Education and debate

Controversies in management: Should methionine be added to every paracetamol tablet?

Edward P Krenzelok, director ^a

^a Pittsburgh Poison Center, 3705 Fifth Avenue, Pittsburgh, PA 15213, USA

Correspondence to: krenzee@chplink.chp.edu

	Introduction

Top Introduction Poison or remedy? Antidotes Financial justification Disadvantages Limited possibilities References

The paracetamol era began in 1886 when it was recognised that acetanilide had analgesic and antipyretic properties.¹ What went unrecognised for years was that acetanilide's therapeutic properties were secondary to paracetamol. The toxicity of acetanilide's other metabolite, aniline, was unacceptable, and various derivatives were synthesised to find a suitable alternative with analgesic and antipyretic properties. Phenacetin was soon recognised as a viable alternative, and paracetamol was first used for medicinal purposes in 1893.¹ However, it did not become popular until 1949.¹ In 1995 paracetamol sales in the United States were roughly $965m (personal communication, IMS America, Plymouth Meeting, PA 19462-1048).

	Poison or remedy?

Top Introduction Poison or remedy? Antidotes Financial justification Disadvantages Limited possibilities References

To paraphrase the Swiss philosopher and physician Paracelsus: only the dose differentiates a poison from a remedy. Paracetamol is not an exception to this rule. At therapeutic doses paracetamol is relatively benign, but when it is ingested in excessive amounts endogenous hepatic glutathione is depleted and the toxic metabolite of paracetamol (N-acetyl- p-benzoquinoneimine) binds covalently with hepatocytes causing cellular death and hepatic necrosis.² In 1991-5 paracetamol exposure was the most common incident reported to American poison centres, accounting for 5.5% of all exposures.^{3 4 5 6 7} Furthermore, paracetamol overdose was the leading cause of death from poisoning, being implicated in 9.9% of such deaths.

All poisonings are not reported to poison information centres, and it is estimated that full reporting would lead to about 58% more exposures.⁷ Extrapolating this to the paracetamol data for 1991-5, the number of poisonings would increase from 518 205 to 1 233 821 and the number of deaths from 355 to 845. An additional 4250 people would suffer life threatening sequelae. The number of people treated in a healthcare facility would rise from 130 968 patients to 311 829. These data represent the United States only, and the world figures would be staggering. Paracetamol poisoning is clearly a serious problem—what are the solutions?

	Antidotes

Top Introduction Poison or remedy? Antidotes Financial justification Disadvantages Limited possibilities References

The glutathione surrogate or precursors cysteamine, methionine and N-acetylcysteine have been used successfully to treat paracetamol poisoning.² Currently in the United States patients are given oral N-acetylcysteine, and other countries use intravenous N-acetylcysteine (which is not approved in America).² N-Acetylcysteine is especially effective when used soon after the overdose.⁸ Since early intervention is important the idea of incorporating a prophylactic antidote, such as methionine, into each paracetamol tablet was proposed in 1974.⁹ As a precedent, naloxone was already incorporated into pentazocine tablets as a deterrent to abuse.¹⁰ However, adding methionine was dismissed as costly and discriminating against the majority of people who use paracetamol properly. Given the large numbers of fatal and life threatening exposures to paracetamol, is it time to reconsider incorporation of methionine into every paracetamol tablet?

	Financial justification

Top Introduction Poison or remedy? Antidotes Financial justification Disadvantages Limited possibilities References

The financial implications of hospital treatment, liver transplantation, and death make adding methionine very appealing. The mean cost of hospital treatment for paracetamol poisoning in America is about $8700/case (£5400).¹¹ If half of the patients who were treated in a healthcare facility for paracetamol poisoning were admitted to hospital over $1.36bn would have been spent on their care. The number of liver transplants related to paracetamol poisoning is unknown, but the costs range from $165 000 to $327 000, excluding the lifelong expenses for antirejection drugs and other treatment.^{12 13} If each lost life was valued at $3.6m,¹⁴ paracetamol related deaths would have cost over $3bn.

View larger version (69K): [in this window] [in a new window]   Adding methionine to paracetamol makes it more expensive, but would the benefits justify the expense?

The expenses incurred for only five years make a compelling argument for adding methionine to each paracetamol tablet. But do the financial advantages outweigh the disadvantages?

	Disadvantages

Top Introduction Poison or remedy? Antidotes Financial justification Disadvantages Limited possibilities References

Cost is promoted as the main disincentive. Methionine costs around £7.50/kg. If 250 mg methionine were added to each paracetamol tablet the cost of 100 tablets would increase by £1.90. However, methionine would be considerably less expensive if purchased in large quantities. Nevertheless, this cost seems a small price to pay considering the enormous financial burden associated with overdoses.

There are contentions that methionine may be mutagenic and carcinogenic. Since some people take paracetamol daily this could have serious implications. When sodium chloride and sodium nitrite were incubated with meat, methionine caused a mutation in Salmonella typhimurium TA 1535.¹⁵ However, this does not imply that methionine is a universal mutagen. Methionine has prevented the progression of hepatic cancer in rats.¹⁶ In contrast, methionine deprivation is thought to have some antitumour activity.¹⁷ Excessive methionine in the diet may induce atherosclerosis in lagomorphs¹⁸ and reduce serum folate concentrations in humans.¹⁹ Clearly, the arguments for and against adding methionine can be rationalised by using selective research. There is still much to be learnt about methionine and its role in many physiological processes.

	Limited possibilities

Top Introduction Poison or remedy? Antidotes Financial justification Disadvantages Limited possibilities References

What are the alternatives to methionine? In developed countries N-acetylcysteine is abundantly available and relatively inexpensive,²⁰ although the associated hospital costs add considerably to the price of treatment. In these countries it seems better to treat paracetamol poisoning reactively rather than expose the majority of people to an unnecessary and more costly substance. However, my experience in developing nations has shown that N-acetylcysteine and methionine are not universally available. If a paracetamol-methionine combination can be produced economically it may be ethical to encourage its use in developing nations, where the introduction of paracetamol often precedes the availability of N-acetylcysteine and where there are insufficient financial resources to justify the expense of treatment.

	References

Top Introduction Poison or remedy? Antidotes Financial justification Disadvantages Limited possibilities References

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18. Toborek M, Kopieczna-Grzebieniak E, Drozdz M, Weiczorek M. Increased lipid peroxidation as a mechanism of methionine-induced atherosclerosis in rabbits. Atherosclerosis 1995;115:217-24.
19. Connor H, Newton DJ, Preston FE, Woods HF. Oral methionine loading as a cause of acute serum folate deficiency: its relevance to parenteral nutrition. Postgrad Med J 1978;54:318-20. [Abstract]
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