Sustained-release morphine may benefit patients with COPD

Regular, low-dose, oral sustained-release morphine improved the health status of patients with moderate-to-very-severe chronic breathlessness due to chronic obstructive pulmonary disease (COPD), the MORDYC* trial has shown, validating its palliative role for chronic breathlessness.

One of the most reported COPD symptoms, chronic breathlessness markedly impacts quality of life, functional status, and prognosis. [J Palliat Med 2011;14:735-743; Eur Respir J 2017;49:1602277] “[Therefore,] breathlessness management is an important treatment goal,” said the researchers.

Low-dose opioids reportedly have a palliative effect on refractory breathlessness. [Thorax 2009;64:910-915; Chest 2010;137:674-691] However, apart from limited data, clinicians often hesitate to prescribe opioids for fear of respiratory depression. [Can Fam Physician 2012;58:e401-e407; Chron Respir Dis 2015;12:85-92]

“[Our findings showed that] morphine for 4 weeks improved disease-specific health status in patients with COPD … These effects were obtained without any change in respiratory outcomes or functional performance … [M]orphine was [also] well-tolerated, with only mild opioid-related adverse effects,” they said. [JAMA Intern Med 2020;doi:10.1001/jamainternmed.2020.3134]

Mean CAT** score difference was –2.18 points (p=0.03) favouring morphine over placebo. “[This is] a significant and clinically relevant improvement in CAT after morphine treatment,” said the researchers. While this did not reach the predetermined MCID*** used for sample size calculation, the MCID has been redefined as a change of 2–3 points. [Lancet Respir Med 2014;2:195-203; J Am Med Dir Assoc 2017;18:53-58] “Therefore … the reported [CAT] differences … are on the lower bound of clinical relevance for this population,” they explained.

Moreover, there was a significant difference for walking stairs/hill in favour of morphine vs placebo (–0.43 points; p=0.02), which as per the researchers, was ‘interesting’. “[While] we cannot exclude that this improvement … masks the expected effect on breathlessness, [this illustrates that] palliative treatment may allow patients to be more active in daily living. Patients will be able to do more before reaching the same level of breathlessness,” they explained.

In terms of respiratory outcomes, there was no significant difference between morphine and placebo in terms of change in PaCO₂^# (1.19 mm Hg; p=0.55).

About 80 percent of morphine recipients reported ≥1 adverse event of interest^##. Sixteen percent of participants had a moderate-to-severe COPD exacerbation treated with antibiotics and/or corticosteroids. No morphine-related hospital admissions or deaths were reported.

Conquering the fear

One-hundred eleven participants (mean age 65 years, 54 percent male) were randomized 1:1 to receive either morphine 10 mg or placebo BID for 4 weeks. Nonresponders may increase their dosage to TID after 1 or 2 weeks.

“Our study clearly illustrates that fear of respiratory depression or other respiratory adverse effects cannot be substantiated. Respiratory rate decreased without a change in PaCO₂ or PaO₂^###, indicating no clinically relevant differences in alveolar ventilation,” explained the researchers. “[Therefore,] low-dose morphine … seems to be safe even in this group of patients with moderate-to-very-severe COPD. These results suggest that [physicians’] fear of respiratory depression … might be unfounded.”

Nonetheless, they called for trials evaluating COPD patients with severe-to-very-severe chronic breathlessness and optimized pharmacologic and non-pharmacologic treatments. Studies incorporating measures of daily physical activity may also help validate the CAT score results, while longer-term trials are warranted to confirm the efficacy and safety of morphine in this setting.