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

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.

Morphine inhalation by cancer patients: a comparison of different nebulization techniques using pharmacokinetic, spirometric, and gasometric parameters.

Despite numerous case reports suggesting the value of morphine (M) nebulization in the treatment of breathlessness, only a few clinical trials have been able to support this. The reason for this could lie in the lack of understanding of the localization of opioid receptors in the airways and the biopharmaceutics and pharmacokinetics of nebulized morphine. In the present study, we compared two different methods of pneumodosimetric nebulization: the Bronchial Control Treatment System-Sidestream (BCTS-S) and the Bronchial Control Treatment System-Micro Cirrus (BCTS-MC). The first method delivers relatively large aerosol particles (2-5microm) preferentially to the bronchial tree and trachea. In the BCTS-MC method, small aerosol particles (0.5-2microm) mostly reach the alveoli. Ten patients with cancer were randomly assigned to either the BCTS-S or BCTS-MC inhalation of 5 mg morphine HCl. Patients using the BCTS-S method inhaled a morphine dose in 6.6+/-2 minutes, whereas with the BCTS-MC method, the inhalation time was 28.8+/-8 minutes. The areas under the curve of morphine and glucuronides were several times higher after BCTS-S than after BCTS-MC. The proportion of morphine-3-glucuronide to morphine-6-glucuronide (M6) was, on average, close to one for both methods. From the same amount of morphine in the BCTS-S method, five times more M6 was produced. In both methods, the time to maximum concentration for morphine metabolites was 20-40 minutes, much shorter than expected from oral, intranasal, or intravenous administration. The study shows that the method of inhalation may have a profound effect on the pharmacokinetics of morphine. It is possible that the lungs metabolize morphine to glucuronides themselves and in different proportions from those seen after systemic administration. The BCTS-S method was found to be potentially superior to the BCTS-MC method in local action in the lungs.

Air humidity may influence the aerosol distribution of normal saline administered by closed or vented nebulizers operated continuously or dosimetrically.

In clinical practice the majority of inhaled agents require deposition in the most distant regions of the bronchial tree. Contrary to this, it is likely that morphine delivery in breathlessness and chronic cough should be directed to the tracheobronchial area. The aim of the present study was to assess how an environmental condition such as air humidity might influence the particle distribution of normal saline administered by closed or vented nebulizers operated continuously or dosimetrically. Aerosol generated as a saline solution was assessed for BCTSS (Bronchial Control Treatment System-Sidestream) and BCTS-MC (Bronchial Control Treatment System-Micro Cirrus), together with two pneumatic delivery systems: Pneumatic Inhalation-Sidestream (PI-S) and Pneumatic Inhalation-Micro Cirrus (PI-MC). To clarify the influence of humidity on the aerosol we introduced a fifth method, BCTS-S/C, which included a vented nebulizer operated continuously. The impact of different air humidity on the size of particles was examined. Only in the case of the vented methods (BCTS-S and BCTSS/C) of nebulization did air humidifying lead to a significant enlargement of particle size. Moreover, the mean particle size at 90% was almost twice as large with the use of BCTS-S than with BCTS-S/C. Our experiment demonstrated that ambient humidity has a greater effect on particle size with vented rather than nonvented nebulizers and the effect might be potentiated by the pulsative method of nebulization.

[Vasodilatator testing with nitric oxide (bronchial control treatment system--BCTS) in patients with pulmonary hypertension]. / Testy wziewnego, sterowanego oddychaniem podawania tlenku azotu u chorych z nadcisnieniem plucnym.

Nitric oxide (NO) is one of the most important mediators produced in the human organism. It participates in the regulation of blood vessel lumens, activation of leucocytes and platelet; it is a mediator in the nervous system and in inflammation reactions. It was proved that in cases of patients with pulmonary hypertension, a decreased secretion of nitric oxide and an increased synthesis of endothelin-1 is observed. Therefore, in case of patients with pulmonary hypertension the exogenous, inhaled nitric oxide (iNO) is applied. It is added to the respiratory mixture and it passes through the alveolar-capillary barrier to the smooth muscle cells where it activates a guanyle cyclase, similarly to the physiologically produced nitric oxide. It was proved that it decreases pulmonary vascular resistance (PVR) and pulmonary artery pressure (PAP). Inhaled nitric oxide is applied for treatment purposes to patients after cardiosurgical operations, mainly heart transplantation and correction of valvular defects with accompanying pulmonary hypertension, as well as after implantation of the left ventricular assist device in order to relieve the right chamber. In case of patients qualified for cardiosurgical operations with the accompanying pulmonary hypertension as well as in case of patients with the arterial pulmonary hypertension a diagnostical test using iNO is carried out in order to determine further course of therapeutical treatment. The application of the new method of iNO administration by the BCTS (Bronchial Control Treatment System) method allows for a precise administration of accurately determined doses of iNO and its full utilisation through addition to the respiratory mixture in the initial phase of inspiration. The risk of side effects is also decreased; so far no influence on the circulatory system or an increase of the level of methemoglobin was observed.