Effects of legislation restricting pack sizes of paracetamol and salicylate on self poisoning in the United Kingdom: before and after study

Yes it is true that suicides have decreased as a result of the amount
of paracetamol tablets available to be sold in one box over the counter.
But it is not solely because of this., there are also mental health crisis
teams that offer services to clients who present as suicidal or at risk of
self harm, to attempt to prevent overdose or actual suicides occuring so
clients can access the services appropiate for them. The team I work in
has seen a significant decline in suicide rates since it was first set up
2 1/2yrs ago. This team offers a diverse service, but respond to those in
mental health crisis and clients can refer themselves.

EDITOR

Legislation Restricting Pack Sizes.

In view of the evidence
that restricting pack sizes of paracetamol and salicylate reduces
excessive consumption (BMJ 19 May). Should the medical profession lobby
for a reduction in pack size of cigarettes?

Rory J Shaw
Medical Director and Professor of Respiratory Medicine

Hammersmith Hospitals NHS Trust, London W12 OHS

Paracetamol overdose is the most common cause of acute hepatic failure. Hepatocytes become sensitive to paracetamol metabolites and inflammatory mediators1-3 when intracellular glutathione (GSH) is depleted due to paracetamol metabolism4. For this reason, many clinical conditions associated with GSH depletion place patients at greater risk of paracetamol toxicity, even at therapeutic paracetamol dosings. These predisposing conditions include chronic alcohol abuse, HIV, sepsis, multi-organ system failure, chemotherapy, other types of hepatic failure, certain metabolic diseases, and chronic CNS disease. In addition, patients without predisposing disease are at risk because over-the-counter cold remedies and similar preparations frequently contain paracetamol and represent sources of potential overdose due to excessive, concomitant or chronic use.

Importantly, Hawton, Townsend, Deeks, Appleby, Gunnell, Bennewith, and Cooper now report that morbidity and mortality from paracetamol overdose decreased in the years following UK legislation to restrict the package sizes of the drug5. However, as these authors note, restricting the package size did not completely resolve the problem.
N-acetylcysteine (NAC), which provides the cysteine necessary to replenish glutathione (GSH) depleted by paracetamol, is used to treat paracetamol overdose6,7.

Intravenous NAC treatment protocols are used in some regions. However, oral treatment protocols have been shown to be highly effective. Treatment is most effective when started soon after paracetamol ingestion8,9; delays should be avoided but are still common10. Therefore, we suggest that toxicity caused by intentional or unintentional paracetamol overdoses is best treated by prevention, i.e., by formulating or packaging paracetamol with sufficient amounts of NAC to largely prevent toxicity .

NAC preserves the antipyretic and analgesic properties of paracetamol. Therefore, co-administration should not interfere with paracetamol effectiveness. Further, since NAC has been used for many years at high doses with minimal (or no) toxicity, administration at the estimated doses together with paracetamol should not pose any safety issues. The disagreeable odor and taste characteristic of some NAC formulations, particularly those used clinically in the United States, would appear to be a problem. However, the contaminants responsible for the bad taste and odor are not present in appropriately manufactured NAC formulations. Our estimates indicate that including less than 200 mg of NAC per 500 mg of paracetamol would accomplish the necessary prevention of toxicity. Therefore, we foresee no obstacles to the introduction of NAC/paracetamol products. Efficacy of such formulations for preventing morbidity and mortality should be evaluated.

James P. Andrus, MD#

Lenore A. Herzenberg, PhD+

Leonard A. Herzenberg, PhD+

Stephen C. DeRosa, MD+

Departments of Pediatric Critical Care# and Genetics+,
Stanford University School of Medicine, Stanford, CA 94305-5318

Corresponding author: James Andrus,
Andrus@darwin.stanford.edu

Citations

1. Luster MI, Simeonova PP, Gallucci RM, Bruccoleri A, Blazka ME, Yucesoy B. Role of inflammation in chemical-induced hepatotoxicity. Toxicol Lett 2001;120(1-3):317-21.

2. Laskin DL, Laskin JD. Role of macrophages and inflammatory mediators in chemically induced toxicity. Toxicology 2001;160(1-3):111-8.

3. Walsh TS, Wigmore SJ, Hopton P, Richardson R, Lee A. Energy expenditure in acetaminophen-induced fulminant hepatic failure. Crit Care Med 2000;28(3):649-54.

4. McClain CJ, Price S, Barve S, Devalarja R, Shedlofsky S. Acetaminophen hepatotoxicity: An update. Curr Gastroenterol Rep 1999;1(1):42-9.

5. Hawton K, Townsend E, Deeks J, Appleby L, Gunnell D, Bennewith O, et al. Effects of legislation restricting pack sizes of paracetamol and salicylate on self poisoning in the United Kingdom: before and after study. Bmj 2001;322(7296):1203.

6. Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985). N Engl J Med 1988;319(24):1557-62.

7. Kind B, Krahenbuhl S, Wyss PA, Meier-Abt PJ. [Clinical-toxicological case (1). Dosage of N-acetylcysteine in acute paracetamol poisoning]. Schweiz Rundsch Med Prax 1996;85(31-32):935-8.

8. Donovan JW. Medical fortune-telling: predicting acetaminophen toxicity. Acad Emerg Med 1999;6(11):1079-82.

9. Smilkstein MJ, Bronstein AC, Linden C, Augenstein WL, Kulig KW, Rumack BH. Acetaminophen overdose: a 48-hour intravenous N-acetylcysteine treatment protocol. Ann Emerg Med 1991;20(10):1058-63.

10. McCormick PA, Casey P, Barry P, Laffoy M, Treacy J. Delays in administration of acetylcysteine in paracetamol overdose. Ir Med J 2000;93(3):77-8.

EDITOR -- Hawton et al’s paper (1) reports a decrease (at least over
the first year) in the number of deaths from paracetomol and salicylate
self poisoning after the introduction of legislation restricting the pack
sizes. This is certainly encouraging.

However, there remains the problem of self poisoning with prescribed
medication. Co-proxamol, a prescription only drug, is a combination of
dextropropoxyphene and paracetomol. In overdosage, the opioid component
produces respiratory depression and coma, and, in combination with
alcohol, acute cardiovascular collapse. (2)

In 1994, Farmer (3) reported that co-proxamol and paracetomol
accounted for the majority of suicides in analgesia overdosage. When
examining young suicides, Hawton et al’s study (4) found that the most
frequently used drug in overdosage was co-proxamol, and the medication had
usually been prescribed for someone other than the young person who had
committed suicide. If the number of suicides using co-proxamol is
increasing – and this was postulated at the recent Mental Health 2001
Conference in London – then action is required.

But what is effective action? Hawton et al (1) report that warnings
on packets are generally ineffective. Restricting sales is only possible
on OTC medication. Perhaps some of the responsibility rests with the
prescriber, to help limit the availability of prescribed analgesics,
particularly co-proxamol.

(1) Hawton, K., Townsend, E., Deeks, J., Appleby, L., Gunnell, D.,
Bennewith, O. et al. Effects of legislation restricting pack sizes of
paracetomol and salicylate on self poisoning in the United Kingdom: before
and after study. BMJ 2001; 322:1203-6.

(2) British National Formulary, March 2001

(3) Farmer, R.D.T. Suicide and poisons. Human Psychopharmacology
1994; 9 (suppl): S11-19.

(4) Hawton, K., Houston. K., and Shepperd, R. Suicide in young
people. Study of 174 cases, aged under 25 years, based on coroners’ and
medical records. British Journal of Psychiatry 1999; 175: 271-276.