Research Review By Dr. Demetry Assimakopoulos©

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Date Posted:

October 2015

Study Title:

Efficacy and Safety of Paracetamol for Spinal Pain and Osteoarthritis: Systematic Review and Meta-Analysis of Randomized Placebo Controlled Trials

Authors:

Machado GC, Maher CG, Ferreira PH et al.

Author's Affiliations:

The George Institute for Global Health (Sydney Medical School), Faculty of Health Sciences & Faculty of Pharmacy, University of Sydney, Australia; Department of Clinical Pharmacology, St. Vincent’s Hospital and University of New South Wales, Sydney, Australia; School of Medical Sciences, Department of Medicine, University of South Wales, Sydney, Australia; Institute of Bone and Joint Research, The Kolling Institute, Sydney Medical School, University of Sydney, Australia.

Publication Information:

British Medical Journal 2015; 350: h1225 doi: 10.1136/bmj.h1225

Background Information:

Neck pain, back pain and osteoarthritis are extremely common, painful conditions. Together, these issues account for approximately 20% of the total healthcare expenditure in the United Kingdom. Prescription of Paracetamol (also known as acetaminophen, or Tylenol [commercially] in North America) is a very common first line treatment for these issues (1-5). In fact, many of the clinical guidelines for the treatment of low back pain and osteoarthritis endorse the use of Paracetamol for pain related to these conditions. However, the effectiveness of this medication for low back pain and osteoarthritis-related pain has been heavily scrutinized of late. Following this trend, the authors of this study systematically reviewed the evidence on the effectiveness of Paracetamol in patients with spinal pain, and hip/knee osteorarthritis. They also sought to understand the medication’s potential adverse effects, patient adherence and how often patients took additional medication on top of Paracetamol to augment pain relief.

Pertinent Results:

A total of 13 RCTs met the inclusion criteria. Ten of them evaluated the efficacy of Paracetamol in patients with OA of the hip or knee, and 3 trials investigated its effect on low back pain. Paracetamol was primarily administered orally (one trial used IV preparations in participants with chronic low back pain). The total oral dose varied across trials, ranging from 3000-4000 mg/day in divided doses (Writer’s note: it is important to recognize, that the ‘ceiling’ daily dose for acetaminophen is 4 g or 4000 mg /day. Dosing above this value can lead to irreparable and even fatal liver damage). Six trials reported data from people with chronic pain, while 2 studies reported data on acute pain. The remaining studies did not distinguish between chronic and acute pain conditions. None of the studies reported data for long term follow-up. There was a risk for bias in many of the included studies, to varying degrees.

Spinal Pain:
There was no effect of Paracetamol on pain, disability or quality of life in the immediate term (≤ 2 weeks; 2 trials) or short term follow-up (≥ 2 weeks but ≤ 3 months; 1 trial) periods. The quality of evidence for pain relief in the immediate term was rated as ‘moderate quality’ according to the GRADE criteria. The evidence was rated as ‘high quality’ for pain in all other domains. No meta-analysis could be performed on spinal pain trials.

Osteoarthritis of the Hip and/or Knee:
Five trials were included in a meta-analysis, which evaluated the immediate effect (≤ 2 weeks from the time of drug dosing) of Paracetamol to reduce pain. The drug had a small effect on pain reduction when compared to placebo (‘high quality evidence’). Paracetamol showed no immediate effect on disability (‘moderate quality’; 3 trials). In the short term follow-up condition (≥ 2 weeks but ≤ 3 months), there were small but significant effect favouring Paracetamol for pain and disability reduction (‘high quality’).

Adverse Effects:
A total of 9 trials reported adverse effects. There was no difference in the number of adverse events between the Paracetamol group and placebo (‘moderate quality’). However, participants taking Paracetamol were nearly 4x as likely to have abnormal results on liver function tests (‘high quality’).

Patient Adherence:
This was defined as the number of patients reporting consumption of more than 70-80% of the recommended dose. There was no difference in the number of participants adhering to study treatments.

Use of Rescue Medication:
This was defined as the number of patients using either over the counter naproxen or ibuprofen for additional pain relief. There was no difference between groups.

Clinical Application & Conclusions:

There is high quality evidence that Paracetamol has a significant but small positive effect on patients with hip or knee OA compared to placebo in the short term. While present, these small effects (< 4 points on a 0-100 point scale) are not likely to be clinically meaningful. The evidence also showed that Paracetamol is ineffective for low back pain and creates an increased risk of having abnormal results on liver function tests. Interestingly, there was no difference in the need for additional ‘rescue medication’ to augment pain relief between experimental and placebo groups. These findings certainly suggest that practice guidelines should reconsider endorsement of Paracetamol in the treatment of hip/knee OA and low back pain.

Study Methods:

The authors performed a systematic review. They accessed randomized controlled trials from a number of different medical and pharmaceutical databases.

Inclusion criteria:
  • RCTs comparing Paracetamol vs. placebo
  • Patients with non-specific spinal pain (neck or back), or osteoarthritis of the hip or knee. Studies which included both cohorts were also included.
  • Trials including patients with a history of prior spinal, hip or knee surgery were included (but trials on immediate post-operative analgesia were not).
  • Studies reporting pain intensity, disability status and quality of life as primary outcome measures.
  • Studies reporting safety/adverse effects, patient adherence and use of rescue medication as secondary outcome measures.
Exclusion criteria:
  • Studies which included patients with serious spinal pathology
  • Studies which included patients with mixed rheumatoid and osteoarthritis conditions.
  • Articles studying pain in the immediate post-operative period.
The quality of the data was analyzed and judged using the GRADE system. Evidence quality was downgraded by one level if there were limitations in study design (i.e. high risk of bias), inconsistency of results (i.e. large trial heterogeneity) and presence of publication bias. Evidence was judged as ‘high quality’, ‘moderate quality’, ‘low quality’ and ‘very low quality’.

The researchers used 4 data points: immediate term (≤ 2 weeks), short term (≥ 2 weeks but ≤ 3 months), intermediate term (> 3 months, but ≤ 12 months) and long term (> 12 months). Scores for pain and disability were converted to a 0-100 scale, where 0 was no pain or disability, and 100 was worse pain or disability. Pain intensity measures to calculate treatment effect were graded using a numeric rating scale score (0-10) or the visual analogue scale (0-100 mm; minimal clinically important difference of 9 mm). Other pain measures were visual analogue scales obtained from the WOMAC pain subscale and from the multi-dimensional health assessment questionnaire (MDHAQ) pain subscale. Disability was also measured using the WOMAC total score.

Study Strengths / Weaknesses:

Strengths:
  1. Only placebo controlled trials were included in the review, a higher level of study quality in pharmaceutical trials.
  2. A meta-analysis was performed in one condition, which is the highest level of evidence possible.
  3. The interpretation of results was refined by use of precise estimates, functional scales and clinically interpretable scores on 0-100 point scales of both pain and disability.
  4. The quality of the evidence found was ranked as ‘high’ according to the GRADE system.
  5. The authors reported on the measurement of liver function – a common concern with use of Paracetamol.
Weaknesses:
  1. Not many of the studies distinguished between chronic and acute pain conditions. Chronic pain can sensitize the nervous system, both centrally and peripherally, which may render Paracetamol ineffective. This could have be of particular concern when you take into consideration the psychosocial status of individuals suffering from chronic pain. We need more research into the interplay between type of pain and potential responses to all kinds of treatment, whether manual or pharmaceutical.
  2. Drug dosing was not uniform, which was to be expected, but worth mentioning.

Additional References:

  1. Chou R, Qaseem A, Snow V, et al. Diagnosis and treatment of low back pain: a joint clinical practice guideline from the American College of Physicians and the American Pain Society. Ann Intern Med 2007; 147: 478–91.
  2. Zhang W, Doherty M, Arden N, et al. EULAR evidence based recommendations for the management of hip osteoarthritis: report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2005; 64: 669–81.
  3. Jordan KM, Arden NK, Doherty M, et al. EULAR Recommendations 2003: an evidence based approach to the management of knee osteoarthritis: Report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis 2003; 62: 1145–55.
  4. Hochberg MC, Altman RD, April KT, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res 2012; 64: 465–74.
  5. McAlindon TE, Bannuru RR, Sullivan MC, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage 2014; 22: 363–88.