Table 4.

Centrally acting antitussive medications for refractory chronic cough.

Study author/s	Type of study	N	Drug treatment dose and duration	Primary efficacy outcome	Primary study results and conclusion/s	Adverse/side effects	Methodological weaknesses
Bastian et al., 2006 [26]	Prospective cohort, consecutive patients	12	10 mg amitriptyline daily for 21 days	Patient self-report on 0% to 100% scale	10 of 12 patients had ≥50% response; 6 of 8 patients ≥50% response >20 days off amitriptyline. One patient had no benefit with amitriptyline but did with subsequent gabapentin (dose not given).	No side effects.	No placebo comparator group. No objective cough measures. Small sample size.
Jeyakumar et al., 2006 [86]	Randomized controlled trial.	28	10 mg Amitriptyline daily, n = 15 vs. 10–100 mg/5 ml or 10 ml codeine/guaifenesin every 6 awake hours, n = 13 for 10 days	Patient self-report % reduction in cough frequency and severity; cough quality-of-life (QOL) questionnaire	13 of 15 (87%) in amitriptyline group had ≥50% cough improvement compared with 1 of 13 (8%) in codeine/guaifenesin group, NNT = 1.3; improved CQLQ scores were associated with amitriptyline (change in score from baseline 24.5 compared to guaifenesin-codeine of 2.9), p = 0.0007.	None reported.	No objective cough measure, no placebo control group comparator. No power calculation. No baseline characteristics comparison between groups. High risk of selection bias (patients where randomized by chart numbers and presence of nasal allergies).
Norris & Schweinfurth, 2010 [87]	Retrospective case series	10^	Amitriptyline used as the first-line neuromodulator, n = 5 (median dose 25 mg/day, maximum dose 100 mg/day). Patients with nonresponse or intolerable side effects to amitriptyline were prescribed gabapentin, n = 3 (median dose 300 mg/tid). Gabapentin only, n = 1. No neuromodulator, n = 1.	Patient self-reported subjective improvement (Yes/No).	The mean time from the initiation of therapy to improvement or resolution of symptoms was 2 months (range, 1 to 5 months). 86% of patients with evidence of motor neuropathy responded to the neuromodulator therapy, versus zero response among those without evidence of motor neuropathy. It was thought that the patient’s condition must first be medically optimized with control of laryngopharyngeal reflux disease, postnasal drip, and/or discontinuation of potentially causative medications.	3 (30%) of patients taking either amitriptyline or gabapentin experienced a dry mouth. One (10%) patient reported fatigue on a dose of 75 mg amitriptyline.	Retrospective chart review. No objective measures of improvement. Small sample size. No comparator group.
Lee & Woo, 2005 [25]	Case series	28	Gabapentin 100–900 mg daily over 4 weeks, nonresponders stop at 4 weeks, responders continue dose for 3 months and then taper, intolerant carbamazepine 100 mg tid	Symptom response (unclear if patient or clinician reported).	Nineteen (68%) patients had a clinically positive response to gabapentin and those patients identified with superior or recurrent laryngeal neuropathy responded even more favorably (80%) In the workup for laryngeal neuropathy videostroboscopy and L-EMG are invaluable tools in diagnosis.	Five patients (17.8%) complained of dizziness or somnolence that caused them to taper or discontinue the medication.	Prior workup included however, not systematic or uniform across patients. Efficacy outcome not clear or objective. No control group for comparison.
Mintz & Lee, 2006 [101]	Case series	6	Gabapentin 100 mg bid to 1600 mg daily dose	Clinician assessment	5 of 6 patients had either complete resolution or substantial improvement in cough. One patient relapsed on therapy and gained control by an increase in dose.	Fatigue in 1 (17%), drowsiness for 1 week in 1 (17%).	Treated patients according the ADP and when patients were refractory to this gabapentin was trialed. Prior workup criteria and subsequent treatments not explained. No objective cough measure. No comparator group. Small sample size.
Ryan et al., 2012 [89]	Randomized, double-blind, placebo-controlled parallel trial	62	Gabapentin 6 capsules (1800 mg) daily (n = 32) versus matching placebo 6 capsules daily (n = 30).*	Primary outcome was cough QOL measured by the LCQ. Secondary outcomes were cough severity (VAS), cough frequency (LCM®). Capsaicin cough reflex sensitivity testing was used to assess treatment mechanism. Other outcomes were urge to cough score and laryngeal dysfunction score (LDQ).	Gabapentin significantly improved cough-specific quality of life compared with placebo-between group difference in LCQ score during treatment period 1.80, 95% CI 0.56–3.04; p = 0.004; clinical improvement in LCQ score of >1.3 (the smallest change in score regarded as clinically meaningful) for the gabapentin group compared to the placebo group (20/27 [74.1%] versus 12/26 [46.2%]; p = 0.038). Number needed to treat = 3.58. The treatment of refractory chronic cough with gabapentin is both effective and well tolerated. These positive effects suggest that central reflex sensitization is a relevant mechanism in refractory chronic cough.	Side effects occurred in both groups with the most common in the Gabapentin group being nausea, stomach pain [4/17], dizziness [3/17], and fatigue [3/17]. For the Placebo group most common side effects were dizziness [1/6], nausea, stomach pain [2/6], and fatigue [1/6].	Non-validated short-duration cough frequency recording during the capsaicin cough reflex sensitivity test rather than 24 h cough frequency recording was used; however, any potential bias was controlled by using a placebo group. No long-term treatment or follow-up of patients. However, gabapentin treatment effect had not reached a plateau by 8 weeks suggesting that longer-term treatment may be required for some patients. A risk versus benefits analysis would need to be done for individual patients.
Halum et al., 2009 [102]	Retrospective chart review of consecutive patients prescribed pregabalin for symptoms of LSN including CC.	5	Pregabalin 75–150 mg bid	Pre- and posttreatment questionnaires asking patients to rate symptoms on a scale from 0 to 5	3 of 5 improved cough severity None of the patients developed drug tolerance effects over time.	Sedation in 4 (80%), of whom half tolerated, half discontinued medication	Retrospective chart review. No objective measures of improvement. Small sample size. No comparator group.
Vertigan et al., 2016 [90]	Randomized, double-blind, placebo-controlled parallel trial	40	Speech pathology (SPT) with 300 mg pregabalin (PREG) treatment (n = 20) versus SPT with placebo (PLAC) treatment (n = 20).	Primary outcomes were cough QOL measured by the LCQ, cough severity (VAS), cough frequency (LCM®). Secondary outcomes were capsaicin cough reflex sensitivity, urge to cough score and laryngeal function measures.	Cough severity, cough frequency and cough QOL improved in both groups. The degree of improvement in the LCQ was greater with SPT + PREG (mean difference; 3.5 [95% CI 1.1 to 5.8] than for placebo (SPT + PLAC), p = 0.024. The degree of improvement in the cough severity (VAS) was greater with SPT + PREG (mean difference; 25.1, [95% CI 10.6 to 39.6] than for placebo (SPT+PLAC), p = 0.002. The degree of improvement in cough frequency was greater with SPT+PREG (mean difference; 11.2 [95% CI 2.6 to -19.7] than for placebo (SPT + PLAC), p = 0.013. Combined SPT+PREG treatment is beneficial in reducing symptoms in refractory CC with the benefit continuing for at least 4 weeks after cessation of pregabalin. Results are consistent with sensory hyperresponsiveness being a mechanism of refractory CC.	Side effects occurred in both groups with the most common in the SPT + PREG group being dizziness [9/20], fatigue [7/20] and cognitive changes [6/20]. These resolved after pregabalin was ceased. For the SPT + PLAC group gastrointestinal [7/20], and fatigue [6/20] were the most common side effects reported.	Low recruitment rate. No comparison to pregabalin alone or placebo alone. More than one primary outcome. Baseline imbalance across groups for cough duration-longer for SPT + Placebo group.
Morice et al., 2007 [88]	Randomized double-blind placebo-controlled crossover trial	27	5 mg twice daily slow-release morphine sulfate or matching placebo for 4 weeks of treatment. An open-label extension of the study was done in a subgroup of patients using 10 mg twice daily for 3 months.	Primary efficacy outcome was cough QOL measured by the LCQ. Secondary outcomes were citric acid cough challenge (C2 and C5) and cough severity assessed on a scale of 0 to 9 recorded in a daily diary entry.	There was a significant improvement in LCQ with morphine treatment compared to placebo. Mean score for LCQ was 13.3 (2.5) at baseline, 13.5 (2.7) on placebo (NS) and 15.5 (2.7) on morphine (p < 0.01 vs. baseline, p < 0.02 vs. placebo). The average improvement in total LCQ score was higher than 2.56 which has been demonstrated to be clinically significant. Maximum benefit for responders was achieved by Day 5 and this benefit was sustained through the 4 weeks of the study. There was no change in the citric cough reflex sensitivity test. At the end of 3 months, there was a similar improvement in cough between the 5 and 10 mg groups.	Most common side effects noted were constipation in 10 (40%) and drowsiness in 7 (25%) patients. In the subgroup who increased morphine dose to 10 mg twice daily the incidence of drowsiness doubled.	Not strictly refractory chronic cough cohort, 16 from 27 patients had a productive cough. Studies of psychoactive drugs like morphine cannot be completely blinded as the patient is conscious of the affects a quarter of the patients in this study noted mild and transient sedation. Long-term effects of low-dose morphine in patients with CC were not assessed in this study. Strength of this study was that it was a controlled trial of opiate therapy in clinically significant cough.
Dion et al., 2017 [112]	Prospective case series on consecutive patients	16	Tramadol 50 mg every 8 h as needed.	Efficacy outcomes were cough severity index (CSI) and Leicester Cough Questionnaire (LCQ) at ≥14 days of treatment. A number of investigations and review by a gastroenterologist or speech-language therapist determined subjects meeting diagnostic criteria for neurogenic cough.	All subjects reported at least some improvement in their cough symptoms. CSI scores improved from 23 to 14 and LCQ scores improved from 74 to 103 (p = 0.003 and p = 0.005, respectively) pre- vs. posttreatment in patients with neurogenic cough. The results of this study suggest that tramadol warrants additional evaluation as a treatment of neurogenic cough.	Four (25%) patients reported somnolence and were recommended to reduce their dosage or frequency to combat symptoms.	Limitations of a preliminary study including small sample size and no control group for comparison. Variable treatment time from 15 to 1029 days. Used LCQ scoring was not consistent with the validated 19-item LCQ score. Here LCQ was assessed on scale of 0 to 133 with 0 most severe. Some follow-up assessments were short at 2 weeks.