Chronic Refractory Cough: what to do when

inhalers, nasal sprays and pills don’t work

Stephen K. Field Clinical Professor of Medicine Cumming School of Medicine

University of Calgary

CRC Vancouver

April 14, 2018

Disclosure statement Funding, honoraria: University of Calgary Alberta Health Services Alberta Lung Association Canadian Thoracic Society American College of Chest Physicians American College of Physicians Canadian Lung Association TB services AstraZeneca Boehringer-Ingelheim GSK

Grifols Health Canada Insmed/Synertec Merck Novartis Public Health Agency of Canada Roche Takeda TEVA

Research Funding: Principal Investigator:

AstraZeneca

Boehringer-Ingelheim

Canadian Institute Health Research

Calgary Health Region GSK

Insmed/Synertec

Novartis

Co-investigator:

Allergen

AstraZeneca

Bayer

Ception

Genentech

GSK

Novartis

Sanofi ScheringPlough (Merck) TEVA Innovation funding: Calgary Zone Region Advisory boards: AstraZeneca Boehringer-Ingelheim Grifols GSK Novartis Roche TEVA Trials pending Boehringer-Ingelheim Chiesi CIHR GSK NeRReTherapeutics

Chronic cough

• Discuss the limitations of the anatomic-based approach to diagnosis & management

• Chronic refractory cough refers to those patients that don’t respond to this approach

• And I’ll discuss the management of these patients

Chronic cough

• Cough is the most common symptomatic complaint in ambulatory clinics1

• Most are self-limited but some persist

• Chronic cough is defined as one lasting ≥8 weeks2

• Rarely dangerous but they may have a major impact on QOL3

1. Schappert SM, Burt CW. Vital Health Stat 2006;13:1-66 2. Irwin RS et al. ARRD 1981;123:413 3. French CT et al. Arch Intern Med 1998;158:1657

Chronic cough, normal chest x-ray

• Interferes with sleep, work, or school & may preclude social activities e.g. concerts or religious services

• Cough syncope-unable to drive, operate machinery, etc

• Can’t talk on the phone, ill & tired so often miss time from work

• Absenteeism-loss of job, failure at school

• Considerable medical & indirect costs

• Family discord

Medical consequences

• Headache, sleep disruption, stress incontinence, urinary +/-fecal, retching/vomiting, syncope, rib fractures & hernias1,2

• Chronic cough causes social isolation, anxiety & depression3,4

1. Ruhl CE, Everhart JE. Am J Epidemiol 2007, 2. Rothstein E, Edwards K. Ped Infect Dis 2005 3. Dicpinigaitis PV et al. Chest 2006, 4. McGarvey LP et al. Cough 2006

Chronic cough guidelines

• Recommend that in the absence of sinister features, an anatomic-based approach to diagnose & to direct empiric treatment of the common causes including: upper airway, asthma, eosinophilic bronchitis, gastroesophageal reflux, angiotensin converting enzyme inhibitors, or obstructive sleep apnea, be undertaken Irwin RS et al. Chest 2006;129:1S

Anatomic-based treatment approach • Early reports suggested this approach was successful in virtually all

chronic cough patients1,2

• Since then there is a greater awareness of the condition & common causes, & most receive some treatment trials before referral

• Straightforward patients are more likely to be treated in primary care, proportionately more of the difficult-to-diagnose & treat cough cases are referred to specialty clinics

• 20 to 46% presenting to specialty clinics have cough that does not respond to the standard anatomic approach3

1.Irwin RS ARRD 1990;158:1657 2.Hoffstein V CRJ 1994;1:40 3.Gibson PG Pulm Pharmacol Ther 2015

Chronic cough: significant burden on respiratory resources

• Up to 40% of referrals to respiratory specialists are for chronic cough1

• Frustrating cases since most are benign, often not due to lung disease.

• In Calgary, some specialists were refusing to see these patients ->resulting in long wait lists for these patients

• To deal with the backlog we suggested that CREs could deal with these patients since the differential diagnosis overlaps with asthma

• CREs see an average of 215 new referrals/year

1. Irwin RS et al. ARRD 1990141:640

CRE protocol

• Screened out referred cases with a potentially sinister cause, e.g. hemoptysis, systemic symptoms, abnormal CXR, history of lung disease, malignancy or other serious comorbidities

• Randomized 198/490 referrals to CRE or respirologist care for 8 weeks

• CREs followed a strict protocol. Initial visit, phone call at 2 & 6 weeks, visit at 4 & 8 weeks.

• Respirologists, usual care

• Primary outcome was cough-specific QOL (CQLQ*) completed at initial visit & at 8 weeks in both study arms

*University of Massachusetts cough-specific quality of life questionnaire (R Irwin et al)

Field S K et al. Chest 2009;136:1021-1028 ©2009 by American College of Chest Physicians

Field SK et al. Chest 2009;136:1021-1028

©2009 by American College of Chest Physicians

Impact of intervention on cough

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% with unchanged cough

Can Respir J 2009 Chest 2009

Anatomic-based approach

• Over an intervention period of 8 weeks, cough responded favorably in 72% of the CRE patients with a systematic anatomic-based protocol1

• A third presenting to specialty clinics do not improve with this approach2

• What is the etiology of cough in patients without an obvious underlying condition?

1. Can Respir J 2009 2. Pulm Pharmacol Ther 2015

Chronic Refractory Cough (CRC)

• Has also been called idiopathic, unexplained & cough hypersensitivity syndrome but CRC is preferred term since it describes cough that persists despite a systematic evaluation for known associated conditions such as asthma, rhinitis & GERD1

• Dry irritated cough with discomfort around the larynx • Symptoms may also include globus, dyspnea & dysphonia2

• Associated with increased laryngeal tension & paradoxical vocal cord movement

1. Pulm Pharmacol Ther 2009;22:159 2. BMJ 2015 3. Morrison M et al. J Voice 1999;13:447

Chronic Refractory Cough

• In 1/3 of patients, cough onset is attributed to a viral infection1

• Others have noted postviral vocal cord dysfunction in patients with CRC

• Triggers include environmental stimuli such as odors, airborne particles, chemicals, food, refluxate & voice use may also trigger symptoms

1.Taramarcaz P et al. JACI 2004;114:1471

Is CRC the result of a neuropathic disorder?

• Cranial nerves can be affected by inflammatory neuropathic processes, e.g. Bell’s palsy, trigeminal neuralgia

• It has been hypothesized that CRC results from a postviral vagal neuropathy

Jeyakumar A et al. Laryngoscope 2006;116:2108

Is CRC the result of a neuropathic disorder? • Rhinovirus can infect neuronal cells & upregulate cough receptors

(transient receptor potential Vanillin V1[TRPV1]2 & TRP Ankyrin[TRPA1]3)1

• Increased expression of neuropeptide*-containing neurons in bronchial epithelium in patients with chronic cough4

Capsaicin, citric acid receptors are present in the vagal-afferent limb of cough reflex2 activated by air pollution, smoke (acrolein), formalin, allicin (garlic), wasabi, etc.3

*CGRP-calcitonin gene-related peptide4

1. Abdullah H et al. Thorax 2014;69:46 2. Pulm Pharmacol Ther 2011;24:280 3. Pulm Pharmacol Ther 2011;24:286 4. O’Connell F et al. AJRCCM 1995;152:2068

Is CRC a neuropathic disorder? • Neuropathic pain is characterized by paresthesia, hyperalgesia, allodynia

• Parallel characteristics in CRC1

• Laryngeal paresthesia: abnormal laryngeal sensation in the absence of stimulation, e.g. itch or tickle sensation

• Hypertussia: exaggerated response to low level tussive stimuli, e.g. smoke

Can be measured by capsaicin sensitivity.

• Allotussia: cough hypersensitivity to non-cough stimuli, e.g. temperature change, vocalization, exercise

• Above features, laryngeal motor dysfunction with hoarseness & paradoxical vocal cord movement suggest a disorder of airway sensory neural function2,3

1.Gibson PG, Vertigan AE BMJ 2015:351:h5590 2.Ryan NM et al. Lancet 2012;380:1583 3.Niimi A, Chung KF. Pulm Pharmacol Ther 2015;35:100

Treatment of CRC

Nonpharmacologic treatment • CRC may improve with a speech pathology therapy (SPT) approach which

includes:

• Education: avoid irritating behavior, e.g. throat clearing

• Vocal hygiene: avoid passive smoke exposure, mouth breathing, behavioural management of GERD, maintain adequate hydration

• Cough suppressant strategies: e.g. cough suppression swallow, relaxed throat breathing

• Psychoeducational counseling: emphasize there is no easy cure. Teach them to internalize control over their cough.

• Similar approach to the methods used to treat hyperfunctional voice disorders & paradoxical vocal cord movement

BMJ 2015351:h5590

Pharmacologic management • Centrally, neuromodulators act on neural hypersensitization in patients with CRC

• Morphine, baclofen, amitriptyline, gabapentin & pregabalin have all been shown to improve cough-specific quality of life in patients with CRC but adverse effects are limiting1

• Morphine: slow release MOS, up to 10 mg BID. Significant improvement in cough-specific QOL (LCQ) without any change in citric acid challenge. Constipation 40%, drowsiness 25%2

• Baclofen: 12 of 16 given 20 mg TID was added to omeprazole were able to continue therapy & 9 noted cough improvement. Main adverse effects were somnolence, dizziness, & fatigue3

• Amitriptyline 10 mg HS: better subjective response than codeine/guaifenesin. Side effects were not mentioned4

1. CHEST 2016;149:27 2. AJRCCM 2007;175:312 3. World J Gastroenterol 2013;19:4386 4. Laryngoscope 2006;116:2108

Gabapentin • Case series 19 of 29 improved with 100 to 900 mg/d for up to 3 months1

• Randomized trial Gabapentin (n=32) vs placebo (n=30)2

• Increase 300 mg/d to maximum of 1800 mg/d X 8 weeks, then taper 300 mg/d

• Improved cough-specific QOL (LCQ) 1.8[CI 0.56-3.04] (MCID 1.3) vs placebo p=0.0042

• Gabapentin reduced cough frequency & severity, both statistically significant

• Capsaicin sensitivity was not different between groups

• 10 withdrew from study: 6 Gabapentin & 4 placebo

• 10/32 side effects, primarily nausea & fatigue vs 3/30 on placebo2

• Vocal fold motion abnormalities, typical of CRC, noted in 15/16 Gabapentin responders vs 5/9 nonresponders3

1.Lee B, Woo P Ann Otol Rhinol Laryngol 2005;114:253 2.Ryan NM Lancet 2012;380:1583 3.Giliberto JP et al. JAMA Otol Head Neck Surg 2017;143:1081

Pregabalin added to speech pathology therapy (SPT) Vertigan AE et al. Chest 2016;149:639

• 40 patients randomized to pregabalin (PREG) or placebo added to SPT

• Cough severity, cough frequency & cough-specific QOL (LCQ) improved in both groups

• LCQ improved more in PREG p=0.024

• Cough severity improved more in the pregabalin group, p=0.002

• Change in capsaicin sensitivity was greater in the pregabalin group

• The change in cough frequency was similar in the two groups, p=0.67

• Blurred vision, cognitive changes, dizziness & weight gain were more common with pregabalin

Updated ACCP CRC Guideline-recommended treatment Gibson P et al. Chest 2016;149:27

• ‘In adult patients with chronic cough, we suggest that unexplained chronic cough be defined as a cough that persists >8 weeks & remains unexplained after investigation, & supervised therapeutic trial(s) conducted according to published best-practice guidelines.’ Ungraded consensus-based statement

• ‘In unexplained chronic cough, we suggest a therapeutic trial of multimodality speech pathology therapy’ Grade 2C recommendation

• ‘In adult patients with unexplained chronic cough, we suggest a therapeutic trial of gabapentin* as long as the potential side effects and the risk-benefit profile are discussed with patients before use of the medication, & there is a reassessment of the risk-benefit profile at 6 months before continuing the drug.’ Grade 2C recommendation

*Pregabalin data was published after the lit search for the guideline was completed.

Summary • The anatomic diagnostic approach to chronic cough is effective for the

majority of chronic cough patients

• Approximately 1/3 of chronic coughs will not respond

• CRC is characterized by itch or tickle sensation, throat clearing, hoarseness +/-vocal cord dysfunction

• Features suggest neural hypersensitivity as an underlying cause

• Speech Pathology Therapy will work in a large number but some will require neuromodulatory medications such as gabapentin or pregabalin

Acknowledgments

• CREs: Diane Conley, Leslie (Paramchuk) Jones, Joanna Clarke, Margot Underwood, Shirley Revitt, Amin Thawer, Janel Carley, Patrick Leung, Amin Thawer, Kathy Haywood, Hilary Pischke

• Bob Cowie, Richard Leigh, Brandie Walker

• Cough clinic >2500 patients since inception

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Questions?

The End!

Nonpharmacologic treatment • CRC may improve with a speech pathology approach which includes

education, vocal hygiene, cough suppressant strategies & psychoeducational counseling

• Education: avoid behaviours which may cause irritation & perpetuate the cough, e.g. throat clearing

• Vocal hygiene: strategies to reduce coughing & throat clearing. Avoid passive smoke exposure, mouth breathing, minimize dehydrating substances, behavioural management of GERD, maintain adequate hydration.

BMJ 2015351:h5590

Nonpharmacologic treatment • Cough suppression strategies: voluntarily suppress cough with

distraction techniques-cough suppression swallow1 or relaxed throat breathing2

1. Forceful swallowing action with head flexed & isometric pushing hands together.

2. Relaxed throat breathing with an abdominal breathing pattern with exhalation on a voiceless fricative sound (f or v) to increase oral pressure causing vocal cord abduction.

• Exercises to reduce laryngeal constriction

• Psychoeducational counseling: emphasize that there is no easy cure. Person needs to internalize control over their cough & belief that cough is a response to irritation rather than a phenomenon outside of their control.

BMJ 2015351:h5590

P2X3 receptor antagonist in CRC

• Vagal afferent C fibres (chemoreceptors) & Aδ fibres (mechanoreceptors) express P2X3 receptors which are ATP-gated ion channels

• Patients with CRC, double-blind, randomized to a P2X3 antagonist, AF-219 600 mg BID or matched placebo in a two period, crossover design with a 2 week washout period

• Cough frequency was reduced by 75% while on AF-219 vs placebo

• 6/24 withdrew because of dysgeusia

• Perhaps lower dose will control cough without intolerable dysgeusia

Abdulqawi R et al. Lancet 2015;385:1198

Investigational drugs

• Substance P, a neurokinin, is released centrally & peripherally from pulmonary sensory neurons1

• Substance P levels are elevated in adults coughing >3 weeks

• Neurokinin antagonist, aprepitant, reduced objective cough frequency & subjective cough scores in patients with nonsmall cell lung cancer2

• Human studies with TRPV1 and sodium channel receptor antagonists have been disappointing2,3

1. Keller JA et al. Chest 2017;152(4):833-41 2. Harle ASM et al. J Clin Oncol 2015;33(suppl 29):2 abstract. 3. Khalid S et al. J Allergy Clin Immunol 2014;134:56-62