Portal de Periódicos da CAPES

Nebulized Morphine

2004; Elsevier BV; Volume: 125; Issue: 2 Linguagem: Inglês

10.1378/chest.125.2.363

1931-3543

Ahmet Baydur,

Respiratory and Cough-Related Research

Opioids have been used for many years to relieve breathlessness in patients with advanced COPD. They may possess several mechanisms by which they relieve dyspnea, both peripheral and central in origin. At the same time, their systemic use for this purpose gives rise to a concern about respiratory depression. Morphine also may be administered by the inhalational route to relieve breathlessness without inducing side effects that might be encountered if given systemically. In this issue of CHEST (see page 691), Foral and colleagues reviewed seven studies in patients with a variety of cardiorespiratory disorders who received nebulized morphine and whose dyspnea responses were subsequently assessed. Five of the studies were conducted in patients with COPD, while another study evaluated a mix of pulmonary and nonpulmonary patients, and the seventh studied a small cohort of patients with interstitial lung disease (ILD). All but one of the studies were prospective and double-blinded. Five studies were crossover in design, and only four studies (three in COPD patients) made use of placebos. In some studies, dyspnea was evaluated by means of a modified Borg scale or visual analog scale (VAS) during exercise. The authors' conclusion was that the evidence did not support the use of nebulized morphine for the relief of dyspnea or in the improvement of exercise tolerance in patients with COPD or ILD. They recognized that differences in dose, differences in administration schedule, and inconsistent use of oxygen and bronchodilators could have contributed to the variability in results. In addition, all the prospective studies evaluated small numbers of patients (range, 6 to 16 patients). The retrospective investigation assessed 54 patients with different diagnoses. Most studies used morphine sulfate as the opiate, while another used glucuronide or chlorohydrate salt. In some studies, bronchodilators were administered before the morphine was nebulized. The doses and frequency of morphine use varied widely among the studies. Cumulatively, side effects were few and mild. The depth and effectiveness of an inhaled drug depend on many factors, such as the size and physical characteristics of the aerosol particles, the amount of aerosol produced, the geometry of the airways, and the control of ventilation. Therapeutic aerosols are generally composed of a wide range of particle sizes and shapes. In those studies reviewed by Foral et al assessing mainly COPD patients, in which particle size was indicated to be 2.3 to 3 μm, a solution of morphine was more likely to deposit in the peripheral airways during tidal breathing than in those studies in which particle size was 4.9 μm, which tends to cause impaction in the central airways.1Wissing DR Humidity and aerosol therapy.in: Cairo JM Pilbeam SP Mosby's respiratory care equipment. Mosby, St. Louis, MO1999: 90-137Google Scholar Indeed, only in the study in which the particle size was 2.3 μm was there a statistically significant increase in exercise endurance time. This suggests that opioid receptors are present mainly in the peripheral airways, or that systemic absorption of the narcotic was enhanced. Furthermore, the underlying disease for which the aerosol is delivered may influence the deposition of particles. Secretions, bronchoconstriction, or dynamic collapse may trap aerosolized drugs in the major airways. By contrast, the airways of patients with ILD may permit peripheral penetration of drugs since their caliber is large in relation to the lung volume because of increased elastic recoil and they are generally devoid of secretions. At the same time, this feature may be counteracted by an increased respiratory rate that promotes deposition of the aerosol in the upper airway. In the small study with ILD patients, the use of morphine in two different doses (ie, 2.5 and 5 mg) did not result in a significant relief of dyspnea, perhaps because of upper airway deposition, or because the dose of morphine was too small. The dosing frequency of morphine also varied among the studies reviewed by Foral et al, which may have further clouded the issue. In four of the five prospective studies that primarily were of COPD patients, and in the one conducted in patients with ILD, dyspnea was evaluated after the subjects received single doses of inhaled opioids. In the fifth study, which consisted predominantly of COPD patients, relief of dyspnea was evaluated after 4 days of administering morphine with or without oxygen. In most of these studies, there were no significant effects on dyspnea. In the one uncontrolled retrospective study, which also assessed the most patients (54), 78% of the patients inhaled morphine every 4 h for > 1 to > 15 days. The majority of these patients reported some form of rapid dyspnea relief that lasted for > 4 h. These findings may reflect the effect of cumulative dosing over time, something that was not achieved in the controlled, single-dose studies. The manner in which dyspnea was evaluated also bears some thought. The sensitivity of the VAS has to do with its ability to detect changes in breathlessness. Most laboratories induce breathlessness by exercise to calibrate the VAS. Verbal descriptions of the sensation may differ between laboratories and thus may lead to variations in standardization, such as may have occurred in the studies described by Foral et al. The rating of perceived exertion (Borg scale) is now widely used. Wilson and Jones2Wilson RC Jones PW A comparison of the visual analogue scale and modified Borg scale for the measurement of dyspnoea during exercise.Clin Sci (Lond). 1989; 76: 277-282Crossref PubMed Scopus (374) Google Scholar found greater reproducibility with the Borg scale, but suggested that the VAS might have greater precision and sensitivity. The specificity of the Borg scale depends on the instructions given to the subject. Finally, the studies described by Foral et al did not present data that plot breathlessness against ventilation or oxygen uptake, a more standardized way of quantifying the sensation for a given level of activity.3Stark RD Dyspnoea: assessment and pharmacologic manipulation.Eur Respir J. 1988; 1: 280-287PubMed Google Scholar Unless the opioids were absorbed systemically in adequate quantities (thereby affecting central pain receptors), it is understandable why most studies failed to show a significant effect. It is not even known whether there are opiate receptors in the human chest wall or lung. There are experimental data in animals demonstrating the presence of opiate receptors in the lung involved in the control of breathing, but afferent pulmonary receptors in humans have not been described.4Jankelson D Hosseini K Mather LE et al.Lack of effect of high doses of inhaled morphine on exercise endurance in patients with chronic obstructive pulmonary disease.Eur Respir J. 1997; 10: 2270-2274Crossref PubMed Scopus (39) Google Scholar In any case, if they are present, they are not affected by the doses of morphine used in the studies reviewed by Floral et al. Furthermore, most studies demonstrating the systemic absorption of morphine fail to result in improvement in the dyspnea score during exercise testing. Jankelson et al4Jankelson D Hosseini K Mather LE et al.Lack of effect of high doses of inhaled morphine on exercise endurance in patients with chronic obstructive pulmonary disease.Eur Respir J. 1997; 10: 2270-2274Crossref PubMed Scopus (39) Google Scholar found that plasma concentrations of 40 mg nebulized morphine were similar to those resulting 15 min after IV doses of 1 to 2.5 mg, indicating efficient absorption across the lung. Yet, their study did not provide evidence for or against the presence of opiate receptors in the lung. Conversely, if there were an opiate that relieved dyspnea through central mechanisms, then the inhalational route could provide rapid drug delivery. Higher doses than those used in the studies reviewed by Foral et al, however, would have to be used for adequate dyspnea relief. Ultimately, if aerosolized opiates are found to be effective in relieving dyspnea, appropriate studies would need to be conducted to compare this form of drug administration with systemic use. Nebulized opiates may also be better tolerated at higher doses than systemic administration, although, as Foral et al point out, rare cases of respiratory depression and bronchoconstriction have been described. On the other hand, the use of morphine, whether or not used in combination with other drugs, such as phenothiazines or benzodiazepines, is probably more convenient when orally administered, and may be devoid of serious side effects.5Stark RD Stark AC Russell NJW Dyspnea: a possible target for pharmacological intervention.in: Adams L Guz A Respiratory sensation: lung biology in health and disease (vol 90). Marcel Dekker, New York, NY1996: 341-363Google Scholar It may be that patients with different illnesses need different drugs and routes of administration for achieving optimum relief of breathlessness. Such a goal is desirable, and indeed imperative, in order to improve the chronic impairment of quality of life in patients with advanced respiratory or cardiac illness.