naloxone and Dyspnea

To review the mechanisms for the perception of dyspnea and to consider the plausibility of interventions that palliate dyspnea after optimal treatment of the underlying disease.. Activation of sensory receptors by blood gas abnormalities, mechanical respiratory loads, and hyperinflation provides afferent information to the central nervous system for integration and processing. It has been proposed that a discriminative pathway processes afferent impulses to the somatosensory cortex that reflects the intensity of dyspnea, whereas an affective pathway projects afferent impulses to structures of the limbic system that reflects the unpleasantness of dyspnea. In one study, patients with chronic obstructive pulmonary disease reported consistently higher ratings of breathlessness after administration of naloxone, an opioid receptor antagonist, compared with physiological saline during high-intensity treadmill exercise. This finding supports the role of endogenous opioids in modulating dyspnea. Nebulized furosemide, anti-inflammatory therapy, and chest wall vibration are potential approaches for modulating lung and chest wall receptors to relieve dyspnea.. Targets for palliating dyspnea in patients with advanced disease include sensory receptors within the lung/chest wall and the central nervous system. The opioid system plays an important role in palliating dyspnea. Both endogenous (β-endorphins) and exogenous (morphine) opioids modulate breathlessness.

Topics: Afferent Pathways; Central Nervous System; Dyspnea; Efferent Pathways; Endorphins; Humans; Naloxone; Narcotic Antagonists; Neurotransmitter Agents; Palliative Care; Panic Disorder; Pulmonary Disease, Chronic Obstructive; Sensory Receptor Cells

The objective of this study was to investigate whether substance P, an excitatory neuropeptide, modulates the perception of breathlessness by administering aprepitant, a selective antagonist that blocks neurokinin (NK)-1 receptor signaling. Individual targeted resistive load breathing (RLB) was used to provoke breathlessness. In Study 1, sixteen patients (age, 70±6 years) with chronic obstructive pulmonary disease (COPD) reported similar ratings of breathlessness during RLB between oral aprepitant (125mg) and placebo. After aprepitant, but not with placebo, there were significant increases in blood levels of substance P (+54±39%) and beta-endorphin (+27±17%). A similar design was used in Study 2 except that naloxone (10mg) was administered intravenously prior to RLB to block any effect of endogenous opioids. Nine patients with COPD reported comparable breathlessness ratings during RLB between aprepitant and placebo. Our results do not support a role for the substance P-NK-1 pathway in the perception of breathlessness in patients with COPD. With selective antagonism of NK-1 signaling, there was co-transmission of substance P and beta-endorphin neuropeptides.

Topics: Aged; Aprepitant; beta-Endorphin; Double-Blind Method; Dyspnea; Female; Humans; Male; Morpholines; Naloxone; Narcotic Antagonists; Neurokinin-1 Receptor Antagonists; Perception; Pulmonary Disease, Chronic Obstructive; Respiration; Substance P; Time Factors; Treatment Outcome

Exogenous opioid drugs, such as morphine, relieve breathlessness. The present study hypothesis was that endogenous opioids, released during the stress of exercise, modify dyspnoea in patients with chronic obstructive pulmonary disease. After familiarisation, patients performed an incremental treadmill exercise test followed by constant work on the treadmill for 10 min. At subsequent visits (2 to 3 days apart), patients received two puffs of albuterol, had a catheter placed in an arm vein for removal of blood to measure beta-endorphin immunoreactivity, received normal saline or 10 mg of naloxone intravenously in randomised order, and then performed high-intensity constant work rate exercise on the treadmill. The mean+/-sd age of the 17 patients (eight females and nine males) was 63+/-7 yrs, and post-bronchodilator forced expiratory volume in one second was 50+/-17% predicted. In both conditions, beta-endorphin levels increased three-fold from rest to end-exercise. The regression slope of breathlessness as a function of oxygen consumption (primary outcome), mean ratings of breathlessness throughout exercise and peak ratings of breathlessness were significantly higher with naloxone than normal saline. There were no differences in physiological responses throughout exercise between conditions. In conclusion, endogenous opioids modify dyspnoea during treadmill exercise in patients with chronic obstructive pulmonary disease by apparent alteration of central perception.

Topics: Adrenal Cortex Hormones; Adrenergic beta-Agonists; Albuterol; beta-Endorphin; Bronchodilator Agents; Double-Blind Method; Dyspnea; Exercise Test; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Opioid Peptides; Oxygen Consumption; Pulmonary Disease, Chronic Obstructive; Spirometry; Theophylline

Severe respiratory stress causes dyspnea, and a sudden release of this stress frequently accompanies a euphoric sensation. We hypothesized that acute severe respiratory stress may result in an elaboration of endogenous opioids within the central nervous system, and that these opioids may play significant roles in relieving dyspnea and generating euphoric sensation after a sudden removal of the stress. To test this hypothesis, we examined the effects of naloxone (0.04 mg/kg, I.V.) and the placebo (normal saline) on changes in respiratory sensation before and after the release of severe respiratory stress in a double-blind, randomized, crossover study in 14 healthy adults. Acute severe respiratory stress was induced by loaded breathing with a combination of resistive loading and hypercapnia. The subjects rated their changes in sensation by using a bidirectional visual analogue scale. Naloxone pretreatment affected neither the ventilation nor the development of dyspneic sensation during loaded breathing. Naloxone pretreatment only slightly attentuated the euphoric sensation developed after the release of severe respiratory stress. These findings suggest a small role of opioids in relieving dyspnea and in generating euphoria before and after a sudden removal of stress.

Topics: Adult; Analysis of Variance; Area Under Curve; Dyspnea; Euphoria; Humans; Hypercapnia; Male; Naloxone; Respiration; Respiratory Mechanics; Sensation; Stress, Physiological

To clarify whether endogenous opioids modulate the dyspnea intensity and, if so, by what mechanism they act on it, we examined 12 healthy male volunteers aged 19-27 yr for ventilatory and peak mouth pressure (Pm) responses to hypoxic progressive hypercapnia with inspiratory flow-resistive loading after the intravenous infusion of 3 mg of naloxone or saline. The intensity of dyspnea was simultaneously assessed by visual analogue scaling every 15 s. Naloxone administration increased both ventilatory and Pm responses to hypoxic progressive hypercapnia (P < 0.05 for both). The increase in dyspnea intensity for a given increase in end-tidal PCO2 was significantly greater after naloxone infusion than after saline (P < 0.05). However, there were no differences in the increase in dyspnea intensity for a given increase in minute ventilation or Pm. These results suggest that the endogenous opioid system suppresses the respiratory output under a strong, acute respiratory stress in normal adults and that this system may relieve the dyspnea sensation secondary to the suppression of the brain stem respiratory center without specific effects on the processing of respiratory sensations in the higher brain.

Topics: Adult; Carbon Dioxide; Double-Blind Method; Dyspnea; Humans; Male; Naloxone; Neurons, Afferent; Oxygen; Respiration; Respiratory Mechanics; Stress, Physiological

The aim of this study was to evaluate whether endogenous opioids are involved in the regulation of breathing pattern and respiratory drive during bronchoconstriction induced by methacholine (MCh). We studied six male asymptomatic asthmatics 18 to 35 yr of age. In a preliminary study we determined the concentration of MCh causing a 60% fall in FEV1 (PC60 FEV1). On two subsequent days, we measured breathing pattern, dyspnea sensation (Borg scale), mouth occlusion pressure (P0.1), and FEV1 before and 10 min after an intravenous injection of either naloxone (0.1 mg/kg) or saline according to a randomized double-blind crossover design. A MCh concentration equal to the PC60 FEV1 was then inhaled, and measurements were repeated 5 min later. Neither placebo nor naloxone affected baseline breathing pattern, P0.1, and FEV1. Naloxone pretreatment did not influence airway response to MCh; the mean percent fall in FEV1 was 65.9 +/- 1.3 and 64.7 +/- 1.2% (mean +/- 1 SE) on the placebo day and the naloxone day, respectively. After MCh inhalation no significant changes in VE, VT, and breathing frequency occurred when patients received placebo. However, P0.1 increased from 1.48 +/- 0.17 to 3.43 +/- 0.70 cm H2O (p less than 0.05), and VT/TI fell from 0.66 +/- 0.08 to 0.52 +/- 0.04 L/s (p less than 0.05). Naloxone pretreatment resulted in an increase in breathing frequency (from 18.2 +/- 1.7 to 22.8 +/- 2.6 breaths/min; p less than 0.05) and VT/TI (from 0.58 +/- 0.06 to 0.74 +/- 0.05 L/s; p less than 0.05) after MCh.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Adolescent; Adult; Asthma; Bronchial Provocation Tests; Bronchoconstriction; Double-Blind Method; Dyspnea; Endorphins; Humans; Male; Methacholine Chloride; Middle Aged; Naloxone; Random Allocation; Respiration; Respiratory Mechanics

Endogenous opioids are naturally occurring peptides released by the brain in response to noxious stimuli. Although these naturally occurring peptides modulate pain, it is unknown whether endogenous opioids affect the perception of breathlessness associated with a specific respiratory challenge. The hypothesis is that intravenous administration of naloxone, used to block opioid signaling and inhibit neural pathways, will increase ratings of breathlessness during resistive load breathing (RLB) in patients with chronic obstructive pulmonary disease (COPD).. Fourteen patients with COPD (age, 64 ± 9 years) inspired through resistances during practice sessions to identify an individualized target load that caused ratings of intensity and/or unpleasantness of breathlessness ≥ 50 mm on a 100 mm visual analog scale. At two intervention visits, serum beta-endorphins were measured, naloxone (10 mg/25 ml) or normal saline (25 ml) was administered intravenously, and patients rated the two dimensions of breathlessness each minute during RLB.. Patient ratings of intensity (p = 0.0004) and unpleasantness (p = 0.024) of breathlessness were higher with naloxone compared with normal saline. Eleven patients (79%) reported that it was easier to breathe during RLB with normal saline (p = 0.025). RLB led to significant increases in serum beta-endorphin immunoreactivity and decreases in inspiratory capacity. There were no significant differences in physiological responses between interventions.. Endogenous opioids modulate the intensity and the unpleasantness of breathlessness in patients with COPD. Differences in breathlessness ratings between interventions were clinically relevant based on the patients' global assessment.

Topics: Aged; Airway Resistance; beta-Endorphin; Cross-Over Studies; Double-Blind Method; Dyspnea; Female; Humans; Inspiratory Capacity; Male; Middle Aged; Naloxone; Narcotic Antagonists; Pulmonary Disease, Chronic Obstructive; Random Allocation; Respiration

Topics: Aged; Aged, 80 and over; Analgesics, Opioid; Dyspnea; Female; Humans; Male; Naloxone; Narcotic Antagonists; Palliative Care; Pulmonary Disease, Chronic Obstructive; Respiratory Insufficiency

To clarify whether endogenous opioids play modulatory roles in control of breathing and have any specific effects on the intensity of dyspnea, healthy volunteers were examined for two protocols of ventilatory response tests. 1) The ventilatory response to hypercapnic progressive hypoxia and the withdrawal response to assess peripheral chemoreceptor activity were compared before and after intravenous infusion of 3 mg naloxone in 21 healthy adults. The average ventilatory response increased significantly after naloxone infusion (p less than 0.05), whereas there were no significant changes between two tests with normal saline in the control study (n = 7). Because there was considerable interindividual variation in the response to naloxone administration, "high responders" (n = 8) who showed larger increases with naloxone than the upper limit of the 95% confidence interval for the change with the second saline in the control study were selected. They showed greater ventilatory responses before naloxone infusion than did the other subjects (p less than 0.01). There was no significant change in the withdrawal response before and after naloxone infusion, even in such high responders. 2) The ventilatory and peak mouth pressure responses to hypoxic progressive hypercapnia with inspiratory flow-resistive loading were measured after the intravenous infusion of 3 mg naloxone or saline in 11 male volunteers, while the intensity of dyspnea was simultaneously assessed. Naloxone administration increased the peak mouth pressure response (p less than 0.05) although the increase in ventilatory response did not reach statistical significance. The intensity of dyspnea tended to be greater after naloxone infusion than after saline infusion at end-tidal PCO2 levels of 55 Torr and 60 Torr (p = 0.06 and 0.09, respectively). However, the intensity of dyspnea was quite similar between trials with and without naloxone when compared at equivalent levels of either minute ventilation or peak mouth pressure. These findings suggest that endogenous opioids suppress respiratory outputs under a strong, acute respiratory stress in normal humans. This may be particularly true for those subjects who have greater chemosensitivity. Endogenous opioids appear to act centrally rather than peripherally, but do not have any specific modulatory role on the sensation of dyspnea.

Topics: Adult; Aged; Dyspnea; Endorphins; Female; Humans; Hypercapnia; Male; Middle Aged; Naloxone; Respiration

1) Ambient temperature (Ta) significantly influenced the display of 4 of the 14 naloxone-precipitated withdrawal signs (nesting, flat posture, vocalization, dyspnea) in morphine-dependent, non-hibernating ground squirrels (Citellus lateralis). 2) Analysis of variance performed on the six quantified signs revealed that Ta during withdrawal, but not during the development of physical dependence, was a significant factor in determining the expression of two signs (nesting and vocalization). 3) The interaction between the influence of Ta during the periods of morphine administration and abstinence was a significant factor in determining the expression of nesting behavior, a finding that is consistent with the natural role of nesting as a behavioral thermoregulatory response. 4) We conclude that environmental temperature modulates the expression of selected components of the naloxone-precipitated abstinence syndrome in C. lateralis without exerting a measurable influence on the development of morphine physical dependence itself.

Topics: Animals; Dyspnea; Female; Humans; Male; Morphine Dependence; Naloxone; Nesting Behavior; Posture; Sciuridae; Substance Withdrawal Syndrome; Temperature; Vocalization, Animal

The newborn rabbit responds to acute anoxia, as a result of breathing nitrogen, with successive periods of dyspnoea, primary apnoea, gasping and terminal apnoea. Pethidine caused an increase in the period of primary apnoea and a decrease in the duration and rate of gasping. When nalorphine was combined with pethidine the period of primary apnoea was still increased although the duration and number of gasps were restored to control values. Naloxone, in contrast, acted as a mild respiratory stimulant, shown as a longer phase of dyspnoea. Also it completely abolished the respiratory depression produced by pethidine. Naloxone may be preferable to nalorphine as a drug to reverse the effects of pethidine immediately after birth.

Topics: Animals; Apnea; Dyspnea; Humans; Hypoxia; Infant, Newborn; Meperidine; Morphine; Nalorphine; Naloxone; Nitrogen; Rabbits; Respiration