Background for Fast Fact #199 Cough is a common, and at times distressing, symptom affecting patients with serious illness. Up to 40% of advanced cancer patients report cough, and while a smaller percentage find their cough distressing, severe cough can lead to dyspnea, nausea/vomiting, sleep impairment, chest and throat pain, and impaired communication. This Fast Fact will focus on the use of opioids for the symptomatic treatment of cough. Fast Fact #200 will address other agents for cough.

Etiologies and evaluation Common etiologies of cough include infections of the upper and lower airway, asthma and COPD, lung cancer or lung metastases, interstitial pulmonary processes (such as lymphangitic tumor spread or pulmonary edema), gastroesophageal reflux, aspiration, and drugs. Common drug causes include ACE inhibitors, NSAIDs, and inhalant medications. Evaluating for reversible causes is appropriate if consistent with the goals of care and prognosis. There is no validated tool for the assessment of cough in patients with serious illness, however, if feasible, treatment should be directed at the underlying cause. Many patients however will benefit from symptomatic therapy for a distressing cough while waiting for acute therapy to work or have a chronic cough (defined as a cough lasting >8 weeks) not amenable to treatment (e.g., cough due to advanced lung cancer).

Opioids are the only clearly effective centrally acting anti-tussive drugs and are thought to work by suppressing the brainstem cough center through mu and kappa opioid receptor agonism. All opioids used to treat cough have typical side effects such as sedation, constipation, and nausea. In general, use of long-acting opioids for cough are less common and less studied.

• Short-acting, full agonist “strong” opioids (e.g., morphine, oxycodone, hydromorphone) are the first-line symptomatic treatment for severe, distressing cough. In many studies they are dosed every 12 hours or twice a day, however, they are commonly prescribed in shorter intervals (e.g., every 4 hours) as needed to address significant coughing fits.
• Codeine: small placebo-controlled trials support its effectiveness as an anti-tussive for chronic and acute cough. Furthermore, codeine is widely available to treat cough in elixirs with guaifenesin and in general, easier to prescribe since it is a controlled III substance vs controlled II. However, recent studies have highlighted concerns about the metabolism, side effect profile, and safety of codeine, especially among pediatric patients. Therefore, many experts suggest that clinicians utilize low doses of “strong” immediate release opioids (e.g., morphine 2-5 mg oral solution, hydrocodone 5 mg, or oxycodone 2.5 mg) instead of codeine which is considered by many a “weak opioid.”
• Dextromethorphan: The most prescribed anti-tussive, dextromethorphan is a synthetic, centrally acting medication that is structurally similar to codeine. It affects NMDA, serotonin, and norepinephrine receptors to suppress the CNS. Duration of action 3-6 hours; usual adult dose is 10-20 mg every 4-6 hours. Confirmed to be as effective as codeine for chronic cough and with less gastrointestinal and neurologic side effects in multiple studies. See Fast Fact #200 regarding its controversy of use to treat transient cough from an upper respiratory infection. It is available alone or as an elixir with guaifenesin. It inhibits the cytochrome P450 system and thereby affects the metabolism of many drugs. When co-prescribed with other serotonergic drugs (e.g., antidepressants) it can increase the risk for serotonin syndrome.
• Hydrocodone: While considered a “strong,” full agonist by some experts, it is only available as a combination product in the US: either as a short-acting elixir with the anticholinergic drug homatropine or as an extended-release elixir with the antihistamine chlorpheniramine (dosed at 10 mg every 12 hours). Duration of action 4-6 hours; usual dose 5-10 mg every 4 hours. These other agents magnify hydrocodone’s sedative effects and limit the maximum daily dose. Hydrocodone has been shown to be as effective as codeine in head-to-head studies but with fewer gastrointestinal side-effects.
• Tramadol: considered a “weak”, synthetic opioid, there is limited available evidence supporting its use as an antitussive dosed 50 mg orally twice a day.
• All opioid analgesics have anti-tussive activity and their use has been mostly based on convention; there is no strong evidence that any one opioid has superior efficacy for cough. For patients already taking opioids for pain, it is unclear whether adding a second opioid such as codeine is effective for cough. One uncontrolled, open-label study showed hydrocodone to be helpful in this setting; it has not been repeated (Homsi 2001).

Fast Fact #200 will discuss non-opioid agents for cough, as well as address some general treatment strategies.

References

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Conflict of Interest Statement: the authors have disclosed no relevant conflicts of interest.
Authors’ Affiliations: Medical College of Wisconsin, Milwaukee, WI (SM); University of Minnesota Medical School and Fairview Health Services, Minneapolis, MN (DAR).
Version History: Originally published March 2008. 2nd edition published in July 2013; 3rd edition published July 2015; 4th edition published January 2024