Use of Specific Neuromodulators in the Treatment of Chronic Idiopathic Cough a Systematic Review

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Otolaryngol Head Neck Surg. Author manuscript; bachelor in PMC 2018 Feb 15.

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PMCID: PMC5813813

NIHMSID: NIHMS887282

Use of Specific Neuromodulators in the Handling of Chronic, Idiopathic Coughing: A Systematic Review

Seth K. Cohen

^aneKnuckles Voice Care Centre, Partitioning of Otolaryngology–Head & Neck Surgery, Knuckles University Medical Center, Durham, Due north Carolina, USA

Stephanie Misono

²Academy of Minnesota Department of Otolaryngology–Caput & Neck Surgery, Minneapolis, Minnesota, U.s.

Abstract

Objective

The goal of this systematic review was to examine the evidence for the apply of the neuromodulating agents, amitriptyline, gabapentin, pregabalin, and baclofen, in the management of chronic, idiopathic cough patients.

Information Sources

Online databases, including PubMed, Embase, Cochrane Review, and Spider web of Scientific discipline, and publications cited in bibliographies were used.

Review Methods

Literature was searched by the ii authors with a priori criteria for study selection.

Results

Eight relevant manufactures were identified, including 2 randomized controlled trials, 2 prospective cohort or case-serial designs with sequent patients, 1 retrospective instance serial of consecutive patients, 1 retrospective instance series whose consecutive status was non known, and ii instance reports of 6 and 2 patients, respectively. Improvements in cough-specific quality of life were noted in the randomized controlled trials. Cough severity was reduced in studies that measured this upshot measure. In the remaining studies, cough symptoms were less after neuromodulator treatment.

Determination

Benefit from neuromodulator handling with amitriptyline, gabapentin, pregabalin, and baclofen in chronic, idiopathic cough patients was demonstrated. Further investigations using objective and subjective outcome measures are needed as well every bit studies exploring optimal dose, length of treatment, and relapse rates posttreatment.

Keywords: chronic cough, idiopathic cough, neuromodulator, handling, amitriptyline, gabapentin, pregabalin, baclofen

Chronic cough has significant public wellness implications. The cantankerous-sectional prevalence of cough in a community population sample was 17.ix%.ⁱ In National Ambulatory Medical Intendance Survey information, coughing was the most common patient-reported symptom prompting a doctor visit.² In 2010, over-the-counter costs for cough and common cold remedies were $4 billion.ⁱⁱⁱ Patients may accept associated concrete problems such as syncope, urinary incontinence, chest paint, sleep disturbance, and impaired quality of life (QOL), with 53% of chronic cough patients having depressive symptoms.^4–7

Although a sequential, algorithmic approach can ameliorate a chronic cough, some patients' cough persists.⁸ Amidst specialty cough clinics, between 12% and 42% of patients accept a refractory, idiopathic cough despite evaluation and handling trials related to reflux, pulmonary disease, sinonasal affliction, and stopping angiotensin-converting enzyme inhibitors (ACEI), among other mutual pathology.^ix,10 The role of laryngeal irritability and the concept of idiopathic, chronic coughing as a sensory neuropathy provide new potential treatment options for this challenging clinical problem.^eleven Some patients accept evidence of a neuropathy involving the recurrent or superior laryngeal nerve on laryngoscopy or laryngeal electromyography.^12,13 Similar to patients with other neuralgias, chronic coughing patients have been reported to have a trigger phenomenon where particular stimuli can induce coughing episodes.¹⁴ Consequently, the apply of neuromodulating agents, such equally amitriptyline, gabapentin, baclofen, and pregabalin, oftentimes used in the management of chronic, neuropathic pain, may provide some benefit in chronic cough patients.^eleven–14 This is further supported by information showing that in salubrious volunteers, baclofen raised the cough threshold during exposure to irritants such equally capsaicin.^xv

Systematically examining the evidence regarding the use of neuromodulating medications in the treatment of idiopathic chronic cough patients may provide insights about their utility and a amend agreement of the literature regarding this emerging management strategy. Current systematic reviews have focused on acute cough, reflux handling in coughing without master lung disease, and pharmacologic and nonpharmacologic interventions in respiratory and nonrespiratory illness, to proper noun a few.^sixteen–18 Thus, this systematic review was conducted to assess the literature concerning the use of amitriptyline, gabapentin, baclofen, and pregabalin in the management of idiopathic, chronic cough.

Methods

An online search strategy completed on April ane, 2012, was developed in conjunction with an information specialist at the Duke University Medical Center Library and University of Minnesota Medical Center Library. The PubMed, Exerpta Medica Database (Embase), Web of Science, and Cochrane Review databases were searched to place potentially relevant articles using the post-obit combinations: (cough or bronchitis or respiratory tract infections or idiopathic cough or postviral coughing or irritable larynx or pharyngeal diseases or laryngeal diseases or postviral vagal neuropathy) and (elavil or amitriptyline or neurontin or gabapentin or lyrica or pregabalin or dibenzocycloheptenes or cyclohexanecarboxylic acids or gamma-aminobutryic acid). The terms dibenzocycloheptenes, cyclohexanecarboxylic acrid, gamma-aminobutryic acid, or dimethylamines were 1 level college in the MeSH tree and were incorporated to augment the search and aid in identifying relevant articles.

The inclusion criteria included articles in English language, involving adults with cough of unknown etiology of at least 6 weeks' duration, and the use of the neuromodulating agents of interest in cough treatment. Articles involving patients younger than 18 years, fauna studies, acute coughing less than 6 weeks' elapsing, cough due to other conditions (such as reflux disease, sinonasal pathology, allergy, pulmonary diseases, ACEIs), and other treatment modalities were excluded. All resulting abstracts were assessed by at least i reviewer to eliminate duplicate publications and unrelated topics. All relevant article bibliographies were examined to place additional publications. Authors were contacted when needed to obtain full-text publications or publications in English language.

A information abstraction class was developed a priori to facilitate consistent data extraction. The reference, country of origin, medications studied, medication regimen, diagnoses included, definition of chronic cough, report blueprint, type of study outcome, number and blazon of participants, study setting, follow-up data, study inclusion and exclusion criteria, definition of treatment success, and medication side furnishings were noted for each report. All relevant studies were independently evaluated past 2 reviewers and consensus reached for written report inclusion. Report validity was assessed qualitatively past describing the study design, including consecutive status of patients for nonrandomized controlled studies, type of study outcome, whether study outcome was chosen a priori, and inclusion/exclusion criteria for patient enrollment.

Because of the small numbers of studies, variability in the quality of studies, and inconsistent reporting of results, formal meta-analysis was not conducted. A qualitative analysis was performed. In studies in which patients with symptoms other than cough were included, data for the individuals with chronic cough were extracted.^12,13,19 Patients with associated symptoms of throat immigration, chronic laryngitis, dysphonia, laryngeal spasm, globus, dysphagia, and pain were included if they also presented with an idiopathic chronic cough. Mean follow-upwardly fourth dimension was presented for all subjects included in a given study if it was non possible to determine mean follow-up time merely for the subjects of relevance to this review.

Results

Forty-six potentially relevant studies were identified by the search strategy (Figure 1). 30-eight were excluded because they were review articles without new data, used salubrious volunteers, did not involve the utilize of i of the neuromodulating agents of interest, were letters to the editor without new data, and/or included multiple concurrent handling modalities in conjunction with a neuromodulator. In particular, two articles were excluded because they involved the use of neuromodulators in patients with chronic coughing and postviral vagal neuropathy (of which some patients had a cough as role of their symptom circuitous) but likewise included other treatment modalities, making it difficult to appraise the specific impact of the neuromodulating agent.^20,21 Although an English translation of an Italian article involving baclofen in 2 patients with a chronic cough was obtained, it was excluded as each patient had pulmonary affliction that may have rendered his or her cough not idiopathic.²²

Flowchart for study pick.

Eight relevant articles were included for farther analysis (Table 1). Two articles were randomized controlled trials (RCTs). The RCT involving gabapentin was placebo controlled, and study participants and enquiry staff were blinded (investigators assessing the consequence were not blinded).²³ The other prospective RCT compared amitriptyline with codeine, just whether clinicians or patients were blinded could not be ascertained.²⁴ Two studies were a prospective cohort or case serial design of consecutive patients.^xiii,14 One study was a retrospective example series of consecutive patients.^xix Whether consecutive patients were evaluated in the other retrospective case series is not articulate.¹² The final studies were a case series of half-dozen patients whose consecutive status was non known and a instance study of ii patients who underwent a placebo crossover handling algorithm.^25,26

Tabular array 1

Study Blazon, Intervention, Sample Size, and Patient Age Range of Included Studies

Author	Study Type	Intervention	N	Patient Age, y
Bastian et alxiv	Prospective cohort, sequent patients	10 mg amitriptyline daily for 21 days	8 male person, iv female	Median 52; range, twenty–75
Norris and Schweinfurth12	Retrospective example series, consecutive unknown	25–100 mg amitriptyline, failures treated with gabapentin or pregabalin, unknown duration of treatment	1 male, 7 female	Mean 67.3; range, 52–77; median 71.5
Lee and Woo13	Prospective case series, sequent	Gabapentin 100–900 mg daily over 4 weeks, nonresponders finish at 4 weeks, responders continue dose for 3 months and and so taper, intolerant carbamazepine 100 mg tid	ix male person, 17 female	Mean (SD) 51.2 (17.0); range, xiv–lxxx; median 50.5
Halum et alnineteen	Retrospective cohort, sequent	Pregabalin 75–150 mg bid	2 male, 3 female person	Mean (SD) 51.vi (17.1); range, 34–76; median 52
Jeyakumar et al24	Randomized controlled trial; randomized by nautical chart numbers and presence of nasal allergies	Amitriptyline 10 mg daily vs codeine/guaifenesin x mL every 6 hours for 10 days	Amitriptyline: viii male person, 7 female; codeine: 5 male person, 8 female	Amitriptyline: median 54.vi Codeine: 49.7
Ryan et al23	Randomized, double-blinded, placebo-controlled trial. Note that patients and research staff were blinded; investigators assessing outcomes were not blinded. Block randomization, sex stratified	Gabapentin (300-1800 mg daily) vs placebo for x weeks. Included ane calendar week taper on, 8 weeks handling, 1 week taper off	Gabapentin: 12 male, 20 female; placebo: 10 male, 20 female person	Gabapentin: mean (SD) 62.vii (fourteen.0) Placebo: mean (SD) 60.9 (12.9)
Mintz and Lee25	Case serial, consecutive condition unknown	Gabapentin 100 mg bid to 1600 mg daily dose	6 females	59; range, 34–77
Dicpinigaitis and Rauf26	Case report with placebo crossover handling, sequent status unknown	Baclofen 10 mg tid	ii female	37, 69

Two studies were supported past funding from national research agency grants.^nineteen,23 The remaining studies did non comment on financial disclosures, which could reverberate the absence of specific funding for the studies or variable journal publishing guidelines.

All studies included patients with cough of at least half-dozen weeks' duration (Tabular array two). Included patients had a negative evaluation for reflux, pulmonary disease, and allergy/postnasal drip in 5 studies,^{12,fourteen,19,23,24} ACEI use in 3 studies,^12,14,24 tobacco use in four studies,^14,23,24,26 and psychiatric affliction in 2 studies.^14,19 In the study past Lee and Woo,¹³ near patients had a previous workup, including reflux handling, modified barium consume, computed tomography, magnetic resonance imaging, and pH monitoring, only information technology was not known whether these had been systematically performed across all patients. In the study by Mintz and Lee,²⁵ not all patients had evaluations for postnasal drip but did accept prior reflux treatment trials and investigations for pulmonary disease in some style, and they were not on an ACEI. Ane of the 2 patients in Dicpingaitis and Rauf²⁶ had nonspecific interstitial changes on radiographic studies of the chest but was included as handling trials with prednisone and albuterol had failed.

Table ii

Diseases Excluded, Follow-up, and Cough Duration of Included Studies

Author	Diseases Excluded	Follow-up	Duration of Coughing
Bastian et alxiv	Smoking ACEI Postnasal drip Pulmonary disease Reflux Psychogenic cough	xx days afterward completing 21-day trial	Median elapsing 24 months
Norris and Schweinfurth12	Laryngeal cancer ACEI Postnasal drip Pulmonary disease Reflux	Mean twenty.4 months; range, two–61 months	8 weeks
Lee and Woo13	Prior workup included (not systematic or uniform across patients): Modified barium consume CT MRI pH testing	Hateful follow-up unknown	Median 7.5 months; range, ane.5–240 months
Halum et alnineteen	Pulmonary illness Allergy Psychiatric affliction Reflux, cricopharyngeal dysfunction	Hateful 6.8 months; range, v–20 months for all enrolled in written report	Median 11 months; range, 4–36 months
Jeyakumar et al24	Reflux Smoking Pulmonary disease ACEI Postnasal baste	10-twenty-four hours trial	All patients amitriptyline: months; codeine: 6 months; median 15.1 eleven.4 months
Ryan et al23	Smoking Pulmonary disease or infection (including asthma, productive cough) Reflux Postnasal drip ACEI Pregnant/breastfeeding Dumb liver role	Primary outcome assessed subsequently 8 weeks of treatment; additional assessment 4 weeks later on drug stopped	Gabapentin: median 36 months; interquartile range, xviii–150 Placebo: median 48 months; interquartile range, 18–156
Mintz and Lee25	Not systematic or uniform across patients: Reflux, asthma, postnasal drip exclusion mentioned in the abstract; manuscript mentions prior workup, including modified barium swallow written report, CT, MRI, and pH monitoring	12 months	Median 7.5 months; range, one.5–240 months; mean (SD) 31.iv, (57.4)
Dicpinigaitis and Rauf26	Smoking one patient failed oral inhalers, oral steroids, antihistamine/decongestants, ranitidine 1 patient failed oral steroid and albuterol, had interstitial infiltrates that were nonspecific	xiv days later terminate of 28-day handling catamenia (14 days of baclofen and 14 days of placebo)	1-year and 10-yr history of cough

Diverse outcome measures were used to make up one's mind the clinical response to neuromodulating agents (Table three). The RCTs employed both cough-specific QOL instruments as well as patient cocky-report, and Ryan et al²³ besides incorporated an objective coughing monitor to evaluation cough frequency. Ii studies categorized treatment response based on self-reported percent improvement.^14,24 Halum et al¹⁹ employed a self-report cough severity rating on a vi-indicate Likert calibration. Ii other studies noted binary improvement or not based on patient self-study to assess outcome, with Mintz and Lee²⁵ using clinician reports to assess handling response.^12,13 Ii studies besides assessed objective result using the capsaicin cough challenge, in which patients' cough threshold in response to the chemical tussive capsaicin was assessed.^23,26 Whether the result variables were chosen a priori was non clear in 2 studies^xiii,25 but appeared to be decided a priori in the remaining 6 studies.^{12–xiv,19,23,24}

Table 3

Upshot Measure, Results, and Side Effects of Included Studies

Author	Issue	Results	Side Effects
Bastian et al14	Patient cocky-report on 0% to 100% calibration	10 of 12 patients had ≥50% response; 6 of viii patients ≥50% response >20 days off amitriptyline. One patient had no do good with amitriptyline but did with subsequent gabapentin.	None noted
Norris and Schweinfurth12	Patient self-report (yeah or no)	6 of 8 improved	Dry mouth in 30% of all enrolled patients
Lee and Woothirteen	Symptom response (unclear if clinician or patient written report), yes or no	69% improved. Variable responses depending on presence of neuropathy upon laryngeal electromyography	Dizziness or somnolence in eighteen% of all enrolled patients
Halum et al19	Troublesome cough, patient self-report on 6-point Likert scale	3 of 5 improved cough severity	Sedation in 80%, of whom one-half tolerated, half discontinued medication
Jeyakumar et al24	Patient cocky-report % reduction in coughing frequency and severity; cough quality-of-life (QOL) questionnaire	13 of xv in amitriptyline group had l% comeback as compared with one of 13 in codeine/guaifenesin group; improved QOL scores associated with amitriptyline	No mention of agin effects
Ryan et al23	Primary end point: cough-specific quality of life Secondary end points: coughing severity, capsaicin cough reflux sensitivity, coughing frequency using objective cough monitor, urge-to-cough score, laryngeal dysfunction score	Improved cough-specific QOL scores, cough severity, cough frequency compared with placebo; no outcome on capsaicin cough reflex sensitivity. Effects not sustained afterward handling cessation	Adverse events reported in 31% of gabapentin group: confusion, dizziness, dry oral fissure, fatigue, and/or nausea; blurred vision, headache, and retention loss reported in simply 1 patient each; adverse events reported in 10% of placebo group
Mintz and Lee25	Clinician assessment	iii of 6 complete resolution, 1 10% to 15% improved, 1 probably improved, ane decreased frequency and intensity of cough	Fatigue in 17%, drowsiness for i week in 17%
Dicpinigaitis and Rauf26	Capsaicin coughing challenge, subject diary (frequency and severity of cough)	Both patients had decreased cough frequency and severity and increased cough threshold	No patients reported adverse reactions

Neuromodulator treatment improved cough symptoms (Tabular array 3). In the RCTs involving amitriptyline and gabapentin, improvements were seen in cough-specific QOL as well every bit a reduction in coughing severity.^23,24 Capsaicin cough reflex sensitivity did non change significantly with neuromodulator treatment in the RCT involving gabapentin, but in the baclofen report, capsaicin cough reflux sensitivity increased past 3 and 5, doubling concentrations in ii patients.²³ Halum et al^nineteen also demonstrated an improvement in patients' cough severity ratings. When pct improvement in cough symptoms was used as an consequence measure, betwixt 86.seven% and 83.three% of patients experienced at least a l% response.^14,24 Using a binary rating of comeback, rates of treatment response ranged from 69% to 80%, and treatment response was greater in patients with some show of motor or sensory neuropathy.^12,xiii In the report using clinician-assessed response, 50% of patients had complete resolution and the remaining l% some degree of comeback in coughing.²⁵ Iii studies likewise examined the fourth dimension to symptom improvement and found a maximum benefit after a median of 5 days (range, 1–10 days), hateful time of two months (range, 1–5 months), and handling event inside iv weeks.^12,14,23 Although Bastian et al¹⁴ observed improved cough at least 20 days off amitriptyline in 75% of patients, Ryan et al²³ did not note a sustained treatment response after discontinuing gabapentin.

Side effects may event from neuromodulator treatment of cough (Tabular array 3). Reported side effects included dry out mouth, sedation, and dizziness.^12,13,19,25 Rates of patient-reported side effects in chronic cough patients ranged from 80% to 0% with varying degrees of severity.^{12–14,19,25} In one study, in that location was no specific mention of a patient query for adverse effects.²⁴ The RCT involving gabapentin found side effects in 31% of patients taking gabapentin vs 10% in the placebo group, including blurred vision, confusion, dizziness, dry mouth, fatigue, headache, memory loss, and nausea or tum pain.²³

Give-and-take

Because of the significant health intendance burden associated with cough, examining handling modalities, particularly for patients with chronic, idiopathic cough, is of import. Diverse changes occur that may promote a cough, including plasticity of the cough pathways due to alterations in nervus transmitter release, the excitability of neurons, or the structure of neurons equally well as tissue remodeling in the airway mucosa.²⁷ The use of neuromodulators, such as amitriptyline, gabapentin, baclofen, and pregabalin, has recently been identified as a promising treatment modality for chronic idiopathic cough patients. This systematic review examined the information in the current literature regarding this management strategy.

There was considerable variation in the type and quality of articles describing handling of idiopathic, chronic cough using the neuromodulators of involvement. Although two RCTs were identified, bug regarding sample size calculation could not be fully assessed.^23,24 The remaining studies included not-controlled prospective series of consecutive patients, a non-controlled retrospective analysis of consecutive patients, and a retrospective case series and two instance reports for which the sequent status is not known.^{12–fourteen,xix,25,26} Although all included studies involved patients with cough of at to the lowest degree half dozen weeks who had other etiologies ruled out, articles varied in the prior investigations and prior treatment trials of studied patients. Variability regarding how detail diagnoses, such as reflux or asthma, were ruled out may have introduced some heterogeneity.

Despite the use of different outcome measures, benefit from amitriptyline, gabapentin, baclofen, and pregabalin was demonstrated. Patients experienced improvements in cough-specific QOL and cough severity measures.^19,23,24,26 In add-on, more than two-thirds of patients had some handling response, and more than 80% had at least a l% reduction in cough symptoms.^12–xiv,24 However, some questions remain, such as the optimal dose, length of treatment, time to maximum benefit, and symptom relapse rates after handling. Although Bastian et al^xiv found that 6 of eight patients had a treatment response more than twenty days off amitriptyline treatment, Ryan et al²³ did not notice a sustained response four weeks after cessation of gabapentin. Both Norris and Schweinfurth¹² and Lee and Woo¹³ found higher handling response in patients with bear witness of a motor or sensory neuropathy based on laryngeal test and/or laryngeal electromyography (EMG). Several reports included patients with additional symptoms attributable to laryngeal irritability, such as globus, pharynx clearing, and laryngospasm.^{12,thirteen,19} Further studies examining the role of laryngeal neuropathy and the influence of additional symptoms of laryngeal irritability on treatment response may help place patient subsets likely to do good from neuromodulator handling of their cough. Comparing studies of the handling response from amitriptyline, gabapentin, baclofen, and pregabalin are also needed.

Although the current literature shows promise of these neuromodulators in the treatment of cough, further investigation is warranted. In considering future trials, Birring²⁸ has identified important issues that should be addressed. Coughing should be the primary symptom, and considering cough often persists despite treatment for reflux and rhinitis, patients with these comorbidities as well as those with idiopathic cough could be suitable subjects.²⁸ Since cough reflux sensitivity is affected past age and sex, command groups should be matched for these variables.²⁹ The potential side effects from neuromodulators may make blinding hard. Thus, comparing to codeine might be more advantageous than placebo and would allow an assessment of handling response and side effects between handling arms.²⁸ Last, a combination of outcome measures could be used to measure out various coughing characteristics. Cough monitors, such every bit the Leicester cough monitor, objectively measure out the coughing frequency.^thirty The coughing reflex sensitivity to inhaled tussive agents objectively measures the reflex cough, but correlation to coughing symptoms is poor.^31,32 Cough symptom scales record patients' self-written report of coughing severity. Diverse cough-specific QOL measures are likewise bachelor to evaluate the physical and psychosocial impact of cough.³³

Continued investigation into the mechanism of activity of chronic coughing and its treatment is essential. One family unit of coughing receptors, the transient receptor potential (TRP) nociceptors, appears upregulated in patients with chronic cough and may mediate the hypersensitive cough response in such patients.³⁴ In beast models, blocking this receptor inhibited the coughing reflux from capsaicin and citric acid.³⁵ The TRP receptor may be a useful target for future therapeutic trials.

Certain methodological limitations must be addressed. The evaluation of diseases for exclusion varied between studies and, in some cases, potentially among written report participants. Some other concern is the potential for publication bias in which studies that did non find a do good from amitriptyline, gabapentin, baclofen, or pregabalin were not published. Although amitriptyline, gabapentin, baclofen, and pregabalin are dissimilar drugs with various and potentially unknown mechanisms of activity, they are interventions that have been used, similar to the treatment of chronic pain, in managing chronic, idiopathic cough. Consequently, these neuromodulating agents were selected as the subject of this systematic review of chronic cough, a condition with significant public wellness implications. The variation in the study design, medication, dosing, and outcomes did not allow for a formal meta-analysis. This systematic review demonstrated credible benefit in the apply of neuromodulating agents for patients with chronic cough, and further studies are needed.

Conclusion

Although the type and quality of written report varied, do good from amitriptyline, gabapentin, baclofen, and pregabalin was noted in patients with chronic, idiopathic cough. Time to come investigations should explore comparative evaluations of unlike dosing and medication protocols, incorporate control groups equally well as objective and subjective validated consequence measures, and examine treatment elapsing and symptom relapse after handling abeyance.

Acknowledgments

The authors thank Judith Stanke, University of Minnesota Medical Middle Library, and Brandi Tuttle, Knuckles University Medical Center Library, for their assistance in designing and executing the search strategy.

Sponsorships: This study was supported in part by the American Academy of Otolaryngology–Caput & Cervix Surgery Cochrane Travel Grant to the 19th Cochrane Colloquium.

Funding source: None.

Footnotes

Author Contributions

Seth M. Cohen, conception, design, data analysis, writing, concluding approval; Stephanie Misono, conception, design, data analysis, writing, final approval.

Disclosures

Competing interests: None.

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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5813813/

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