias, and the GRADE approach was used to evaluate the quality of evidence and summarise conclusions.
RESULTS: 12 reports (13 randomised trials) were included. There was "high quality" evidence that paracetamol is ineffective for reducing pain intensity (weighted mean difference -0.5, 95% confidence interval -2.9 to 1.9) and disability (0.4, -1.7 to 2.5) or improving quality of life (0.4, -0.9 to 1.7) in the short term in people with low back pain. For hip or knee osteoarthritis there was "high quality" evidence that paracetamol provides a significant, although not clinically important, effect on pain (-3.7, -5.5 to -1.9) and disability (-2.9, -4.9 to -0.9) in the short term. The number of patients reporting any adverse event (risk ratio 1.0, 95% confidence interval 0.9 to 1.1), any serious adverse event (1.2, 0.7 to 2.1), or withdrawn from the study because of adverse events (1.2, 0.9 to 1.5) was similar in the paracetamol and placebo groups. Patient adherence to treatment (1.0, 0.9 to 1.1) and use of rescue medication (0.7, 0.4 to 1.3) was also similar between groups. "High quality" evidence showed that patients taking paracetamol are nearly four times more likely to have abnormal results on liver function tests (3.8, 1.9 to 7.4), but the clinical importance of this effect is uncertain.
CONCLUSIONS: Paracetamol is ineffective in the treatment of low back pain and provides minimal short term benefit for people with osteoarthritis. These results support the reconsideration of recommendations to use paracetamol for patients with low back pain and osteoarthritis of the hip or knee in clinical practice guidelines.
SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42013006367.
Antidepressants are commonly used to treat low back pain and spine-related leg pain. However, their benefits and harms are uncertain. This is an update of a 2008 Cochrane review of antidepressants for non-specific low back pain.
OBJECTIVES:
To assess the benefits and harms of antidepressants for non-specific low back pain and spine-related leg pain.
SEARCH METHODS:
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform, and EU Clinical Trials Register from inception to 14 November 2024.
SELECTION CRITERIA:
We included randomised controlled trials that compared antidepressants with placebo, usual care, or no treatment/waiting list. Participants were 18 years of age or older with non-specific low back pain or spine-related leg pain of any duration. We excluded participants with low back pain due to spinal fracture, inflammatory disease, aortic dissection, malignancy, or infection. Primary outcomes were pain intensity and disability, measured at short-term follow-up (> 4 to 14 weeks post-randomisation), and total adverse events. Secondary outcomes were serious adverse events, withdrawals due to adverse events, depressive symptoms, and health-related quality of life.
DATA COLLECTION AND ANALYSIS:
Two review authors independently screened records to determine study inclusion, extracted data, and evaluated risk of bias using RoB 1 tool. Where possible, we conducted meta-analyses. We used GRADE to assess the certainty of evidence.
MAIN RESULTS:
We included 26 randomised controlled trials. Eighteen studies included 2535 participants with non-specific low back pain, seven studies included 329 participants with spine-related leg pain, and one study included 68 participants with either condition. Most participants had pain lasting more than three months, with a mean duration between 18 months and 20 years. Mean ages ranged from 27 to 59 years. Studies evaluated serotonin and norepinephrine reuptake inhibitors (SNRIs; eight studies), selective serotonin reuptake inhibitors (SSRIs; two studies), tricyclic antidepressants (TCAs; 14 studies), tetracyclic antidepressants (TeCAs; two studies), or 'other antidepressants' (two studies). All studies were placebo-controlled. Outcomes were measured at short-term follow-up in 73% of studies. All included studies had at least one domain judged at high risk of bias, with 69% at high risk of attrition bias. Non-specific low back pain (benefits) Moderate-certainty evidence demonstrated that SNRIs probably have a small effect on pain intensity (mean difference (MD) (0 to 100 scale) -5.25, 95% confidence interval (CI) -7.17 to -3.34; I2 = 0; 4 studies, 1415 participants) and a trivial effect on disability (MD (0 to 24 scale) -0.91, 95% CI -1.30 to -0.51; I2 = 0; 4 studies, 1348 participants) at short-term follow-up. Low-certainty evidence showed that SSRIs may have little to no effect on pain intensity (MD 1.20, 95% CI -4.90 to 7.30; I2 = 0; 3 studies, 199 participants) and disability (MD -2.20 (0 to 100 scale), 95% CI -8.11 to 3.71; 1 study, 92 participants) at short-term follow-up. Moderate-certainty evidence demonstrated that TCAs probably have little to no effect on pain intensity (MD -2.00, 95% CI -7.25 to 3.24; I² = 31%; 4 studies, 417 participants), but probably have a small effect on disability (MD (0 to 24 scale) -1.76, 95% CI -2.70 to -0.82; I2 = 0; 3 studies, 330 participants) at short-term follow-up. The effects of TeCAs (MD -4.50, 95% CI -17.59 to 8.59; 1 study, 52 participants) and other antidepressants (MD -5.40, 95% CI -23.08 to 12.28; 1 study, 39 participants) on pain intensity at short-term follow-up are unclear (very low-certainty evidence). No studies assessed the effects of TeCAs or other antidepressants on disability. Spine-related leg pain (benefits) The effects of SNRIs on pain intensity (MD -46.10, 95% CI -89.29 to -2.91; 1 study, 11 participants) and disability (MD (0 to 100 scale) -4.40, 95% CI -20.25 to 11.45; 1 study, 11 participants) at short-term follow-up are very uncertain (very low-certainty evidence). Low-certainty evidence showed TCAs may have a large effect on pain intensity at short-term follow-up (MD -23.00, 95% CI -32.12 to -13.88; 1 study, 60 participants), and a moderate effect on disability (MD (0 to 100 scale) -13.00, 95% CI -19.42 to -6.58; 1 study, 60 participants). There were no studies that assessed the effects of SSRIs, TeCAs, or other antidepressants in people with spine-related leg pain. Non-specific low back pain and spine-related leg pain (harms) Moderate-certainty evidence demonstrated that SNRIs probably increase the risk of adverse events (risk ratio (RR) 1.17, 95% CI 1.07 to 1.27; I2 = 0%; 5 studies, 1510 participants), but it is unclear whether they increase the risk of serious adverse events (Peto odds ratio (OR) 1.75, 95% CI 0.79 to 3.89; 5 studies, 1510 participants; very low-certainty evidence). It is unclear whether TCAs increase the risk of adverse events (RR 1.76, 95% CI 0.79 to 3.90; 7 studies, 474 participants; low-certainty evidence) or serious adverse events (Peto OR 6.64, 95% CI 0.41 to 106.72; I² = 0%; 1 study, 142 participants; very low-certainty evidence). It is unclear whether SSRIs (RR 1.83, 95% CI 0.14 to 24.19; I² = 95%; 2 studies, 107 participants; very low-certainty evidence) or TeCAs increase the risk of adverse events (RR 0.93, 95% CI 0.79 to 1.09; 1 study, 52 participants; very low-certainty evidence). No studies assessed the risk of serious adverse events for these classes. No studies measured total adverse events for other antidepressants. It is unclear whether other antidepressants increase the risk of serious adverse events (Peto OR 0.90, 95% CI 0.16 to 4.96; 1 study, 42 participants; very low-certainty evidence).
AUTHORS' CONCLUSIONS:
We found that in people with non-specific low back pain, SNRIs probably have small effects on pain intensity, trivial effects on disability, and are probably associated with adverse effects. TCAs probably do not reduce low back pain intensity, but may have a small effect on disability. The effects of antidepressants on spine-related leg pain are uncertain, though SNRIs and TCAs might be prioritised over other classes for future investigations. Evidence for the safety of SSRIs, TCAs, TeCAs, and other antidepressants in non-specific low back pain and spine-related leg pain remains unclear.
