icc keynote presentation 2013 n ryan

RECENT ADDITIONS IN THE

TREATMENT OF COUGH

D R . N I C O L E R Y A N , A / D I P A P P S C , B S C , P H D

P R I O R I T Y R E S E A R C H C E N T R E F O R A S T H M A

A N D R E S P I R A T O R Y D I S E A S E

F A C U L T Y O F H E A L T H A N D M E D I C I N E

T H E U N I V E R S I T Y O F N E W C A S T L E

A N D H U N T E R M E D I C A L R E S E A R C H I N S T I T U T E ( H M R I )

1 S T I N T E R N A T I O N A L C H I N E S E C O U G H C O N F E R E N C E ,

8 - 1 0 N O V E M B E R 2 0 1 3 .

I C C 2 0 1 3 K E Y N O T E S P E A K E R P R E S E N T A T I O N |

W W W . N E W C A S T L E . E D U . A U

2

Recent Additions in the Treatment of Cough

• What Are They?

• Non-Pharmacological (Behavioural)

• Pharmacological

• Why Needed?

• Cough: Huge clinical problem

• Worldwide

• High prevalence of ‘Refractory’

Cough

• Treatments limited and ineffective


W W W . N E W C A S T L E . E D U . A U3

• Where Did They Come From?

• Otolaryngology: Recognition of upper

airway involvement

• Proximity

• Inputs from upper and lower airways

into larynx/pharynx

• Laryngeal Hypersensitivity

• Cough Hypersensitivity Syndrome

• Allied Health: Speech

Pathologists/Physiotherapists

Recent Additions in the Treatment of Cough

4

•Refractory chronic cough primarily occurs in:• middle-aged women w long-standing dry CC

• often follows a RTI

• causes significant symptoms and quality of life impairment.

• Potential explanations for refractory chronic cough:• organ-specific autoimmune disease of the airways

• neurogenic airway inflammation

• non-acid gastro-oesophageal reflux

• a laryngeal sensory neuropathy or irritability.

REFRACTORY CHRONIC COUGH



5

Laryngeal Hypersensitivity

common element

different initiating mechanisms

Inflammation

injury from chemical and/or mechanical causes

much in common with neuralgias and

neuropathic pain syndromes

recognised ‘trigger’

Provides new insights

potential mechanisms

treatments for refractory cough



NON-PHARMACOLOGICAL TREATMENTS FOR CC

• Speech Pathology

• Gay et al, J Clin Psychiatry. 1987

• Blager et al, J Commun Disord. 1988

• Murry et al, Annals of Otology, Rhinology &

Laryngology. 2006

• SPEICH-C (Vertigan, 2006; Ryan, 2009 & 2010)

• Physiotherapy (Patel, 2011)

• Psychotherapy

• Gay & Blager (case reports include psychotherapy)

• and SPEICH-C (Vertigan RCT, Ryan studies include

Psychoeducational counselling)



FOCUS: SPEECH PATHOLOGY MANAGEMENT FOR

COUGH





Demographic data and co-morbid medical conditions of study

participants that had been treated before inclusion in the study, Vertigan

et al, Thorax 2006.

Mean (SD) age (years) 59.4 (13.6)

Sex (M/F) 64/23

Asthma* 18 (20.7%)

Reflux_ 41 (47%)

ACE inhibitors 10 (11.5%)

Allergies 52 (59.8%)

PNDS` 44 (50.6%)

Smoking 2 (2.3%)ACE, angiotensin converting enzyme; PNDS, postnasal drip syndrome. *Previous asthma treatment included inhaled corticosteroid

and long acting bronchodilator. _Previous reflux treatment was proton pump inhibitors. `Previous PNDS treatment included topical

nasal steroids and ingested antihistamines.



Comparison of mean (SD) pre-intervention symptom scores for

participants in the treatment and placebo groups (Mann-Whitney U

test)

Score Treatment (N=43) Placebo (N=44) P-value

Total symptom 32.9 (16.0) 30.4 (12.9) 0.634

Breathing 7.5 (4.1) 6.9 (4.1) 0.591

Cough 8.6 (3.0) 7.7 (3.4) 0.119

Voice 7.0 (5.8 7.8 (4.7) 0.892

Upper Airway 8.5 (6.4) 7.8 (5.1) 0.878



0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

Breathing p<.001

Cough p=.003 Voice p=.049 Upper airwayp=.034

Treatment Placebo

RESULTS

CAUSE FOR FURTHER INVESTIGATION

FROM THE VERTIGAN RCT INVESTIGATING THE

EFFICACY OF SPEECH PATHOLOGY

MANAGEMENT OF CHRONIC COUGH THE

FOLLOWING QUESTIONS REMAINED:

1) MECHANISM BEHIND IMPROVEMENT

2) COUGH SUPPRESSION=REDUCED COUGH

SENSITIVITY?

3) LARYNGEAL HYPERSENSITIVITY: PVCM/VCD

PRESENTS WITH COUGH, DOES SPEECH

PATHOLOGY INTERVENTION ADDRESS BOTH?

11I C C 2 0 1 3 K E Y N O T E S P E A K E R P R E S E N T A T I O N |


12

PVCM and EAHR are both manifestations of laryngeal

hypersensitivity. 56% of CC patients have PVCM.



-1.0 -0.5 0.5 1.0 1.5 2.0

-1.50

-1.25

-1.00

-0.75

-0.50

-0.25

0.25

0.50

0.75

Log CRS

Lo

g D

RS

r= -0.65, p= 0.02



Subject Characteristics, Median (IQR) unless otherwise stated

Number, (M/F) 17 (8/9)

Age, years 61 (20)

Age Range, years 34-83

Cough Duration, months 60 (147)

FEV1, %predicted 88.2 (16.7)

FVC, %predicted 88.5 (20.3)

Auditory perceptual voice analysis, % abnormal 63



pre Rx post Rx0

5

10

15

20

*

LC

Q S

co

re (

un

its

)

Pre Rx Post Rx0

1

2

3

4

5

6

7

8

9

10

11

*

Co

ug

h S

co

re (

un

its)

P=0.002

P=0.003

P=0.04

Results

pre Rx post Rx0

1

2

3

4

5

6

7

8

*

LD

Q S

co

re (

un

its)



Change in C5 and CT after Speech Pathology

Intervention on Cough Reflex Sensitivity

Baseline Post Rx0

1

2

3

p<0.0001

Co

ug

h R

efl

ex S

en

sit

ivit

y

Lo

g1

0C

5 (

uM

ol/

L)

Baseline Post Rx0

1

2

3p=0.001

Lo

g10C

ou

gh

Th

resh

old

(uM

ol/

L)

Mea

n



Change in Cough Frequency* and UTC after Speech

Pathology Intervention for Chronic Cough

Base Post Rx0

50

p=0.009

95

145

195

Co

ug

h F

req

uen

cy d

uri

ng

Ob

jecti

ve

Testi

ng

(co

ug

hs/h

r)

Base Post Rx0

2

4

6

8

10

p=0.01

Urg

e t

o C

ou

gh

(u

nit

s)

Mean

SPEECH PATHOLOGY TREATMENT FOR

OUTPATIENTS

SP standard treatment for adult chronic cough

patients in Australia, ref: CICADA Australian cough

guidelines and assessment, 2010.

At JHH in Newcastle the SP program is tailored to

individuals based on assessment and ongoing

management.

Recently, the LCM was utilised into the cough clinic

with the intent of having an objective cough measure

before and after treatment.



PHARMACOLOGICAL TREATMENTS FOR CCChronic/Neuropathic Pain medication

Gabapentin

Case Series: 1) Lee & Woo, Ann Otol Rhinol Laryngol

2005; 2) Mintz & Lee, Am J Med, 2006

RCT: Ryan et al, The Lancet, 2012

Retrospective study: Van de Kerkhove et al, Cough, 2012

Amitriptyline

Case Series: Bastian et al, Otolaryngol Head Neck Surg,

2006

RCT: Jeyakumar et al, Laryngoscope, 2006

Pregabalin

Retrospective Audit: Halum et al, Laryngoscope, 2009 for

SLN



Neuropathic Pain

abnormal sensation

pain triggered by a

lower level exposure

to a known painful

stimulus

pain triggered by a

non-painful stimulus

20

Refractory CC

abnormal throat

sensation

increased cough

sensitivity in response

to known tussigens

cough triggered in

response to

nontussive stimuli

such as talking or cold

air

neuropathic response



suggests sensitisation

of the cough reflex

FOCUS: GABAPENTIN FOR COUGH



AIM: Establish whether gabapentin is an effective

treatment in patients with refractory CC.

HOW: Investigate subjective and objective

measures of cough before, during and after

treatment.

Hypothesis: People with RCC will have ↓ cough

severity and CF & ↑ cough quality of life after Rx

with gabapentin compared to placebo.



PARTICIPANT CHARACTERISTICS AT

BASELINE

Placebo Gabapentin p-value

N 30 32

Age, yr # 60·9 (12·9) 62·7 (14·0) 0·596

Male/Female 10/20 12/20 0·732

Non/ex-smoker 16/14 20/12 0·465

Pack years * 5 (13) 4 (5) 0·101

Cough duration,

months *

48 (138) 36 (132) 0·746

# Mean(sd), student’s t test; * Median (IQR), Wilcoxon ranksum test



PARTICIPANT CHARACTERISTICS AT

BASELINEEfficacy Variables Placebo Gabapentin p-value

LCQ # 12·1 (3·9) 13·3 (3·1) 0·145

Cough VAS, mm # 44·2 (21·3) 43·6 (29·6) 0·934

CRS C5, GEM

(logSD), µM

4·31 (0·49) 6.31 (0·6) 0·297

Cough frequency,

GEM (logSD)

coughs/hour

68·8 (1·9) 45·3 (1·9) 0·102

# Mean(sd), student’s t test; * Median (IQR), Wilcoxon ranksum test; § n(%), chi square test or Fisher’s exact test.





Gabapentin/Placebo Dose Schedule

INCLUSION CRITERIA

26

• Chronic cough (> 8 weeks duration)

• Male or female between ages of 18 and 80 years

• Non-smoker or ex-smoker

•Negative investigations and/or treatment trials:

• asthma, GORD and rhinitis

•Informed consent obtained



27

Randomisation

1. Assessed for eligibility

(n =65)

2. Excluded (n = 3)

3. Randomised (n = 62)

4a. Allocated to

intervention

(Gabapentin) (n = 32)

Allo

ca

tio

n

En

rolm

en

t

4b. Allocated to

intervention

(Placebo) (n = 30)

Fo

llo

w u

p 6a. Lost to follow up

(n = 2) (DNA) Discontinued intervention (n = 4)

6b. Lost to follow up (n = 0) Discontinued intervention

(n = 4)

An

aly

sis

7a. Analysed (n = 32) Excluded from analysis

(n = 0)

7b. Analysed (n = 30) Excluded from analysis

(n = 0)

ADVERSE EVENTS



CNS G

I

Oth

er

CNS G

I

Oth

er

0

5

10

15

20

25Gabapentin

Placebo

Adverse Event%

Pre

vale

nce

Adverse effects were

managed by temporarily

reducing the dose

(gabapentin: n=6/32,

18·8%; placebo: n=3/30,

10%), or withdrawal

(gabapentin n=1,

placebo n=1).

PRIMARY OUTCOME: THE LCQ

29

0 1 2 3 4 510

11

12

13

14

15

16

17

18

Visit No

LC

Q

On Rx Reducing Rx to

Withdrawal

P=0.004



Gabapentin

OUTCOME MEASURE: COUGH SEVERITY BY VAS

30

0 1 2 3 4 520

35

50

65

Visit No

Co

ug

h V

AS

(m

m)

Gabapentin

On Rx Reducing Rx to

Withdrawal



P=0.029

OTHER OUTCOME MEASURES FOR GABAPENTIN VS

PLACEBO IN REFRACTORY CHRONIC COUGH

Outcome Placebo mean

change from

baseline to

treatment

period^

Gabapentin mean

change from

baseline to

treatment period^

Difference between

treatment groups during

the treatment period *

Coefficient (95% CI)

p-value

Cough

Frequency,

(coughs/h)

-4·3 -22·5 -27·31 (-51·75, -2·88) 0·028

CRS, C5 (µM) +5·1 +15·1 3·12 (-13·59, 19·82) 0·72

Urge to Cough

Score

-1·4 -0·7 0·59 (-0·52, 1·7) 0·30

LDQ Score -1·5 -1·6 0·048 (-0·82, 0·92) 0·91

CENTRAL SENSITISATION RESPONSE TO GABAPENTIN

32

LCQ Placebo-CS Placebo+CS Gaba-CS Gaba+CS p-value

N, (%) 10/30 (33·3%) 20/30 (66·7%) 13/32 (40·6%) 19/32 (59·4%)

Baseline, V1 12·2(9·9) 12·9(9·5) 13·9(9·5) 13·5(8·6)

V2 14·1(11·5) 13·6(10·7) 15·0(9·5) 16·2(10·1) ≥0·213

V3 13·7(12·2) 14·2(10·4) 15·3(8·7) 17·1(10·6)* 0·001

Adjusted p-value for significance is 0 ·0042, *p=0·0006 v Placebo-CS, p=0·0003 v Placebo+CS, p=0·021 v GABA-CS, V=Visit.



CONCLUSIONS

Double-blind RCT investigating the Rx of refractory

chronic cough w gabapentin.

Gabapentin improved patients’ symptoms; cough

quality of life, cough severity, and cough

frequency.

Therefore may be considered as a potential

treatment option.

This study supports a central mechanism

33 I C C 2 0 1 3 K E Y N O T E S P E A K E R P R E S E N T A T I O N |


COUGH RECEPTOR ANTAGONISTS

For TRPV1

V112220

BCTC

JNJ17203212

For TRPA1

GRC 17536 (Also effective in neuropathic pain, good

safety profile)

HC – 030031 (comparative to pregabalin for

neuropathic pain)



SUMMARY

Significant clinical problem: limited, often ineffective

Rxs

‘Cough hypersensitivity syndrome’: unifying

diagnosis for cough phenotypes

Sensory neuropathic chronic cough, Laryngeal

Hypersensitivity

investigation of new and effective treatments

Recent Additions in the Treatment of Cough:

Non-pharmaceutical, eg:Speech Pathology

Pharmaceutical:neuromodulating drugs used in chronic

neuropathic pain, eg: Gabapentin

TRPV1 and TRPA1 antagonists

35 I C C 2 0 1 3 K E Y N O T E S P E A K E R P R E S E N T A T I O N |


Acknowledgements: Professor Peter Gibson

Dr Anne Vertigan

Ms Sarah Bone

Dr Surinder Birring

Funding: John Hunter Hospital Charitable Trust Fellowship

HMRI Early Career Travel Award, sponsored by Stroud Rodeo, and

The First International Chinese Cough Conference.

icc keynote presentation 2013 n ryan

Documents