Cough challenge
tests
Cough challenge relies on the delivery of tussive agents as aerosols
from an inhalation device and the subsequent recording of the number of
induced coughs. The agents can be administered as liquid droplets using
jet or ultrasonic nebulisers (through a mouthpiece or facemask) or
powders using breath-actuated dry powder inhalers. Nebulisers are often
used with a dosimeter to control the inspiratory flow rate, as it can
affect the cough response. The dosimeter generates a burst of compressed
air that initiates a fixed duration of nebulization. In each challenge,
the agent is delivered in increasing concentrations. The concentration
that induces at least two coughs per inhalation is reported. Commonly
used tussive agents include capsaicin, citric acid and mannitol.
Capsaicin has been used extensively for cough challenge as it induces
cough in a dose-dependent and reproducible manner
(Midgren, Hansson, Karlsson, Simonsson &
Persson, 1992). Capsicin dissolved in alcohol is serially diluted in
isotonic saline to prepare different concentrations between 0.15 – 305
µg/mL. Nebulised capsaicin aerosol is thought to induce cough through
activating C-fibres via TRPV1 in the airways
(Fuller, Dixon & Barnes, 1985).
Furthermore, oral administration of capsaicin can also desensitise the
cough reflex by acting on TRPV1 receptors in the gastrointestinal
system, known as central reflex desensitisation
(Ternesten-Hasseus, Johansson &
Millqvist, 2015). Citric acid is another commonly used tussive agent
that induces cough through the C-fibres. In addition, nebulised citric
acid aerosols have been reported to stimulate RARs within the larynx and
the upper airways (Morice, Kastelik &
Thompson, 2001). The traditional cough provocation tests using
capsaicin or citric acid usually show a wide normal range of responses.
The cough sensitivity achieved by this method poorly correlated with the
symptoms (Buday, Kovacikova, Ruzinak &
Plevkova, 2017).
Mannitol challenge test is a regulatory approved bronchial provocation
test that uses dry powder mannitol with a handheld dry powder inhaler.
Similar to hypertonic saline, mannitol provides an osmotic stimulus to
airways and provokes cough. The subject inhales mannitol powders with
increasing doses of 0, 5, 10, 20, 40, 80, 160, 160, and 160 mg, with a
maximum cumulative dose of 635 mg. Inhaled mannitol was initially
developed as a bronchial hyper-responsiveness test for asthma diagnosis
(Koskela, Lake, Wong & Brannan, 2018),
and then later found its utility as a cough challenge test. A recent
study by Kanth et al. demonstrated that cough induced by
nebulised mannitol (40 mg/mL, 220 mOsm/L) is dependent on the particle
size distribution (Kanth, Alaienia &
Smaldone, 2018). No subjects coughed when inhaling 1.2 µm mannitol
aerosols, while 6.5 µm particles caused coughs in 86% of the subjects.
Both liquid and dry powder aerosols containing tussive agents can induce
cough. Patients as well as healthy subjects experience coughs upon
inhalation, though the severity and number of induced coughs may vary.
The likelihood of inducing coughs increases with higher delivered doses
of tussive agents. Furthermore, the dose required to induce coughs
depends on the compound. For example, capsaicin is used in the microgram
range whereas milligrams of mannitol is used for cough challenge tests.
Factors in inhalational products contributing to cough
Advance in particle engineering techniques and novel device designs have
widened the variety of inhalation formulations
(Zhou, Leung, Tang, Parumasivam, Loh &
Chan, 2015). Inhalation products are often designed and engineered to
minimise systemic side effects or to avoid first-pass metabolism. On the
other hand, large molecules, such as insulin, are inhaled to allow deep
lung deposition for systemic delivery. Orally inhaled drugs can deposit
in the extra-thoracic region (mouth, oropharynx, and larynx), the
central airways, and peripheral lung. Even with highly efficient
inhalation delivery platforms, some of the dose may still deposit in the
extra-thoracic region and be swallowed. Particle deposition in the deep
lung could be enhanced using particles with a small aerodynamic diameter
of 0.1–2 μm coupled with a low inspiratory flow (<20 L/min).
Smaller particles (<0.1 μm) will result in low deposition due
to high amounts of them being exhaled. Larger particles will likely
deposit in the upper and large airways where the majority of cough and
expiration reflex receptors are located
(Mazzone & Undem, 2016). Therefore, to
avoid coughs, it would be beneficial to design the aerosol delivery so
that the particles preferentially deposit in the small airways.
5.1 Dose of inhalation
products
In most cases, increasing the dose of inhaled drug can increase the
chance of cough. It may be due to the increased concentration of the
drug at the cough receptors. In a Phase I study on inhaled capreomycin
powder, capsules loaded with a spray dried powder consisting of 25 mg
capreomycin and 5 mg of L-leucine were used with a Cyclohaler. Drug
doses of 25 mg, 75 mg, 150 mg, and 300 mg were investigated, which
corresponded to inhaling from 1, 3, 6, and 12 capsules. Coughing
occurred in five of the 20 healthy subjects across all doses. The coughs
ranged from mild (for 25 mg and 75 mg) to moderate (for 150 mg and 300
mg) and subsided within five minutes after inhaling powder from the last
capsule. (Dharmadhikari, Kabadi, Gerety,
Hickey, Fourie & Nardell, 2013). It may be argued from this study that
the severity of the cough increased, albeit slightly, with the inhaled
drug dose. However, another phase I clinical study showed a lack of
relationship between increases in the dose and reports of cough
(Jansat, Lamarca, de Miquel, Schrodter,
Miletzki & Gurniak, 2009). Only two cases of cough were reported in 16
healthy volunteers who received 200, 400, and 800 µg of aclidinium or
placebo. This phenomenon can be explained by the fact that long-acting
muscarinic receptor antagonists (LAMAs), including aclidinium and
tiotropium, can downregulate the cough reflex. These two LAMAs have
antitussive effects in anaesthetised rabbits in response to citric acid
challenge. These effects may be related to the downregulation of TRPV1,
ASIC, and mechanoreceptors of cough-related airway sensory afferent
neurons (Mutolo, Cinelli, Iovino, Pantaleo
& Bongianni, 2016).
Poorly dispersed powders that deposit in large airways are more likely
to initiate a cough response through the touch-sensitive
mechanosensitive nerves. Furthermore, the occurrence of coughing may be
related to the amount of powder inhaled per bolus and its subsequent
osmotic effect, which is dependent on the extent of dispersion and
deposition (Velkov, Abdul Rahim, Zhou,
Chan & Li, 2015). Minimizing the use of excipients in the aerosol
formulation may reduce the chance of coughing. Budesonide formulation
without any excipients as a dry powder (lower powder dose) caused less
cough than when using a metered dose inhaler (MDI) that contained
propellants and lubricants (Engel, Heinig,
Malling, Scharling, Nikander & Madsen, 1989). However, different
deposition in the airways from these two products could be a confounding
factor to the difference in cough. Although cough is generally
associated with the inhaled dose, the same dose of tobramycin inhalation
solution (TIS) delivered using the same nebuliser showed different cough
profiles, probably due to patients’ former exposure (hence acclimatized)
to inhaled aerosols (Konstan et al.,
2011). However, individual variation in the upper airway anatomical
features and deposition in the large airways may also contribute to the
difference observed.
5.2 Dry vs wet
aerosols
Direct comparison of powder and liquid aerosols in cough production is
difficult as device- or patient-related factors may also be involved.
The EAGER trial assessed the safety of tobramycin inhalation powder
(TIPTM) and solution (TIS, TOBI®)
(Konstan et al., 2011). TIP (112 mg) and
TIS (300 mg/5 mL) were delivered using a Novartis T-326 Inhaler and a
PARI LC PLUS® nebuliser, respectively. Cough was
frequently reported for both forms of aerosol (48% and 31% for TIP and
TIS, respectively). The higher cough incidents in TIP-treated patients
across all age groups (Geller, Nasr,
Piggott, He, Angyalosi & Higgins, 2014) may be due to the faster
administration, i.e. more airway receptors were activated within a
shorter timeframe. Furthermore, the open-label design of this study as
well as prior TIS-use in some patients may have had an impact on the
tendency to report cough as an adverse event. Nonetheless, cough
severity was mostly mild and moderate, with <4% and 1% of
TIP and TIS-treated patients discontinuing the treatment due to
coughing, respectively. In another study, mild and self-limited coughs
were observed in 20% of TIP subjects and none in TIS
(Geller, Konstan, Smith, Noonberg &
Conrad, 2007). TIS subjects (85%) were previously exposed to this
treatment as part of their usual therapy so it is difficult to directly
compare the two types of aerosol formulations. Furthermore, 92% of TIP
subjects reported coughing prior to TIP administration, which implies
that this adverse event might be disease- or patient-related. Other
studies have also reported coughing as a common adverse event after TIS
treatment in cystic fibrosis (CF)
(Greenwood et al., 2017;
Hubert et al., 2009;
Lenney, Edenborough, Kho & Kovarik,
2011; Mazurek et al., 2014) and
bronchiectasis (Barker et al., 2000;
Scheinberg & Shore, 2005) patients.
Nebulised colistimethate sodium also caused coughing in a small
proportion of CF subjects (Greenwood et
al., 2017). Although TIP induced coughs, the post-inhalation cough
rates reduced over time with repeated dosing, probably due to
acclimatization of the airways and cough receptors.
Nebulised colistin sulphometate in normal saline (160 mg) did not cause
coughing in healthy subjects (Le Brun et
al., 2002a).. However, moderate-to-severe coughs were induced by
colistin sulfate powder (25 mg) (Le Brun
et al., 2002a) and high incidence of cough with colistimethate sodium
powder (125 mg) (Schuster, Haliburn,
Doring & Goldman, 2013) in CF subjects after inhalation of the
powders. The varied cough profiles could be due multiple factors,
including differences in molecular forms of colistin, aerosol
performance (inhaler and formulation) and deposition in the respiratory
tract. Nebulised colistin sulphomethate produced no cough and was better
tolerated than colistin sulfate, which induced throat irritation and
severe coughing (Le Brun et al., 2002a;
Westerman et al., 2007;
Westerman, Le Brun, Touw, Frijlink &
Heijerman, 2004). However, it is still not possible to pinpoint whether
the difference observed is solely due to the chemical nature of the
drugs and/or differences in the solution properties (pH
~7.4 and 5, osmolality 366 and 306 mOsm/kg, for the
colistin sulphomethate and colistin sulphate solutions,
respectively)(Westerman, Le Brun, Touw,
Frijlink & Heijerman, 2004).
As mentioned previously, Aδ and C fibres are sensitive to changes in pH
and osmolarity. Inhaled solid particles, if they are soluble, may
increase the osmolality in the airways more than droplets as the latter
have higher water content. Moreover, the pH and osmolarity of a liquid
formulation can be easily controlled, thus minimising the potential to
induce coughs.
A major difference between inhaled powder and liquid formulations is
that the dispersion and deposition of solid particles are affected by
the patient’s inhalation profile. The T-326 Inhaler used for delivering
TIP is a low-resistance inhaler, so high inspiratory flows can be
achieved easily. This may result in the impaction of particles in the
oropharynx and central airways, consequently causing cough (an
expiratory reflex); though expiratory reflex can be present in the
tracheobronchial tree (Widdicombe, 1995).
The optimal inhalation profile for aerosol generation is
formulation-dependent for a given inhaler. TIP particles are porous and
dispersible with a small aerodynamic diameter. They only require slow
and deep inhalation for effective dispersion. For other dry powder
formulations, a high inspiratory flow rate may be needed to generate a
sufficiently large fraction of fine particles to reach the peripheral
airways. Particle deposition in the lungs of healthy subjects for TIP
delivered using the T-326 Inhaler was three time higher than that for
TIS with the PARI LC PLUS® nebuliser
(Challoner et al., 2001;
Newhouse et al., 2003). Therefore, the
distribution of drugs in the lungs achieved by inhaled solid and liquid
aerosols may be different due to aerosol output, size distribution and
inter-patient differences in the inhalation profiles. This may explain
varying reports in cough-related adverse events between studies.
5.3 Salt form vs free base of
drugs
Most of the studies on inhaled tobramycin mentioned above used the
sulfate salt. Interestingly, inhaled tobramycin free base showed a low
incidence of cough. Only two out of eight subjects coughed during one of
the four visits (Hoppentocht et al.,
2016). This may be due to the lower oropharyngeal deposition from the
relatively low flow rate (34 L/min) produced through the Cyclops inhaler
and/or the lower powder dose required with the free base of the drug
compared to that with its sulfate form. This effect of different salt
forms of a drug on coughing was also apparent when 25 mg colistin
sulfate from a DPI was less tolerable than 160 mg nebulised colistin
sulphomethate, with the former inducing moderate-to-severe cough
(Le Brun et al., 2002a). However, the
observed trend was confounded by the different types of inhaler (DPI vs
nebuliser), formulation (solid vs liquid), and inhalation pattern. There
are no studies so far that study the effect of the physical form of a
drug on cough alone, with all other variables controlled.
5.4 Particle
size
The level of throat irritation and cough depend on the aerodynamic
particle size. Fine and ultrafine particles depositing in the alveoli,
where there are no cough receptors, will not cause coughing. On the
other hand, coarse particles (>5 µm) inhaled at high
inspiratory flow rates primarily deposit in the extrathoracic region
where they can induce cough by stimulating cough and expiratory reflex
receptors (Zwozdziaka, Gini & Samek,
2017). Small particles in inhaled formulations <5 µm can
minimize upper airway deposition and reduce the risk of coughing.
However, the availability of fine particles in an aerosol depends on the
dispersibility of the powder formulation, inhalation flow and anatomical
features of the airway of the patient. These will become confounding
factors in consideration of particle deposition and cough.
5.5 Inhaler
devices
DPIs, pMDIs, and nebulisers are the three major devices for respiratory
drug delivery. DPIs and pMDIs are small, portable devices for general
use, whereas nebulisers are typically used in emergency care or at home
for children and infants to deliver high doses of drugs
(Backman, Adelmann, Petersson & Jones,
2014). Nebulisers were found to induce less coughing than pMDIs or DPIs
in patients with chronic cough for the administration of corticosteroids
(Kamimura et al., 2012).
The type of inhalation device and the required mode of inhalation affect
the drug delivery into the lungs. Some DPIs need high inhalation flow
rates for dispersion and deagglomeration. Consequently, the particles
may deposit in the upper airways due to inertial impaction and induce
cough. Two breath-actuated DPIs, Turbohaler® (500 µg
terbutaline) and Diskhaler® (400 µg salbutamol) were
compared in chronic asthma patients
(Brown, Lenney, Armstrong, Ning &
Crompton, 1992). Despite differences in the drug, dose, and device
design, both products showed very similar rates of cough and therapeutic
effects (Table 2).
pMDIs generate aerosols that travel rapidly and require coordination
between actuation and inhalation. The impaction problem can be addressed
for pMDIs by using a spacer, which is essentially a chamber into which
the dose is aerosolised, from which the patient inhales by breathing
tidally. The spacer allows the propellant to evaporate to form smaller
particles and decelerates the aerosol cloud, thereby reducing upper
airway deposition. Despite this, spacers cannot eliminate coughing
completely.
Dubus et al (2003) studied the local side effects in asthmatic children
treated with fluticasone propionate, budesonide, or beclomethasone
dipropionate delivered from pMDIs with small or large volume spacers
(Dubus, Mely, Huiart, Marguet, Le Roux &
Reseau de Recherche Clinique en Pneumologie, 2003). About 54% of the
patients coughed after inhaling each corticosteroid, with 30% of them
also coughed after inhaling β2-agonists. All three
corticosteroids showed similar tendency of inducing cough, despite the
pMDIs containing different propellants. This suggests that the induced
cough was more likely to be dependent on the delivery device rather than
the formulation. Coughing was not found to be associated with the
severity of asthma but was related to the use of long-acting β2-agonist
(LABA) and duration of treatment. The type/volume of the spacer and the
use of mouthpiece/facemask were deemed to not affect coughing (Table 2).
A study compared the efficacy and safety of inhaled budesonide (800 or
1600 µg) administered via a pMDI coupled to a 750 mL spacer and via a
Turbohaler® in patients with stable asthma. The
Turbohaler® showed significantly less coughs 5 minutes
after inhalation than the pMDI with spacer
(Engel, Heinig, Malling, Scharling,
Nikander & Madsen, 1989). This might be due to the absence of
excipients in the Turbohaler® product as the powder
only contained budesonide (Table 2). Other confounding factors such as
the regional deposition in the airways and the dose deposited could also
contribute to the difference in the cough.
Incorrect use of the device and/or inhalation technique may also be
associated with chronic cough and wheezing
(Lavorini et al., 2008). Before studying
the rate of cough, the participants in the study must be sufficiently
trained in using the device correctly and inhaling properly. Deep
inspiration of corticosteroids from pMDIs in patients complaining of
coughing induced large, but transient, specific airway resistance and
bronchoconstriction (Dubus, Mely, Huiart,
Marguet, Le Roux & Reseau de Recherche Clinique en Pneumologie, 2003).
Although deep inspiration may stimulate SAR and RAR receptors that
normally does not evoke cough, these stretch fibres may change their
phenotype and express RTPV1 receptors due to airway inflammation. The
bronchoconstriction may be caused by pulmonary mechanoreceptor
activation secondary to the release of ATP as discussed above
(Mazzone & Undem, 2016).
5.6 Active
ingredients
Drugs may cause coughs by various mechanisms, such as stimulating cough
receptors by changing the local acidity, osmolarity, and/or ATP release.
They may also downregulate the cough response. Some drugs provoke more
coughs than others, which highlights the importance of thorough clinical
safety assessment.
5.6.1
Corticosteroids
Corticosteroids are important in the treatment of asthma and COPD owing
to their anti-inflammatory effects. However, their role in the
alleviation of chronic coughs has not been confirmed
(Johnstone, Chang, Fong, Bowman & Yang,
2013). A clinical study showed that budesonide and beclomethasone pMDIs
showed equal tendency in causing coughs in 34% of the asthmatic
patients (Williamson, Matusiewicz, Brown,
Greening & Crompton, 1995). High prevalence of coughs (53.7%) was
observed in asthmatic children receiving inhaled beclomethasone
dipropionate, budesonide, or fluticasone propionate
(Dubus, Mely, Huiart, Marguet, Le Roux &
Reseau de Recherche Clinique en Pneumologie, 2003) and was closely
associated with therapy duration and combination-therapy with LABA.
Coughing was more common in patients using higher daily doses of inhaled
corticosteroid (>1500 µg/day) from pMDIs, although the
difference in prevalence compared to that at lower doses was not
statistically significant (Williamson,
Matusiewicz, Brown, Greening & Crompton, 1995). Using the pMDIs with a
spacer did not prevent coughs. The cause of coughing by the
corticosteroid pMDIs is yet unknown. An early study noted that a
beclomethasone pMDI caused coughs in asthma patients whereas a
triamcinolone pMDI did not (Shim &
Williams, 1987b). However, besides their different drugs and doses,
those two pMDIs contained different propellants and excipients so it was
difficult to identify the reason/s for the different cough responses. It
may or may not be due to the drug. Interplay between the various
formulation and aerosolization parameters may also be possible.
5.6.2
Doxorubicin
Cough was the most frequent adverse event in a Phase I study of inhaled
doxorubicin (Otterson et al., 2007).
Increased cough was observed in 50% of the patients with metastatic
tumours to the lung. The irritant nature of the drug and acidic
alcoholic formulation at pH 3 may contribute to the high rate of cough
(Table 2).
5.6.3 Antibiotics
Inhaled antibiotics are commonly used for treating lung infections in
patients with cystic fibrosis and bronchiectasis. Coughs after inhaling
antibiotics have been reported as mild and transient
(Barker et al., 2000;
Conole & Keating, 2014;
Konstan, Geller, Minic, Brockhaus, Zhang
& Angyalosi, 2011). Although the incidence of cough was high after the
administration of antibiotics, the coughs reduced after 28 days of
treatment (Conole & Keating, 2014). This
might be due to an alleviation of the inflammation and infection in the
lungs, which strongly provoke cough. Cough prevalence was reduced in the
28-day treatment Cycles 4 to 6 (21-22%) compared to Cycle 1 (31.4%) in
patients receiving inhaled tobramycin
(Sommerwerck, Virella-Lowell, Angyalosi,
Viegas, Cao & Debonnett, 2016). In patients with cystic fibrosis, the
rationale for the 28-day on/28-day off cycle of inhaled antibiotic
administration depends on the peak increase in lung function after 28
days of continuous antibiotic administration. The 28-day off period
reduces the likelihood of the emergence of antibiotic-resistant
organisms (Table 2). In a study by Geller et al (2007), cough was only
observed in patients receiving TIP (20%)
(Geller, Konstan, Smith, Noonberg &
Conrad, 2007). None in the TIS group coughed. As mentioned in Section
5.2, TIS patients had prior exposure to inhaled antibiotics treatment.
Thus it is difficult to conclude that the reduced cough incidence was
associated with the improvement in patients’ symptoms because it could
be due to adaptation to the therapy
(Geller, Konstan, Smith, Noonberg &
Conrad, 2007). Tobramycin has anti-inflammatory effects beyond its
antimicrobial activity (Gziut, MacGregor,
Nevell, Mason, Laight & Shute, 2013). Other antibiotics, such as
macrolides, doxycycline, moxifloxacin, and polymyxin B, can also reduce
inflammation in the lungs (Huckle,
Fairclough & Todd, 2018; Lin et al.,
2017). Thus, besides treating the underlying infection, antibiotics may
decrease the stimulation of C-fibres and consequent reduce cough by
reducing inflammation in the airways. The fact that they can also
provoke cough point to other molecular and/or formulation factors.
5.6.4 β2-adrenergic receptor
agonists
Indacaterol is formulated as a once-daily inhaled LABA for COPD
treatment. A 12-week, double-blind study tested inhaled indacaterol (150
µg from a DPI) in patients with moderate-to-severe COPD
(Feldman, Fakorede, Minutello, Bergman,
Moussa & Wong, 2010). The overall rates of cough in
indacaterol-treated and placebo groups were comparable (Table 2). No
association between coughing and bronchospasm was found. Inhalation of
salbutamol and terbutaline from a DPI caused coughing in one third of
patients with chronic asthma in another study (Table 2)
(Brown, Lenney, Armstrong, Ning &
Crompton, 1992). Pre-treatment with inhaled salbutamol did not prevent
saline hypertonicity-induced coughs in healthy volunteers
(Koskela, Purokivi, Kontra, Taivainen &
Tukiainen, 2008).
β2-adrenergic receptors (β2-ARs) have been proposed to be involved in
the cough reflex. However, they have different effects in animal cough
models. Dose-dependent inhibition of coughs was observed in naïve and
ovalbumin-sensitised guinea pigs, whereas formoterol and salmeterol
tended to reduce coughs (Wex & Bouyssou,
2015). Interestingly, indacaterol demonstrated pro-tussive properties
with increased coughing in both animal groups. Although these data
cannot be translated directly to β2-ARs in humans, it shows that drug
molecules can have different effects on cough receptors.
5.6.5 Antimuscarinic
drugs
Jansat et al assessed the tolerability of inhaled aclidinium bromide, a
long-acting antimuscarinic drug (Jansat,
Lamarca, de Miquel, Schrodter, Miletzki & Gurniak, 2009). Healthy
subjects received 200, 400, or 800 μg of aclidinium bromide or placebo
from a DPI for 5 days, with ≥7 days washout periods. The frequency of
adverse events was comparable between the treated and placebo groups.
Only two participants reported mild and probably treatment-related
coughs. Aclidinium and tiotropium may downregulate the cough reflex and
interact with TRPV1 receptors, acid-sensing ion channels, and
mechanoreceptors in the airway nerves
(Mutolo, Cinelli, Iovino, Pantaleo &
Bongianni, 2016).
5.6.6
Insulin
Despite successful efficacy of inhaled insulin, the rate of reported
cough was high compared to conventional subcutaneous insulin in Type 2
diabetes patients and healthy volunteers (Table 2). One of the reasons
for withdrawing inhaled insulin powder (Exubera®) was
the persistent reports of respiratory adverse effects, including cough.
The high prevalence of cough may be related to the complex formulation
containing sodium citrate, mannitol, glycine, sodium hydroxide, which
are cough inducers. The rate of coughing was much less with
Technosphere® insulin (TI) in
Afrezza®, another inhaled insulin DPI product. This
powder contains fumaryl diketopiperazine as an excipient
(Angelo, Rousseau, Grant, Leone-Bay &
Richardson, 2009). The rate of mild-to-moderate coughs after the
administration of Exubera® was much higher than that
for subcutaneous insulin injection (27% vs 5%, respectively)
(Quattrin, Belanger, Bohannon, Schwartz &
Exubera Phase, 2004). On the other hand, TI showed similar cough
incidents as the placebo powder (23.7% vs 19.9, respectively)
(Rosenstock et al., 2015), suggesting
that the coughs were due to the excipients rather than insulin. The
coughs triggered by inhaled insulin, whether due to the excipients or
insulin itself, are mild and will gradually subside with treatment
(Ceglia, Lau & Pittas, 2006). This could
be due to acclimatization to the inhaled formulation. The coughs are not
associated with changes in pulmonary function
(Ceglia, Lau & Pittas, 2006), despite
the pathological association of diabetes with modest pulmonary function
impairment (van den Borst, Gosker, Zeegers
& Schols, 2010).
5.6.7
Mannitol
Mannitol has been identified to trigger cough and used to identify
subjects with chronic cough and diagnose asthma (see Section 4)
(Koskela, Lake, Wong & Brannan, 2018;
Minasian, Wallis, Metcalfe & Bush,
2008). Inhaled mannitol or other hyperosmolar agents can stimulate the
release of bronchoconstricting mediators in the airways and provoke
cough (Lowry, Wood & Higenbottam, 1988).
Mannitol also increases mucociliary clearance in the airways and assists
mucus removal in cystic fibrosis patients. Mannitol decreases the
viscosity of phlegm, hydrates the airway surface liquid, and increase
mucociliary activity (Flume et al.,
2015). The rate of cough caused by inhaled mannitol powder was much
higher in asthmatic (85.3%) (Brannan et
al., 2005) compared to cystic fibrosis patients (25.4%)
(Bilton et al., 2011), despite the lower
administered doses (Table 2).
5.6.8
Treprostinil
Treprostinil is a tricyclic benzindene prostacyclin analogue used for
the treatment of pulmonary arterial hypertension (PAH)
(McLaughlin et al., 2010). PAH patients
suffer from reduced prostacyclin synthase activity, which leads to
inadequate prostacyclin I2 production. The prostacyclin deficiency
causes vascular proliferation, vasoconstriction, and platelet
aggregation. Activation of prostacyclin receptors in the lung can
reverse these effects (Kingman,
Archer-Chicko, Bartlett, Beckmann, Hohsfield & Lombardi, 2017). In a
randomised clinical trial, inhaled treprostinil via an Optineb nebuliser
in addition to oral therapy, 54% of patients coughed in contrast to the
29% in the placebo group (McLaughlin et
al., 2010). Inhalation of treprostinil in dog and guinea pigs also
caused coughing (Corboz et al., 2017).
The pro-tussive effect may be attributed to the drug being acidic.
5.7
Excipients
Table 2 shows that coughing has been reported for placebo formulations
in some clinical trials, including the study on treprostinil
(McLaughlin et al., 2010) and tobramycin
(Konstan, Geller, Minic, Brockhaus, Zhang
& Angyalosi, 2011). This indicates that excipients can also cause
cough. Powder formulations containing engineered particles can contain
complex excipients which trigger cough as described for insulin (Section
5.5.6).
Oleic acid and fluorocarbon propellants from pMDIs can cause coughs in
asthmatic patients (Shim & Williams,
1987a; Shim & Williams, 1987b).
Aerosols containing the above excipients with and without beclomethasone
caused coughs 31 and 19 times, respectively
(Shim & Williams, 1987a). Since the
reduction in FEV1 was similar in both groups (22%), the
broncoconstriction was caused by the excipients rather than the drug.
Inhaled triamcinolone acetonide was better tolerated than beclomethasone
in another study(Shim & Williams,
1987a). It was proposed that the excipients, particularly oleic acid,
caused cough and bronchoconstriction. Sterling and Battern demonstrated
that sorbitol triolates and lecithin can cause cough and
bronchoconstriction in asthmatic patients (13 and 21% reduction in
airway conductance, respectively)
(Sterling & Batten, 1969). In healthy
subjects they decreased airway conductance by 5.3 and 9.7%,
respectively, but were unlikely to be clinically significant.
Some preservatives used in inhalation products in the past, including
phenol, can cause airway irritation, coughing, and bronchoconstriction.
Sodium bisulfite and ethylenediaminetetraacetic acid (EDTA) are still
permitted in various pharmaceutical inhalation products to enhance
chemical stability but they can both cause bronchoconstriction
(Pilcer & Amighi, 2010).