Prepared by Margaret McCredie, Cancer Epidemiology Research Unit, New South Wales Cancer Council,

Dr Ian Roddick of Launceston, Tasmania, has written to Australian Prescriber to ask about the safety of prescribing paracetamol with a non-steroidal anti-inflammatory drug (NSAID). Australian Prescriber has previously reviewed the toxicity of older formulations, such as Bex and Vincent's powders, which combined aspirin with phenacetin.1

Dr Roddick's question arises because aspirin is a NSAID and paracetamol is a metabolite of phenacetin.

I agree that many rheumatologists are now recommending paracetamol plus a NSAID, when required, for analgesia. It has been suggested that the prostaglandin-mediated anti-inflammatory effects of NSAIDs are only marginally increased by higher doses and that the non-prostaglandin-mediated analgesia obtained at high doses may instead be obtained by supplementing NSAIDs with paracetamol.2 There is evidence that paracetamol supplementation does increase the effect of NSAIDs. A lower dose of a NSAID taken with paracetamol has the same analgesic effect and a lower prevalence of adverse effects than a higher dose of the same NSAID taken without paracetamol. This has been shown for naproxen and paracetamol in arthritis at the hip3, naproxen and paracetamol in rheumatoid arthritis4, and indomethacin and paracetamol in rheumatoid arthritis.3

The basis of the nephrotoxicity of combinations of aspirin with phenacetin (or paracetamol) is that aspirin depletes renal glutathione which normally protects the kidney against the toxic metabolites of phenacetin and paracetamol (the main metabolite of phenacetin). In relation to whether NSAIDs other than aspirin deplete renal glutathione, I have been unable to find any published evidence. As many Australian patients are taking NSAIDs with paracetamol without adverse renal effects, it seems unlikely that these drugs deplete glutathione.


  1. McCredie M. Analgesic nephropathy revisited. Aust Prescr 1990;13:55-8.
  2. Seideman P. Additive effect of combined naproxen and paracetamol in rheumatoid arthritis. Br J Rheumatol 1993;32:1077-82.
  3. Seideman P, Samuelson P, Neander G. Naproxen and paracetamol compared with naproxen only in coxarthrosis. Increased effect of the combination in 18 patients. Acta Orthop Scand 1993;64:285-8.
  4. Seideman P. Paracetamol in rheumatoid arthritis. Agents Actions Suppl 1993;44:7-12.
  5. Seideman P, Melander A. Equianalgesic effects of paracetamol and indomethacin in rheumatoid arthritis. Br J Rheumatol 1988;27:117-22.