Inhaled Opioids for the Treatment of Dyspnea
Inhaled Opioids for the Treatment of Dyspnea
The Clinical Consultation column provides brief recommendations on handling specific pharmacothera-peutic problems in clinical practice. The problems addressed may be general or specialized but of wide interest. The column provides readers with relevant insights into optimum drug-therapy management by pharmacists. Recommendations are made on the basis of scientific literature and the author's clinical judgment and personal experience. Pharmacists in various settings, including drug information centers, are encouraged to submit manuscripts, ideas, and comments to AJHP ( ajhp@ashp.org ).
Dyspneacan be described as shortness of breath or difficulty breathing. Not always an un-pleasant sensation, it becomes so when a small amount of exertion leads to a disproportionately large increase in ventilatory needs. The causes of dyspneacan vary from physical exercise to pulmonary, car-diac, and neuromusculardisease to psychogenic factors like anxiety.
In the end stages of a terminal disease, dyspnea is a distressing and common symptom. Up to 70% of patients with advanced cancer of all types have dyspnea near the end of life. Drug therapy aimed attreating the underlying cause is likely to be maximized; interventions such as thoracentesis and increased oxygen administration may yield minimal benefit. Morphine and other opioids given in small doses orally, sublin-gually, by injection, or by inhalation can provide dramatic relief for many patients without causing respiratory depression. Nonpharmacologic interventions, such as pursed-lip breathing, relaxation, meditation, and the use of a fan or open window to move air over the face may also provide relief before medications are turned to.
The exact mechanism by which opioids palliate dyspneais unclear. The drugs' cardiovascular effects are thought to be most likely responsible for relieving dyspnea. Therapeutic doses of opioids produce peripheral vasodilation, reduce peripheral vascular resistance, and inhibit baro receptor responses; they also decrease brainstem responsiveness to carbon dioxide (the primary mechanism of opioid induced respiratory depression) and lessen the reflex vasoconstriction caused by increased blood PCO2levels so that the perception of dyspnea is reduced. Furthermore, opioids reduce the anxiety associated with dyspnea. There is also speculation that they may act directly on opioid receptors present in the airways.
The nebulization of opioids delivers medication directly into the airways and hence into the pulmonary circulation. Hepatic first-pass metabolism is avoided, and this route has been advocated as causing fewer adverse reactions, such as drowsiness, nausea, vomiting, and constipation.
Inhaled opioids achieve rapid but erratic plasma drug levels. Masood and Thomas demonstrated that nebulized morphine achieved peak plasma levels rapidly in all subjects (within 10 minutes) compared with oral morphine but that the variability was greater-from 10 to 30 minutes. Bioavailability was 5.5% (range, 3.2-7.8%) for delivery by inhalation and 24% (15-33%) after oral administration. A previous study had found that the bioavailability of inhaled morphine in subjects on a ventilator ranged from 9% to 35% (mean, 17%).
Controlled trials evaluating inhaled opioids in the treatment of dyspnea in patients with chronic lung diseases have tended to be small and have yielded mixed results. Masood et al. observed that inhaled morphine had no effect on exercise-induced breathlessness in healthy individuals. No improvement in exercise tolerance was demonstrated in several studies of patients with chronic obstructive pulmonary disease. A systematic review of 18 randomized, double-blind, controlled trials of opioids for the symptomatic control of dyspnea in terminally ill patients (of which 9 trials used nebulized opioids) concluded that, while there was evidence to support the use of oral or i.v. agents, there was no evidence to support nebulized administration.
The inhalational route avoids the first pass through the liver, but one may still see adverse effects, including sedation, nausea, and vomiting, especially in patients who have not previously had opioid exposure. In general, however, inhaled opioids are well tolerated. Constipation may occur, and stimulant laxatives should be used. Morphine and hydromorphone can cause histamine release that may lead to bronchoconstriction, especially in asthmatics. Some clinicians prefer fentanyl for this reason. There has been one report of respiratory depression requiring mechanical ventilation after the administration of nebulized morphine.
A variety of opioids have been administered via inhalation for dyspnea. Nonpreserved injectable solutions should be used to avoid respiratory irritation from preservatives, excipients, and so on. The drug is typically diluted in 2 mL of 0.9% so-dium chloride injection prior to administration. Doses vary depending on the previous use of opioids and can be adjusted to effect. Morphine sulfate 2.5-10 mg, hydromorphone hydro-chloride 0.25-1 mg, and fentanyl cit-rate 25 µg are the most commonly used doses in the United States.
The disadvantages of nebulized opioids compared with other dosage forms include increased costs (for the nebulizer, preservative-free injectable drugs, and supplies), a more complicated method of delivery (requiring patients or their care givers to manipulate medication vials, needles, and syringes), system nonportability due to the size and requirement of electricity of the nebulizer, and the possibility that patients may be unable to use a nebulizer properly because of debility or minimal inspiratory ability.
Controlled trials show no clear benefit of inhaled opioids over oral or i.v. administration in the treatment of dyspnea. Low-dose oral or sublingual opioids are effective in treating dyspnea. Most patients, especially in the palliative care setting, tolerate and benefit from noninhaled opioids for dyspnea. The use of nebulized opioids may be advantageous for those unwilling or unable to take an oral agent and those who have had intolerable adverse effects after systemic administration.
The Clinical Consultation column provides brief recommendations on handling specific pharmacothera-peutic problems in clinical practice. The problems addressed may be general or specialized but of wide interest. The column provides readers with relevant insights into optimum drug-therapy management by pharmacists. Recommendations are made on the basis of scientific literature and the author's clinical judgment and personal experience. Pharmacists in various settings, including drug information centers, are encouraged to submit manuscripts, ideas, and comments to AJHP ( ajhp@ashp.org ).
Dyspneacan be described as shortness of breath or difficulty breathing. Not always an un-pleasant sensation, it becomes so when a small amount of exertion leads to a disproportionately large increase in ventilatory needs. The causes of dyspneacan vary from physical exercise to pulmonary, car-diac, and neuromusculardisease to psychogenic factors like anxiety.
In the end stages of a terminal disease, dyspnea is a distressing and common symptom. Up to 70% of patients with advanced cancer of all types have dyspnea near the end of life. Drug therapy aimed attreating the underlying cause is likely to be maximized; interventions such as thoracentesis and increased oxygen administration may yield minimal benefit. Morphine and other opioids given in small doses orally, sublin-gually, by injection, or by inhalation can provide dramatic relief for many patients without causing respiratory depression. Nonpharmacologic interventions, such as pursed-lip breathing, relaxation, meditation, and the use of a fan or open window to move air over the face may also provide relief before medications are turned to.
The exact mechanism by which opioids palliate dyspneais unclear. The drugs' cardiovascular effects are thought to be most likely responsible for relieving dyspnea. Therapeutic doses of opioids produce peripheral vasodilation, reduce peripheral vascular resistance, and inhibit baro receptor responses; they also decrease brainstem responsiveness to carbon dioxide (the primary mechanism of opioid induced respiratory depression) and lessen the reflex vasoconstriction caused by increased blood PCO2levels so that the perception of dyspnea is reduced. Furthermore, opioids reduce the anxiety associated with dyspnea. There is also speculation that they may act directly on opioid receptors present in the airways.
The nebulization of opioids delivers medication directly into the airways and hence into the pulmonary circulation. Hepatic first-pass metabolism is avoided, and this route has been advocated as causing fewer adverse reactions, such as drowsiness, nausea, vomiting, and constipation.
Inhaled opioids achieve rapid but erratic plasma drug levels. Masood and Thomas demonstrated that nebulized morphine achieved peak plasma levels rapidly in all subjects (within 10 minutes) compared with oral morphine but that the variability was greater-from 10 to 30 minutes. Bioavailability was 5.5% (range, 3.2-7.8%) for delivery by inhalation and 24% (15-33%) after oral administration. A previous study had found that the bioavailability of inhaled morphine in subjects on a ventilator ranged from 9% to 35% (mean, 17%).
Controlled trials evaluating inhaled opioids in the treatment of dyspnea in patients with chronic lung diseases have tended to be small and have yielded mixed results. Masood et al. observed that inhaled morphine had no effect on exercise-induced breathlessness in healthy individuals. No improvement in exercise tolerance was demonstrated in several studies of patients with chronic obstructive pulmonary disease. A systematic review of 18 randomized, double-blind, controlled trials of opioids for the symptomatic control of dyspnea in terminally ill patients (of which 9 trials used nebulized opioids) concluded that, while there was evidence to support the use of oral or i.v. agents, there was no evidence to support nebulized administration.
The inhalational route avoids the first pass through the liver, but one may still see adverse effects, including sedation, nausea, and vomiting, especially in patients who have not previously had opioid exposure. In general, however, inhaled opioids are well tolerated. Constipation may occur, and stimulant laxatives should be used. Morphine and hydromorphone can cause histamine release that may lead to bronchoconstriction, especially in asthmatics. Some clinicians prefer fentanyl for this reason. There has been one report of respiratory depression requiring mechanical ventilation after the administration of nebulized morphine.
A variety of opioids have been administered via inhalation for dyspnea. Nonpreserved injectable solutions should be used to avoid respiratory irritation from preservatives, excipients, and so on. The drug is typically diluted in 2 mL of 0.9% so-dium chloride injection prior to administration. Doses vary depending on the previous use of opioids and can be adjusted to effect. Morphine sulfate 2.5-10 mg, hydromorphone hydro-chloride 0.25-1 mg, and fentanyl cit-rate 25 µg are the most commonly used doses in the United States.
The disadvantages of nebulized opioids compared with other dosage forms include increased costs (for the nebulizer, preservative-free injectable drugs, and supplies), a more complicated method of delivery (requiring patients or their care givers to manipulate medication vials, needles, and syringes), system nonportability due to the size and requirement of electricity of the nebulizer, and the possibility that patients may be unable to use a nebulizer properly because of debility or minimal inspiratory ability.
Controlled trials show no clear benefit of inhaled opioids over oral or i.v. administration in the treatment of dyspnea. Low-dose oral or sublingual opioids are effective in treating dyspnea. Most patients, especially in the palliative care setting, tolerate and benefit from noninhaled opioids for dyspnea. The use of nebulized opioids may be advantageous for those unwilling or unable to take an oral agent and those who have had intolerable adverse effects after systemic administration.
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