Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo controlled trials

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Machado GC, et al. "Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo controlled trials". BMJ. 2015. 350:1-13.
PubMed

Clinical Question

In patients with spinal pain and osteoarthritis, is the use of paracetamol safe and efficacious compared to no therapy?

Bottom Line

The use of paracetamol is ineffective in the treatment of low back pain. Minimal benefit is shown in patients with osteoarthritis of the hip or knee. Recommendations to use paracetamol should be reconsidered in patients with spinal pain and osteoarthritis.

Major Points

Osteoarthritis affects almost 22% of the United States population, costing approximately $95 billion dollars annually.[1] Similarly, lower back pain affects between 14% to 23% of adults each year and costs $30 billion annually in days missed from work in the US.[2] Many patients do not seek medication attention from a physician, depending on over the counter medications to alleviate pain.[3] Numerous guidelines currently suggest paracetamol as first line therapy for the treatment of both osteoarthritis and spinal pain.In most cases, these guidelines suggest doses of paracetamol close to the 4,000 mg/day maximum daily dose. Patient adherence and safety is a common concern in patients taking high doses of paracetamol.

Recent studies showing evidence of no therapeutic benefit from paracetamol for patients with osteoarthritis and spinal pain were controversial and heavily debated. This systematic review and meta-analysis aimed to further understand the safety and efficacy of paracetamol using only placebo-controlled studies.

5,366 patients were included in this study, and the primary outcomes studied included pain intensity, disability status, and quality of life. Secondary outcomes included adverse effects, patient adherence, and use of rescue medication.

Guidelines

American Academy of Orthopedic Surgeons. AAOS Clinical Practice Guideline on Osteoarthritis of the Knee[4]

  • Inconclusive regarding the use of acetaminophen, opioids, or pain patches for patients with osteoarthritis of the knee (Strength of Recommendation: Inconclusive).

EBM Guidelines. Osteoarthritis[5]

  • Paracetamol is the drug of choice. It is not quite as effective as Non-Steroidal Anti-inflammatory drugs (NSAIDs), but has few adverse effects with long-term use (Level of Evidence A).
  • NSAIDs may be added to paracetamol if needed for 7-21 days at a time. The choice of NSAIDs should be based on tolerability and safety.
  • Opioids are sometimes needed in severe osteoarthritic pain (Level of Evidence A).

University of Michigan Health System. Knee pain or swelling: acute or chronic[6]

  • Acetaminophen and/or topical capsaicin are the initial drugs of choice (Level of Evidence A).

Singapore Ministry of Health. Osteoarthritis of the knees[7]

  • Paracetamol is the first line treatment for relieving pain and improving physical functioning in osteoarthritis (Grade A, Level 1+).

Design

  • Systematic review, meta-analysis and randomized control studies
  • N= 5366 (11 studies were included)
    • Spinal Pain N=1825
    • Osteoarthritis N=3541
  • Enrollment: 1983-2014
  • Mean Follow Up:
    • Immediate term (≤2 weeks)
    • Short term (>2 weeks but ≤ 3 months)
    • Intermediate term (>3 months but ≤12 months)
    • Long term (>12 months)
  • Primary Outcomes (Meta-analysis):
    • Osteoarthritis and spinal pain intensity
    • Quality of life
    • Disability status

Population

Inclusion Criteria

  • Eligible studies included at least one of the following primary outcome measures: pain intensity, disability status, and quality of life
  • Secondary outcome measures: Adverse effects, patient adherence, and use of rescue medication
  • Included only randomized controlled trials comparing the efficacy of paracetamol vs. placebo
  • Trials had to include participants with non-specific spinal pain or osteoarthritis of the hip or knee
  • Only full articles (no abstracts)
  • The intensity and duration of symptoms was not restricted
  • Studies in which participants had previous spinal, hip, or knee surgery remained eligible

Exclusion Criteria

  • Mixed populations of patients with spinal pain and osteoarthritis
  • Studies that included patients with serious spinal pathologies
  • Studies with mixed populations of patients with rheumatoid arthritis and osteoarthritis
  • Trials evaluating analgesia in immediate postoperative patients

Baseline Characteristics

  • Total Patients: 5366 patients
  • Duration of pain
    • Acute: 2 studies
    • Chronic: 6 studies
    • Not reported: 5 studies
  • Patients with spinal pain
    • Average patients per trial: 609
    • Mean ages: 38-57.2
  • Patients with osteoarthritis
    • Average patients per trial: 355
    • Mean ages: 55.3-70

Interventions

  • Randomized to a group based on age and diagnosis of osteoarthritis or spinal pain
  • Patients were randomly assigned to different durations (acute, <6 weeks, chronic, >6 months)
    • Spinal pain:
      • Oral- 1 trial:
        • Group 1: paracetamol 500 mg, 2 tablets 4 times daily
        • Group 2: oral placebo
      • Intravenous- 1 trial:
        • Group 1: single intravenous paracetamol 1000 mg dose
        • Group 2: intravenous placebo
      • Oral- 1 trial:
        • Group 1: paracetamol 665 mg, 2 tablets 3 times daily
        • Group 2: paracetamol 500 mg, 1-2 tablets as needed, 4-6 hours apart, maximum of 8 tablets per day
        • Group 3: oral placebo
    • Osteoarthritis:
      • Oral- 2 trials:
        • Group 1: paracetamol 500 mg, 2 tablets 4 times daily
        • Group 2: oral placebo
      • Effervescent:
        • Group 1: effervescent paracetamol 500 mg, 2 tablets 3 times daily
        • Group 2: effervescent placebo
      • Oral- 4 trials:
        • Group 1: paracetamol 1000 mg, 1 tablet 4 times daily
        • Group 2: oral placebo
      • Oral- 1 trial:
        • Group 1: paracetamol 1000 mg, 1 tablet 3 times daily
        • Group 2: oral placebo
      • Oral Extended Release (ER)- 1 trial:
        • Group 1: paracetamol ER 1300 mg, 1 tablet 3 times daily
        • Group 2: paracetamol 650 mg, 2 tablets 3 times daily
        • Group 3: oral placebo
      • Oral Extended Release (ER)- 1 trial:
        • Group 1: paracetamol ER 650 mg, 2 tablets 3 times daily
        • Group 2: oral placebo

Outcomes

Primary Outcomes

Mean Difference (95% CI); P-value, NNT

Osteoarthritis and Spinal Pain Intensity

  • Osteoarthritis (Immediate-term)
    • -3.3 (-5.8 to -0.8), S, 31
  • Osteoarthritis (Short-term)
    • -3.7 (-5.5 to -1.9), S, 28
  • Other outcomes were not significant

Disability Status

  • Osteoarthritis (Short-term)
    • -2.9 (-4.9 to -0.9), S, 35
  • Other outcomes were not significant

Quality of Life

  • Outcomes were not significant

Secondary Outcomes

  • Outcomes were not significant

Subgroup Analysis

  • No significant difference between any of the subgroups

Criticisms

  • This study only gives high quality evidence showing that paracetamol does not provide a positive effect on spinal pain or osteoporosis short term, but it does not provide information of its effects from long term use of paracetamol.
  • There were no trials included involving patients with neck pain therefore there is no known answer on the effect of paracetamol in patients with neck pain.
  • The number of studies included in this systematic review was small.
  • The review states that patients taking paracetamol are more likely to have abnormal liver function tests but doesn’t explain what effect these abnormal liver function tests have on the body.[8]
  • This systematic review did not look at enough studies in order to make a change to international guidelines.[9]
  • The systematic review only contains one study pertaining to low back pain therefore there is not enough data to draw a conclusion for use of paracetamol in patients with back pain.[10]

Funding

This research was not funded by grants from any specific public, commercial, or not-for-profit agencies.

Further Reading

  1. Palacio, LE. Osteoarthritis. In: Essential Evidence Plus. Hoboken (NJ): John Wiley & Sons, 2012. Updated 2015 Feb 19; accessed 2016 Apr 17.
  2. Matthews ML et al. Back Pain (low, chronic). In: Essential Evidence Plus. Hoboken (NJ): John Wiley & Sons, 2012. updated 2016 Jul 7; accessed 2016 Apr 17.
  3. Boyd L et al. Neck Pain. In: Essential Evidence Plus. Hoboken (NJ): John Wiley & Sons, 2012. updated 2016 Jan 21; accessed 2016 Apr 17.
  4. Clinical Practice Guideline on Osteoarthritis of the Knee. Rosemont (IL): American Academy of Orthopaedic Surgeons. Published 2013 May; accessed 2016 Apr 17.
  5. Osteoarthritis EBM Guidelines. In: Essential Evidence Plus. Hoboken (NJ): John Wiley & Sons, 2012. Updated 2014 May 8; accessed 2016 Apr 17.
  6. University of Michigan Health System. Knee pain or swelling: acute or chronic. Ann Arbor (MI): University of Michigan Health. Published 2005 Apr 13; accessed 2016 Apr 17.
  7. Singapore Ministry of Health. Osteoarthritis of the knee. Singapore: Singapore Ministry of Health; 2007
  8. Fernando Kemta Lekpa. Letters to the editor. Efficacy and safety of paracetamol for spinal pain and osteoarthritis. BMJ 2015;350:h1225
  9. Claus Manniche. Letters to the editor. Efficacy and safety of paracetamol for spinal pain and osteoarthritis. BMJ 2015;350:h1225
  10. Lily A Dryburgh-Smith. Letters to the editor. Efficacy and safety of paracetamol for spinal pain and osteoarthritis. BMJ 2015;350:h1225