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Chronische hoest bij volwassenen

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Hoestdempende middelen

Publicatiedatum: 08-06-2026
Beoordeeld op geldigheid: 08-06-2026

Uitgangsvraag

Wat is de plaats van hoestdempende medicatie (opioïden, gabapentine, pregabaline, tricyclische antidepressiva, gefapixant) bij de behandeling van volwassen patiënten met onverklaarde of refractaire chronische hoest?

Aanbeveling

Bespreek met de patiënt het mogelijk starten van centraal en/of perifeer werkende hoestdempende middelen als proefbehandeling bij patiënten met chronische hoest die behandeld zijn voor treatable traits en hoestlogopedie hebben gehad zonder voldoende resultaat.

 

Bespreek met de patiënt:

  • De mogelijke voordelen en bijwerkingen van de hoestdempende middelen (per medicatie verschillend).
  • Kosten bij het gebruik van codeïne en gefapixant.
  • Dat het gebruik van de medicatie mogelijk off-label is.
  • Het gebrek aan wetenschappelijk bewijs.

Beslis samen met de patiënt een termijn voor een proefperiode (wisselt per medicatie maar bij voorkeur minimaal 4 weken) waarna gezamenlijke evaluatie van het effect plaatsvindt.

 

Stop de behandeling wanneer er na tenminste 4 weken geen effect op de last van het hoesten wordt ervaren.

Overwegingen

Balans tussen gewenste en ongewenste effecten

Opioïden

Morfine

Er is een systematische review uitgevoerd naar het effect van opioïden vergeleken met placebo op patiënten met onverklaarde/refractaire chronische hoest. Morfine heeft waarschijnlijk een positief klinisch relevant effect op de cruciale uitkomstmaten hoest-gerelateerde kwaliteit van leven en de ernst van de hoest. Er werden geen gerandomiseerde studies gevonden die de cruciale uitkomstmaat hoestfrequentie onderzochten.

 

Codeïne

Er is een systematische review uitgevoerd naar het effect van codeïne vergeleken met placebo op patiënten met onverklaarde/refractaire chronische hoest. Er werden geen gerandomiseerde studies gevonden die de cruciale uitkomstmaten hoest-gerelateerde kwaliteit van leven, ernst van de hoest en hoestfrequentie onderzochten

 

Gabapentine

Er is een systematische review uitgevoerd naar het effect van gabapentine vergeleken met placebo op patiënten met onverklaarde/refractaire chronische hoest. Gabapentine heeft waarschijnlijk een positief klinisch relevant effect op de cruciale uitkomstmaten hoest-gerelateerde kwaliteit van leven, de ernst van de hoest en de hoestfrequentie.

 

Pregabaline

Er is een systematische review uitgevoerd naar het effect van pregabaline vergeleken met placebo op patiënten met onverklaarde/refractaire chronische hoest. Pregabaline heeft waarschijnlijk een positief klinisch relevant effect op de cruciale uitkomstmaten hoest-gerelateerde kwaliteit van leven, de ernst van de hoest en de hoestfrequentie.

 

Tricyclische antidepressiva (amitriptyline en nortriptyline)

Er is een systematische review uitgevoerd naar het effect van tricyclische antidepressiva (amitriptyline en nortriptyline) vergeleken met placebo op patiënten met onverklaarde/refractaire chronische hoest. Er werden geen gerandomiseerde studies gevonden die de cruciale uitkomstmaten hoest-gerelateerde kwaliteit van leven, ernst van de hoest en hoestfrequentie onderzochten.

 

P2X3 remmers (gefapixant)

Er is een systematische review uitgevoerd naar het effect van gefapixant vergeleken met placebo op patiënten met onverklaarde/refractaire chronische hoest. Gefapixant lijkt geen klinisch relevant effect te hebben op de cruciale uitkomstmaten hoest-gerelateerde kwaliteit van leven en de ernst van de hoest. Dit geldt ook voor de hoestfrequentie bij een lage dosis. Hierbij moet worden opgemerkt dat er relatief grote verbeteringen te zien waren in de placebogroep, waardoor het verschil tussen interventie- en placebogroep niet de klinisch relevante grenzen haalde. Bij een gemiddelde dosis gefapixant worden geen conclusies getrokken door inconsistentie van de studies. Bij een hoge dosis lijkt het effect wel positief klinisch relevant te zijn voor kwaliteit van leven terwijl en voor ernst door hoest (gemeten met behulp van VAS) terwijl ernst van VAS gemeten door CSD geen relevante verschillen laat zien.

Kwaliteit van bewijs

Opioïden

Morfine

De overall kwaliteit van bewijs is zeer laag, vanwege de afwezigheid van studies voor de uitkomstmaat hoestfrequentie. Dit betekent dat we zeer onzeker zijn over het gevonden geschatte effect van de cruciale uitkomstmaten.

 

Codeïne

De kwaliteit van het bewijs kon niet worden vastgesteld vanwege de afwezigheid van studies die voldeden aan de PICO.

 

Gabapentine

De overall kwaliteit van bewijs is redelijk. Dit betekent dat we redelijk zeker zijn over het gevonden geschatte effect van de cruciale uitkomstmaten.

 

Er is afgewaardeerd vanwege ernstige imprecisie: onnauwkeurigheid, omdat het betrouwbaarheidsinterval de grens van klinische relevantie overschrijdt.

 

Pregabaline

De overall kwaliteit van bewijs is redelijk. Dit betekent dat we redelijk zeker zijn over het gevonden geschatte effect van de cruciale uitkomstmaten.

 

Er is afgewaardeerd vanwege ernstige imprecisie: onnauwkeurigheid, omdat het betrouwbaarheidsinterval de grens/beide grenzen van klinische relevantie overschrijdt en de optimale steekproefgrootte niet voor alle uitkomstmaten wordt gehaald.

 

Tricyclische antidepressiva (amitriptyline en nortriptyline)

De kwaliteit van het bewijs kon niet worden vastgesteld vanwege de afwezigheid van studies die voldeden aan de PICO.

 

P2X3 remmers (gefapixant)

De overall kwaliteit van bewijs is laag. Dit betekent dat we niet zeker zijn over het gevonden geschatte effect van de cruciale uitkomstmaten.

 

Er is afgewaardeerd vanwege zeer ernstige imprecisie: onnauwkeurigheid, omdat het betrouwbaarheidsinterval de grens/beide grenzen van klinische relevantie overschrijdt. Ondanks dat de studies zijn gefinancierd door een farmaceutische partij, is niet afgewaardeerd omdat er geen aanwijzingen zijn voor publicatiebias.

 

Waarden en voorkeuren van patiënten (en eventueel hun naasten/verzorgers)

Patiënten met chronische hoest waarbij treatable traits zijn uitgesloten of behandeld (OCH/RCH) en die hoestlogopedie hebben gehad, daarbij kan het gebruik van centraal en/of perifeer werkende hoestdempende middelen besproken worden en eventueel een proefbehandeling worden gestart.

 

Beslis samen met de patiënt of de gewenste effecten van deze hoestdempende middelen die op groepsniveau zijn onderzocht opwegen tegen de mogelijk ongewenste effecten die op groepsniveau zijn onderzocht (voor zover gerapporteerd) en hoe die zich verhouden tot de waarden en voorkeuren van de individuele patiënt en diens naaste(n). De afweging is voor iedereen anders. Bespreek met de patiënt een periode van gebruik, waarna gezamenlijk evaluatie van het effect plaatsvindt. Stop de behandeling, wanneer er geen effect op de last van het hoesten wordt ervaren of wanneer er vervelende bijwerkingen zijn. 

 

Kostenaspecten

De interventie zal meer kosten ten opzichte van de controlebehandeling. Echter, bij niet behandelen, zijn er ook kosten, zoals kosten voor over-the-counter middelen, frequent bezoek aan de huisarts en ziekteverzuim. De extra kosten van de interventie wegen wel op tegen het verschil in effectiviteit.

 

Codeïne en de P2X3-remmer gefapixant worden op dit moment (2026) niet vergoed, en moeten dus door de patiënt zelf betaald worden.

 

Gelijkheid ((health) equity/equitable)

De interventie leidt tot een mogelijke afname van gezondheidsgelijkheid. Een aantal behandelingen kan op basis van de basisverzekering door iedereen gevolgd worden, maar niet iedere behandeling is beschikbaar voor iedere patiënt. Op basis van co morbiditeit is niet bij iedereen de gelijke behandeling mogelijk. Gefapixant en codeïne worden niet vergoed door de zorgverzekeraar.

 

Aanvaardbaarheid:

Ethische aanvaardbaarheid

De interventie lijkt aanvaardbaar voor de betrokkenen. Er zijn geen ethische bezwaren.

 

Duurzaamheid

Bij de interventie spelen duurzaamheidsaspecten een rol, zoals bij iedere vorm van medicamenteuze behandeling. Van belang is de interventie te staken na de gestelde proefperiode wanneer er geen effect heeft opgetreden of eerder indien ongewenste bijwerkingen optreden. Dit beperkt onnodig gebruik van (langdurig) medicatie gebruik.

 

Haalbaarheid

De interventie lijkt haalbaar. Wel voorziet de werkgroep belemmeringen in vergoeding van Gefapixant (P2X3 remmers) en codeïne. Ook is het belangrijk dat gebruik van centraal en/of perifeer werkende hoestdempende middelen gestopt wordt wanneer er geen klinisch relevant effect wordt bereikt. Daarnaast dient het starten en stoppen van de behandeling geïnitieerd te worden door de longarts en wordt er gedurende de proefbehandeling niet terugverwezen.

 

Rationale van de aanbeveling: weging van argumenten voor en tegen de interventies

Bij patiënten met chronische hoest, waarbij treatable traits zijn behandeld (OCH/RCH) en die hoestlogopedie hebben gehad, kan het gebruik van centraal en/of perifeer werkende hoestdempende middelen besproken worden en eventueel een proefbehandeling worden gestart. Bij voorkeur beslist een arts met ervaring in het gebruik van hoestdempende middelen samen met de patiënt. Daarbij moet de afweging gemaakt worden of de gewenste effecten van deze hoestdempende middelen opwegen tegen de mogelijke ongewenste effecten die beide op groepsniveau zijn onderzocht (voor zover gerapporteerd) en hoe die zich verhouden tot de waarden en voorkeuren van de individuele patiënt.

 

Eindoordeel:

Er is een zwakke aanbeveling voor het gebruik van centraal en perifeer werkende hoestdempende middelen. Bepaal gezamenlijk met de patiënt het eventueel starten/proberen hiervan.

Onderbouwing

Introduction

Unexplained (UCC) of refractory chronic cough (RCC) is considered a neuropathy (chronic cough syndrome), which causes the cough reflex to be enhanced. When speech therapy/cough control therapy did not reduce the burden of coughing enough, a clearly defined strategy for the (empirical) application of neuromodulatory medication in these patients is desirable.

Opioids (morphine and codeine)

Population: Patients with unexplained/refractory chronic cough

Intervention: Morphine

Comparator: Placebo

Outcome

 

Study results and measurements

Absolute effect estimates

Certainty of the evidence

(Quality of evidence)

Summary

Placebo

Opioids (morphine)

Cough-specific quality of life (critical)

 

Measured by: LCQ

Scale: -
High better

 

Based on data from 54 participants in 1 study

 

Follow up 4 weeks

 

(Mean)
-

 

(Mean)
-

Moderate

Due to serious imprecision1

Morphine probably increases cough-specific quality of life when compared to placebo in patients with chronic refractory cough.

 

(Morice, 2007)

Difference: MD 2 higher

(CI 95% 0.93 higher - 3.07 higher)

Cough severity (critical)

 

Measured by self-reported

Scale: 0 - 9
Lower better

 

Based on data from 54 participants in 1 study

 

Follow up 4 weeks

 

(Mean)
-

 

(Mean)
-

Moderate

Due to serious imprecision2

Morphine probably reduces cough severity when compared to placebo in patients with chronic refractory cough.

 

(Morice, 2007)

Difference: MD 1.96 lower

(CI 95% 2.11 lower - 1.09 lower)

Cough frequency (critical)

 

-

 

 


-

 

-

 

No Grade
(No evidence was found)

No evidence was found regarding the effect of opioids when compared to placebo in patients with unexplained/refractory chronic cough.

-

 
  1. Imprecision: serious. Wide confidence intervals crossing one border of clinical relevance;
  2. Imprecision: serious. Low number of patients (optimal information size not met);

References

[1] Morice AH1, Menon MS, Mulrennan SA, Everett CF, Wright C, Jackson J, Thompson R. Opiate therapy in chronic cough. Am J Respir Crit Care Med. 2007 Feb 15;175(4):312-5.

 

Codeine

No studies investigating the effect of codeine specific opioids in patients with unexplained/refractory chronic cough were included in this summary of literature.

 

Gabapentin

Population: Patients with unexplained/refractory chronic cough

Intervention: Gabapentin

Comparator: Placebo

Outcome

 

Study results and measurements

Absolute effect estimates

Certainty of the evidence

(Quality of evidence)

Summary

Placebo

Gabapentin

Cough-specific quality of life (critical)

 

Measured by: LCQ

Scale:  - 

High better

 

Based on data from 62 participants in 1 study

 

Follow up 8 weeks

 

(Mean)
-

 

(Mean)
-

Moderate

Due to serious imprecision1

Gabapentin probably increases cough-specific quality of life when compared to placebo in patients with chronic refractory cough.

 

(Ryan, 2012)

Difference: MD 1.8 higher

(CI 95% 0.56 higher - 3.04 higher)

Cough severity (critical)

 

Measured by: VAS

Scale: 0 - 100 Lower better

 

Based on data from 62 participants in 1 study

 

Follow up 8 weeks

 

(Mean)
-

 

(Mean)
-

Moderate

Due to serious imprecision2

Gabapentin probably reduces cough severity when compared to placebo in patients with chronic refractory cough.

 

(Ryan, 2012)

Difference: MD 12.23 lower

(CI 95% 23.23 lower - 1.23 lower)

Cough frequency (critical)

 

Measured by: Number of coughs per hour

Lower better

 

Based on data from 62 participants in 1 study

 

Follow up 8 weeks

 

(Mean)
-

 

(Mean)
-

Moderate

Due to serious imprecision3

Gabapentin probably reduces cough frequency when compared to placebo in patients with chronic refractory cough.

 

(Ryan, 2012)

Difference: MD 27.31 lower

(CI 95% 51.75 lower - 2.87 lower)
  1. Imprecision: serious. Wide confidence intervals crossing one border of clinical relevance.
  2. Imprecision: serious. Wide confidence intervals crossing one border of clinical relevance.
  3. Imprecision: serious. Wide confidence intervals crossing one border of clinical relevance.

References

[1] Ryan NM1, Birring SS, Gibson PG. Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trial. Lancet. 2012 Nov 3;380(9853):1583-9.

 

Pregabalin

Population: Patients with unexplained/refractory chronic cough

Intervention: Pregabalin

Comparator: Placebo

Outcome

 

Study results and measurements

Absolute effect estimates

Certainty of the evidence

(Quality of evidence)

Summary

Placebo

Pregabalin

Cough-specific quality of life (critical)

 

Measured by: LCQ

Scale:  - 

High better

 

Based on data from 70 participants in 2 studies

 

Follow up 4 to 14 weeks

 

Adeli
(2023):
44.44

(Mean)

 

Vertigan (2016):
(Mean)

-

 


Adelli (2023):
39.07

(Mean)

Vertigan (2016):
(Mean)

-

 

Moderate

Due to serious imprecision1

Pregabalin probably increases cough-specific quality of life when compared to placebo in patients with chronic refractory cough.

 

(Adeli, 2023; Vertigan, 2016)

Difference:

Adeli (2023):
MD 5.37 higher

(CI 95% - )

Vertigan (2016)
MD 3.5 higher

(CI 95% 1.11 higher – 5.89 higher)

Cough severity (critical)

 

Measured by: VAS

Scale: 0 - 100 Lower better

 

Based on data from 40 participants in 1 study

 

Follow up 14 weeks

 

(Mean)
-

 

(Mean)
-

Moderate

Due to serious imprecision2

Pregabalin probably reduces cough severity when compared to placebo in patients with chronic refractory cough.

 

(Vertigan, 2016)

Difference: MD 25.1 lower

(CI 95% 39.6 lower – 10.6 lower)

Cough frequency (critical)

 

Measured by: Number of coughs per hour

Lower better

 

Based on data from 40 participants in 1 study

 

Follow up 14 weeks

 

(Mean)
-

 

(Mean)
-

Low

Due to serious imprecision3

Pregabalin might reduce cough frequency when compared to placebo in patients with chronic refractory cough.

 

(Vertigan, 2016)

Difference: MD 2.3 lower

(CI 95% 13.58 lower – 8.98 higher)
  1. Imprecision: serious. Wide confidence intervals crossing one border of clinical relevance and unknown confidence interval.
  2. Imprecision: serious. Low number of patients (optimal information size not met).
  3. Imprecision: serious. Wide confidence intervals crossing two borders of clinical relevance.

References

[1] Adeli SH, Beigi AM, Ahmadpour S, Habibi MA, Pashaei MR, Sharifipour E, Shakeri M, Asghari A. Effects of Pregabalin as a Neural Pathway Inhibitor for the Treatment of Resistant Subacute and Chronic Cough: A Pilot Clinical Trials Study. Rev Recent Clin Trials. 2023;18(4):269-274. doi: 10.2174/0115748871262516230919070559. PMID: 37888808
[2] Vertigan AE, Kapela SL, Ryan NM, Birring SS, McElduff P, Gibson PG. Pregabalin and Speech Pathology Combination Therapy for Refractory Chronic Cough: A Randomized Controlled Trial. Chest. 2016 Mar;149(3):639-48.

 

Tricyclic antidepressants (amitriptyline and nortriptyline)

No studies investigating the effect of tricyclic antidepressants in patients with unexplained/refractory chronic cough were included in this summary of literature.

 

P2X3 receptor antagonist (Gefapixant)

Population: Patients with unexplained/refractory chronic cough

Intervention: Gefapixant low dose

Comparator: Placebo

Outcome

 

Study results and measurements

Absolute effect estimates

Certainty of the evidence

(Quality of evidence)

Summary

Placebo

Gefapixant

Cough-specific quality of life (critical)

 

Measured by: LCQ

Scale: -
High better

 

Based on data from 120 participants in 1 study

 

Follow up 12 weeks

13.8

Mean:

14.8

(Mean)

Low

Due to very serious imprecision1

Gefapixant at low dose may not increase cough-specific quality of life when compared to placebo in patients with unexplained/refractory chronic cough.

 

(Smith, 2020)

Difference:
1.0 higher (MD)
(CI95% 0.37 lower to 2.37 higher)

 

Cough severity
 VAS
(critical)

 

Measured by: VAS

Scale: 0 - 100
Lower better

 

Based on data from 120 participants in 1 study

 

Follow up 12 weeks

39.3

(Mean)

35

(Mean)

Low

Due to very serious imprecision1

Gefapixant at low dose may not reduce cough severity (VAS) when compared to placebo in patients with chronic refractory cough.

 

(Smith, 2020)

Difference:

4.3 lower (MD)
(CI95% 13.57 lower to 4.97 higher)

 

Cough severity
 CSD
(critical)

 

Measured by: CSD

Scale: 0 - 10
Lower better

 

 

Based on data from 120 participants in 1 study

 

Follow up 12 weeks

3.0

(Mean)

2.5

(Mean)

Moderate

Due to very serious imprecision1

Gefapixant at low dose probably not reduces cough severity (CSD) when compared to placebo in patients with chronic refractory cough.

 

(Smith, 2020)

Difference:

0.5 lower (MD)
(CI95% 1.27 lower to 0.27 higher)

 

Cough frequency (critical)

 

Measured by: Number of coughs per hour

Lower better

 

Based on data from 120 participants in 1 study

 

Follow up 12 weeks

 

13.7

(Mean)

10.8

(Mean)

Low

Due to very serious imprecision1

Gefapixant at low dose may not reduce cough frequency when compared to placebo in patients with chronic refractory cough.

 

(Smith, 2020)

Difference:

2.9 lower (MD)
(CI95% 4.07 lower to 1.73 higher)

 
  1. Imprecision: very serious. Wide confidence intervals crossing one border of clinical relevance and small sample size.

References

[1] Smith JA, Kitt MM, Morice AH, Birring SS, McGarvey LP, Sher MR, Li YP, Wu WC, Xu ZJ, Muccino DR, Ford AP; Protocol 012 Investigators. Gefapixant, a P2X3 receptor antagonist, for the treatment of refractory or unexplained chronic cough: a randomised, double-blind, controlled, parallel-group, phase 2b trial. Lancet Respir Med. 2020 Aug;8(8):775-785. doi: 10.1016/S2213-2600(19)30471-0. Epub 2020 Feb 25. PMID: 32109425.

 

Population: Patients with unexplained/refractory chronic cough

Intervention: Gefapixant medium dose

Comparator: Placebo

Outcome

 

Study results and measurements

Absolute effect estimates

Certainty of the evidence

(Quality of evidence)

Summary

Placebo

Gefapixant

Cough-specific quality of life (critical)

 

Measured by: LCQ

Scale: -
High better

 

Based on data from 120 participants in 1 study

 

Follow up 12 weeks

13.8

Mean:

14.8

(Mean)

Low

Due to very serious imprecision1

Gefapixant at medium dose may not increase cough-specific quality of life when compared to placebo in patients with unexplained/refractory chronic cough.

 

(Smith, 2020)

Difference:
1.0 higher (MD)
(CI95% 0.38 lower to 2.38 higher)

 

Cough severity
 VAS
(critical)

 

Measured by: VAS

Scale: 0 - 100
Lower better

 

Based on data from 120 participants in 1 study

 

Follow up 12 weeks

39.3

(Mean)

34

(Mean)

Low

Due to very serious imprecision1

Gefapixant at medium dose may not reduce cough severity (VAS) when compared to placebo in patients with chronic refractory cough.

 

(Smith, 2020)

Difference:

5.3 lower (MD)
(CI95% 15.12 lower to 4.52 higher)

 

Cough severity
 CSD
(critical)

 

Measured by: CSD

Scale: 0 - 10
Lower better

 

Based on data from 120 participants in 1 study

 

Follow up 12 weeks

3.0

(Mean)

2.4

(Mean)

Low

Due to very serious imprecision1

Gefapixant at medium dose may not reduce cough severity (CSD) when compared to placebo in patients with chronic refractory cough.

 

(Smith, 2020)

Difference:

0.6 lower (MD)
(CI95% 1.34 lower to 0.14 higher)

Cough frequency (critical)

 

Measured by: Number of coughs per hour

Lower better

 

Based on data from 569 participants in 2 studies

 

Follow up 12 weeks

 

McGarvey (2022)
10.3

(Mean)

 

Smith

(2020)
13.7

(Mean)

McGarvey (2022)

9.7

(Mean)

 

Smith

(2020)

8.8

(Mean)

No GRADE
Due to inconsistent effects2

The evidence is unclear about the effect of gefapixant at medium dose on cough frequency due to inconsistent results. (McGarvey, 2022 and Smith, 2020)

 

Difference:

McGarvey (2022)

0.6 lower (MD)
(CI95% -)

 

Smith

(2020)

4.9 lower (MD)
(CI95% 6.17 lower to 3.63 higher)
  1. Imprecision: very serious. Wide confidence intervals crossing one border of clinical relevance and small sample size.
  2. Inconsistent effects: study reported inconsistent results but cannot further be graded since the study of McGarvey (2022) did not report any measure of dispersion.

References

[1] Smith JA, Kitt MM, Morice AH, Birring SS, McGarvey LP, Sher MR, Li YP, Wu WC, Xu ZJ, Muccino DR, Ford AP; Protocol 012 Investigators. Gefapixant, a P2X3 receptor antagonist, for the treatment of refractory or unexplained chronic cough: a randomised, double-blind, controlled, parallel-group, phase 2b trial. Lancet Respir Med. 2020 Aug;8(8):775-785. doi: 10.1016/S2213-2600(19)30471-0. Epub 2020 Feb 25. PMID: 32109425.
[2] McGarvey LP, Birring SS, Morice AH, Dicpinigaitis PV, Pavord ID, Schelfhout J, Nguyen AM, Li Q, Tzontcheva A, Iskold B, Green SA, Rosa C, Muccino DR, Smith JA; COUGH-1 and COUGH-2 Investigators. Efficacy and safety of gefapixant, a P2X3 receptor antagonist, in refractory chronic cough and unexplained chronic cough (COUGH-1 and COUGH-2): results from two double-blind, randomised, parallel-group, placebo-controlled, phase 3 trials. Lancet. 2022 Mar 5;399(10328):909-923. doi: 10.1016/S0140-6736(21)02348-5. PMID: 35248186.

 

Population: Patients with unexplained/refractory chronic cough

Intervention: Gefapixant high dose

Comparator: Placebo

Outcome

 

Study results and measurements

Absolute effect estimates

Certainty of the evidence

(Quality of evidence)

Summary

Placebo

Gefapixant

Cough-specific quality of life (critical)

 

Measured by: LCQ

Scale: -
High better

 

Based on data from 118 participants in 1 study

 

Follow up 12 weeks

13.8

Mean:

15.3

(Mean)

Low

Due to very serious imprecision1

Gefapixant at high dose might increase cough-specific quality of life when compared to placebo in patients with unexplained/refractory chronic cough.

 

(Smith, 2020)

Difference:
1.5 higher (MD)
(CI95% 0.13 lower to 2.87 higher)

 

Cough severity
 VAS
(critical)

 

Measured by: VAS

Scale: 0 - 100
Lower better

 

Based on data from 118 participants in 1 study

 

Follow up 12 weeks

39.3

(Mean)

27.9

(Mean)

Low

Due to very serious imprecision1

Gefapixant at high dose may reduce cough severity (VAS) when compared to placebo in patients with chronic refractory cough.

 

(Smith, 2020)

Difference:

11.4 lower (MD)
(CI95% 20.54 lower to 2.26 lower)

 

Cough severity
 CSD
(critical)

 

Measured by: CSD

Scale: 0 - 10
Lower better

 

Based on data from 118 participants in 1 study

 

Follow up 12 weeks

3.0

(Mean)

2.4

(Mean)

Low

Due to very serious imprecision1

Gefapixant at high dose may not reduce cough severity (CSD) when compared to placebo in patients with chronic refractory cough.

 

(Smith, 2020)

Difference:

0.6 lower (MD)
(CI95% 1.30 lower to 0.10 higher)

 

Cough frequency (critical)

 

Measured by: Number of coughs per hour

Lower better

 

Based on data from 558 participants in 2 studies

 

Follow up 12 weeks

 

McGarvey (2022)
10.3

(Mean)

 

Smith

(2020)
13.7

(Mean)

McGarvey (2022)

7.1

(Mean)

 

Smith

(2020)

8.5

(Mean)

No GRADE
Due to inconsistent effects2

The evidence is unclear about the effect of gefapixant at high dose on cough frequency due to inconsistent results.

 

(McGarvey, 2022 and Smith, 2020)

 

Difference:

McGarvey (2022)

3.2 lower (MD)
(CI95% -)

Smith

(2020)

5.2 lower (MD)
(CI95% 6.23 lower to 4.17 higher)
  1. Imprecision: very serious. Wide confidence intervals crossing one border of clinical relevance and low sample size.
  2. Inconsistent effects: study reported inconsistent results but cannot further be graded since the study of McGarvey (2022) did not report any measure of dispersion.

References

[1] Smith JA, Kitt MM, Morice AH, Birring SS, McGarvey LP, Sher MR, Li YP, Wu WC, Xu ZJ, Muccino DR, Ford AP; Protocol 012 Investigators. Gefapixant, a P2X3 receptor antagonist, for the treatment of refractory or unexplained chronic cough: a randomised, double-blind, controlled, parallel-group, phase 2b trial. Lancet Respir Med. 2020 Aug;8(8):775-785. doi: 10.1016/S2213-2600(19)30471-0. Epub 2020 Feb 25. PMID: 32109425.
[2] McGarvey LP, Birring SS, Morice AH, Dicpinigaitis PV, Pavord ID, Schelfhout J, Nguyen AM, Li Q, Tzontcheva A, Iskold B, Green SA, Rosa C, Muccino DR, Smith JA; COUGH-1 and COUGH-2 Investigators. Efficacy and safety of gefapixant, a P2X3 receptor antagonist, in refractory chronic cough and unexplained chronic cough (COUGH-1 and COUGH-2): results from two double-blind, randomised, parallel-group, placebo-controlled, phase 3 trials. Lancet. 2022 Mar 5;399(10328):909-923. doi: 10.1016/S0140-6736(21)02348-5. PMID: 35248186.

Summary of literature

Description of studies

A total of seven studies were included in the analysis of the literature. Important study characteristics and results are summarized in table 2. The assessment of the risk of bias is summarized in the risk of bias tables (under the tab ‘Evidence tabellen’).

 

Opioids

Morphine

The ERS guideline (Morice, 2020) included one randomized controlled trial (Morice, 2007) investigating the effect of opioids in patients with unexplained/refractory chronic cough.

 

Codeine

No studies investigating the effect of codeine specific opioids in patients with unexplained/refractory chronic cough were included in this summary of literature.

 

Gabapentin

The ERS guideline (Morice, 2020) included one randomized controlled trial (Ryan, 2012) investigating the effect of gabapentin in patients with unexplained/refractory chronic cough.

 

Pregabalin

The ERS guideline (Morice, 2020) included one randomized controlled trial (Vertigan, 2016) investigating the effect of pregabalin in patients with unexplained/refractory chronic cough. One additional randomized controlled trial (Adeli, 2023) investigated the effect of pregabalin in patients with refractory chronic cough was identified.

 

Tricyclic antidepressants (amitriptyline and nortriptyline)

No studies investigating the effect of tricyclic antidepressants in patients with unexplained/refractory chronic cough were included in this summary of literature.

 

P2X3 receptor antagonist (gefapixant)

Three randomized controlled trials (McGarvey, 2022; McGarvey, 2023; Smith, 2020) investigating the effect of gefapixant in patients with unexplained/refractory chronic cough were identified.

  

Table 2. Characteristics of included studies

Study

Participants

Comparison

Follow-up

Outcome measures

Comments

Risk of bias (per outcome measure)*

Opioids

Included in ERS guideline (Morice, 2020)

Morice, 2007

N at baseline

Intervention: 27

Control: 27

 

Age (mean, SD)

Not reported in ERS guideline

 

Sex

Not reported in ERS guideline

Intervention:
5-10mg morphine twice daily

 

Control: Placebo

Not reported in ERS guideline

 

cough-specific quality of life,

cough severity

Patients with chronic refractory cough

ERS guideline reports: not serious for all outcome measures

Gabapentin

Included in ERS guideline (Morice, 2020)

Ryan, 2012

N at baseline

Intervention: 32

Control: 30

 

Age (mean, SD)

Not reported in ERS guideline

 

Sex

Not reported in ERS guideline

Intervention:
maximum tolerable daily dose of 1800mg gabapentin

 

Control:

Placebo

8 weeks for cough frequency and cough severity,
not reported in ERS guideline for other outcomes

cough-specific quality of life,
cough severity, cough frequency

Patients with chronic refractory cough

ERS guideline reports: not serious for all outcome measures

Pregabalin

Included in ERS guideline (Morice, 2020)

Vertigan, 2016

N at baseline

Intervention: 20

Control: 20

 

Age (mean, SD)

Not reported in ERS guideline

 

Sex

Not reported in ERS guideline

Intervention:
Speech pathology therapy + pregabalin

 

Control:
Speech pathologie therapy + placebo

14 weeks for cough frequency and cough severity,
not reported in ERS guideline for other outcomes

cough-specific quality of life,
cough severity, cough frequency

Patients with chronic refractory cough

ERS guideline reports: not serious for all outcome measures

Individual studies

Adeli, 2023

N at baseline

Intervention: 16

Control: 14

 

Age (mean, SD)

Only reported for total study group: 56.7 (18.2) years

 

Sex (n, % female)

Intervention: 11, 68.8%

Control: 8, 57.1%

 

Having an underlying disease (n, % yes)

Intervention: 13, 81.2%
Control: 13, 92.9%

Intervention:

Dextromethorphan (15mg, every 8 hours) + pregabalin (50mg, per day) for at least two weeks

Control: Dextromethorphan (15mg, every 8 hours) + placebo for at least two weeks

4 weeks after start of treatment

cough-specific quality of life

Single center study

 

Patients with chronic refractory cough > 8 weeks

 

After 4 weeks, doses pregabalin were increased if unsufficient improvement was noted

Low risk of bias for all outcome measures

Gefapixant

McGarvey, 2022

N at baseline

Intervention: 1a: 244

1b: 440

2a: 243

2b: 239

Control:

a: 243

b:435

 

Age (mean, SD)

Intervention:

1a: 59.6 (11.7) year

1b: 58.6 (11.4) years

2a: 59.4 (13.1) years

2b: 57.8 (12.4) years

Control:

a: 579 (13.1) years

b: 58 (12.6) years

 

Sex (n, %female)

Intervention:

1a: 181, 74.5%

1b: 329, 74.8%

2a: 180, 74.1%

2b: 329, 74.9%

Control:

a: 181, 74.5%

b: 326, 73.9%

Intervention 1a: gefapixant 15mg twice daily for 12 weeks

 

Intervention 1b: gefapixant 15mg twice daily for 24 weeks

 

Intervention 2a: gefapixant 45mg twice daily for 12 weeks

 

Intervention 2b: gefapixant 45mg BID for 24 weeks

 

Control a:

placebo for 12 weeks

 

Control b: placebo for 24 weeks

 

12/24 weeks

cough-specific quality of life, cough severity,
cough frequency

Multi-center study:
 a: 146 sites

 b: 175 sites

 

Chronic cough >12 months
a:
Refractory: 58.6%
Unexplained: 41.4%
b:
Refractory: 63.1%
Unexplained: 36.924 h%

Some concerns due to sponsoring Merck & Co

McGarvey, 2023

N at baseline

Intervention: 206

Control: 209

 

Age (mean, SD)

Intervention:  52.5 (13.8 years)

Control: 52.5 (13.8 years)

 

Sex (n,%female)

Intervention: 134, 65%

Control:
134, 64.1%

 

Comorbid cough-associated conditions (n,%):
Intervention:
Asthma: 88,42.7%
Gastroesophageal reflux disease: 63, 30.6%
Alergic rhinitus: 35, 17%
Chornic gastritis: 35, 17%
Control:
Asthma: 82, 39.2%
Gastroesophageal reflux disease: 61, 29.2%
Alergic rhinitus: 34, 16.3%
Chornic gastritis: 23, 11%

Intervention: gefapixant 45mg twice daily for 12 weeks

Control: placebo

12 weeks after start treatment

cough-specific quality of life, cough severity

Multicenter study

 

Chronic cough <12 months:
Refractory: 71%
Unexplained: 29%

Some concerns due to sponsoring Merck & Co

Smith, 2020

N at baseline

Intervention:
1: 64

2: 63

3: 63

Control: 63

 

 

Age (mean, SD)

Intervention:

1: 59.9 (10.5) years

2: 61.8 (9.1) years

3: 59.3 (9.2) years

Control: 60.0 (10.9) years

 

Sex (n, %female)

Intervention:

1: 48 (75%)

2: 48 (76%)

3: 50 (79%)

Control: 47 (75%)

Intervention 1: gefapixant 7.5mg twice daily for 84 days

Intervention 2: gefapxiant 20mg twice daily for 84 days

Intervention 3: gefapixant 50mg twice daily for 84 days

Control: placebo

12 weeks after start treatment

cough-specific quality of life, cough severity,
cough frequency

Mutlicenter study: 44 centers

 

Chronic cough >12 months

 

Some concerns due to sponsoring Merck & Co

*For further details, see risk of bias table in the appendix

 

Results

Opioids

Morphine

Cough-specific quality of life (critical)

The ERS guideline included one study (Morice, 2007) investigating the effect of morphine on cough-specific quality of life (LCQ) in adults with chronic refractory cough after 4 weeks of treatment (Morice, 2020). No new studies were added. See Summary of Findings (SoF) table for the results and conclusions.

 

Cough severity (critical)

The ERS guideline included one study (Morice, 2007) investigating the effect of morphine cough severity (cough severity score) in adults with chronic refractory cough after 4 weeks of treatment (Morice, 2020). No new studies were added. See Summary of Findings (SoF) table for the results and conclusions.

 

Cough frequency (critical)

No studies investigating cough frequency were included in this summary of literature.

 

Codeine

No studies investigating the effect of codeine specific opioids in patients with unexplained/refractory chronic cough were included in this summary of literature.

 

Gabapentin

Cough-specific quality of life (critical)

The ERS guideline included one study (Ryan, 2012) investigating the effect of gabapentin on cough-specific quality of life (LCQ) in adults with chronic refractory cough after 8 weeks of treatment (Morice, 2020). No new studies were added. See Summary of Findings (SoF) table for the results and conclusions.

 

Cough severity (critical)

The ERS guideline included one study (Ryan, 2012) investigating the effect of gabapentin on cough severity (VAS-scale 0-100) in adults with chronic refractory cough after 8 weeks of treatment (Morice, 2020). No new studies were added. See Summary of Findings (SoF) table for the results and conclusions.

 

Cough frequency (critical)

The ERS guideline included one study (Ryan, 2012) investigating the effect of gabapentin on cough frequency (number of coughs per hour) in adults with chronic refractory cough after 8 weeks of treatment (Morice, 2020). No new studies were added. See Summary of Findings (SoF) table for the results and conclusions.

 

Pregabalin

Cough-specific quality of life (critical)

The ERS guideline included one study (Vertigan, 2016) investigating the effect of pregabalin on cough-specific quality of life (LCQ) in adults with chronic refractory cough after 14 weeks of treatment (Morice, 2020). Both groups also received speech therapy. Adeli (2023) investigated cough-specific quality of life (LCQ) in adults with chronic refractory cough after 4 weeks of treatment. Results of both studies are reported in table 3. Both studies reported a clinically relevant difference (>1.3) in favor of patients treated with pregabalin.


 

Table 3. Cough-specific quality of life scores (LCQ) in patients with chronic refractory cough after pregabalin vs. placebo treatment

 

Intervention

Control

 

 

N

Mean (SD)

N

Mean (SD)

Mean difference (95%CI)

Adeli, 2023

16

44.44 (NR)

14

39.07 (NR)

5.37 (NR)

Vertigan, 2016
(Results extracted from Morice, 2020)

20

NR

20

NR

3.5 (1.11 to 5.89)

NR: not reported

 

Cough severity (critical)

The ERS guideline included one study (Vertigan, 2016) investigating cough severity (VAS-scale 0-100) in adults with chronic refractory cough after 14 weeks of treatment with pregabalin (Morice, 2020). No new studies were added. See Summary of Findings (SoF) table for the results and conclusions.

 

Cough frequency (critical)

The ERS guideline included one study (Vertigan, 2016) investigating cough frequency (number of coughs per hour) in adults with chronic refractory cough after 14 weeks of treatment with pregabalin (Morice, 2020). No new studies were added. See Summary of Findings (SoF) table for the results and conclusions.

 

Tricyclic antidepressants (critical)

No studies investigating the effect of tricyclic antidepressants in patients with unexplained/refractory chronic cough were included in this summary of literature.

 

P2X3 receptor antagonist (gefapixant)

Cough-specific quality of life (critical)

Three studies investigating the effect of gefapixant on cough-specific quality of life (LCQ) in adults with unexplained/refractory chronic cough after 12 weeks of treatment (McGarvey, 2022; McGarvey, 2023; Smith, 2020). Individual study results are reported in table 4.

 

Note that results reported alternatively (% of responders) are reported in grey and not further evaluated. This also applies for estimated results by a statistical model, as it was not clear how used confounders were chosen.

 

Reported differences were not clinically relevant for patients treated with low and medium doses of gefapixant. A clinically relevant effect (³ 1.3 points) was reported in favor of patients treated with a high dose of gefapixant.

 

Table 4. Cough-specific quality of life scores (LCQ) at 12 weeks in patients with unexplained/refractory chronic cough after gefapixant vs. placebo treatment

 

Intervention

Control

 

 

N

Effect

N

Effect

Mean difference (95%CI)

OR (95%CI)

Low dose (7.5mg twice a day)

 

Smith, 2020

59

Mean (SD):
14.8 (3.86)

61

Mean (SD):
13.8 (3.81)

1.0 (-0.37 to 2.37)

NA

59

Mean change (95%CI), estimated by model:
3.3 (2.4 to 4.2)

61

Mean change (95%CI), estimated by model:
2.1 (1.3 to 3.0)

1.2

(–0.1 to 2.4)1

NA

Medium dose (15mg or 20mg twice a day)

 

McGarvey, 2022

226

Responders*: 68.8%

217

Responders: 61.3%

7.5% (NR)2

1.39 (0.92 to 2.12)

McGarvey, 2023

199

Mean change, estimated by model corrected for confounding factors: mean (95%CI):

 

4.34 (3.84 to 4.83)

199

Mean change, estimated by model corrected for confounding factors: mean (95%CI):

 

3.59 (3.09 to 4.09)

0.75 (0.06 to 1.44) 1

NA

202

Responders:
80.6%

208

Responders: 67.4%

13.19% (3.46 to 22.81) 2

2.01 (1.2 to 3.32)

Smith, 2020

59

Mean (SD):
14.8 (3.90)

61

Mean (SD):
13.8 (3.81)

1.0 (-0.38 to 2.38)

NA

59

Mean change (95%CI), estimated by model:
3.2 (2.3 to 4.0)

61

Mean change (95%CI), estimated by model:
2.1 (1.3 to 3.0)

1.0

(–0.2 to 2.3) 1

NA

High dose (45mg or 50mg twice a day)

 

McGarvey, 2022

214

Responders:
67.3%

217

Responders: 61.3%

6.0% (NR) 2

1.30 (0.85 to 1.98)

Smith 2020

57

Mean (SD):
15.3 (3.77)

61

Mean (SD):
13.8 (3.81)

1.5 (0.13 to 2.87)

NA

57

Mean change (95%CI), estimated by model:
4.0 (3.1 to 4.9)

61

Mean change (95%CI), estimated by model:
2.1 (1.3 to 3.0)

1.9

(0.7 to 3.1) 1

NA

1.Results that are reported by using an estimated model are reported in the summary but are not further evaluated by the means of GRADE, as it was not clear how the used confounders were chosesn.
2. Results that er reported alternatively (%of responders) are not further evaluated. 

*Responders: change ³ 1.3 points
NR: not reported

NA: not applicable

 

Additionally, McGarvey (2022) investigated the effect of gefapixant on cough-specific quality of life (LCQ) in adults with unexplained/refractory chronic cough after 24 weeks of treatment. Note that all results were reported alternatively (% of responders) and therefore not further evaluated.

 

Table 5. Cough-specific quality of life scores (LCQ) at 24 weeks in patients with unexplained/refractory chronic cough after gefapixant vs. placebo treatment

 

Intervention

Control

 

 

N

Effect

N

Effect

Mean difference (95%CI)

OR (95%CI)

Medium dose (15mg twice a day)

 

McGarvey, 2022

404

Responders*:
75.9%

406

Responders:
70.1%

5.8% (NR)1

1.34 (0.97 to 1.85)

High dose (45mg twice a day)

 

McGarvey, 2022

399

Responders*:
76.8%

406

Responders:
70.1%

6.7% (NR)1

1.41 (1.02 to 1.96)

1. Results that er reported alternatively (%of responders) are not further evaluated. 
NR: not reported

*Responders: change ³ 1.3 points per week

 

Cough severity (critical)

Three studies investigating the effect of gefapixant on cough severity (VAS, CSD) in adults with unexplained/refractory chronic cough after 12 weeks of treatment (McGarvey, 2022; McGarvey, 2023; Smith, 2020). As McGarvey (2022) reported a percentage of responders and related odds ratio based on a different threshold for clinical relevance as the working group defined, data was not presented in the current summary of literature. Individual study results for the other studies are reported in table 6 and 7.

Note that estimated results by a statistical model, are reported in grey and not further evaluated as it was not clear how used confounders were chosen.

 

Reported differences in VAS and CSD scores were not clinically relevant for patients treated with low and medium doses of gefapixant. For patients treated with high doses of gefapixant, Smith reported conflicting results for VAS versus CSD scores. A clinically relevant effect (10mm points) on VAS-score in favor of patients treated with gefapixant was reported for VAS, but not for CSD.

 

Table 6. Cough severity scores (VAS) at 12 weeks in patients with unexplained/refractory chronic cough after gefapixant vs. placebo treatment

 

Intervention

Control

 

 

N

Effect

N

Effect

Mean difference (95%CI)

Low dose (7.5mg twice a day)

Smith, 2020

59

Mean (SD):
35 (23.6)

61

Mean (SD):
39.3 (28.11)

-4.3 (-13.57 to 4.97)

59

Mean change (95%CI), estimated by model:
-21.1 (-27.2 to -15.1)

61

Mean change (95%CI), estimated by model:
-16.7 (-22.7 to -10.7)

-4.4 (-12.9 to 4.0) 1

Medium dose (20mg twice a day)

Smith, 2020

59

Mean (SD):
34.0 (26.8)

61

Mean (SD):
39.3 (28.11)

-5.3 (-15.12 to 4.52)

59

Mean change (95%CI), estimated by model:
-23.1

(-29.1 to -17.0)

61

Mean change (95%CI), estimated by model:
-16.7 (-22.7 to -10.7)

-6.4

(-14.8 to 2.0) 1

High dose (45 or 50mg twice a day)

McGarvey, 2023

201

Mean change, estimated by model corrected for confounding factors: mean (95%CI):

 

−2.79 (−3.08 to −2.49)

205

Mean change, estimated by model corrected for confounding factors: mean (95%CI):

 

−2.32 (−2.61 to −2.03)

−0.47 (−0.88 to −0.06)1

Smith 2020

57

Mean (SD):
27.9 (22.39)

61

Mean (SD):
39.3 (28.11)

-11.4 (-20.54 to -2.26)

57

Mean change (95%CI), estimated by model:
-27.9

(-34.1 to -21.6)

61

Mean change (95%CI), estimated by model:
-16.7 (-22.7 to -10.7)

-11.2

(-19.7 to -2.6) 1

1.Results that are reported by using an estimated model are reported in the summary but are not further evaluated by the means of GRADE, as it was not clear how the used confounders were chosen. 
NR: not reported

 

Table 7. Cough severity scores (CSD) at 12 weeks in patients with unexplained/refractory chronic cough after gefapixant vs. placebo treatment

 

Intervention

Control

 

 

N

Effect

N

Effect

Mean difference (95%CI)

Low dose (7.5mg twice a day)

Smith, 2020

59

Mean (SD):
2.5 (2.18)

61

Mean (SD):
3.0 (2.12)

-0.5 (-1.27 to 0.27)

59

Mean change (95%CI), estimated by model:
-1.5 (-2.0 to -1.1)

61

Mean change (95%CI), estimated by model:
-1.2 (-1.6 to -0.7)

-0.4

(–1.0 to 0.3)1

Medium dose (45mg daily; 20mg twice a day)

Smith, 2020

59

Mean (SD):
2.4 (2.01)

61

Mean (SD):
3.0 (2.12)

-0.6 (-1.34 to 0.14)

59

Mean change (95%CI), estimated by model:
-1.7 (-2.2 to -1.3)

61

Mean change (95%CI), estimated by model:
-1.2 (-1.6 to -0.7)

-0.6 (-1.2 to 0.0)1

High dose (45 or 50mg twice a day)

McGarvey, 2023

201

Mean change, estimated by model corrected for confounding factors: mean (95%CI):

 

−2.79 (−3.08 to −2.49)

205

Mean change, estimated by model corrected for confounding factors: mean (95%CI):

 

−2.32 (−2.61 to −2.03)

−0.47 (−0.88 to −0.06)1

Smith 2020

57

Mean (SD):
2.4 (1.76)

61

Mean (SD):
3.0 (2.12)

-0.6 (-1.30 to 0.10)

57

Mean change (95%CI), estimated by model:
-1.9 (-2.4 to -1.4)

61

Mean change (95%CI), estimated by model:
-1.2 (-1.6 to -0.7)

-0.7 (-1.4 to -0.1)1

1.Results that are reported by using an estimated model are reported in the summary but are not further evaluated by the means of GRADE, as it was not clear how the used confounders were chosen. 
NR: not reported

 

Additionally, McGarvey (2022) investigated the effect of gefapixant on cough severity (VAS, CSD) in adults with unexplained/refractory chronic cough after 24 weeks of treatment. However, effects were presented as a percentage of responders and related odds ratio based on a different threshold for clinical relevance as the working group defined. Therefore, data was not presented in the current summary of literature.

 

Cough frequency (critical)

Two studies investigating the effect of gefapixant on cough frequency (coughs per hour) in adults with unexplained/refractory chronic cough after 12 weeks of treatment (McGarvey, 2022; Smith, 2020). Individual study results for the other studies are reported in table 8.

 

Reported differences in cough frequency were not clinically relevant for patients treated with low dose of gefapixant. For patients treated with medium or high dose of gefapixant, results were conflicting. Smith (2020) reported clinically relevant differences whereas McGarvey (2022) did not report clinically relevant findings at 12 weeks. Note that estimated results by a statistical model (relative change) estimation based on model), are not further evaluated as it was not clear how used confounders were chosen.

 

Table 8. Cough frequency (coughs per hour) at 12 weeks in patients with unexplained/refractory chronic cough after gefapixant vs. placebo treatment

 

Intervention

Control



 

N

Effect

N

Effect

Mean difference (95%CI)

Low dose (7.5mg twice a day)

Smith, 2020

59

Mean (SD):
10.8 (3.6)

61

Mean (SD):
13.7 (2.9)

-2.9 (-4.07 to 1.73)

59

NR

61

NR

Relative change, estimation based on model (%)

-21.0%

(-40.3 to 4.6)1

Medium dose (15mg or 20mg twice a day)

McGarvey, 2022

227

Mean (SD):
9.7 (NR)

222

Mean (SD):
10.3 (NR)

-0.6 (NR)

227

Mean reduction (95%CI), estimated by model:

52% (45 to 59)

222

Mean reduction (95%CI), estimated by model:

53% (46 to 59)

Relative change, estimation based on model (%)

 

-1.56% (-22.99 to 16.13)1

Smith, 2020

59

Mean (SD):
8.8 (4.1)

61

Mean (SD):
13.7 (2.9)

-4.9 (-6.17 to -3.63)

59

NR

61

NR

Relative change, estimation based on model (%)

-22.1% (-41.1 to 3.2)1

High dose (45mg or 50mg twice a day)

McGarvey (2022)

217

Mean (SD):
7.1 (NR)

222

Mean (SD):
10.3 (NR)

-3.2 (NR)

 

Mean reduction (95%CI), estimated by model:

62% (56 to 67)

 

Mean reduction (95%CI), estimated by model:

53% (46 to 59

Relative change, estimation based on model (%)

 

18.45% (0.86 to 32.92)1

Smith 2020

57

Mean (SD):
8.5 (2.8)

61

Mean (SD):
13.7 (2.9)

-5.2 (-6.23 to -4.17)

57

NR

61

NR

Relative change, estimation based on model (%)

-37.6%

(-53.1 to -16.9)1

1.Results that are reported by using an estimated model are reported in the summary but are not further evaluated by the means of GRADE, as it was not clear how the used confounders were chosen. 
NR: not reported

 

Additionally, Smith (2020) investigated the effect of gefapixant on cough frequency (coughs per hour) in adults with unexplained/refractory chronic cough at 4 and 8 weeks. Reported differences in cough frequency were not clinically relevant for patients treated with low or medium doses of gefapixant. For patients treated with high dose of gefapixant, results were significant (Smith, 2020) at 4 weeks. Smith (2020) report clinical differences for all different doses of gefapixant.

 

McGarvey (2022) investigated the effect of gabapentin on cough frequency (coughs per hour) in adults with unexplained/refractory chronic cough after 24 weeks of treatment. Clinically significant results were only reported for high dose of gefapixant.

 

Note that estimated results by a statistical model, are reported in grey and not further evaluated as it was not clear how used confounders were chosen.

 

Table 9. Cough frequency (coughs per hour) at 4 weeks in patients with unexplained/refractory chronic cough after gefapixant vs. placebo treatment

 

Intervention

Control



 

N

Effect

N

Effect

Mean difference (95%CI)

Low dose (7.5mg twice a day)

Smith, 2020

59

Mean (SD):
10.5 (3.4)

61

Mean (SD):
13.1 (2.7)

-2.6 (-3.7 to -1.5)

59

NR

61

NR

Relative change, estimation based on model (%)

-17.0%

(-37.3 to 9.8)1

Medium dose (20mg twice a day)

Smith, 2020

59

Mean (SD):
10.8 (3.3)

61

Mean (SD):
13.1 (2.7)

-2.3 (-3.38 to -1.22)

59

NR

61

NR

Relative change, estimation based on model (%)

-5.1%

(-28.1 to 25.2)1

High dose (50mg twice a day)

Smith 2020

57

Mean (SD):
8.7 (3.2)

61

Mean (SD):
13.1 (2.7)

-4.4 (-5.47 to -3.33)

57

NR

61

NR

Relative change, estimation based on model (%)

-40.6%

(-55.2 to 21.4)1

1.Results that are reported by using an estimated model are reported in the summary but are not further evaluated by the means of GRADE, as it was not clear how the used confounders were chosen. 

Table 10. Cough frequency (coughs per hour) at 8 weeks in patients with unexplained/refractory chronic cough after gefapixant vs. placebo treatment

 

Intervention

Control



 

N

Effect

N

Effect

Mean difference (95%CI)

Low dose (7.5mg twice a day)

Smith, 2020

59

Mean (SD):
9.2 (3.9)

61

Mean (SD):
14.5 (2.3)

-5.30 (-6.45 to -4.15)

59

NR

61

NR

Relative change, estimation based on model (%):

-33.1% (-50.7 to -9.3)1

Medium dose (20mg twice a day)

Smith, 2020

59

Mean (SD):
9.5 (4.1)

61

Mean (SD):
14.5 (2.3)

-5.0 (-6.19 to -3.81)

59

NR

61

NR

Relative change, estimation based on model (%)

-24.5% (-44.2 to 2.3)1

High dose (50mg twice a day)

Smith 2020

57

Mean (SD):
7.0 (3.2)

61

Mean (SD):
14.5 (2.3)

-7.5 (-8.51 to -6.49)

57

NR

61

NR

Relative change, estimation based on model (%)

-46.0%

(-60.4 to -26.4)1

1.Results that are reported by using an estimated model are reported in the summary but are not further evaluated by the means of GRADE, as it was not clear how the used confounders were chosen. 

Table 11. Cough frequency (coughs per hour) at 24 weeks in patients with unexplained/refractory chronic cough after gefapixant vs. placebo treatment

 

Intervention

Control

 

 

N

Effect

N

Effect

Mean difference (95%CI)

Medium dose (15mg twice a day)

McGarvey (2022)

415

Mean (SD):
8.1 (NR)

419

Mean (SD):
8.3 (NR)

-0.2 (NR)1

 

 

Mean reduction (95%CI), estimated by model:

57% (53 to 62)

 

Mean reduction (95%CI), estimated by model:

57% (53 to 62)

Relative change, estimation based on model (%)

 

14.64% (1.43 to 26.07)2

High dose (45mg twice a day)

McGarvey (2022)

409

Mean (SD):
6.8 (NR)

419

Mean (SD):
3.3 (NR)

-3.5 (NR)1

 

 

Mean reduction (95%CI), estimated by model:

63% (59 to 67)

 

Mean reduction (95%CI), estimated by model:

57% (53 to 62)

Relative change, estimation based on model (%)

 

1.14 (-14.02 to 14.27)2

1. Results that do not report measures of dispersion such as confidence intervals and standard deviation are not further evaluated by means of GRADE.
2.Results that are reported by using an estimated model are reported in the summary but are not further evaluated by the means of GRADE, as it was not clear how the used confounders were chosen. 

*Responders: change ³ 1.3 points per week
NR: not reported

 

Search and select

A systematic review of the literature was performed to answer the following question(s):

What is the effectiveness and safety of neuromodulatory drugs compared to a control to treat adult patients with unexplained/refractory chronic cough?

 

Table 1. PICO

Patients

Patients (≥18 years old) with unexplained/refractory chronic cough for a minimum of 8 weeks

Intervention

neuromodulatory drugs (opiates, opioids (codeine specifically), gabapentin, pregabalin, tricyclic antidepressants, gefapixant), given for at least two weeks

Control

placebo

Outcomes

cough-specific quality of life, cough severity, cough frequency,

Other selection criteria

Study design: systematic reviews and randomized controlled trials

Follow-up: at least two weeks after start of treatment

Studies focusing on groups with co-morbidities (like asthma) only were excluded

Relevant outcome measures

The guideline panel considered cough-specific quality of life, cough severity and cough frequency as critical outcome measures for decision making; and no outcome measures were defined as important outcome measures for decision making.

 

The guideline panel defined the outcome measures as follows:

 

1. Cough-specific quality of life, measured by:

  • Cough Quality of Life Questionnaire (CQLQ); a 28-items questionnaire where higher score indicates worse cough-related quality of life;
  • Leicester Cough Questionnaire (LCQ): a 19-items scale where higher scores indicate a better cough-related quality of life.
  • St. George respiratory questionnaire: a 50-items questionnaire, with scores from 0 to 100 and where higher scores indicate more limitations.
  • Other cough-specific questionnaires as defined in the included studies.

2. Cough severity, measured by:

  • Cough severity diary (CSD): as defined by the included study or score of patients cough severity within the last 24 hours on three domains: cough frequency, cough intensity, and impact of cough on life and sleep. Range 0 to 10 per domain, the sum of CSD scores represents the severity of cough where a higher score indicates worse outcome (Wang, 2019).
  • Visual Analogue Scale (VAS): range 0 to 100 point; higher score indicates higher severity.
  • Cough symptom score (CSS): questionnaire with a range 0 to 5 points; higher score indicates more severe cough.
  • Other cough severity measurements as defined in the included studies.

3. Cough frequency: as defined in the included studies

 

The guideline panel defined clinical relevance boundaries as follows:

1. Cough specific quality of life

  • CQLQ: minimal important difference of 13 points (Wang, 2019).
  • LCQ: minimal important difference of 1.3 points (Wang, 2019).
  • St. George respiratory questionnaire: minimal important difference of 4 points (Wang, 2019).

2. Cough severity

  • Cough severity diary: mean difference of 10%.
  • VAS: minimal important difference of at least 10 points.
  • Cough symptom score: minimal important difference of 10% in score (0.5 points).

3. Cough frequency (per hour, 24 hours or as defined by studies): minimal important mean difference of 30% compared to control group (McGarvey, 2023; Smith, 2020).

 

Standardized mean difference (SMD’s) are also reported. The guideline defined SMD’s of >0.5 clinically relevant.

 

Search and select (Methods)

Initially, the outcome of the search reported in the ERS guideline of Chronic cough (Morice, 2020) was used. Three studies were included. Additionally, this search was updated by a medical information specialist using the following bibliographic databases: Embase.com and Ovid/Medline. Gefapixant was added to this search strategy. Both databases were searched from 2018 to 24 June 2024 for systematic reviews, RCTs and observational studies. Systematic searches were completed using a combination of controlled vocabulary/subject headings (e.g., Emtree-terms, MeSH) wherever they were available and natural language keywords. The overall search strategy was derived from two primary search concepts: (1) chronic cough and (2) neuromodulary agents. Duplicates were removed using EndNote software. After deduplication a total of 156 records were imported for title/abstract screening. Initially, 20 studies were selected based on title and abstract screening. After reading the full text, 16 studies were excluded (see the exclusion table under the tab ‘Evidence tabellen’), and four studies were included.

  1. Adeli SH, Beigi AM, Ahmadpour S, Habibi MA, Pashaei MR, Sharifipour E, Shakeri M, Asghari A. Effects of Pregabalin as a Neural Pathway Inhibitor for the Treatment of Resistant Subacute and Chronic Cough: A Pilot Clinical Trials Study. Rev Recent Clin Trials. 2023;18(4):269-274. doi: 10.2174/0115748871262516230919070559. PMID: 37888808.
  2. McGarvey LP, Birring SS, Morice AH, Dicpinigaitis PV, Pavord ID, Schelfhout J, Nguyen AM, Li Q, Tzontcheva A, Iskold B, Green SA, Rosa C, Muccino DR, Smith JA; COUGH-1 and COUGH-2 Investigators. Efficacy and safety of gefapixant, a P2X3 receptor antagonist, in refractory chronic cough and unexplained chronic cough (COUGH-1 and COUGH-2): results from two double-blind, randomised, parallel-group, placebo-controlled, phase 3 trials. Lancet. 2022 Mar 5;399(10328):909-923. doi: 10.1016/S0140-6736(21)02348-5. PMID: 35248186.
  3. McGarvey L, Sher M, Shvarts YG, Lu S, Wu WC, Xu P, Schelfhout J, La Rosa C, Nguyen AM, Reyfman PA, Afzal AS. The Efficacy and Safety of Gefapixant in a Phase 3b Trial of Patients with Recent-Onset Chronic Cough. Lung. 2023 Apr;201(2):111-118. doi: 10.1007/s00408-023-00606-w. Epub 2023 Mar 6. PMID: 36879087; PMCID: PMC10115701.
  4. Morice AH1, Menon MS, Mulrennan SA, Everett CF, Wright C, Jackson J, Thompson R. Opiate therapy in chronic cough. Am J Respir Crit Care Med. 2007 Feb 15;175(4):312-5.
  5. Morice AH, Millqvist E, Bieksiene K, Birring SS, Dicpinigaitis P, Domingo Ribas C, Hilton Boon M, Kantar A, Lai K, McGarvey L, Rigau D, Satia I, Smith J, Song WJ, Tonia T, van den Berg JWK, van Manen MJG, Zacharasiewicz A. ERS guidelines on the diagnosis and treatment of chronic cough in adults and children. Eur Respir J. 2020 Jan 2;55(1):1901136. doi: 10.1183/13993003.01136-2019. Erratum in: Eur Respir J. 2020 Nov 19;56(5):1951136. doi: 10.1183/13993003.51136-2019. PMID: 31515408; PMCID: PMC6942543.
  6. Smith JA, Kitt MM, Morice AH, Birring SS, McGarvey LP, Sher MR, Li YP, Wu WC, Xu ZJ, Muccino DR, Ford AP; Protocol 012 Investigators. Gefapixant, a P2X3 receptor antagonist, for the treatment of refractory or unexplained chronic cough: a randomised, double-blind, controlled, parallel-group, phase 2b trial. Lancet Respir Med. 2020 Aug;8(8):775-785. doi: 10.1016/S2213-2600(19)30471-0. Epub 2020 Feb 25. PMID: 32109425.
  7. Ryan NM1, Birring SS, Gibson PG. Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trial. Lancet. 2012 Nov 3;380(9853):1583-9.
  8. Vertigan AE, Kapela SL, Ryan NM, Birring SS, McElduff P, Gibson PG. Pregabalin and Speech Pathology Combination Therapy for Refractory Chronic Cough: A Randomized Controlled Trial. Chest. 2016 Mar;149(3):639-48.

Risk of Bias table

Study reference

 

(first author, publication year)

Was the allocation sequence adequately generated?

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Definitely yes

Probably yes

Probably no

Definitely no

Was the allocation adequately concealed?

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Definitely yes

Probably yes

Probably no

Definitely no

Blinding: Was knowledge of the allocated

interventions adequately prevented?

 

Were patients blinded?

 

Were healthcare providers blinded?

 

Were data collectors blinded?

 

Were outcome assessors blinded?

 

Were data analysts blinded?

 

Definitely yes

Probably yes

Probably no

Definitely no

Was loss to follow-up (missing outcome data) infrequent?

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Definitely yes

Probably yes

Probably no

Definitely no

Are reports of the study free of selective outcome reporting?

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Definitely yes

Probably yes

Probably no

Definitely no

Was the study apparently free of other problems that could put it at a risk of bias?

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Definitely yes

Probably yes

Probably no

Definitely no

Overall risk of bias

If applicable/necessary, per outcome measure

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

LOW

Some concerns

HIGH

 

Morice, 2007

Probably yes;

 

Reason: No RoB reported by ERS guideline (Morice, 2020)

Probably yes;

 

Reason: No RoB reported by ERS guideline (Morice, 2020)

Probably yes;

 

Reason: No RoB reported by ERS guideline (Morice, 2020)

Probably yes;

 

Reason: No RoB reported by ERS guideline (Morice, 2020)

Probably yes;

 

Reason: No RoB reported by ERS guideline (Morice, 2020)

Probably yes;

 

Reason: No RoB reported by ERS guideline (Morice, 2020)

LOW

As reported by ERS guideline (Morice, 2020)

Ryan, 2012

Probably yes;

 

Reason: No RoB reported by ERS guideline (Morice, 2020)

Probably yes;

 

Reason: No RoB reported by ERS guideline (Morice, 2020)

Probably yes;

 

Reason: No RoB reported by ERS guideline (Morice, 2020)

Probably yes;

 

Reason: No RoB reported by ERS guideline (Morice, 2020)

Probably yes;

 

Reason: No RoB reported by ERS guideline (Morice, 2020)

Probably yes;

 

Reason: No RoB reported by ERS guideline (Morice, 2020)

LOW

 

As reported by ERS guideline (Morice, 2020)

Vertigan, 2016

Probably yes;

 

Reason: No RoB reported by ERS guideline (Morice, 2020)

Probably yes;

 

Reason: No RoB reported by ERS guideline (Morice, 2020)

Probably yes;

 

Reason: No RoB reported by ERS guideline (Morice, 2020)

Probably yes;

 

Reason: No RoB reported by ERS guideline (Morice, 2020)

Probably yes;

 

Reason: No RoB reported by ERS guideline (Morice, 2020)

Probably no;

 

Reason:
ERS guideline (Morice, 2020) reports: “No comparison to pregabalin or placebo alone. Mean cough duration is longer in the placebo group (151 months) than in the pregabalin group (94 months). Mean baseline

LCQ score is higher in the placebo group (12.3) than in the pregabalin group (10.8).”

LOW

 

As reported by ERS guideline (Morice, 2020)

Adeli, 2023

Probably yes;

 

Reason: ‘randomly divieded'; nog further reported

Probably yes;

 

Reason: ‘Randomized double blind trial’; not further reported

Probably yes;

 

Reason: ‘Randomized double blind trial’; not further reported

Definitely yes;

 

Reason: no missing data reported

Probably yes;

 

Reason: All outcome measures mentioned in the methods paragraph were addressed

 

Probably yes;

Reason: not noticed

LOW

McGarvey, 2022

Definitely yes:

 

Reason: ‘by a centralised interactive voice or

web response system’; computer generated

Definitely yes:

 

Reason:
‘by a centralised interactive voice or

web response system’

Definitely yes:

 

Reason:
‘patients and all personnel involved with the conduct and the

interpretation of the study were masked’

Probably yes:

Reason:
missing data reported and not imputed, but similar over groups

Definitely yes:

 

Reason:

All outcomes of interest are reported

Probably no;

Reason: Sponsoring Merck & Co

Some Concerns

McGarvey, 2023

Definitely yes:

Reason:
‘by a centralized interactive response technology system. The

randomization schedule was computer generated.’

Definitely yes:

Reason:
‘by a centralized interactive response technology system. The

randomization schedule was computer generated.’

Definetely yes:

 

Reason:
‘participants and all personnel

involved with the conduct and the interpretation of

the study were blinded to study treatment’

Probably yes:

Reason:
missing data reported and not imputed, but similar over groups

Definitely yes:

 

Reason:

All outcome measures mentioned in the methods paragraph were addressed

Probably no;

Reason: Sponsoring Merck & Co

Some Concerns

Smith, 2020

Definitely yes:

Reason:
‘by a centralized interactive response technology system. The

randomization schedule was computer generated.’

Definitely yes:

Reason:
‘by a centralized interactive response technology system. The

randomization schedule was computer generated.’

Definetely yes:

 

Reason:
‘participants and all personnel

involved with the conduct and the interpretation of

the study were blinded to study treatment’

Probably yes:

Reason:
missing data reported and not imputed, but similar over groups

Definitely yes:

 

Reason:

All outcomes of interest are reported

Probably no;

Reason: Sponsoring Merck & Co

Some Concerns

 

Table of excluded studies

Reference

Reason for exclusion

Bali V, Kardos P, Page C, Rogliani P, Calzetta L, Adriano A, Byrne A, Adeyemi A, Frederickson A, Schelfhout J. Systematic literature review of treatments used for refractory or unexplained chronic cough in adults. Ann Thorac Med. 2024 Jan-Mar;19(1):56-73. doi: 10.4103/atm.atm_105_23. Epub 2024 Jan 25. PMID: 38444993; PMCID: PMC10911236.

Systematic review with more recent searchdate available.

Chuang MH, Chen IW, Chen JY, Kang FC, Ho CN, Wu SC, Yew M, Lan KM, Hung KC. Efficacy and safety of gefapixant for chronic cough: a meta-analysis of randomised controlled trials. Eur Respir Rev. 2023 May 17;32(168):220219. doi: 10.1183/16000617.0219-2022. PMID: 37197770; PMCID: PMC10189640.

Systematic review with more recent searchdate available.

Kum E, Patel M, Diab N, Wahab M, Zeraatkar D, Chu DK, O'Byrne PM, Guyatt GH, Satia I. Efficacy and Tolerability of Gefapixant for Treatment of Refractory or Unexplained Chronic Cough: A Systematic Review and Dose-Response Meta-Analysis. JAMA. 2023 Oct 10;330(14):1359-1369. doi: 10.1001/jama.2023.18035. PMID: 37694849; PMCID: PMC10495930.

Wrong study objective (this article focusses specifically on dosis response models, rather than reporting outcome measurements). Systematic review with more recent searchdate available.

O’Hare, C., Rahman, T., & Williams, N. T. (2020). Treatment of chronic refractory cough in adults: focus on neuromodulators and other therapeutic modalities. Journal of Pharmacy Technology, 36(6), 251-264.

Wrong study design (narrative review).

Ramadan A, El-Samahy M, Elrosasy A, Al-Tawil M, Abdelaziz A, Soliman MA, Abouzid M. Safety and efficacy of P2X3 receptor antagonist for the treatment of refractory or unexplained chronic cough: A systematic review and meta-analysis of 11 randomized controlled trials. Pulm Pharmacol Ther. 2023 Dec;83:102252. doi: 10.1016/j.pupt.2023.102252. Epub 2023 Sep 9. PMID: 37678663.

Relevant studies were included individually:
Klein (2022): excluded - wrong population (healthy males), wrong intervention (no stable  treatment dose for two weeks);
Friedrich (2020): excluded - wrong ppopulation (healthy males);
McGarvey (2022): included;
McGarvey (2023): excluded - wrong intervention (sivopixant);
Morice (2021): excluded - wrong intervention (no stable treatment period for two weeks);
Martinez (2021): excuded - wrong population (IPF);
Nimi (2022): excluded - wrong intervention (sivopixant);
Morice (2019): excluded - wrong intervention (treatment period < 2 weeks);
Smith (2020 s1/s2): excluded - wrong intervention (no stable treatment dose for two weeks);
Smith (2020 s3): included;
Abdulqawi (2015): excluded: study results before cross-over not available.

Martinez FJ, Afzal AS, Smith JA, Ford AP, Li JJ, Li Y, Kitt MM; Chronic Cough in IPF Study Group. Treatment of Persistent Cough in Subjects with Idiopathic Pulmonary Fibrosis (IPF) with Gefapixant, a P2X3 Antagonist, in a Randomized, Placebo-Controlled Clinical Trial. Pulm Ther. 2021 Dec;7(2):471-486. doi: 10.1007/s41030-021-00162-9. Epub 2021 Jun 21. PMID: 34152585; PMCID: PMC8589896.

Wrong study population (IPF).

Zhang M, Zhu Y, Dong R, Qiu Z. Gabapentin versus baclofen for treatment of refractory gastroesophageal reflux-induced chronic cough. J Thorac Dis. 2020 Sep;12(9):5243-5250. doi: 10.21037/jtd-2020-icc-002. PMID: 33145100; PMCID: PMC7578446.

Wrong study population? (GERC induced).

Abu-Zaid A, Aljaili AK, Althaqib A, Adem F, Alhalal DA, Almubarak AF, Aldughaither SM, Alghabban SA, Alfaraj G, Masoud AT, Alsuhaibani NA. Safety and efficacy of gefapixant, a novel drug for the treatment of chronic cough: A systematic review and meta-analysis of randomized controlled trials. Ann Thorac Med. 2021 Apr-Jun;16(2):127-140. doi: 10.4103/atm.ATM_417_20. Epub 2021 Apr 17. PMID: 34012479; PMCID: PMC8109686.

More recent review available.

Friedrich C, Francke K, Gashaw I, Scheerans C, Klein S, Fels L, Smith JA, Hummel T, Morice A. Safety, Pharmacodynamics, and Pharmacokinetics of P2X3 Receptor Antagonist Eliapixant (BAY 1817080) in Healthy Subjects: Double-Blind Randomized Study. Clin Pharmacokinet. 2022 Aug;61(8):1143-1156. doi: 10.1007/s40262-022-01126-1. Epub 2022 May 28. PMID: 35624408; PMCID: PMC9349145.

Wrong study population (healthy subjects). Wrong objective (pharmacokinetics).

Ghiasi, F., & Fatahi-Meiabadi, M. (2018). The effect of gabapentin on the number and severity of cough in the patients with resistant chronic cough. Journal of Isfahan Medical School, 36(490), 877-883.

Full english text not available (Iran).

Lee SP, Lee SM, Lee BJ, Kang SY. Effectiveness and Safety of Codeine and Levodropropizine in Patients With Chronic Cough. J Korean Med Sci. 2022 Sep 19;37(36):e275. doi: 10.3346/jkms.2022.37.e275. PMID: 36123964; PMCID: PMC9485064.

Wrong control (no placebo).

Morice A, Smith JA, McGarvey L, Birring SS, Parker SM, Turner A, Hummel T, Gashaw I, Fels L, Klein S, Francke K, Friedrich C. Eliapixant (BAY 1817080), a P2X3 receptor antagonist, in refractory chronic cough: a randomised, placebo-controlled, crossover phase 2a study. Eur Respir J. 2021 Nov 18;58(5):2004240. doi: 10.1183/13993003.04240-2020. PMID: 33986030; PMCID: PMC8607926.

Follow up duration (one week per dose of medication).

Morice, A. H., Kitt, M. M., Ford, A. P., Tershakovec, A. M., Wu, W. C., Brindle, K., ... & Wright, C. (2019). The effect of gefapixant, a P2X3 antagonist, on cough reflex sensitivity: a randomised placebo-controlled study. European Respiratory Journal, 54(1).

Wrong follow up duration/study design (measurements are taken several hours after tussive challenge -> it is not a trial with longer duration).

Niimi A, Sagara H, Kikuchi M, Arano I, Sato A, Shirakawa M, La Rosa C, Muccino D. A phase 3, randomized, double-blind, clinical study to evaluate the long-term safety and efficacy of gefapixant in Japanese adult participants with refractory or unexplained chronic cough. Allergol Int. 2022 Oct;71(4):498-504. doi: 10.1016/j.alit.2022.05.006. Epub 2022 Jun 23. PMID: 35752582.

Wrong comparison (other treatment is another dose of medication).

Niimi A, Saito J, Kamei T, Shinkai M, Ishihara H, Machida M, Miyazaki S. Randomised trial of the P2X3receptor antagonist sivopixant for refractory chronic cough. Eur Respir J. 2022 Jun 2;59(6):2100725. doi: 10.1183/13993003.00725-2021. PMID: 34649978; PMCID: PMC9176336.

Wrong interventin (sivopixant).

Smith JA, Kitt MM, Butera P, Smith SA, Li Y, Xu ZJ, Holt K, Sen S, Sher MR, Ford AP. Gefapixant in two randomised dose-escalation studies in chronic cough. Eur Respir J. 2020 Mar 20;55(3):1901615. doi: 10.1183/13993003.01615-2019. PMID: 31949115.

Wrong study duration.

Beoordelingsdatum en geldigheid

Publicatiedatum  : 08-06-2026

Beoordeeld op geldigheid  : 08-06-2026

Initiatief en autorisatie

Initiatief:
  • Nederlandse Vereniging van Artsen voor Longziekten en Tuberculose

Algemene gegevens

De ontwikkeling van deze richtlijnmodule werd ondersteund door het Kennisinstituut van de Federatie Medisch Specialisten (www.demedischspecialist.nl/kennisinstituut) en werd gefinancierd door de Stichting Kwaliteitsgelden Medisch Specialisten (SKMS).

 

De financier heeft geen enkele invloed gehad op de inhoud van de richtlijnmodule.

Samenstelling werkgroep

Voor het ontwikkelen van deze richtlijn is in 2023 een multidisciplinaire werkgroep ingesteld, bestaande uit vertegenwoordigers van relevante specialismen die betrokken zijn bij de zorg rondom chronische hoest bij volwassen patiënten. De richtlijn is gelijktijdig ontwikkeld met de richtlijn Hoesten in de palliatieve fase voor volwassenen.

 

Werkgroep

  • Dr. J.W.K. (Jan Willem) van den Berg (NVALT), longarts, voorzitter werkgroep
  • Drs. E.J. (Eva) Japenga (NVALT), longarts
  • Dr. J. (José) de Kluijver (NVALT), longarts
  • Dr. M. (Martijn) Goosens (NVALT), longarts
  • Dr. A.J. (Arent Jan) Michels (NVALT), longarts
  • Dr. D.A. (Derrek) Heuveling (NVKNO), KNO-arts
  • Dr. E.M.J.M. (Emke) van den Broek (NVKNO), KNO-arts
  • Dr. H.W.M. (Marleen) van Casteren (Verenso), specialist ouderengeneeskunde en kaderarts palliatieve zorg
  • Dr. N.J.J. (Eline) Neels (NHG), huisarts
  • Dr. F.Y.F.L. (Filip) de Vos (NIV), Internist-oncoloog en kaderarts palliatieve zorg

Klankbordgroep

  • Dr. E. (Ellen) Ricke, Longfonds, Sr. Beleidsadviseur
  • Dr. L.R. (Laura) de Baaij (NVMDL), maag-darm-lever arts
  • Dr. B.D.L. (Lidewij) Broekhuizen (NHG), huisarts
  • H. (Heleen) van Woudenberg (NVLF), stem- en hoestlogopedist 
  • M. (Marjolein) Frelier (NVLF), stem- en hoestlogopedist

Met ondersteuning van

  • Dhr. H. (Hans) Ket, Literatuurspecialist, Maatschap Van Dusseldorp, Delavux & Ket
  • Dr. A.C. (Anniek) van Westing, Adviseur, Kennisinstituut van de Federatie Medisch Specialisten
  • Dr. J.C. (José) Maas, Senior-adviseur, Kennisinstituut van de Federatie Medisch Specialisten
  • Drs. P.G. (Phylisha) Bloemen - van Heemskerken, Junior-adviseur, Kennisinstituut van de Federatie Medisch Specialisten
  • Dr. N.L. (Nikita) van der Zwaluw, Senior-adviseur, Kennisinstituut van de Federatie Medisch Specialisten, tot september 2025
  • Dr. M.S. (Matthijs) Ruiter, Senior-adviseur, Kennisinstituut van de Federatie Medisch Specialisten, vanaf september 2025

Belangenverklaringen

Een overzicht van de belangen van werkgroepleden en het oordeel over het omgaan met eventuele belangen vindt u in onderstaande tabel. De ondertekende belangenverklaringen zijn op te vragen bij het secretariaat van het Kennisinstituut van de Federatie Medisch Specialisten via secretariaat@kennisinstituut.nl.

 

Tabel Gemelde (neven)functies en belangen werkgroep 

Naam

Hoofdfunctie

Nevenwerkzaamheden

Persoonlijke Financiële Belangen

Persoonlijke Relaties

Extern gefinancierd onderzoek

Intell. belangen en reputatie

Overige belangen

Datum

Actie

Arent Jan

Michels

Longarts vrij gevestigd

Voorzitter MSB Anna ziekenhuis (onkostenvergoeding)
voorzitter Medische Staf Anna ziekenhuis (onbetaald)

geen vast dienstverband;

2024 geen betaald adviseurschap
2023 adviesbijeenkomst MSD

Geen

Geen

Hoestpolikliniek

Geen

31-12-2024

Geen restricties

Derrek Heuveling

Lid, NVKNO

Lid standpuntnota benigne speekselklierpathologie. NVKNO.
Lid Kerngroep Laryngologie NVKNO.
Penningmeester MSBMiddenNederland UA.
KNO-arts MMC.

Geen

Geen

Geen

Geen

Geen

11-05-2024

Geen restricties

Eline Neels

* Huisarts, praktijkhouder
* Kaderhuisarts Palliatieve zorg

* Medisch coördinator Hospice Clarahotje (betaald)
* Lid CPT (betaald)
* Commissie richtlijn: toedienen van vocht in de palliatieve fase (betaald)

-

Nee

-

-

-

5-05-2024

Geen restricties

Emke van den Broek

UMC Utrecht

Cluster laryngologie en kerngroep laryngologie

Niet van toepassing

Niet van toepassing

Niet van toepassing

Zie boven gedeeld belang wv kno

Niet van toepassing

26-03-2024

Geen restricties

Eva Japenga

Longarts
Haaglanden medisch centrum Den Haag

Geen

Geen

Geen

Geen

Geen

Eenmalige bijeenkomst MSD-adviesraad Gefapixant (12-4-23)

26-01-2024

Geen restricties

Jan Willem van den Berg (voorzitter)

longarts,
Isala ziekenhuis Zwolle

Geen

Geen

Geen

Ja:
* MSD - Demografie, kwaliteit van leven, Isala Hoestpoli - Projectleider
* MSD - The patient journey of patients diagnosed with unexplained and refractory chronic cough in the Isla – Projectleider.

 

Participatie BUS-P3-01 CALM-1-studie, GSK, P2X3 remmer

Hoestpoli; national lead Neurocough CRC ERS

Dienstverlening (adviesraad, spreker etc.)
2020 MSD

2021
GSK, MSD

2023   MSD

16-01-2024

Geen restricties. Onderwerpen van extern gefinancierd onderzoek komen niet terug in de uitgangsvragen.

Advies om te stoppen met dienstverlening aan MSD gedurende het richtlijntraject.

José de Kluijver

Longarts
Reinier de Graaf Ziekenhuis

Hoofdredactieraad NTvAAKI (onbetaald) – eind 2025 gestaakt

Niet van toepassing

Niet van toepassing

Niet van toepassing

Hoestpoli Reinier de Graaf Ziekenhuis

Niet van toepassing

5-01-2024

Geen restricties

Marleen van Casteren

Specialist ouderengeneeskunde bij St. Kalorama, betaald voor 0,8 FTE

Palliatief consulent bij PZNL voor ongeveer 1 uur per week
Gastdocent bij Hogeschool Arnhem Nijmegen voor ongeveer 12 uur per jaar
Beide worden betaald via mijn werkgever.

Geen

Geen

PALSED studie:
* Horizon2020 EU funding - Palliative sedation in patiënts with cancer - Geen projectleider

Geen

Geen

28-02-2024

Geen restricties

Martijn Goosens

longarts
Gelre Ziekenhuizen, CMSG (Coöperatie Medisch Specialisten Gelre)

Principal investigator meerdere trials, waaronder momenteel 1x studie chronische hoest met een P2X3-receptor antagonist.

Incidenteel adviesraden voor farmaceutische industrie, waaronder voor MSD mbt Gefapixant, 2x in 2023.

Geen actuele belangen

Neen

BUS-P3-01 CALM-1-studie:
* Bellus Health/GSK - Fase 3 onderzoek P2x3 - Projectleider

geen

geen

3-03-2024

Restricties op besluitvorming over P2X3-receptor antagonist.
Advies om adviesraden te staken gedurende de richtlijnontwikkeling.

Filip de Vos

Internist-oncoloog en kaderarts palliatieve zorg
UMC Utrecht

Geen

Geen

Geen

Ja:
* Foundation STOPbraintumors.org - Effect tumorgroei bij vrouwen met laaggradige gliomen - Projectleider
* BMS - BET remmer in combinatie met standaard chemoradiatie als eerste lijnsbehandeling bij glioblastoom - Geen projectleider
* Novartis - LAG remmer na falen immuuntherapie bij solide tumoren - Geen projectleider
* EORTC - Marizomib bij standaard chemoradiatie bij glioblastoom - Projectleider
* Pfizer en Ipsen Plharma - Compassionate use medicatie - Geen projectleider

Nee

BMS Advisory Board; Faculty member ESMO CNS tumors; Quality of Care commission Dutch Society of Medical Oncology;
Quality Assurance commission EORTC

20-12-2023

Geen restricties. Extern gefinancierd onderzoek buiten bestek van de richtlijn.

Klankbordgroep

 

 

 

 

 

 

 

 

  

Ellen Ricke (tot 2025)

Sr beleidsadviseur bij Longfonds

Niet van toepassing

Niet van toepassing

Niet van toepassing

Niet van toepassing

Niet van toepassing

Niet van toepassing

29-01-2024

Geen restricties

Pascale Lubbers

Beleidsadviseur Longfonds

Geen

Geen

Geen

Geen

Geen

Geen

21-05-2025

 

Laura de Baaij

Maag-darm-leverarts, Reinier de Graaf Gasthuis
Verlenen van medisch specialistische zorg op het gebied Maag-darm- en leverziekten, betaald.

Geen

Geen

Geen

Geen

Geen

Geen

24-10-2024

Geen restricties

Lidewij Broekhuizen

Huisarts/praktijkhouder in
Huisartspraktijk de Bongerd
7271 CG Borculo

Kaderarts astma COPD

Geen

Geen

Nee

Commissielid van de NHG-standaard COPD en Astma voor Volwassenen

Geen

22-08-2024

Geen restricties

Heleen van Woudenberg

Logopedie Voorburg - eigen praktijk
behandeling van patiënten met vnl. hoest-, stem- en globusklachten.
3 dagen per week, betaald

Geen

Geen

Geen

Geen

Geen

Geen

29-01-2025

Geen restricties

Marjolein Frelier

Logopedist
Logopedie Voorburg

gastlessen op scholen/opleidingen incidenteel

Geen

Geen

Geen

Geen

Geen

04-02-2025

Geen restricties 

Inbreng patiëntenperspectief

De werkgroep besteedde aandacht aan het patiëntenperspectief door afvaardiging van de Longfonds in de klankbordgroep en het uitnodigen van het Longfonds en de Patiëntenfederatie voor de knelpunteninventarisatie. De verkregen input is meegenomen bij het opstellen van de uitgangsvragen, de keuze voor de uitkomstmaten en bij het opstellen van de overwegingen. De conceptrichtlijn is tevens voor commentaar voorgelegd aan het Longfonds en de Patiëntenfederatie en de eventueel aangeleverde commentaren zijn bekeken en verwerkt.

 

Kwalitatieve raming van mogelijke financiële gevolgen in het kader van de Wkkgz

Bij de richtlijnmodule voerde de werkgroep conform de Wet kwaliteit, klachten en geschillen zorg (Wkkgz) een kwalitatieve raming uit om te beoordelen of de aanbevelingen mogelijk leiden tot substantiële financiële gevolgen. Bij het uitvoeren van deze beoordeling is de richtlijnmodule op verschillende domeinen getoetst (zie het stroomschema bij Werkwijze).

Module

Uitkomst raming

Toelichting

Module Hoestdempende middelen bij de behandeling van volwassen patiënten met chronische hoest.

Geen financiële gevolgen

Hoewel uit de toetsing volgt dat de aanbeveling(en) breed toepasbaar zijn (>40.000 patiënten), volgt ook uit de toetsing dat het geen nieuwe manier van zorgverlening of andere organisatie van zorgverlening betreft. Er worden daarom geen substantiële financiële gevolgen verwacht.

 

Werkwijze

Voor meer details over de gebruikte richtlijnmethodologie verwijzen wij u naar de Werkwijze. Relevante informatie voor de ontwikkeling/herziening van deze richtlijnmodule is hieronder weergegeven.

Zoekverantwoording

Literature search strategy

Algemene informatie

Database(s):  Ovid/Medline, Embase.com

Datum:  24 juni 2024

Periode: vanaf 2018

Talen: geen restrictie

 

Zoekopbrengst

 

OVID/MEDLINE

EMBASE

Ontdubbeld

SR

20

43

43

RCT

69

93

113

Totaal

89

136

156*

*in Rayyan

 

Zoekstrategieën

Ovid/Medline

Ovid MEDLINE(R) ALL <1946 to June 21, 2024>

1

"Bronchitis, Chronic"/ or (chronic*.ti,ab,kf. and ("Bronchitis"/ or exp "Cough"/ or cough.ti,ab,kf. or coughing.ti,ab,kf. or coughs.ti,ab,kf. or bronchitis.ti,ab,kf. or bronchitic.ti,ab,kf.))

27214

2

"Pregabalin"/ or exp "Antidepressive Agents, Tricyclic"/ or exp "Amitriptyline"/ or exp "Clomipramine"/ or exp "Desipramine"/ or exp "Dothiepin"/ or exp "Doxepin"/ or exp "Analgesics, Opioid"/ or exp "Imipramine"/ or exp "Lofepramine"/ or exp "Iprindole"/ or exp "Nortriptyline"/ or exp "Opipramol"/ or exp "Protriptyline"/ or exp "Trimipramine"/ or exp "Opium"/ or "Opiate Alkaloids"/ or exp "Morphine"/ or exp "Codeine"/ or "pholcodine".nm. or "gabapentin".nm. or "gefapixant".nm. or (acetexa or adapin or adepress or adepril or algerika or algopan or alivax or allegron or altapin or altilev or alyse or alzain or ambivalon or amilit or amimetilina or amineurin or amiplin or amiprin or amirol or amitid or amitril or amitrip* or amitryp* or amplit or amyline or amytril or amytriptilin* or amytriptylin* or amytryptilin* or amyzol or anaesthetic-analgesic* or anafranil* or anafranyl or analgesic-anaesthetic* or analgesic-anesthetic* or anapsique or andogablin* or anesthetic-analgesic* or antalin* or anten or antidep or antideprin or antitriptylin* or apo-imipramin* or aponal or aprion or astilin or ateben or atilev or avantyl or aventyl or averopreg or axalid or axual or balfibro or berkomin or biocalyptol or biopon or bonqat or brieka or chlomipramin* or chlorimipramin* or chloroimipramin* or chrytemin or clasica or clofranil or clomicalm or clomipramin* or clomipramine or clopress or codein* or codicaps or codipertussin or codyl or cofapon or collobel or concordin or convugabalin* or curatin or cyclobenzaprin* or damilen* or damitriptylin* or damylene or daypress or demethylimipramin* or deprelio or depresym or deprexan or deprinol or depsol or depsonil or deptran or desidox or desimipramin* or desipramin* or desipramin* or desitriptylin* or desmethylamitriptylin* or desmethyldoxepin or desmethylimipramin* or desmethylimipramine or despiramin* or dibenzepin* or dineurin or dinsidon or dismedox or dolica or domical or domipramin* or doneurin or dosulepin* or dothapax or dothiepin or doxal or doxepin* or dragonor or dropizol or duromorph or ecubalin* or elatrol* or elavil or enafon or endep or enovil or ensidon or epica or epimorph or epiron or equinorm or etafon or etafron or ethipramin* or ethnine or euplit or eusidon or expan or feprapax or flexeril or flucalyptol or folcodine or folkodin or fronil or gabalept or gabaliquid or gabanext or gaba-p or gabapen* or gabarol or gabatin or gabica or gablin* or gablovac or gabrika or galenphol or gamanil or gamonil or gantin or gavin or gefapixant or gefzuris or gialtyn or gilex or glonervya or glycodine or gralise or gromin or helimon or herphonal or hexgabalin* or homocodein* or hydiphen or idom or imavate or imidol or imipramide or imipramin* or imipramin* or imipramin* or imipramine or imiprin or imizin* or infantussin or insidon or iprindol* or irenypathic or janimin* or kabian or kaptin or kemirica or keneil or kineptia or lantron or laroxal or laroxyl or laudanon or laudanum or laudopan or lecaent or lentizol or lingabat or linprel or lofepramin* or lofepramine or lopramin* or lyfnua or lyribastad or lyric or lyrica or lyrineur or lyrolin* or lyzalon or maracex or mareen or martesiaor or martimil or maxgalin* or maximed or melipramin* or melitracen* or memin* or metapramin* or methylmorfin* or methylmorphin* or miketorin or miro or mirtazapin* or monochlorimipramin* or monochloroimipramin* or morfin* or morphia or morphin* or morphium or mystika or narcotic-analgesic or narcotic-analgesic* or narcotic-analgesics or narcotic-analgetic* or nebril or nepenthe or nervalin* or neugaba or neuragabalin* or neurega or neurica or neuristan or neurolin* or neurontin* or neurotonin* or neurovan or neurum or nisidan or noramitriptylin* or norimipramin* or noritren or norline or norpramin or norpramin* or norpramin* or norpress or nortimil or nortrilen* or nortriptilin* or nortriptylin or nortriptylin* or nortriptylin* or nortrix or nortryptilin* or nortryptylin* or nortylin* or norventyl or noveril or novopramin* or novoprotect or noxiptilin or nupentin or nuramed or nurogab or omnopon or opial or opiate* or opioid* or opipramol* or opium or opon or oposal or opso or ormal or ortrip or paden or pagadin or pagamax or painica or pamelor or pantopon* or papaveretum or pavacol or pavon or paxtibi or pentrofane or pentuss or pergadel or pertofran* or pertofrin or pertrofran or petrofran* or petylyl or pholcodex or pholcodin* or pinsaun or placil or plenica or pragiola or pramin* or pramolan or prebanal or prebel or prebictal or prebien or prefaxil or pregabalin* or pregalin* or pregalodos or pregamid or pregan or pregastar or pregatrend or pregavalex or pregeb or pregobin or prelin or prepadin* or presamin* or priga or primonil or proheptadien or prothiaden* or prothiadien* or prothiadin* or protiaden* or protriphylin* or protriptylin* or protriptylin* or protryptilin* or protryptylin* or provelyn or prudoxin or pryleugan or psychoforin* or psychostyl or qualitriptin* or quitaxon or redomex or regapen or remeron or rhotrimin* or sapilent or sarboten or sarotard or saroten or sarotena or sarotex or sefelsa or sendolor or sensaval or sensival or serada or sermonil or sertofren or servipramin* or silenor or sinequan* or sinquan* or skenan or stangyl or stelminal or sumontil or surmontil or sylvemid or symra or syneudon or syneydon or talpramin* or teperin or terepin or tetrapon or tianeptin* or tofranil or tofranil or trepilin* or tricyclic-antidepress* or tridep or trimepramin* or trimeprimin* or trimepropimin* or trimipramin* or trimipramin* or trimoprimin* or triopead or tripress or tripta or triptanol or triptil or triptizol or triptyl* or trofanil or trynol or tryptanol or tryptizol or trytomer or tussicalm or tydamin* or tymelyt or uxen or vanatrip or venefon or vivactil or vividyl or vronogabic or weifacodin or xablin* or xil or zoiral or zonalon).ti,ab,kf.

287168

3

1 and 2

403

4

limit 3 to yr="2018 -Current"

188

5

4 not ((exp "Adolescent"/ or exp "Child"/ or exp "Infant"/) not exp "Adult"/)

187

6

meta-analysis/ or meta-analysis as topic/ or (metaanaly* or meta-analy* or metanaly*).ti,ab,kf. or systematic review/ or cochrane.jw. or (prisma or prospero).ti,ab,kf. or ((systemati* or scoping or umbrella or "structured literature") adj3 (review* or overview*)).ti,ab,kf. or (systemic* adj1 review*).ti,ab,kf. or ((systemati* or literature or database* or data-base*) adj10 search*).ti,ab,kf. or ((structured or comprehensive* or systemic*) adj3 search*).ti,ab,kf. or ((literature adj3 review*) and (search* or database* or data-base*)).ti,ab,kf. or (("data extraction" or "data source*") and "study selection").ti,ab,kf. or ("search strategy" and "selection criteria").ti,ab,kf. or ("data source*" and "data synthesis").ti,ab,kf. or (medline or pubmed or embase or cochrane).ab. or ((critical or rapid) adj2 (review* or overview* or synthes*)).ti. or (((critical* or rapid*) adj3 (review* or overview* or synthes*)) and (search* or database* or data-base*)).ab. or (metasynthes* or meta-synthes*).ti,ab,kf.

754524

7

5 and 6

20

8

exp clinical trial/ or randomized controlled trial/ or exp clinical trials as topic/ or randomized controlled trials as topic/ or Random Allocation/ or Double-Blind Method/ or Single-Blind Method/ or (clinical trial, phase i or clinical trial, phase ii or clinical trial, phase iii or clinical trial, phase iv or controlled clinical trial or randomized controlled trial or multicenter study or clinical trial).pt. or random*.ti,ab. or (clinic* adj trial*).tw. or ((singl* or doubl* or treb* or tripl*) adj (blind$3 or mask$3)).tw. or Placebos/ or placebo*.tw.

2741694

9

5 and 8

84

10

9 not 7

69

 

Embase.com

No.

Query

Results

#11

#10 NOT #8

93

#10

#6 AND #9

112

#9

'randomized controlled trial'/exp OR random*:ti,ab OR (((pragmatic OR practical) NEAR/1 'clinical trial*'):ti,ab) OR ((('non inferiority' OR noninferiority OR superiority OR equivalence) NEAR/3 trial*):ti,ab) OR rct:ti,ab,kw

2214581

#8

#6 AND #7

43

#7

'meta analysis'/exp OR 'meta analysis (topic)'/exp OR metaanaly*:ti,ab OR 'meta analy*':ti,ab OR metanaly*:ti,ab OR 'systematic review'/de OR 'cochrane database of systematic reviews'/jt OR prisma:ti,ab OR prospero:ti,ab OR (((systemati* OR scoping OR umbrella OR 'structured literature') NEAR/3 (review* OR overview*)):ti,ab) OR ((systemic* NEAR/1 review*):ti,ab) OR (((systemati* OR literature OR database* OR 'data base*') NEAR/10 search*):ti,ab) OR (((structured OR comprehensive* OR systemic*) NEAR/3 search*):ti,ab) OR (((literature NEAR/3 review*):ti,ab) AND (search*:ti,ab OR database*:ti,ab OR 'data base*':ti,ab)) OR (('data extraction':ti,ab OR 'data source*':ti,ab) AND 'study selection':ti,ab) OR ('search strategy':ti,ab AND 'selection criteria':ti,ab) OR ('data source*':ti,ab AND 'data synthesis':ti,ab) OR medline:ab OR pubmed:ab OR embase:ab OR cochrane:ab OR (((critical OR rapid) NEAR/2 (review* OR overview* OR synthes*)):ti) OR ((((critical* OR rapid*) NEAR/3 (review* OR overview* OR synthes*)):ab) AND (search*:ab OR database*:ab OR 'data base*':ab)) OR metasynthes*:ti,ab OR 'meta synthes*':ti,ab

1040030

#6

#5 NOT ('conference abstract'/it OR 'editorial'/it OR 'letter'/it OR 'note'/it) NOT (('animal'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'nonhuman'/exp) NOT 'human'/exp)

521

#5

#4 NOT (('adolescent'/exp OR 'child'/exp) NOT ('adult'/exp OR 'aged'/exp OR 'middle aged'/exp))

817

#4

#1 AND #2 AND [2018-2024]/py

837

#3

#1 AND #2

1807

#2

'amitriptyline'/exp OR 'pregabalin'/exp OR 'tricyclic antidepressant agent'/exp OR 'clomipramine'/exp OR 'desipramine'/exp OR 'dosulepin'/exp OR 'doxepin'/exp OR 'narcotic analgesic agent'/exp OR 'imipramine'/exp OR 'lofepramine'/exp OR 'iprindole'/exp OR 'nortriptyline'/exp OR 'opipramol'/exp OR 'protriptyline'/exp OR 'trimipramine'/exp OR 'opiate'/exp OR 'morphine'/exp OR 'codeine'/exp OR 'pholcodine'/exp OR 'gabapentin'/exp OR 'gefapixant'/exp OR acetexa:ti,ab,kw OR adapin:ti,ab,kw OR adepress:ti,ab,kw OR adepril:ti,ab,kw OR algerika:ti,ab,kw OR algopan:ti,ab,kw OR alivax:ti,ab,kw OR allegron:ti,ab,kw OR altapin:ti,ab,kw OR altilev:ti,ab,kw OR alyse:ti,ab,kw OR alzain:ti,ab,kw OR ambivalon:ti,ab,kw OR amilit:ti,ab,kw OR amimetilina:ti,ab,kw OR amineurin:ti,ab,kw OR amiplin:ti,ab,kw OR amiprin:ti,ab,kw OR amirol:ti,ab,kw OR amitid:ti,ab,kw OR amitril:ti,ab,kw OR amitrip*:ti,ab,kw OR amitryp*:ti,ab,kw OR amplit:ti,ab,kw OR amyline:ti,ab,kw OR amytril:ti,ab,kw OR amytriptilin*:ti,ab,kw OR amytriptylin*:ti,ab,kw OR amytryptilin*:ti,ab,kw OR amyzol:ti,ab,kw OR 'anaesthetic analgesic*':ti,ab,kw OR anafranil*:ti,ab,kw OR anafranyl:ti,ab,kw OR 'analgesic anaesthetic*':ti,ab,kw OR 'analgesic anesthetic*':ti,ab,kw OR anapsique:ti,ab,kw OR andogablin*:ti,ab,kw OR 'anesthetic analgesic*':ti,ab,kw OR antalin*:ti,ab,kw OR anten:ti,ab,kw OR antidep:ti,ab,kw OR antideprin:ti,ab,kw OR antitriptylin*:ti,ab,kw OR 'apo imipramin*':ti,ab,kw OR aponal:ti,ab,kw OR aprion:ti,ab,kw OR astilin:ti,ab,kw OR ateben:ti,ab,kw OR atilev:ti,ab,kw OR avantyl:ti,ab,kw OR aventyl:ti,ab,kw OR averopreg:ti,ab,kw OR axalid:ti,ab,kw OR axual:ti,ab,kw OR balfibro:ti,ab,kw OR berkomin:ti,ab,kw OR biocalyptol:ti,ab,kw OR biopon:ti,ab,kw OR bonqat:ti,ab,kw OR brieka:ti,ab,kw OR chlomipramin*:ti,ab,kw OR chlorimipramin*:ti,ab,kw OR chloroimipramin*:ti,ab,kw OR chrytemin:ti,ab,kw OR clasica:ti,ab,kw OR clofranil:ti,ab,kw OR clomicalm:ti,ab,kw OR clomipramin*:ti,ab,kw OR clomipramine:ti,ab,kw OR clopress:ti,ab,kw OR codein*:ti,ab,kw OR codicaps:ti,ab,kw OR codipertussin:ti,ab,kw OR codyl:ti,ab,kw OR cofapon:ti,ab,kw OR collobel:ti,ab,kw OR concordin:ti,ab,kw OR convugabalin*:ti,ab,kw OR curatin:ti,ab,kw OR cyclobenzaprin*:ti,ab,kw OR damilen*:ti,ab,kw OR damitriptylin*:ti,ab,kw OR damylene:ti,ab,kw OR daypress:ti,ab,kw OR demethylimipramin*:ti,ab,kw OR deprelio:ti,ab,kw OR depresym:ti,ab,kw OR deprexan:ti,ab,kw OR deprinol:ti,ab,kw OR depsol:ti,ab,kw OR depsonil:ti,ab,kw OR deptran:ti,ab,kw OR desidox:ti,ab,kw OR desimipramin*:ti,ab,kw OR desipramin*:ti,ab,kw OR desitriptylin*:ti,ab,kw OR desmethylamitriptylin*:ti,ab,kw OR desmethyldoxepin:ti,ab,kw OR desmethylimipramin*:ti,ab,kw OR desmethylimipramine:ti,ab,kw OR despiramin*:ti,ab,kw OR dibenzepin*:ti,ab,kw OR dineurin:ti,ab,kw OR dinsidon:ti,ab,kw OR dismedox:ti,ab,kw OR dolica:ti,ab,kw OR domical:ti,ab,kw OR domipramin*:ti,ab,kw OR doneurin:ti,ab,kw OR dosulepin*:ti,ab,kw OR dothapax:ti,ab,kw OR dothiepin:ti,ab,kw OR doxal:ti,ab,kw OR doxepin*:ti,ab,kw OR dragonor:ti,ab,kw OR dropizol:ti,ab,kw OR duromorph:ti,ab,kw OR ecubalin*:ti,ab,kw OR elatrol*:ti,ab,kw OR elavil:ti,ab,kw OR enafon:ti,ab,kw OR endep:ti,ab,kw OR enovil:ti,ab,kw OR ensidon:ti,ab,kw OR epica:ti,ab,kw OR epimorph:ti,ab,kw OR epiron:ti,ab,kw OR equinorm:ti,ab,kw OR etafon:ti,ab,kw OR etafron:ti,ab,kw OR ethipramin*:ti,ab,kw OR ethnine:ti,ab,kw OR euplit:ti,ab,kw OR eusidon:ti,ab,kw OR expan:ti,ab,kw OR feprapax:ti,ab,kw OR flexeril:ti,ab,kw OR flucalyptol:ti,ab,kw OR folcodine:ti,ab,kw OR folkodin:ti,ab,kw OR fronil:ti,ab,kw OR gabalept:ti,ab,kw OR gabaliquid:ti,ab,kw OR gabanext:ti,ab,kw OR 'gaba p':ti,ab,kw OR gabapen*:ti,ab,kw OR gabarol:ti,ab,kw OR gabatin:ti,ab,kw OR gabica:ti,ab,kw OR gablin*:ti,ab,kw OR gablovac:ti,ab,kw OR gabrika:ti,ab,kw OR galenphol:ti,ab,kw OR gamanil:ti,ab,kw OR gamonil:ti,ab,kw OR gantin:ti,ab,kw OR gavin:ti,ab,kw OR gefapixant:ti,ab,kw OR gefzuris:ti,ab,kw OR gialtyn:ti,ab,kw OR gilex:ti,ab,kw OR glonervya:ti,ab,kw OR glycodine:ti,ab,kw OR gralise:ti,ab,kw OR gromin:ti,ab,kw OR helimon:ti,ab,kw OR herphonal:ti,ab,kw OR hexgabalin*:ti,ab,kw OR homocodein*:ti,ab,kw OR hydiphen:ti,ab,kw OR idom:ti,ab,kw OR imavate:ti,ab,kw OR imidol:ti,ab,kw OR imipramide:ti,ab,kw OR imipramin*:ti,ab,kw OR imipramine:ti,ab,kw OR imiprin:ti,ab,kw OR imizin*:ti,ab,kw OR infantussin:ti,ab,kw OR insidon:ti,ab,kw OR iprindol*:ti,ab,kw OR irenypathic:ti,ab,kw OR janimin*:ti,ab,kw OR kabian:ti,ab,kw OR kaptin:ti,ab,kw OR kemirica:ti,ab,kw OR keneil:ti,ab,kw OR kineptia:ti,ab,kw OR lantron:ti,ab,kw OR laroxal:ti,ab,kw OR laroxyl:ti,ab,kw OR laudanon:ti,ab,kw OR laudanum:ti,ab,kw OR laudopan:ti,ab,kw OR lecaent:ti,ab,kw OR lentizol:ti,ab,kw OR lingabat:ti,ab,kw OR linprel:ti,ab,kw OR lofepramin*:ti,ab,kw OR lofepramine:ti,ab,kw OR lopramin*:ti,ab,kw OR lyfnua:ti,ab,kw OR lyribastad:ti,ab,kw OR lyric:ti,ab,kw OR lyrica:ti,ab,kw OR lyrineur:ti,ab,kw OR lyrolin*:ti,ab,kw OR lyzalon:ti,ab,kw OR maracex:ti,ab,kw OR mareen:ti,ab,kw OR martesiaor:ti,ab,kw OR martimil:ti,ab,kw OR maxgalin*:ti,ab,kw OR maximed:ti,ab,kw OR melipramin*:ti,ab,kw OR melitracen*:ti,ab,kw OR memin*:ti,ab,kw OR metapramin*:ti,ab,kw OR methylmorfin*:ti,ab,kw OR methylmorphin*:ti,ab,kw OR miketorin:ti,ab,kw OR miro:ti,ab,kw OR mirtazapin*:ti,ab,kw OR monochlorimipramin*:ti,ab,kw OR monochloroimipramin*:ti,ab,kw OR morfin*:ti,ab,kw OR morphia:ti,ab,kw OR morphin*:ti,ab,kw OR morphium:ti,ab,kw OR mystika:ti,ab,kw OR 'narcotic analgesic':ti,ab,kw OR 'narcotic analgesic*':ti,ab,kw OR 'narcotic analgesics':ti,ab,kw OR 'narcotic analgetic*':ti,ab,kw OR nebril:ti,ab,kw OR nepenthe:ti,ab,kw OR nervalin*:ti,ab,kw OR neugaba:ti,ab,kw OR neuragabalin*:ti,ab,kw OR neurega:ti,ab,kw OR neurica:ti,ab,kw OR neuristan:ti,ab,kw OR neurolin*:ti,ab,kw OR neurontin*:ti,ab,kw OR neurotonin*:ti,ab,kw OR neurovan:ti,ab,kw OR neurum:ti,ab,kw OR nisidan:ti,ab,kw OR noramitriptylin*:ti,ab,kw OR norimipramin*:ti,ab,kw OR noritren:ti,ab,kw OR norline:ti,ab,kw OR norpramin:ti,ab,kw OR norpramin*:ti,ab,kw OR norpress:ti,ab,kw OR nortimil:ti,ab,kw OR nortrilen*:ti,ab,kw OR nortriptilin*:ti,ab,kw OR nortriptylin:ti,ab,kw OR nortriptylin*:ti,ab,kw OR nortrix:ti,ab,kw OR nortryptilin*:ti,ab,kw OR nortryptylin*:ti,ab,kw OR nortylin*:ti,ab,kw OR norventyl:ti,ab,kw OR noveril:ti,ab,kw OR novopramin*:ti,ab,kw OR novoprotect:ti,ab,kw OR noxiptilin:ti,ab,kw OR nupentin:ti,ab,kw OR nuramed:ti,ab,kw OR nurogab:ti,ab,kw OR omnopon:ti,ab,kw OR opial:ti,ab,kw OR opiate*:ti,ab,kw OR opioid*:ti,ab,kw OR opipramol*:ti,ab,kw OR opium:ti,ab,kw OR opon:ti,ab,kw OR oposal:ti,ab,kw OR opso:ti,ab,kw OR ormal:ti,ab,kw OR ortrip:ti,ab,kw OR paden:ti,ab,kw OR pagadin:ti,ab,kw OR pagamax:ti,ab,kw OR painica:ti,ab,kw OR pamelor:ti,ab,kw OR pantopon*:ti,ab,kw OR papaveretum:ti,ab,kw OR pavacol:ti,ab,kw OR pavon:ti,ab,kw OR paxtibi:ti,ab,kw OR pentrofane:ti,ab,kw OR pentuss:ti,ab,kw OR pergadel:ti,ab,kw OR pertofran*:ti,ab,kw OR pertofrin:ti,ab,kw OR pertrofran:ti,ab,kw OR petrofran*:ti,ab,kw OR petylyl:ti,ab,kw OR pholcodex:ti,ab,kw OR pholcodin*:ti,ab,kw OR pinsaun:ti,ab,kw OR placil:ti,ab,kw OR plenica:ti,ab,kw OR pragiola:ti,ab,kw OR pramin*:ti,ab,kw OR pramolan:ti,ab,kw OR prebanal:ti,ab,kw OR prebel:ti,ab,kw OR prebictal:ti,ab,kw OR prebien:ti,ab,kw OR prefaxil:ti,ab,kw OR pregabalin*:ti,ab,kw OR pregalin*:ti,ab,kw OR pregalodos:ti,ab,kw OR pregamid:ti,ab,kw OR pregan:ti,ab,kw OR pregastar:ti,ab,kw OR pregatrend:ti,ab,kw OR pregavalex:ti,ab,kw OR pregeb:ti,ab,kw OR pregobin:ti,ab,kw OR prelin:ti,ab,kw OR prepadin*:ti,ab,kw OR presamin*:ti,ab,kw OR priga:ti,ab,kw OR primonil:ti,ab,kw OR proheptadien:ti,ab,kw OR prothiaden*:ti,ab,kw OR prothiadien*:ti,ab,kw OR prothiadin*:ti,ab,kw OR protiaden*:ti,ab,kw OR protriphylin*:ti,ab,kw OR protriptylin*:ti,ab,kw OR protryptilin*:ti,ab,kw OR protryptylin*:ti,ab,kw OR provelyn:ti,ab,kw OR prudoxin:ti,ab,kw OR pryleugan:ti,ab,kw OR psychoforin*:ti,ab,kw OR psychostyl:ti,ab,kw OR qualitriptin*:ti,ab,kw OR quitaxon:ti,ab,kw OR redomex:ti,ab,kw OR regapen:ti,ab,kw OR remeron:ti,ab,kw OR rhotrimin*:ti,ab,kw OR sapilent:ti,ab,kw OR sarboten:ti,ab,kw OR sarotard:ti,ab,kw OR saroten:ti,ab,kw OR sarotena:ti,ab,kw OR sarotex:ti,ab,kw OR sefelsa:ti,ab,kw OR sendolor:ti,ab,kw OR sensaval:ti,ab,kw OR sensival:ti,ab,kw OR serada:ti,ab,kw OR sermonil:ti,ab,kw OR sertofren:ti,ab,kw OR servipramin*:ti,ab,kw OR silenor:ti,ab,kw OR sinequan*:ti,ab,kw OR sinquan*:ti,ab,kw OR skenan:ti,ab,kw OR stangyl:ti,ab,kw OR stelminal:ti,ab,kw OR sumontil:ti,ab,kw OR surmontil:ti,ab,kw OR sylvemid:ti,ab,kw OR symra:ti,ab,kw OR syneudon:ti,ab,kw OR syneydon:ti,ab,kw OR talpramin*:ti,ab,kw OR teperin:ti,ab,kw OR terepin:ti,ab,kw OR tetrapon:ti,ab,kw OR tianeptin*:ti,ab,kw OR tofranil:ti,ab,kw OR trepilin*:ti,ab,kw OR 'tricyclic antidepress*':ti,ab,kw OR tridep:ti,ab,kw OR trimepramin*:ti,ab,kw OR trimeprimin*:ti,ab,kw OR trimepropimin*:ti,ab,kw OR trimipramin*:ti,ab,kw OR trimoprimin*:ti,ab,kw OR triopead:ti,ab,kw OR tripress:ti,ab,kw OR tripta:ti,ab,kw OR triptanol:ti,ab,kw OR triptil:ti,ab,kw OR triptizol:ti,ab,kw OR triptyl*:ti,ab,kw OR trofanil:ti,ab,kw OR trynol:ti,ab,kw OR tryptanol:ti,ab,kw OR tryptizol:ti,ab,kw OR trytomer:ti,ab,kw OR tussicalm:ti,ab,kw OR tydamin*:ti,ab,kw OR tymelyt:ti,ab,kw OR uxen:ti,ab,kw OR vanatrip:ti,ab,kw OR venefon:ti,ab,kw OR vivactil:ti,ab,kw OR vividyl:ti,ab,kw OR vronogabic:ti,ab,kw OR weifacodin:ti,ab,kw OR xablin*:ti,ab,kw OR xil:ti,ab,kw OR zoiral:ti,ab,kw OR zonalon:ti,ab,kw

645172

#1

'chronic cough'/exp OR 'chronic bronchitis'/exp OR (chronic*:ti,ab,kw AND ('bronchitis'/de OR 'coughing'/exp OR cough:ti,ab,kw OR coughing:ti,ab,kw OR coughs:ti,ab,kw OR bronchitis:ti,ab,kw OR bronchitic:ti,ab,kw))

60162
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