Paracetamol Combination Therapy for Back Pain and Osteoarthritis: A Systematic Review and Meta-Analyses.

BACKGROUND AND OBJECTIVE: Although paracetamol (acetaminophen) combined with other analgesics can reduce pain intensity in some pain conditions, its effectiveness in managing low back pain and osteoarthritis is unclear. This systematic review investigated whether paracetamol combination therapy is more effective and safer than monotherapy or placebo in low back pain and osteoarthritis. METHODS: Online database searches were conducted for randomised trials that evaluated paracetamol combined with another analgesic compared to a placebo or the non-paracetamol ingredient in the combination (monotherapy) in low back pain and osteoarthritis. The primary outcome was a change in pain. Secondary outcomes were (serious) adverse events, changes in disability and quality of life. Follow-up was immediate (≤ 2 weeks), short (> 2 weeks but ≤ 3 months), intermediate (> 3 months but < 12 months) or long term (≥ 12 months). A random-effects meta-analysis was conducted. Risk of bias was assessed using the original Cochrane tool, and quality of evidence using Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: Twenty-two studies were included. Pain was reduced with oral paracetamol plus a non-steroidal anti-inflammatory drug (NSAID) at immediate term in low back pain (paracetamol plus ibuprofen vs ibuprofen [mean difference (MD) - 6.2, 95% confidence interval (CI) -10.4 to -2.0, moderate evidence]) and in osteoarthritis (paracetamol plus aceclofenac vs aceclofenac [MD - 4.7, 95% CI - 8.3 to - 1.2, moderate certainty evidence] and paracetamol plus etodolac vs etodolac [MD - 15.1, 95% CI - 18.5 to - 11.8; moderate certainty evidence]). Paracetamol plus oral tramadol reduced pain compared with placebo at intermediate term for low back pain (MD - 11.7, 95% CI - 19.2 to - 4.3; very low certainty evidence) and osteoarthritis (MD - 6.8, 95% CI - 12.7 to -0.9; moderate certainty evidence). Disability scores improved in half the comparisons. Quality of life was infrequently measured. All paracetamol plus NSAID combinations did not increase the risk of adverse events compared to NSAID monotherapy. CONCLUSIONS: Low-to-moderate quality evidence supports the oral use of some paracetamol plus NSAID combinations for short-term pain relief with no increased risk of harm for low back pain and osteoarthritis compared to its non-paracetamol monotherapy comparator.

Moderators of treatment effect of non-steroidal anti-inflammatory drugs for patients with (sub) acute low back pain: Protocol for a systematic review with individual participant data meta-analysis.

A Cochrane review found that non-steroidal anti-inflammatory drugs (NSAIDs) are slightly more effective than placebo on acute and subacute low back pain (LBP) outcomes (pain intensity, disability, and global improvement). Our objectives are: (1) to assess the overall treatment effect of NSAIDs in adults with acute and subacute LBP; (2) to identify the moderation of baseline patients' characteristics on treatment effect. We will conduct a systematic search of RCTs on effectiveness of NSAIDs compared with placebo in adults with non-chronic LBP in Medline ALL, Embase, Cochrane Central Register of Controlled Trials*. We will screen the records after January 2020, and include eligible RCTs before January 2020 screened by the Cochrane review mentioned above. Our primary outcomes are pain intensity, disability, and health-related quality of life, secondary outcomes are adverse events. Our IPD dataset will consist of the information on each eligible trial characteristics and included variables according to a predefined coding scheme. We will assess risk-of-bias of included RCTs with the Cochrane Risk Of Bias (RoB)-2 assessment tool. We will perform power calculations with closed-form solutions and prioritize a one-stage approach for IPD-MA. For reporting the results, we will adhere to the PRISMA-IPD statement.

Understanding general practitioners' prescribing choices to patients with chronic low back pain: a discrete choice experiment.

BACKGROUND: Although NSAIDs are recommended as a first line analgesic treatment, opioids are very commonly prescribed to patients with low back pain (LBP) despite risks of harms. AIM: This study aimed to determine factors contributing to general practitioners' (GPs') prescribing choices to patients with chronic LBP in a primary care setting. METHOD: This discrete choice experiment (DCE) presented 210 GPs with hypothetical scenarios of a patient with chronic LBP. Participants chose their preferred treatment for each choice set, either the opioid, NSAID or neither. The scenarios varied by two patient attributes; non-specific LBP or LBP with referred leg pain (sciatica) and number of comorbidities. The three treatment attributes also varied, being: the type of opioid or NSAID, degree of pain reduction and number of adverse events. The significance of each attribute in influencing clinical decisions was the primary outcome and the degree to which GPs preferred the alternative based on the number of adverse events or the amount of pain reduction was the secondary outcome. RESULTS: Overall, GPs preferred NSAIDs (45.2%, 95% CI 38.7-51.7%) over opioids (28.8%, 95% CI 23.0-34.7%), however there was no difference between the type of NSAID or opioid preferred. Additionally, the attributes of pain reduction and adverse events did not influence a GP's choice between NSAIDs or opioids for patients with chronic LBP. CONCLUSION: GPs prefer prescribing NSAIDs over opioids for a patient with chronic low back pain regardless of patient factors of comorbidities or the presence of leg pain (i.e. sciatica).

A Second Look at the Risks of Serious Adverse Events with Orthopaedic Manual Therapy, Paracetamol, and NSAID Treatment of Neck Pain.

Letter to the Editor-in-Chief in response to JOSPT article "International Framework for Examination of the Cervical Region for Potential of Vascular Pathologies of the Neck Prior to Musculoskeletal Intervention: International IFOMPT Cervical Framework" by Rushton A, Carlesso LC, Flynn T, et al. J Orthop Sports Phys Ther 2023;53(6):1-2. doi:10.2519/jospt.2023.0202.

Opioid deprescribing: Qualitative perspectives from those with chronic non-cancer pain.

AIM: Deprescribing is the systematic process of discontinuing medications when the harms outweigh the benefits. This study aimed to identify barriers and facilitators in people with chronic non-cancer pain when deprescribing opioid analgesics, and their views on resources that assist with deprescribing. METHODS: A purposive sampling strategy was used to recruit 19 adults with chronic non-cancer pain from the community who were, or had been, on long-term opioid therapy. Recruitment continued until thematic saturation was achieved. Semi-structured telephone interviews were conducted. A five-step framework and thematic analysis method identified themes for each study aim. RESULTS: Themes identifying barriers to opioid deprescribing raised challenges of a lack of available alternatives, managing opioid dependency and withdrawal symptoms or inability to function without opioids when in extreme pain. Facilitating themes described the value of support networks, including a trusting doctor-patient relationship and finding individual coping strategies to address deprescribing barriers. We explored a variety of resources from electronic forms such as websites and apps to paper-based or face to face. Participants expressed that whatever the form, resources need to be educational but also simple and engaging. CONCLUSIONS: Most people suffering from chronic non-cancer pain expressed dissatisfaction with being on opioids but most were still unwilling to deprescribe due to insufficient alternatives, a lack of support from their doctors and lack of information about the deprescribing process. Deprescribing can be facilitated by improving supportive networks and strategies and providing simple and positive educational resources.

Medications for Treating Low Back Pain in Adults. Evidence for the Use of Paracetamol, Opioids, Nonsteroidal Anti-inflammatories, Muscle Relaxants, Antibiotics, and Antidepressants: An Overview for Musculoskeletal Clinicians.

BACKGROUND: Because pharmacological therapies may play an important role in managing musculoskeletal pain, the appropriate use of medicines for common conditions like low back pain (LBP) is critical. New evidence on the effects and safety of paracetamol, nonsteroidal anti-inflammatory drugs (NSAIDs), opioid analgesics, muscle relaxants, antibiotics, and antidepressants for LBP warrants an updated overview for musculoskeletal clinicians on this topic. CLINICAL QUESTION: How effective and safe are paracetamol, NSAIDs, opioid analgesics, muscle relaxants, antibiotics, and antidepressants compared with placebo for treating LBP? KEY RESULTS: For acute LBP (<12 weeks), muscle relaxants and NSAIDs may be superior to placebo for reducing pain, but the effects of opioids, antibiotics, and antidepressants are unknown. Paracetamol provides no additional benefit for acute LBP. For chronic LBP (>12 weeks), NSAIDs, antidepressants, and opioids may be superior to placebo for reducing pain, but opioids have an established profile of harms. Antibiotics may also reduce pain for people with chronic LBP with Modic type 1 changes, although the risks may outweigh their benefits. The effects of paracetamol and muscle relaxants for chronic LBP were unclear. CLINICAL APPLICATION: NSAIDs may have a role in managing acute and chronic LBP, with cautious use in people who may be at greater risk of experiencing adverse events. Paracetamol, opioid analgesics, antibiotics, muscle relaxants, and antidepressants should only be prescribed following a discussion between the treating clinician and the patient, considering the risks and possible benefits, and after or in conjunction with recommended nonpharmacological strategies for improving LBP. J Orthop Sports Phys Ther 2022;52(7):425-431. Epub: 18 May 2022. doi:10.2519/jospt.2022.10788.

Spinal Cord Stimulators: An Analysis of the Adverse Events Reported to the Australian Therapeutic Goods Administration.

BACKGROUND: Spinal cord stimulators are used to treat intractable pain. Placebo-controlled trials of spinal cord stimulators typically involve short-term treatment and follow-up, so long-term safety and efficacy are unclear. AIM: The aim of the study was to describe the adverse events relating to spinal cord stimulators reported to the Therapeutic Goods Administration of Australia between July 2012 and January 2019. METHODS: Adverse events were coded by seriousness, severity, body system affected, type of event, action taken, and attribution of fault. Data on the number of stimulators implanted and removed were sourced from the Admitted Patient Care Minimum Data Set. RESULTS: Five hundred twenty adverse events were reported for spinal cord stimulators. Most events were rated as severe (79%) or life-threatening (13%). Device malfunction was the most common event (56.5%). The most common action taken in response to an adverse event was surgical intervention with or without antibiotics (80%). The ratio of removals to implants was 4 per every 10 implanted. CONCLUSIONS: Spinal cords stimulators have the potential for serious harm, and each year in Australia, many are removed. In view of the low certainty evidence of their long-term safety and effectiveness, our results raise questions about their role in providing long-term management of intractable pain.

Advice and education provide small short-term improvements in pain and disability in people with non-specific spinal pain: a systematic review.

QUESTIONS: What is the effect of advice/education compared with placebo or no advice/education on pain and disability in people with non-specific spinal pain? To what extent do characteristics of the patients, trial or intervention modify the estimate of the treatment effects? DESIGN: A systematic review with meta-analyses of randomised controlled trials. PARTICIPANTS: Adults with non-specific back and/or neck pain with or without radiating leg/arm pain of any duration were included. Trials recruiting pregnant women or surgical patients in the immediate postoperative phase were ineligible. INTERVENTION: Advice or education. OUTCOME MEASURES: The primary outcomes were self-reported pain and disability, and the secondary outcome was adverse events. The following potential effect modifiers were examined: risk of bias, duration of pain, location of pain, intensity of intervention and mode of intervention. RESULTS: Twenty-seven trials involving 7,006 participants were included. Eighteen of the included trials were assessed as being at low risk of bias (≥ 6 on the PEDro scale). There was low-quality evidence that advice had a small effect on pain (MD -8.2, 95% CI -12.5 to -3.9, n = 2,241) and moderate-quality evidence that advice had a small effect on disability (MD -4.5, 95% CI -7.9 to -1.0, n = 2,579) compared with no advice or placebo advice in the short-term. None of the items that were assessed modified the treatment effects. CONCLUSION: Advice provides short-term improvements in pain and disability in non-specific spinal pain, but the effects are small and may be insufficient as the sole treatment for patients with spinal pain. REGISTRATION: PROSPERO CRD42020162008.

Transcutaneous electric nerve stimulation (TENS) for acute low back pain: systematic review.

Background and aims There has been no comprehensive evaluation of the efficacy of transcutaneous electric nerve stimulation (TENS) for acute low back pain (LBP). The aim of this systematic review was to investigate the efficacy and safety of TENS for acute LBP. Methods We searched MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, CENTRAL, CINAHL and PsycINFO (inception to May 2018) for randomised placebo controlled trials. The primary outcome measure was pain relief in the immediate term (within 2-weeks of administration) assessed using the 100 mm visual analogue scale. A mean difference of at least 10 points on the 100-point pain scale was considered clinically significant. Methodological quality of the eligible studies was assessed using the PEDro scale and overall quality assessment rating was assessed using GRADE. Results Three placebo controlled studies (n = 192) were included. One low quality trial (n = 63) provides low quality evidence that ~30 min treatment with TENS in an emergency-care setting provides clinically worthwhile pain relief for moderate to severe acute LBP in the immediate term compared with sham TENS [Mean Difference (MD) - 28.0 (95% CI - 32.7, -23.3)]. Two other studies which administered a course of TENS over 4-5 weeks, in more usual settings provide inconclusive evidence; MD -2.75 (95% CI -11.63, 6.13). There was limited data on adverse events or long term follow-up. Conclusions The current evidence is insufficient to support or dismiss the use of TENS for acute LBP. Implications There is insufficient evidence to guide the use of TENS for acute LBP. There is low quality evidence of moderate improvements in pain with a short course of TENS (~30 min) during emergency transport of patients to the hospital. Future research should evaluate whether TENS has an opioid sparing role in the management of acute LBP.

Clinicopathologic and Prognostic Significance of Programmed Cell Death Ligand 1 Expression in Patients with Non-Medullary Thyroid Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Evidence has shown that programmed cell death ligand 1 (PD-L1) overexpression is associated with poor prognosis and resistance to immune therapies in several human cancers. However, data on the prognostic significance of PD-L1 expression in thyroid cancer are limited and remain controversial. This systematic review and meta-analysis aimed to evaluate comprehensively the clinicopathologic significance and prognostic value of PD-L1 expression in non-medullary thyroid cancers. METHODS: Electronic databases, including Medline/PubMed, EMBASE, and the Cochrane Library, were searched up until July 5, 2017. In total, seven comparisons (from six articles) comprising 1421 patients were included in the pooled analysis. RESULTS: There was moderate quality evidence from four studies (n = 721) that shows positive PD-L1 expression was significantly associated with poor survival among thyroid cancer patients (pooled hazard ratio = 3.73 [confidence interval (CI) 2.75-5.06]). Increased PD-L1 expression was also found to be significantly associated with disease recurrence (odds ratio = 1.95 [CI 1.15-3.32]) and concurrent thyroiditis (odds ratio = 1.65 [CI 1.09-2.51]). CONCLUSIONS: The results confirm the prognostic significance of PD-L1 expression in thyroid cancer patients. PD-L1 expression has the potential to be implemented as a prognostic biomarker used to guide clinicians in identifying patients with more aggressive cancers, and for the selection of individuals that would derive durable clinical benefit from anti-PD-1/PD-L1 immunotherapy. Prospective clinical trials will be useful to support these findings.

Comparison of effect sizes between enriched and nonenriched trials of analgesics for chronic musculoskeletal pain: a systematic review.

AIMS: To investigate the use of an enriched study design on the estimates of treatment effect in analgesic trials for chronic musculoskeletal pain. METHODS: Database searches were conducted from 2004 to 2014. We included randomized placebo-controlled trials evaluating pain medications for chronic musculoskeletal pain. Methodological quality was assessed using the PEDro scale. The estimates of treatment effect on pain and adverse events were compared between enriched and nonenriched designs. Metaregression was used to assess the association between the effect size estimate and the study design controlling for analgesic dose and methodological quality. RESULTS: We included 108 trials, of which 99 were included in the meta-analysis (n = 44 171). There were no overall differences in effect sizes between enriched and nonenriched designs for pain intensity. There was a significant difference for a reduction in any adverse events favouring enriched designs for opioids, but not for other analgesics or the outcome serious adverse events. There was an association between effect size and methodological quality, with failure to blind the outcome assessor and failure to use intention-to-treat analysis being associated with larger effect sizes. CONCLUSIONS: There is no evidence that the use of an enriched study design changes the treatment effect size estimate for pain. There is some evidence that clinical trials that employ enriched designs report a reduced risk of adverse events in trials for chronic musculoskeletal pain, but it is unclear whether enriched designs influence estimates of serious adverse events. Features of trial design and study quality were associated with treatment effect estimates.