A Brief Introduction to Drug Treatment and New Drug Development for Chronic Cough

Chronic cough (CC) is a common disease with a prevalence rate of up to 12%, significantly affecting the quality of life of patients. Currently, there are limited drug options for the treatment of chronic cough beyond treating the underlying cause. Based on the pathogenesis of chronic cough, it has been discovered that some analgesics and antidepressants have antitussive effects, including opioid analgesics such as codeine and morphine, neuropathic pain analgesics like gabapentin and pregabalin, and antidepressants like amitriptyline. However, these drugs do not specifically target chronic cough, and their adverse reactions in clinical treatment can even outweigh their actual antitussive effects. To reduce drug-related adverse reactions, targeted drugs targeting different targets in the cough pathway have gradually come into view and have achieved certain success in clinical trials.

1.Opioid Drugs

Opioid drugs, represented by codeine and morphine, are the most commonly used antitussive drugs in clinical practice. They primarily function by inhibiting the cough center in the brainstem, with codeine once considered the first-choice drug for intractable cough. Since codeine is effective for 50% of patients with chronic cough, and satisfactory results can be achieved within 1 to 2 weeks of treatment for responders, it has been used to treat chronic cough for decades. However, its potential adverse reactions and individual differences in metabolism have severely limited its clinical application. The adverse reactions of codeine mainly include nausea, vomiting, constipation, respiratory depression, and bradycardia. Long-term use can lead to severe dependence. Additionally, codeine is a morphine precursor drug that can be activated into morphine by cytochrome P450 2D6 (CYP2D6) in the liver. Therefore, the efficacy and safety of codeine depend on the activity and genetic polymorphism of CYP2D6, making its biological effects unpredictable due to individual differences. Compared to codeine, morphine has greater potential in treating chronic cough. Firstly, morphine's antitussive ability is 10 times stronger than codeine. Secondly, morphine's metabolism in the body is not affected by individual differences in CYP2D6, making its efficacy and safety predictable. However, similar to codeine, morphine also has strong central inhibitory effects, including drowsiness, respiratory depression, constipation, and addiction.

2.Neuropathic Pain Analgesics

Representative drugs for neuropathic pain analgesics include gabapentin and pregabalin, both used to treat post-herpetic neuralgia. Since the neural pathways of pain are similar to those of chronic cough, these analgesics also have a certain antitussive effect. Gabapentin is not only an analgesic but also has anti-epileptic properties, and its good antitussive effect has been reported in relevant studies. In a randomized controlled trial, gabapentin was found to significantly improve the Leicester Cough Questionnaire (LCQ) score, cough severity, and cough frequency in patients with chronic cough compared to placebo. Pregabalin, another treatment for post-herpetic neuralgia, has also shown good effects in the treatment of chronic cough. Recent clinical studies have found that pregabalin combined with speech pathology therapy for chronic cough can significantly improve patients' LCQ scores and visual analog scale scores compared to using speech pathology therapy alone. However, these drugs also have many adverse reactions, including dizziness, disorientation, confusion, fatigue, and blurred vision, which are often intolerable for patients. In addition, studies using these drugs to treat chronic cough rely heavily on subjective indicators and lack support from objective indicators, leading some to suggest that the significant improvement in LCQ scores and visual analog scale scores is not truly effective but merely attenuates patients' perception of cough.

3.Antidepressants

Tricyclic antidepressants, such as amitriptyline, have been found to have therapeutic effects not only on depression but also on other conditions including anxiety, fibromyalgia, irritable bowel syndrome, subjective tinnitus, and post-herpetic neuralgia. In recent years, amitriptyline has also demonstrated some effectiveness in treating chronic cough. A clinical trial treating chronic cough confirmed that low-dose amitriptyline taken before bedtime was more effective in improving the quality of life and subjective scores of patients with chronic cough compared to the combination of codeine and guaifenesin. A 2-3-year follow-up evaluation of patients with idiopathic cough treated with amitriptyline assessed its short-term and long-term therapeutic effects, demonstrating that amitriptyline exhibits good efficacy and tolerability in treating adult idiopathic cough. This suggests that amitriptyline has certain potential in the treatment of adult idiopathic chronic cough.

4.P2X3 Receptor Blockers

Gefapixant (AF-219/MK-7264), a P2X3 receptor antagonist, is the first selective P2X3 receptor blocker to be approved. In a Phase IIa trial, Gefapixant reduced the 24-hour cough frequency in patients with chronic cough by 74%, significantly outperforming the control group. However, due to the excessive dosage, all patients experienced taste disorders. Subsequent Phase IIb studies showed that a low dose of Gefapixant, 50 mg three times a day, could reduce cough frequency by 37% with only 48% of patients experiencing taste disorders. Randomized controlled trials found that Gefapixant dosages of ≥30 mg significantly improved cough frequency, while dosages ≥150 mg had a greater impact on taste. This fully demonstrates that taste suppression and antitussive effects are dose-dependent, making it crucial to find a balance between the dosage causing taste disorders and the dosage achieving good antitussive effects. On January 20, 2022, the Japanese Ministry of Health, Labour and Welfare (MHLW) approved the launch of Gefapixant tablets (MK-7264, brand name: Lyfnua®) from Merck Sharp & Dohme and Nihon Koki Pharmaceutical Co., Ltd. for the treatment of refractory chronic cough (RCC). In addition, new highly selective P2X3 receptor blockers such as BAY1817080, BAY1902607, S-600918, and BLU-5937 have gradually entered clinical trial stages. These highly selective P2X3 blockers are expected to have lower rates of taste disorders and stronger antitussive effects.

5.Blockers of Transient Receptor Potential (TRP) Channels

① TRPV1 Antagonists. SB-705498 is a highly selective and potent long-acting TRPV1 receptor antagonist. Research results show that SB-705498 significantly improves the increased cough reflex sensitivity caused by capsaicin in patients, but does not affect the 24-hour cough frequency compared to placebo. XEN-D0501 is a novel TRPV1 receptor antagonist that inhibits capsaicin-induced depolarization of guinea pig and human isolated vagus nerves 1000 times more potently than SB-705498. Its inhibitory effect is concentration-dependent and long-lasting. A double-blind, randomized, placebo-controlled crossover study on patients with refractory chronic cough (RCC) showed that XEN-D0501 significantly reduced the maximum cough response to capsaicin, but did not improve spontaneous cough frequency or 24-hour cough frequency. Existing studies indicate that TRPV1 antagonists may not be effective therapeutic targets for patients with RCC or chronic obstructive pulmonary disease (COPD).

② Since cold air is an important trigger for refractory chronic cough, TRPA1 receptors, which are sensitive to low-temperature stimuli and distributed in peripheral neurons, have also been considered as a therapeutic target for treating refractory chronic cough. The TRPA1 antagonist HC-030031 can reduce Ca2+ influx in mouse lung epithelial cells, inhibit the increase in intracellular reactive oxygen species (ROS), and fully or partially inhibit coughing in awake guinea pigs induced by AITC, cinnamaldehyde, prostaglandins, and bradykinin. Pre-treatment of CC guinea pig skin with HC-030031 can block skin TRPA1 channels, reducing the cough hypersensitivity caused by prolonged exposure to cold environments. GRC17536, a selective TRPA1 antagonist, can inhibit AITC-induced Ca2+ influx through TRPA1 channels and citric acid-induced coughing in guinea pigs. Although it has a strong antitussive effect in guinea pig models, GRC17536 did not show significant efficacy in clinical trials on CC patients.

③ TRPV4 is another therapeutic target. Experiments have shown that the release of TRPV4 and ATP is related to the activation of P2X3 channels. The antagonistic effect of TRPV4 can block the activation of P2X3 from upstream, which not only avoids taste disorders but also has an antitussive effect. However, recent reports have found that the selective TRPV4 antagonist GSK2798745 is ineffective for refractory chronic cough, further hindering drug research. Currently, there has been no breakthrough in the development of TRPV4 antagonists, which may be related to receptor compensation (i.e., inhibiting one type of TRP receptor can induce the activation of other receptors) and insufficient dosage. Although preclinical cough experimental models have demonstrated the important role of the TRPV4-ATP-P2X3 axis in inducing cough, there is currently a lack of evidence that TRPV4 inhibitors have significant efficacy in clinical CC treatment. In the future, the dosage of TRPV4 antagonists or their combination with other drugs can be fully considered.

④ AX-8 is an orally administered potent and selective TRPM8 agonist intended for the treatment of chronic cough (CC). Activating the TRPM8-expressing fibers with AX-8 can normalize the upper airway sensitivity of CC patients, thereby reducing coughing (antitussive effect) and throat irritation (counter-irritant effect). In an open-label pilot study involving 12 patients with refractory chronic cough (RCC), a single 5mg dose of AX-8 orally disintegrating tablets significantly reduced the awake cough frequency in RCC patients. At the same time, data showed that AX-8 treatment reduced the severity of coughing, cough irritation, and the desire to cough, indicating that AX-8 has the potential to become a novel drug for the treatment of chronic cough.

6.Other Cough Suppressant Drugs

In addition to the aforementioned drugs, there are also many other drugs that have been proven to have cough suppressant effects. ① Lesogaberan, a peripherally acting γ-aminobutyric acid (GABA) receptor agonist, can inhibit citric acid-induced coughing in guinea pigs, demonstrating its cough-suppressing potential. ② Theobromine can inhibit citric acid-induced coughing and capsaicin-induced coughing in guinea pigs, and was approved in South Korea in 2009 for the treatment of persistent cough. ③ P-substance, an important endogenous trigger for coughing, is widely expressed in the central and peripheral nervous systems and plays a crucial role in chronic cough. It acts on neurokinin-1 receptors (NK1R) to mediate processes such as coughing, pain, vomiting, depression, and neurodegenerative diseases. Recently, Orvepitant, an antagonist of central NK1R, has shown good cough-suppressing potential in a study treating chronic cough. APRAPANT, also an NK1R antagonist, significantly reduced the objective cough frequency in patients with lung cancer-related cough. However, such drugs have displayed numerous neurological adverse reactions during treatment, with dizziness and drowsiness being the most common. ④ Recently, the inhaled form of cromolyn sodium, PA101, has been found to bind to G-protein-coupled receptor GPR35, thereby reducing the activity of C fibers. However, recent studies have found that PA101 only has a cough-suppressing effect on chronic cough caused by pulmonary fibrosis and ACEI, and does not seem to have a significant effect on refractory chronic cough. ⑤ Voltage-gated sodium channel blocker lidocaine inhalation also has a certain cough-suppressing effect, which is attributed to the crucial role of voltage-gated sodium channels in the generation and propagation of action potentials.

With the deepening of people's understanding of chronic cough, more and more cough suppressant drugs have been discovered, making the treatment of chronic cough more targeted. However, the cough-suppressing effects of most drugs are still unclear and require further clinical trials to evaluate their mechanisms, safety, and efficacy in detail. Drug treatment for chronic cough still has a long way to go.

References:

[1] Yao Yue, Wu Hui, Zhang Jiashuo, et al. Research Progress on Cough Treatment Targets and New Drugs [J]. Chinese Journal of New Drugs, 2023, 32(15): 1538-1545.

[2] Zhao Lingyun, Li Hongyun. New Progress in the Treatment of Chronic Cough [J]. Chinese General Practice, 2021, 24(08): 930-940+946.

Author Introduction

Xiaomichong, a pharmaceutical quality researcher, has long been committed to the research of drug quality and the validation of drug analysis methods. Currently, she works in a large domestic pharmaceutical research and development company, engaged in drug inspection, analysis, and analytical method validation.