Rationale: Cough is the most common complaint for which medical attention is sought, and chronic cough can be both physically and mentally debilitating. There is currently no evidence supporting the use of antitussives in chronic treatment-resistant cough.
Objectives: We tested the hypothesis that morphine sulfate in the dose of 5 mg twice daily would bring about a reduction in cough frequency and severity in patients failing to respond to specific measures.
Methods: Patients recruited from the Hull Cough Clinic were enrolled into a randomized double-blind placebo-controlled study using 4 weeks of slow-release morphine sulfate and a corresponding period of matched placebo. An open-labeled extension of the core study allowed dose escalation to 10 mg twice daily. Cough was assessed using the Leicester Cough Questionnaire, daily symptom diary, and citric acid cough challenge.
Results: Twenty-seven patients completed the core study. A significant improvement of 3.2 points over baseline was noted on the Leicester Cough Questionnaire (p < 0.01). A rapid and highly significant reduction by 40% in daily cough scores was noted among patients on slow-release morphine sulfate (p < 0.01). Objective testing of the cough reflex using citric acid cough challenge tests did not show any significant changes. Eighteen patients continued into the extension study. Two-thirds of these patients opted to increase the morphine to 10 mg twice daily. At the end of 3 months, there was a similar improvement in cough between the 5- and 10-mg groups.
Conclusion: Morphine sulfate is an effective antitussive in intractable chronic cough at the doses of 5 to 10 mg twice daily.
Opiates have long been advocated for the suppression of cough (7, 8). However, there are few trial data to support this recommendation. Although small, single-dose studies of codeine in chronic bronchitis have shown some benefit (9–11), a recent trial suggested an effect similar to that of placebo (12). The effect of opiates in intractable chronic cough has never been studied. Indeed, experience in acute cough and with cough challenge in normal volunteers suggests a lack of efficacy (13, 14). The aim of this study was to determine whether low-dose opiates in the form of slow-release morphine has a role in the management of patients with idiopathic cough or in those resistant to conventional treatments.
Some of these results have been previously reported in the form of an abstract (15)
Subjects were recruited from adult patients attending the Hull Cough Clinic who had a chronic, persistent cough of greater than 3 months' duration. Patients were assessed according to our previously published probability-based treatment algorithm (16), which excludes patients with significant lung disease. Those who failed to respond to trials of specific antitussive therapy were enrolled. Approval for the study was obtained from the Medicines and Healthcare Products Regulatory Agency (MHRA) (reference number MF 8000/13102) and Hull and East Riding Local Research and Ethics Committee and registered at www.controlled-trials.com (reference number ISRCTN 18474014). All patients were provided with written information prior to obtaining consent. The study was conducted in compliance with International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use–Good Clinical Practice (ICH-GCP) guidelines.
Because no previous studies of this type exist, a formal power calculation was impossible. Based on the observed effect of morphine in the clinic, the number of patients studied was considered to be sufficient to demonstrate any important effect. Patients were randomized into a double-blind placebo-controlled crossover study by using a computer-generated block randomization code. The patients were required to take 4 weeks of slow-release morphine sulfate (MST) 5 mg twice daily and 4 weeks of matched placebo (DHP Ltd, Monmouthshire, UK). No person involved in the analysis of the data had knowledge of the randomization. During the course of the trial, the patients were required to withhold any other cough remedies, including over-the-counter preparations.
The patients made three visits to the clinical trials unit at 4-week intervals. On each of these visits, they filled in the Leicester Cough Questionnaire (2), a validated and reproducible measure of the impact of chronic cough on activities of daily living. The subjects score the 19-item questionnaire based on physical, social, and psychological effects of cough. An improvement in score here is indicative of a better health status. Spirometry (Jaeger MasterScope; VIASYS, Hoechberg, Germany) with reversibility to 2.5 mg of nebulized salbutamol was performed at the first visit and FEV1 was measured at each subsequent visit. Citric acid cough challenge test was performed at each visit using our established methodology (Mefar, Bresia, Italy) (17) and the C2 and C5 responses (the concentration of citric acid required to elicit 2 and 5 coughs per inhalation) determined. The cough severity was assessed on a scale of 0 to 9 and recorded on a daily diary record card. Adverse events were elicited at each visit by enquiring about the known side effects of opiate therapy from a symptom checklist.
Patients who completed the initial crossover study were given the opportunity to take part in an open-label 3-month extension study and were given the choice of doubling the dose to 10 mg twice daily of MST if they believed that their cough had not been adequately controlled during the core study.
The primary endpoint was change in the Leicester Cough Questionnaire (LCQ). This and the cough challenge data were assessed by analysis of variance–Tukey post hoc test for multiple comparisons between baseline, placebo, and treatment values. The diary data were analyzed separately using the paired t test comparing the treatment arm with the placebo because a baseline reading was not available.
A total of 27 patients (18 female) with a mean (SD) age of 55 (10.6) years were studied. The cough was reported to be productive in 16 patients.
The mean score for the LCQ was 12.3 (2.5) at baseline, 13.5 (2.7) on placebo (not significant) and improving to 15.5 (2.7) on morphine (p < 0.01 vs. baseline, p < 0.02 vs. placebo). The physical, psychological, and social questions of the LCQ showed a significant improvement in all three subgroups (Table 1).
95% Confidence Interval
|LCQ Domain||Mean Value at Baseline||Mean value for Placebo||Mean value for Morphine||Baseline vs. Placebo||Baseline vs. Morphine||Placebo vs. Morphine|
|Physical||4.0||4.8||5.3||−1.3 to –0.3, p < 0.01||−1.8 to −0.8, p < 0.01||−1.1 to −4.3, p < 0.04|
|Psychological||4.1||4.6||5.1||−1.0 to −0.1, p = 0.1||−1.6 to −0.5, p < 0.01||−1.1 to −3.9, p < 0.04|
|Social||3.7||4.2||5.1||−1.4 to 0.3, p = 0.03||−2.2 to −0.5, p < 0.01||−1.7 to −3.0, p < 0.05|
The daily cough diary showed a rapid and highly significant reduction in the cough score on morphine (3.4 [1.8], p < 0.01) (Figure 2), whereas placebo had no discernable effect over baseline (5 [1.7]).
There was no significant difference in the geometric mean of the citric acid cough challenges (C2: 91 mM at baseline vs. 127 mM on placebo and 220  on morphine).
Eighteen patients (eight female) continued into the open-label extension study. One-third of the patients opted to increase the dose of MST to 10 mg twice daily in the first month, 11% joined this group in the second month, and a further 22% chose to increase the dose in Month 3. Thus, two-thirds of the patients opted for a maintenance dose of morphine of 10 mg twice daily.
In those patients opting to stay on the dose of MST 5 mg twice daily at the end of the randomized study, the daily cough score had reduced by 2 compared with 0.7 in those who subsequently opted to increase the dose to 10 mg twice daily. On completion of the extension study, there was no significant difference in the cough severity score: 2 (1) versus 3 (2) for the 5- and 10-mg groups, respectively. In those requesting an increase in dose, the LCQ showed no significant difference between placebo and MST 5 mg (90.3 vs. 97 after the core study), but showed significant improvement on MST 10 mg twice daily (90.3 vs. 107.2) (p < 0.01).
Morphine was well tolerated and no patient dropped out because of adverse events. The most common side effects noted were constipation (40%) and drowsiness (25%).
Specialist cough clinics are known to have a high success rate in the diagnosis and treatment of chronic cough. Various diagnostic and therapeutic strategies have been described to aid in this success (18, 19). Recently, we have suggested a probability-based approach to the diagnosis and treatment of chronic cough (20), which led to the diagnosis and management of 93% of patients with chronic cough. However, despite the use of available protocols and guidelines (16, 21), a percentage of patients continue to have chronic cough without either an obvious cause or a treatable precipitant. Several studies have confirmed the decrement in quality of life suffered by those with chronic cough, which is similar to that seen in severe chronic obstructive pulmonary disease (3). Thus, in patients with chronic refractory cough, there is a pressing need for symptomatic treatment.
The effectiveness of opiates as antitussives is repeatedly described in reviews (22, 23). However, these statements have not been supported by evidence from controlled trials in clinically significant cough. Indeed, a previous study looking into the effects of codeine in upper respiratory tract infection found an essentially negative result (14). Codeine has become the archetypical antitussive opiate, but this probably arises from ease of prescribing due to its noncontrolled drug status rather than any unique pharmacological properties. Consistent therapeutic response to codeine is unlikely because it is a prodrug metabolized to morphine by cytochrome P450–2D6, and so plasma levels depend on the acetylator status, which varies widely in the population (24). We therefore chose morphine as our opiate to minimize variability in response. Studies using morphine in normal subjects have demonstrated a shift in cough reflex sensitivity using cough challenge methodology (25, 26), albeit at high dose. It has been suggested that the antitussive action of morphine is due to sedation. In our study, the degree of sedation was specifically sought and was present only transiently, whereas a significant antitussive effect continued throughout the study.
In the randomized study, a clear benefit was demonstrated in favor of morphine in the severity and frequency of cough by both the diary data and LCQ data analysis. The average improvement in total LCQ score in this study was higher than 2.56, which has been demonstrated to be clinically significant (2). The distribution of response was not normal but appeared to segregate into responders and nonresponders (Figure 1). Response to treatment occurred rapidly, with maximum benefit being achieved by Day 5 in those who responded. This benefit was sustained through the 4 weeks of the study (Figure 2). The rapid response to morphine was in contrast to the absence of any effect of placebo. The placebo effect confounds many studies of antitussive therapy in acute cough and cough challenge testing. Indeed, the pharmacokinetics of the placebo effect has been modeled (27). In chronic cough, significant placebo responses do not seem to occur, possibly because of the prolonged duration of symptoms (mean of 6.5 yr in the Hull Cough Clinic) and multiple previous therapeutic trials. The patients who had a subtherapeutic response to low-dose morphine requested an increase in dose to 10 mg twice daily in the extension phase. This brought about a further significant amelioration of cough scores, suggesting that the optimum dose of morphine in the suppression of chronic cough lies between 5 and 10 mg twice daily.
Although there was a trend to improvement, no significant alteration in cough reflex sensitivity was observed as determined by the citric acid cough challenge. Disparity between cough reflex sensitivity and subjective cough scores has been previously observed (2, 28–30), which brings into question the validity of the citric acid cough challenge testing in the monitoring of clinically important cough.
Side effects and dependence are obvious concerns with opiate therapy for what is a disabling but non–life-threatening condition. Tassain and colleagues looked into the neuropsychological performance in patients receiving 40 to 140 mg/day of sustained release morphine for chronic pain and did not find any disruption of cognitive function, but in fact found moderate improvement in the same resulting from symptom relief (31). Comparisons of similar therapeutic options could be made with those patients with eosinophilic bronchitis/cough variant asthma, some of whom require long-term oral steroid therapy with a consequently worse adverse event profile. In our study, the drug was well tolerated and remediable in comparison with the symptom being treated. With dose escalation to 10 mg twice daily, however, the incidence of drowsiness doubled. We believe that the risk–benefit risk ratio makes low-dose morphine sulfate a credible therapeutic option in patients with chronic cough who fail with specific treatment.
There are two major limitations of this study. Studies conducted on psychoactive drugs like morphine cannot be completely blinded because the subject is conscious of the effects. A quarter of our patients noted mild and transient sedation. Second, we have not addressed the long-term effects of low-dose morphine. In chronic pain, higher doses of morphine are administered without any apparent addictive effects (32, 33). Long-term studies would be needed to confirm that this is the case with chronic cough.
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