Tachyphylaxis and Medication Dependence in Neuromodulator Treatment of Unexplained Chronic Cough

Neuromodulators, such as tricyclic antidepressants and gabapentin, are used in the treatment of unexplained chronic cough (UCC). However, little is known about the patient experience of these treatment regimens.

A single-institution study sought to capture the UCC patient experience of pharmacologic treatment regimens for chronic cough, looking specifically at the rates of relief of symptoms, tachyphylaxis and dependence. Researchers conducted a retrospective review of charts from 68 patients at Cleveland Clinic’s Chronic Cough Clinic from 2010-2014.

“The current state of UCC management does not fully explain the patient experience with regards to treatment duration or successful cessation of treatment,” states the study’s senior author Paul Bryson, MD. “This study gives us a better understanding of symptom relief with specific neuromodulators and describes the patient experience with regards to tachyphylaxis and dependence on these medications to maintain cough control.”

For the purposes of this study, tachyphylaxis is defined as a return of cough symptoms after successful relief with neuromodulators. Dependence is defined as the need to stay on medication, as symptoms return with attempted down titration or drug discontinuation. By definition, tachyphylaxis and dependence occur only in treatment-responsive patients.

Majority of patients get relief from neuromodulators

Twenty-nine of the 68 patients experienced success with the first treatment, and 39 were offered a second treatment. For every additional medication trial, the likelihood of success decreased by 53 percent. All told, 19 of these 39 patients who did not see symptom relief from the first treatment trial did eventually find relief with another medication. Overall, 68 percent of the patients experienced successful treatment with neuromodulators.

Together, tachyphylaxis and dependence impacted more than half of the patient cohort. Forty percent of the patients reported experiencing medication-related side effects, and the most common side effect reported was sedation. “Most patients can tolerate neuromodulator therapy and when they do have a positive response with significant reduction in cough, we typically continue the medication for a minimum of three to six months” states Rachel M Taliercio, DO, a co-author on the study.

Tachyphylaxis was observed in 35 percent of patients, who required higher doses of the medication for continued relief. Nearly one-third of these patients experienced tachyphylaxis following an upper respiratory infection or exacerbation of allergies, indicating that clinicians may be able to intervene with a corticosteroid burst/taper regimen before neuromodulator treatment failure.

Dependence was observed in 27 percent of successfully treated patients. For these patients, the cough returned when down titration was attempted following initially successful treatment, only to be rescued by the same neuromodulator.

“It seems that if coughing returns after attempted discontinuation of neuromodulators, patients may be dependent on these medications to control their cough,” notes Dr. Bryson

Interestingly, patients who underwent concomitant behavior cough suppression therapy had a lower success rate than those who did not. This contradicts other studies, which have identified concomitant behavior therapy as one of the best interventions for chronic cough. According to Dr. Bryson, “The discrepancy may attributed to cough severity, as it has been our clinical experience that the most debilitated coughers—those who have tried numerous treatment regimens without success—are more willing to undergo this intervention.”

A nagging cough

Unexplained chronic cough is a condition that is refractory to treatment and doesn’t have an identifiable cause. The pathophysiology is thought to be similar to that of neuropathic pain: changes in the peripheral and central nervous system leading to hypersensitization of the cough reflex. “This has led to the use of neuromodulators in the management of chronic refractory cough” states Dr. Taliercio.

UCC is typically a diagnosis of exclusion after workup and empiric treatment for reflux, allergy and pulmonary conditions fail to resolve the cough. To help patients who have run the gamut in seeking help for UCC, Cleveland Clinic offers treatment by a multidisciplinary team of physicians in pulmonology, otolaryngology, gastroenterology, allergy and specialized speech-language pathology. These specialists provide patients with a full diagnostic work up to determine the source of and treatment for a chronic, unexplained cough. “While unexplained chronic cough represents a minority of patients who overall seek treatment for chronic cough,” according to Dr. Taliercio, “it accounts for the majority of our patient referrals and we have extensive experience in managing these cases.”