When I use a word: HARMful reactions
Authors: Jeff Aronson
Journal: BMJ (2004)

During the second world war Leopold Meyler, a Dutch physician, developed pulmonary tuberculosis. He later received treatment and suffered an adverse reaction: either dihydrostreptomycin made him deaf or para-aminosalicylic acid made him feverish—the details are disputed. But it stimulated him, bedbound, to retrieve published reports of unwanted effects of drugs and to collect them in a volume that ran to 192 pages and was first published in Dutch in 1951 (Schaldelijke Nevenwerkingen van Geneesmiddelen). An English translation (Side Effects of Drugs) appeared in 1952, and several updates followed. When Meyler died suddenly in 1973, while preparing volume 8, Graham Dukes took over the editorship, started publishing the updates annually (Side Effects of Drugs Annuals), and created an encyclopedic version, Meyler's Side Effects of Drugs.

The title Side Effects of Drugs has stuck, through 14 editions of the encyclopedia and 26 volumes of the annual. But we now recognise that side effects of drugs, as well as toxic effects and hypersusceptibility effects, are particular forms of unwanted effects, and that the term “adverse effects” is preferable (Lancet 2000;356: 1255-60 [PubMed]). A toxic effect is one that occurs at high doses, by exaggeration of the desired therapeutic effect. For example, a cardiac arrhythmia due to digoxin is a toxic effect—it occurs by the same mechanism as the therapeutic effect.

On the other hand, an unwanted side effect (or, better, a collateral effect; see BMJ 2003;327: 1222-5 [PubMed]) occurs at the usual therapeutic dose, usually in some tissue other than the site of the therapeutic effect, and sometimes via some non-therapeutic mechanism. For example, the anticholinergic effect of a tricyclic antidepressant is a side effect, since this action is not responsible for the therapeutic effect. Impaired colour vision caused by sildenafil inhibiting phosphodiesterase type V in the eye is a side effect, since the phosphodiesterase you want to inhibit is in the corpora cavernosa.

Side effects may also be beneficial rather than harmful. For example, treating hypertension with a β blocker may, by β blockade, also relieve angina, a beneficial side effect. Alternatively, a depressed patient with irritable bowel syndrome may incidentally benefit from the anticholinergic side effect of a tricyclic antidepressant as well as from its antidepressant action.

Finally, hypersusceptibility effects typically occur at low doses and are often immunological in mechanism. The term “adverse effect” encompasses all these types of unwanted effects and makes no assumptions about mechanism or relation to dose.

Now, talking about adverse effects looks at things from the point of view of the drug. But it has instead become common to talk about “adverse reactions,” looking at them from the point of view of the patient, and specifically about “adverse drug reactions” (ADRs). However, the term “drug” excludes contaminants (such as in herbal medicines) or supposedly inactive excipients in a formulation. And so, recognising that medicinal products contain ingredients other than active principles, I propose that we should talk about adverse reactions to medicines or medicaments, ARMs rather than ADRs. And don't we all want a farewell to ARMs?

And since Meyler's book is soon to appear in electronic format, with the provisional title Meyler's International Encyclopedia of Adverse Drug Reactions, I like to regard its database as Highlighting Adverse Reactions to Medicines. And where's the HARM in that?