Dosimetrically administered nebulized morphine for breathlessness in very severe chronic obstructive pulmonary disease: a randomized, controlled trial

Abstract

Background: Systemic morphine has evidence to support its use for reducing breathlessness in patients with severe chronic obstructive pulmonary disease (COPD). The effectiveness of the nebulized route, however, has not yet been confirmed. Recent studies have shown that opioid receptors are localized within epithelium of human trachea and large bronchi, a target site for a dosimetric nebulizer. The aim of this study was to compare any clinical or statistical differences in breathlessness intensity between nebulized 2.0% morphine and 0,9% NaCl in patients with very severe COPD.

Methods: The study was a double-blind, controlled, cross-over trial. Participants received morphine or NaCl during two 4-day periods. Sequence of periods was randomized. The primary outcome measure was reduction of breathlessness intensity now by ≥20 mm using a 100 mm visual analogue scale (VAS) at baseline, 15, 30, 60, 120, 180 and 240 min after daily administration, during normal activities.

Results: Ten of 11 patients included completed the study protocol. All patients experienced clinically and statistically significant (p < 0.0001) breathlessness reduction during morphine nebulization. Mean VAS changes for morphine and 0.9% NaCl periods were 25.4 mm (standard deviation (SD): 9.0; median: 23,0; range: 14.0 to 41,5; confidence interval (CI): 95%) and 6.3 mm (SD: 7.8; median: 6.8; range: -11,5 to 19,5; CI: 95%), respectively. No treatment emergent adverse effects were noted.

Discussion: Our study showed superiority of dosimetrically administered nebulized morphine compared to NaCl in reducing breathlessness. This may have been achieved through morphine's direct action on receptors in large airways, although a systemic effect from absorption through the lungs cannot be excluded.

Trial registration: Retrospectively registered (07.03.2017), ISRCTN14865597.

Fig. 1

Trial protocol. BP, blood pressure; PEF, peak expiratory flow; VAS, visual analogue scale; SpO₂, peripheral capillary oxygen saturation; HR, heart rate; RR, respiratory rate

Fig. 2

Mean visual analogue scale breathlessness scores for Groups 1 and 2. VAS, visual analogue scale; baseline, breathlessness assessment made on the first day of treatment, before nebulization. Mean visual analogue scale breathlessness scores for 8 days were calculated from visual analogue scale scores taken in fourth hour after nebulization

Fig. 3

Changes in visual analogue scale breathlessness scores during morphine nebulization. Section A: daily changes in visual analogue scale (VAS) during morphine nebulization; ‘before’ and ‘after’ refer to the moment of morphine nebulization. Section B: minute changes in VAS after morphine nebulization; ‘baseline’ refers to the assessment made on the first day of treatment, before nebulization

Fig. 4

Changes in visual analogue scale breathlessness scores during 0,9% NaCl nebulization. VAS, visual analogue scale; baseline, breathlessness assessment made on the first day of treatment, before nebulization

Fig. 5

Wilcock’s test: number of numbers read. Baseline, Wilcock’s test performed on the first day of treatment, before nebulization. Test results for days 1–8 were taken after nebulization

Fig. 6

Changes in spirometry values, expressed as percentage points; comparison of best and worst values obtained during morphine and 0,9% NaCl periods. MCID, Minimal Clinically Important Difference [24]; VC, Vital Capacity; IVC, Inspiratory Vital Capacity; IC, Inspiratory Capacity

Fig. 7

Changes in peak expiratory flow values, expressed as L/min; comparison of best and worst values obtained during morphine and 0,9% NaCl periods. MCID, Minimal Clinically Important Difference [25]; PEF, Peak Expiratory Flow