Inclusion Criteria
* Chest radiograph or computed tomography (CT) of the thorax within the last 1 year not demonstrating any abnormality considered to be significantly contributing to the refractory chronic cough in the opinion of the Principal Investigator
* Have a diagnosis of refractory chronic cough or unexplained cough for at least one year according to the American College of Chest Physicians guidelines
* Have a score of ≥ 40mm on the Cough Severity VAS at Screening.
* Women of child-bearing potential must agree to use 2 forms of acceptable birth control and make no donation of eggs from Screening through the end of the 8-week study period. Acceptable birth control methods include established use of oral, injected, or implanted hormonal methods of contraception; intrauterine device (IUD) or intrauterine system (IUS); tubal ligation; or male sterilization. Double-barrier method (diaphragm for female subject and condom for male partner with spermicidal) satisfies the requirement for 2 forms of acceptable birth control. When concordant with the preferred lifestyle of the subject, true and complete abstinence (not periodic abstinence) is acceptable.
* Male subjects and their partners of child-bearing potential must use 2 methods of acceptable birth control, 1 of which must be a barrier method, and make no donation of sperm from Screening until 3 months after the last dose of study drug at the end of 8 weeks.
* Have provided written informed consent.
* Are willing and able to comply with all aspects of the protocol.
Exclusion Criteria
* Current smoker (cigarettes, e-cigarettes or marijuana) or former smokers who have smoked within the past 12 months.
* Former smokers with \> 20 pack-year history of smoking
* Ongoing treatment with an ACE-inhibitor that is considered as the potential cause of a subject's cough or requiring treatment with an ACE-inhibitor during the study or within 12 weeks prior to the Screening/Baseline Visit (Day -14 to Day 0).
* FEV1/FVC \< 60%.
* History of upper or lower respiratory tract infection or recent significant change in pulmonary status within 4 weeks of the Screening/Baseline Visit (Day -14 to Day 0)
* History of opioid use specifically prescribed for chronic cough within 2 weeks of the Screening/Baseline Visit (Day -14 to Day 0). Use of opioids for other indications (for example, to treat pain) is permitted.
* History of baclofen use specifically prescribed for chronic cough within 2 weeks of the Screening/Baseline Visit (Day -14 to Day 0). Use of baclofen for other indications (for example, to treat spasticity) is permitted.
* Diagnosis of COPD, bronchiectasis, interstitial lung disease or cystic fibrosis
* Presence of an untreated or undertreated cause for the patient's chronic cough (as determined by the treating/referring physician per ACCP guidelines). e.g. uncontrolled asthma, GERD or post-nasal drainage that could potentially explain the patient's chronic cough.
* Requiring concomitant therapy with prohibited medications (outlined below)
* Treatment with any pharmaceutical or biological investigational therapy (excluding coronavirus disease of 2019 (COVID) vaccination and COVID related monoclonal antibody therapy)
* Participation in another clinical trial that does not allow co-enrollment within 4 weeks prior to the Screening/Baseline Visit (Day -14 to Day 0)
* Total bilirubin, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> 3x the upper limit of normal (ULN) during screening.
* Serum creatinine \< 30 mL/min, hemodialysis or peritoneal dialysis
* Advanced liver disease as defined by the presence of cirrhosis and/or signs of portal hypertension
* History of previous hypersensitivity or intolerance to Duloxetine \& Amitriptyline (patients who have previously been on either amitriptyline or duloxetine for chronic cough or other reasons and have tolerated the medication will be offered participation regardless of previous response to therapy).
* Currently pregnant or breastfeeding female subject.
* Presence of any medical condition or disability that the investigators believe could interfere with the assessment of safety or efficacy in this trial or compromise the safety of the subject.
* Planned or anticipated major surgical procedure or other activity that would interfere with the subject's ability to comply with protocol-mandated assessments (e.g., extended travel) during the subject's participation in the study.
* Currently taking either another SSRI, SNRI or MAO inhibitor which the patient cannot safely discontinue at least 2 weeks prior to the screening period.
* The following therapies are prohibited from 2 week prior to the Screening/Baseline Visit (Day -14 to Day 0) through the end of the 8-week blinded treatment period.
* Opioids (of any kind including tramadol \& codeine) specifically prescribed for treatment of cough
* Dextromethorphan
* Guaifenesin
* Chlorpheniramine
* Benzonatate
* Trazodone
* Pregabalin or gabapentin prescribed for chronic cough
* 1% tetracaine lollipops prescribed for chronic cough
* 4% nebulized lidocaine solution prescribed for chronic cough
* Any SSRI (selective serotonin reuptake inhibitor) e.g. bupropion, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine.
* Any SNRI (serotonin-norepinephrine reuptake inhibitor) e.g. venlafaxine, desvenlafaxine, milnacipran, levomilnacipran
* Any Tricyclic antidepressant e.g. doxepin, clomipramine, nortriptyline, imipramine, protriptyline, amoxapine, trimipramine
* Any MAO (Monoamine oxidase) inhibitor. e.g. phenelzine, selegiline, isocarboxacid or tranylcypromine
* Patients who were previously prescribed either amitriptyline or duloxetine for chronic cough will be eligible for the study as long as they had discontinued the medication at least 12 weeks prior to the Screening/Baseline Visit (Day -14 to Day 0).
* The following therapies are prohibited from 4 week prior to the Screening/Baseline Visit (Day -14 to Day 0) through the end of the 8-week blinded treatment period.
• Investigational biologic or pharmaceutical therapies (excluding COVID vaccination and COVID related monoclonal antibody therapy)
* The following therapies are prohibited from 12 week prior to the Screening/Baseline Visit (Day -14 to Day 0) through the end of the 8-week blinded treatment period.
* Treatment with an ACE-inhibitor
