Easy targets aren't always the right ones
1. Effectiveness and convenience
Figure 1: Number-needed-to-treat (NNT) for oral postoperative analgesics to achieve at least 50% relief of severe or moderate pain compared with placebo
2. Adverse effects
Figure 2: Odds ratios for gastrointestinal complications with NSAIDs by age and by sex
3. The three-pot system
Figures 3 and 4: A simple scheme ('3 pot') for acute and chronic pain relief which uses paracetamol/opioid combination drugs
References

Once more a government committee has taken a side-swipe at combination analgesics:- this time their machinations appear in the British National Formulary (BNF).

'the most expensive range of less suitable drugs are those that work on the central nervous system, such as some of the painkillers. The BNF says combinations of aspirin or paracetamol with opioids, such as codeine, are a bad idea.

Those that contain a full dose of opioid ... also have the full range of opioid side effects, from drowsiness, nausea and vomiting and constipation to the risk of long-term dependence. Yet Solpadol cost the country £8,270,000 and Tylex £10,237,000.' 1

These arguments seem to recur regularly in the developed world and rarely meet opposition from those involved in treating pain.

1. Effectiveness and convenience


The first argument is that the combinations are no more effective than their components. Even in single doses this is incorrect. Figure 1 shows a league table of relative efficacy of oral analgesics used in single dose for postoperative pain 2 .

Figure 1: Number-needed-to-treat (NNT) for oral postoperative analgesics to achieve at least 50% relief of severe or moderate pain compared with placebo

Adding codeine to paracetamol 600 mg provides analgesia equivalent to a bigger (1 gm) dose of paracetamol, and paracetamol 1 gm with codeine 60 mg is the best performer. As yet we do not have the similar analysis for multiple dosing, but extensive clinical experience over many years attests that this will show an even greater effect for patients with chronic pain. We know that the combinations work on different mechanisms to relieve pain. Yes, we could give the components separately, which would delight the purists who dislike combinations of drugs which have different kinetics. But the convenience of just one medication to take is worthwhile, especially for elderly patients on many other drugs. We prescribe sustained release morphine formulations (at huge cost) because it is perceived as more convenient.

2. Adverse effects


The BNF quote above then moves on to adverse effects. Of course these combinations have opioid adverse effects, but we need a touch of common sense. Many elderly patients really should not be prescribed non-steroidal anti-inflammatory drugs (NSAIDs) because of their high risk of gastrointestinal haemorrhage (see http://www.ebandolier.com/ /band52/b52-2.html and Figure 2). Women over 65 years are at several times the risk of major gastrointestinal complications, and these are precisely the patients who present with pain problems.

Figure 2: Odds ratios for gastrointestinal complications with NSAIDs by age and by sex


The combination analgesics are a real and necessary alternative to NSAIDs for this expanding group. The risks with NSAIDs always seem to be downplayed in these discussions. Our working estimate from a systematic review (1.5 million patients) is that the risk of dying from gastrointestinal problems after at least two months on an NSAID is of the order of 1 in 1200 3 . This is a finite risk, and it may be useful to contrast this with the risk of dying on therapeutic doses of combinations of paracetamol with opioid, which is negligible.

Removing drugs from the formulary, or damning them with faint praise, would be professionally legitimate if

  1. there was no evidence of efficacy
  2. there were adverse effect concerns

In the case of these combinations we would argue that there is evidence of efficacy and that concerns about adverse effects which do not take account of the problems with the alternatives are naïve. The only remaining motive would be financial. Again removal of the combinations might make short term savings, but prescription costs of the alternatives would far outweigh any short term saving. We know that 1 in 2800 NSAID prescriptions in the elderly will lead to an episode of ulcer bleeding 4 . The considerable costs of dealing with these complications would then need to be subtracted from the ‘savings' produced by removal of the combinations. A great deal more money would be saved if ibuprofen was prescribed instead of diclofenac. Ibuprofen is three times safer, eight times cheaper and there is no evidence that diclofenac is any more effective than ibuprofen 5 .

3. The three-pot system


A terrible irony of this denigration of the paracetamol combinations is that it comes at a time when the evidence summarised above is being implemented to improve clinical care in both acute and chronic pain. This has led to advocacy of a three pot system, paracetamol, paracetamol and opioid combination and NSAID. Two schemes are in use, one for those who can take NSAIDs, one for those who cannot. Both minimise exposure to opioid and to NSAID. The schemes are shown in Figures 3 and 4. These draw on leaflets in use in Chesterfield UK (JS, personal communication). Before and after comparisons of implementation of the three pot system are under way.

The three pot system is based on best evidence, and uses cheapest available analgesics. It will work for most patients, incorporates the spirit of the WHO analgesic ladder and will minimise the number of patients who need to progress to stronger analgesics such as morphine. The proposals to attack combinations of simple analgesics with opioids are ill-informed and misguided.

Figures 3 and 4: A simple scheme ('3 pot') for acute and chronic pain relief which uses paracetamol/opioid combination drugs

References

  1. Boseley S. £100m bill for wrong NHS drugs. Guardian Oct 27 1998.
  2. McQuay HJ, Moore RA. An evidence-based resource for pain relief. Oxford: Oxford University Press, 1998.
  3. Tramèr MR, Moore RA, Reynolds DJM, McQuay HJ. Death from gastroduodenal complications due to non-steroidal anti-inflammatory drug use for more than two months - A quantitative systematic review. (submitted)
  4. Hawkey CJ, Cullen DJ, Greenwood DC, Wilson JV, Logan RF. Prescribing of nonsteroidal anti-inflammatory drugs in general practice: determinants and consequences. Aliment Pharmacol Ther 1997; 11:293-8.
  5. Collins SL, Moore A, McQuay H.J., Wiffen PJ. Oral ibuprofen and diclofenac in postoperative pain: a quantitative systematic review. European Journal of Pain. 1998; 2:285-291. �