People have inhaled numerous different substances to try and manage asthma symptoms for thousands of years. Ancient Egyptian papyrus scrolls describe people inhaling the vapour of the black henbane plant, while ancient Greeks breathed in burned herbs and in China opium was smoked to try and improve people’s ability to breathe. It was only during the industrial revolution that the first devices resembling modern inhalers were developed, in the forms of nebulisers, dry-powder inhalers and ceramic pot inhalers.
Today, perhaps the most commonly used devices are short acting beta-two agonist (SABA) inhalers. SABAs are typically employed as rescue devices, to provide quick relief from asthma symptoms such as chest tightness, breathlessness and cough. They can even help to mellow full-blown asthma attacks.
But the use of SABA inhalers is increasingly being linked to worsening symptoms. UK National Institute for Health and Care Excellence (NICE) guidelines say that any patient who uses their SABA inhaler for symptomatic relief on three or more days per week is over-reliant on the device. For those patients who need to use their SABA devices more than three times a week, the British Thoracic Society recommends an inhaled corticosteroids (ICS) preventer inhaler – but in practice, these aren’t always prescribed.
So, how did SABA devices come to dominate asthma treatment – and what’s next now they’ve been identified as potentially harmful?
1956: The first metered dose inhaler is approved
The first metered dose inhaler (MDI) wasn’t invented until 1956, when Riker Laboratories president George Maison created the devices using glass vials and valves designed for perfume bottles. The inspiration for the idea came from Maison’s daughter, who suffered from severe asthma and was growing tired of the cumbersome squeeze-bulb nebuliser she had to use to deliver doses of medicine.
When she asked her father why her asthma medication couldn’t instead be put in a perfume-like spray can, the idea stuck. This led Maison to create the first MDI, and in 1956 a new drug application was approved for a PTC bronchodilator Medihaler-Epi (epinephrine), alongside the prescription-only version of Medihaler-Iso (isoproterenol), for the treatment of asthma. This quickly laid the foundation for widespread inhaler use, but soon after risks associated with specific beta-agonists began to emerge.
Early 1960s: asthma ‘epidemic’ sees mortality soar
In the early 1960s asthma morality increased dramatically across the UK, Ireland, Norway, Australia and New Zealand. Researchers were able to conclude that the ‘epidemic’ was real, and not due to changes in disease classification, death certification or diagnostic practice.
Eventually, the sudden increase in asthma deaths in these countries was found to have followed the introduction of pressurised beta-agonist aerosols in 1961 and the subsequent increase in sales, particularly the isoprenaline forte MDI. The relief of symptoms resulting from the use of the devices were enabling patients to tolerate worsening asthma symptoms, inadvertently preventing them from seeking necessary medical help.
The greatest mortality was seen in ten to 19-year olds, potentially due to the propensity of newly-independent adolescents to misuse a self-administered treatment. Asthma deaths declined rapidly following regulatory warnings and a reduction in the use of isoprenaline forte.
1970s: spacers start to hit the market
Many patients who used MDIs found that coordinating pressing down their canister and breathing in was tricky, meaning medication would often build up in their mouth and throat instead of being inhaled. Medicine proved more likely to reach the lungs with a spacer device, a hollow tube which holds the release medication between the inhaler’s cannister and the mouthpiece so the user can inhale at their own pace.
Before commercial spacers began to hit the market in the 70s, people with asthma were using things like toilet paper tubes and plastic cups to essentially create makeshift versions.
1976 – 1989: fenoterol inhalers lead to New Zealand deaths
Asthma mortality rates soared for a second time in New Zealand in the mid-1970s, coinciding with the 1976 release of a new beta-agonist called fenoterol. Much like isoprenaline forte, fenoterol was a potent – but poorly selective – beta-agonist, which was marketed as a high-dose preparation. While it was rapidly adopted in New Zealand, it didn’t take off in most other countries.
While a series of case studies eventually linked fenoterol with increased asthma mortality, the drug remained on the market for thirteen years, until its availability was restricted by the New Zealand government in 1989 when it was removed from the country’s drug tariff. After this, asthma mortality rates in the country reduced by two thirds in just 12 months.
Following these two epidemics, the use of more selective beta-two agonists like salbutamol and terbutaline increased and SABA inhalers became one of the most commonly prescribed medical devices.
1990s: regular SABA use recommended, then scrapped
The demonstrated efficacy of SABA inhalers for relieving asthma symptoms ‘as required’ resulted in them being used as a ‘regular’ inhaled therapy, regardless of symptoms.
While early studies did suggest that a regular SABA regimen could improve asthma control, it later became established that it didn’t really offer any benefit and could actually make the symptoms of the condition worse. By the end of the 1990s, the use of SABA therapy had become as required once more.
2015: UK review associates SABA use with asthma deaths
The UK National Review of Asthma Deaths found that 9% of asthma deaths were in patients treated with SABA as a monotherapy, without any other kind of treatment. A further 39% of deaths were associated with excess prescriptions for SABA, patients who had been prescribed more than 12 SABA inhalers in the year before they died.
2019: GINA guidance drops SABA recommendation
In 2019, the Global Initiative for Asthma (GINA) guidance was altered to no longer recommend SABA as a monotherapy for asthma, citing evidence that while SABA monotherapy can provide short-term symptom control it does not protect against severe asthma exacerbations. Instead, GINA now recommends that all adults and adolescents with asthma should receive symptom-driven treatment only in mild cases and use regular ICS-containing treatment in ore severe ones.
2020: AstraZeneca study confirms harmful SABA impact
A 2020 study from AstraZeneca and Imperial College London’s National Heart and Lung Institute has confirmed a link between SABA inhaler use and increased asthma attacks.
The researchers found that over-reliance on the devices was associated with approximately twice the number of exacerbations or asthma attacks compared with patients who used the devices less often, regardless of asthma severity. The Global Allergy and Airways Patient Platform and its members are now partnering with AstraZeneca to launch a global public health awareness campaign to educate asthma patients about SABA overuse.