Gabapentin improved chronic cough in randomized trial

Chronic cough is the scourge both of the coughers themselves, and the doctors who treat them. Although rarely medically serious, chronic cough can be surprisingly debilitating by disrupting sufferers' social and professional lives. Doctors, for their part, often feel frustrated and powerless in treating chronic cough. Although gastroesophageal reflux disease (GERD), asthma, ACE inhibitor use, and post-nasal drip (upper airway cough syndrome) are the most common causes, there is no reliable test to identify the cause of chronic cough, and many patients do not respond to therapies for these conditions. Antitussives usually don't work either, although slow-release morphine seems to.

Experiments demonstrate that in people with chronic cough, the cough reflex is excessively sensitive -- they cough in response to to irritants or stimuli that wouldn't bother most people. Investigators Nicole Ryan, Surrinder Birring, and Peter Gibson suspected similar mechanisms might operate in chronic cough and neuropathic pain -- in which "central" brain factors amplify the sensitivity to noxious stimuli. Gabapentin (Neurontin) has been shown efficacious in neuropathic pain; could it improve chronic cough? They report their results in the August 27 Lancet, online.

What They Did

Authors enrolled a mere 62 patients with refractory chronic cough at a single clinic in Australia. All patients had had cough for at least 8 weeks, and had failed management with empiric therapies for the usual etiologies. Participants were randomized to receive either gabapentin (at 600 mg t.i.d. if tolerated) or placebo for 10 weeks. They wore microphones for 1 hour at various periods to record their cough frequency. The primary endpoint was the change in quality of life due to cough (the Leicester cough questionnaire score) after 8 weeks of therapy. Ten patients dropped out (roughly equal between groups); 52 completed the study.

What They Found

A 1.3 point change in the cough questionnaire QOL score is considered clinically meaningful (from validation studies). More patients taking gabapentin (74%) compared to placebo (46%) met the primary endpoint, i.e., had improved quality of life related to their cough. They also had reduced cough severity.

However, there was evidence for a negative rebound effect. After treatment was stopped, people in the gabapentin group had their coughs return with greater severity (on a visual analog scale), and had even greater cough reflex sensitivity than they did before entering the trial (measured by cough from inhaled capsaicin using standardized, validated methods). However, they didn't complain of worse cough related quality of life after stopping treatment.

The trial was too small to meaningfully test differences in side effects / adverse events, but there was no difference and gabapentin was considered to be well-tolerated.

What It Means

Frustrated patients and their doctors now have something reasonable to try (besides morphine) to soothe the symptoms of chronic cough, after empiric treatments for the common causes have failed. However, as the authors acknowledge, the results of this small, single center trial could also be due to an "active placebo effect." Gabapentin has significant central nervous system effects -- in other words, you feel it when you take it. In that sense, this trial was not blinded, as many patients surely knew they were taking "the good stuff" and may have responded to that. The fact that almost half of participants had significant improvement in their symptoms over time was also encouraging, and should be emphasized when counseling patients. There's little financial incentive for a large randomized trial testing gabapentin for chronic cough, but pulmonologists and patients would celebrate if this therapy -- or any therapy -- proved effective.

Ryan NM et al. Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trial. Lancet August 27, 2012 ePub online.