AS WINTER settles over Europe and North America, the sound of coughing starts to fill the air. Every year, most of us catch a cough and our hacking torments us by day and drives us mad at night. But the sound is music to pharmacists’ ears. In 2001, Britain alone spent nearly £100 million on over-the-counter cough medicines; in the US the figure is close to $600 million.
But coughs are more than just an expensive nuisance. For people with lung diseases such as asthma and chronic obstructive pulmonary disease, also known as emphysema, a cough can kill. COPD is the world’s sixth-biggest killer, the immediate cause of death being respiratory failure triggered by a bout of coughing. Complications caused by coughing account for about 40 per cent of the cost of caring for COPD patients.
Yet despite this litany of nuisance, lost sleep, expense and death, research into coughing is one of the slowest-moving areas of medicine. Treatments have changed little since the 1950s and there is an ongoing debate over whether they actually work. But in the past five years, neurophysiologists have started to take a closer look at coughing, and what they are finding could blow away decades of inertia.
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For a common cough, the sort most of us catch every year, a quick browse of the pharmacist’s shelves reveals a bewildering choice. Whatever your needs, there is a medicine tailored for you – suppressors to stop dry coughs, demulcents to soothe a tickly throat, expectorants to loosen the phlegm and make chesty coughs more “productive”, and any number of combined cough, cold and sore throat remedies.
Almost every remedy is based on opiates such as codeine and pholcodine, most of which have been in use since at least the early 1950s. It is tempting to describe them as “tried and tested”, except that they’re not. Most of the research into their effectiveness was done long ago and falls well short of today’s rigorous methodological standards. Worse, many cough medicines have unpleasant side effects, including drowsiness and constipation. And they are often addictive.
So it was perhaps high time that someone picked over the old data. Earlier this year, Knut Schroeder and Tom Fahey, who are based in Britain at the division of primary health care at the University of Bristol, did just that. They amassed more than 300 studies from the past 50 years, then weeded out those that did not meet modern standards. When they finished there were only 15 left. Because so much of the work fell foul of their quality-control criteria, they advised caution in interpreting their results. But their conclusion was stark: doctors should stop recommending cough remedies to patients because there was no good evidence that they worked (British Medical Journal, vol 324, p 329).
Not surprisingly, the paper stirred up trouble. Many doctors and pharmacologists applauded it. Others argued that the only possible conclusion was that more research was needed. One family doctor wrote to the BMJ saying that of course cough medicines didn’t work, yet she would carry on telling patients to take them because they gave people a sense of control. And the public is certainly happy with that. In a regular consumer survey carried out by the Proprietary Association of Great Britain, which represents makers of over-the-counter medicines, satisfaction rarely dips below 90 per cent.
Whatever the truth about existing medicines, many of the big pharmaceuticals companies are now searching for new ways to tackle coughing. And thanks to recent work on the neurology of coughing, promising targets for new drugs are starting to come into view.
A cough involves an intake of breath followed by the closure of the glottis – the gap between the vocal cords in the larynx – then a tremendous contraction of the abdominal muscles. When the glottis re-opens, the air in the lungs is forced out explosively at speeds of up to 1000 kilometres an hour, hopefully expelling whatever was causing the trouble.
The reflex action is triggered by stimulation of different groups of sensory receptors in or just under the epithelium that lines the respiratory tract from the larynx to the lungs. These receptors respond to three distinct cough stimuli: mechanical irritants such as smoke particles and mucus, chemical irritants such as acids, and immune-system molecules produced by the body in response to infection. Once stimulated, the receptors fire signals into the brainstem and kick-start the cough reflex.
That all sounds quite straightforward. But as neurophysiologists probe the system, a much more complex picture is emerging. “Coughing was thought to be a simple unity, like the knee-jerk,” says retired respiratory physiologist and cough expert John Widdicombe, now an independent consultant to the pharmaceuticals industry. “We now know it is complex.”
For a start, there are at least three types of sensory pathway, each of which relies on a unique combination of membrane receptors for lung irritants. And the different pathways interact with each other, and this crosstalk can alter the body’s response to cough signals.
The brain’s role in coughing is also proving more complicated than a simple knee-jerk. Once the cough receptors have been triggered, electrical impulses shoot up the nerve fibres via the vagus nerve to a loosely defined “cough centre” in the brainstem. Here, signals are translated into messages instructing the muscles of the diaphragm, larynx and abdomen to run the cough sequence.
But very little is known about the cough centre’s detailed wiring. For example, the opiates we know and love are presumed to act here, but their mechanism remains obscure. There must also be connections to and from the cerebral cortex, otherwise you wouldn’t be able to cough – or stop yourself from coughing – voluntarily. But again, researchers know almost nothing about these connections.
There is light at the end of the tunnel, however. Widdicombe says the past five years have seen an explosion in understanding of the mechanism of coughing, and he predicts that this will soon be converted into therapeutic advances. The front runners are drugs that target the irritant-sensing receptors in the windpipe and lungs. As yet, no compound has made it to clinical trials, and no pharmaceuticals company has officially declared an interest. Even so, Widdicombe says a lot of new compounds have been shown to control coughing in animals and he suspects that several companies are quietly, but vigorously, pursuing them.
The principal cough receptors are the so-called rapidly adapting receptors (RARs), which are found all over the respiratory tract except for the deepest reaches of the lungs. RARs consist of little bunches of nerve endings embedded under the epithelium, whose membranes are studded with receptors. When they receive the right molecular signal they shoot impulses along fine nerve fibres, called Ad fibres, and into the cough centre.
Cough researchers agree that RARs are probably the master switches of coughing, but it has proved difficult to find drugs to block them. One problem is that the receptors lie buried under the epithelium, so getting drugs to them is difficult. Another is that almost nothing is known about the receptors the RARs carry on their surface. RARs respond very strongly to mechanical stimulation and are also sensitive to chemical irritants, especially citric acid, but the exact molecular receptors that these signals hit are unknown.
A more promising target is another class of sensory receptors, called C-fibre receptors. These are identical to the pain receptors in skin. The appeal of the C-fibre receptors is that they are very sensitive to capsaicin, the “hot” ingredient of chilli peppers which is widely used as a cough trigger in experiments on humans and animals. As a result, their structure and mode of action have been closely studied, not only in isolated nerve cells growing in a dish but also in living animals.
The capsaicin-sensing part of the C-fibre receptor is a membrane-bound ion channel called VR1, which is found clustered at the nerve endings. VR1s respond very strongly to capsaicin and, handily, they are also sensitive to another important cough trigger, immune-system molecules.
Exactly how C-fibre receptors trigger coughing remains unknown, although some researchers believe they do so indirectly via the RARs. When stimulated, C-fibre receptors release neurochemicals that instruct the lung lining to secrete mucus. This acts as a mechanical irritant that stimulates the RARs and conjures up a cough. C-fibre receptors and RARs exchange information in other ways too. Their nerve fibres interact on their way to the brain stem and also higher up, in the central nervous system (CNS) itself, although exactly what the effect of this cross-talk is unclear.
Whatever their precise role, because they lie in the epithelium rather than beneath it, and because they are so sensitive to cough signals, C-fibres look to be the most promising target for new drugs. The logical next step is to find agents that block the VR1 receptors.
VR1 receptors aren’t the only possibility. C-fibres also carry another promising membrane-bound receptor molecule, NOP1, which inhibits capsaicin-induced coughing in guinea pigs and cats. There is a lot of interest in harnessing this natural cough suppressor. And further down the line there is an unexplored third type of sensor in the lungs, a hybrid consisting of C-fibre receptors coupled to RAR-style Aδ nerve fibres. These receptors may prove useful drug targets, but until now their role in coughing remains uncertain.
Although plenty of progress is being made in understanding the mechanism of coughing, some researchers don’t see it as the be-all and end-all. At one of AstraZeneca’s British research labs at Loughborough in Leicestershire, global clinical expert Tim Higenbottam warns of the dangers of focusing too hard on the cough reflex. He believes a more fruitful approach is to look at the entire respiratory system. What interests him is the extensive network of slowly adapting receptors (SARs) that lie in the smooth muscle of the airway walls. These are stretch receptors that help regulate breathing. Because SARs don’t play a direct role in coughing, their contribution has been largely ignored. But Higenbottam says that is a mistake.
When inflammation makes the airways constrict, the SARs sense this and start firing more urgently. As a result, breathing becomes faster and more shallow. Higenbottam points out that one thing that often accompanies a cough is constriction of the airways. He believes that persistent firing of SARs also has an effect on the cough response, prompting the CNS to increase the sensitivity of the RARs. The upshot is that constriction of the airways sets the RARs on a hair trigger, making them more sensitive to mechanical stimuli.
There is evidence to support his view. In 2000, a team led by Peter Calverley of Liverpool University’s department of medicine showed that people with asthma or COPD need a much lower dose of capsaicin to trigger coughing. According to Higenbottam, this is because the disease causes airway constriction which puts the RARs on heightened alert. Give these patients a bronchodilator drug to relax the smooth muscle in their airways and their response to capsaicin returns to normal.
Consequently, Higenbottam says, the best way to treat coughs is to use bronchodilators, a class of drugs in which AstraZeneca has a major interest, while at the same time tackling the underlying disease. Arguably, this approach has a major advantage over targeted blocking of the cough receptors. Coughing is part of the body’s natural defences, so suppressing it completely isn’t necessarily a good thing. Consider what would happen if you failed to cough when a bit of food got lodged in your windpipe. The same might apply to the mucus produced as a result of an infection.
Does that mean your best bet is just to grin and bear it? Not necessarily, says Widdicombe. The prevailing medical opinion is that dry coughs have no benefit and can safely be suppressed. Widdicombe believes the same applies to coughs caused by chronic lung disease. He points out that your body does the same when you’re asleep, with no apparent ill effects, as the morning hacking of a smoker confirms. But he admits that this is not the view of most doctors.
Another promising avenue for new therapies is to focus attention back on the cough centre in the CNS. “There could be a magic bullet that would block the cough centre in the brain stem with no secondary or adverse effects,” says Widdicombe. One researcher backing this approach is Junzo Kamei of Hoshi University in Tokyo. He is teasing out the different opioid receptors in the brain in the hope of designing cough drugs without the side effects of the traditional opiates. The interactions are complex: three of the opioid receptors, μ &kgr; and δ2, inhibit coughing, while δ1-opioid receptors appear to encourage it. Although Kamei hasn’t yet tested it in humans, one experimental δ1-opioid receptor blocker has shown marked cough-suppressing effects in mice, rats, guinea pigs and dogs.
Other researchers are putting their money on a CNS drug called dextromethorphan. Ironically, this is already widely available in dozens of cough medicines, so has been tarred somewhat by the same brush as the older opiates. Schroeder and Fahey’s BMJ review includes two studies on dextromethorphan, only one of which found that it has any effect.
But there is evidence that dextromethorphan really works. In another review published just before Schroeder and Fahey’s but probably after it had been submitted, a group from Procter & Gamble – a major manufacturer of dextromethorphan – analysed six studies of its effectiveness (Chest, vol 120, p 1121). They found that the drug caused big improvements in four out of five accepted measures of coughing.
At Procter & Gamble’s Health Sciences Institute in Egham near London, principal scientist in research and development David Hull is trying to work out the precise pathways by which dextromethorphan acts. Once that is done, he will try to produce second-generation versions of the drug that are more selective and more effective. The full results are not yet in, but Hull says he has confidence in the drug. “It’s non-narcotic, it’s non-addictive, and it doesn’t have the side effects that are associated with things like codeine.”
Ultimately, it is very unlikely that the current burst of research will deliver a magical cough cure-all. As Widdicombe points out, there are more than a hundred known clinical causes of coughing, and it is possible that different types are mediated by different pathways and so will respond to different drugs. He says the best hope is a variety of new therapies tailored to different types of cough.
Hull and Kamei agree that there is no reason to believe CNS-acting drugs will prove better than ones targeted at the lungs. Some even argue that the two approaches should be combined. Whatever happens, prepare to be more dazzled than ever by the choice on offer in the cough remedy section of your pharmacy. Your old favourites might disappear, but at least you will be able to buy something that works.
