Methacholine

A diagnostic instrument rather than a medicine, and a good one so long as the result is read in the right direction. A negative test is the strong result; a positive test says the airways are twitchy and leaves the diagnosis open. Treating a positive challenge as proof of asthma is the most common way this drug gets misused.

The hazard here is the intended effect going too far. The label carries a boxed warning that severe bronchoconstriction can result from administration including the lowest dose, and requires that emergency equipment and a rapid-acting inhaled beta-agonist be immediately available. Testing is contraindicated below an FEV1 of 60 percent predicted, or below 1.5 L in adults, and is not recommended in anyone with clinically apparent asthma or wheezing, since those patients will react and there is nothing left to learn.

Beta-blockers are a specific interaction: the label states that responses can be exaggerated or prolonged and may not respond readily to the usual rescue treatment, so the challenge is not performed in people taking them. Beta-agonists, anticholinergics and theophylline blunt the response and are held before the test, which means a false negative is a real risk if they are not. The adverse effects of the procedure itself are headache, throat irritation, light-headedness and itching.

Methacholine is one of the oldest synthetic cholinergic esters still in clinical use; under the name Mecholyl it served for decades as a pharmacological probe of autonomic function, including in dermatology and vascular work, long before it became a lung test. The FDA approved Provocholine, the inhaled powder for solution, on 31 October 1986 for the diagnosis of bronchial airway hyperreactivity. The protocol has changed far more than the molecule: the 2017 European Respiratory Society technical standard moved the reported endpoint from a provocative concentration (PC20) to a delivered provocative dose (PD20) so that results from different nebulisers and dosimeters become comparable, and advised against protocols that require a maximal inhalation to total lung capacity, because a deep breath is itself bronchoprotective and blunts the test ^[1].

Well regarded for what it does and routinely over-read for what it does not. A negative test is the useful result; it argues strongly against current asthma in someone with suggestive symptoms and normal spirometry. A positive test shows the airways are hyperresponsive, which also happens in allergic rhinitis, after viral infection and in COPD, so it supports rather than establishes a diagnosis. A Norwegian birth-cohort study found childhood methacholine responsiveness to be a significant but modest predictor of active asthma six years later, better than an exercise challenge but still explaining only a small part of the variation ^[3].