Opioids are the drugs of choice for the pharmacological management of breathlessness, with good evidence for their oral and parenteral use [1,2]. Traditionally, oral administration of drugs including opioids is the preferred route as patients can self-administer the drug and remain independent. The onset of action of short-acting oral opioids is normally 15–30 min . Alternative routes of drug administration are inhaled nebulized and intranasal forms. Over the last 15 years, several inhaled nebulized and intranasal drugs have been developed and successfully tested mainly for opioids in pain management . The main advantage of these modes of application is the quick onset of action. As breathlessness episodes are short in nature with almost 90% lasting less than 20 min [5,6], drugs with a short onset of action are attractive as they are more likely to reduce patients’ distress.
Inhaled nebulized drugs
The administration of inhaled opioids via nebulizer is attractive because of low cost, ease of use, and ready availability . It has been considered that inhaled nebulized opioids bind to intrapulmonary opioid receptors and relieve breathlessness with minimal or no side-effects because of less systemic absorption [8,9]. The specific opioid receptor ratios in the human lung are not completely known although, in rat lungs, kappa receptors predominate , which in theory might be a reason to use morphine sulfate instead of fentanyl that binds preferentially to the mu receptor. However, it has been suggested that nonconventional opioid receptors are also present in the lung . Thus, both morphine and fentanyl have been tested in inhaled forms in studies testing opioids in breathlessness [7,11].
Nebulized drugs are usually dissolved in 2 ml of isotonic saline in a special device such as a Pari jet nebulizer. Krajnik et al. examined the type of administration of inhaled morphine and its influence on absorption and pharmacokinetics. Large aerosol particles (2–5 μm) were preferentially delivered to the bronchial tree and trachea, whereas small aerosol particles (0.5–2 μm) mostly reached the alveoli. Depending on the type of inhalation of the same amount of morphine, the Bronchial Control Treatment System-Sidestream delivering large particles showed an effect after 6.6 ± 2 min, whereas with the Bronchial Control Treatment System-Micro Cirrus method, delivery of small particles needed 28.8 ± 8 min .
It remains unclear whether the effects of aerosolized opioids on dyspnea are because of modifications in the peripheral afferent signaling that alters proprioception, or that opioids absorbed into the systemic circulation act on central nervous system control of breathing .
Chrubasik et al. reported that serum morphine levels following inhalation varied widely among individuals, with a relative systemic bioavailability of 17% (range 9–35%). The maximum serum morphine concentration was achieved by 45 min and was approximately six times lower than that with intramuscular administration .
Nasal application of drugs has been used for many years for therapeutic agents, psychotropic drugs, and hallucinogens . Drugs can be absorbed via the intranasal mucosa because of its high degree of vascularization and high permeability , and it has been shown that one dose of intranasal fentanyl spray gives significantly higher plasma fentanyl levels and significantly higher bioavailability than oral transmucosal fentanyl . Drug absorption depends on a number of factors such as particle diameter (should be ≥10 μm), the volume administered (should be ≤200 μl, ideally around 100 μl), low molecular weight of the molecule, and high lipophilicity . The main advantages of intranasal drug application are a rapid onset of action and the avoidance of gastrointestinal and hepatic first-pass effects . Time to reach maximum fentanyl plasma concentrations after intranasal administration is 12 min (range 12–21 min) . The onset of the effect for pain relief is within 5 min . The bioavailability of nasal fentanyl is reported to vary between 71 and 89% [20,21]. One of the disadvantages is the fear of higher risk of drug addiction as postulated in the management of noncancer pain . Although intranasal administration is often labeled as easy to use, the spray or bottle has to be secured in a child-resistant container which is challenging to open for very ill and frail patients.
Type of opioids
Not all opioids can be administered via inhaled or intranasal modes. In order to be absorbed by the intranasal or intraoral mucosa, opioids need to be lipophilic. Fentanyl fulfils this criterion as it is highly lipid soluble, whereas morphine is hydrophilic . Therefore, morphine is poorly absorbed via this route .
Morphine has been the most widely used opioid for nebulization as opioid receptors in the lung are predominantly kappa receptors. Also, fewer side-effects have been noted with inhaled morphine compared with injectable routes . However, there is some concern that nebulized morphine can induce bronchospasm . In addition, hydromorphone has also been tested for the relief of breathlessness .
Evidence for the inhaled nebulized and intranasal administration of drugs in the relief of breathlessness is scarce. In 2001, Jennings et al. concluded in their Cochrane Review that there was evidence to support the use of oral and parenteral, but not of nebulized opioids. They also acknowledged that larger studies of nebulized opioids are required that control for dose, nebulizer, and drug . Therefore, this review describes the recent studies evaluating the effectiveness of inhaled nebulized and intranasal application of opioids for patients suffering from refractory breathlessness.
A literature search of peer-reviewed literature was conducted in Medline and Embase via Ovid for articles published between 2012 and April 2014. The following search terms were used: dyspnea (MeSH term and keyword) or breathlessness (keyword) AND opioids (MeSH term and keyword) AND Administration, Intranasal/ or intranasal.mp. (MeSH term and keyword) OR Inhalation/ or Administration, Inhalation/ or inhalation.mp. OR ‘Nebulizers and Vaporizers’/ or nebulize.mp.
Since 2012, one systematic review and three primary studies reported information on the use of inhaled or intranasal opioid application for the relief of breathlessness.
Simon et al.[26▪▪] published a systematic review aiming to analyze and summarize the evidence about the use of fentanyl for the relief of breathlessness by systematically reviewing the available literature. They assessed 13 studies in this review, with most studies being case studies and only 2 randomized controlled trials (RCTs). One RCT, testing inhaled fentanyl, included 12 patients and was planned as a feasibility study [27▪], and the second RCT, also evaluating nebulized fentanyl, actually failed to recruit a sufficient number of patients and stopped recruitment after 18 months with only 2 patients being included .
Nebulized fentanyl citrate was used in five studies including 70 patients [7,27▪,28–30] and intranasal application in two studies (n = 5) [31,32]. Nebulized fentanyl was used in a limited range of 25–100 μg [7,27▪,28–30]. The authors concluded that there is currently no evidence for the effectiveness of fentanyl for the relief of breathlessness because of the lack of sufficiently powered and controlled studies [26▪▪]. Only the RCT conducted by Jensen et al.[27▪] demonstrated a lower intensity of breathlessness after administration of fentanyl compared with placebo, but the difference was not statistically significant. All other quasi-experimental and descriptive studies reported an improvement regarding the relief of breathlessness intensity [26▪▪].
Jensen et al.[27▪] (partially described in the systematic review above) tested a single-dose inhalation of 50 μg nebulized fentanyl citrate on exercise tolerance and dyspnea in chronic obstructive pulmonary disease (COPD) patients in a randomized, double-blind, placebo-controlled, crossover study. The application of fentanyl was associated with significantly increased exercise endurance time and small but consistent increases in dynamic inspiratory capacity. There was no concomitant change in ventilatory demand, breathing pattern, pulmonary gas exchange, and cardiometabolic function during exercise. The mean rate of increase in dyspnea intensity ((1.2 ± 0.3 vs. 2.9 ± 0.8 Borg units/min, P = 0.03) and unpleasantness ratings ((0.5 ± 0.2 vs. 2.9 ± 1.3 Borg units/min, P = 0.06) between isotime and peak exercise was less after treatment with fentanyl citrate vs. placebo [27▪].
In a randomized, controlled, double-blinded trial, Shohrati et al. tested nebulized morphine in 40 patients suffering from COPD because of exposure to sulfur mustard. The intervention group received 1 mg morphine sulfate diluted by 4 ml normal saline 0.5% via a nebulizer once-daily for 5 days. A nebulizer was used that can transport micro-aerocell with 2–3 μmin diameter to lower airways such as bronchiole in adults. The control group only inhaled normal saline as placebo . Breathlessness, cough, and quality of life improved significantly in the intervention group as well as respiratory rate, heart rate, and nighttime wakening.
Harlos et al. reported in a retrospective chart review of 11 of 58 newborns and infants aged 6 months or younger the use of intranasal fentanyl for respiratory distress. Fentanyl was well tolerated; no circumstances of drug-related apnea and no occurrences of chest wall rigidity were reported. In most cases, labored breathing and restlessness settled after the administration of intranasal fentanyl. The authors concluded that intranasal fentanyl was minimally invasive for palliating distress in dying newborns and infants.
Although breathlessness is a common and distressing symptom and the application of inhaled or intranasal opioids seems promising especially for acute episodes of breathlessness because of rapid onset of action and ease of use, there is a surprising paucity of robust studies evaluating the effectiveness of these modes of administration.
During the last 2 years, one systematic review evaluated the use and effectiveness of different modes of application of fentanyl [26▪▪], including inhaled nebulized and intranasal fentanyl; one RCT of nebulized fentanyl [27▪] and one RCT on nebulized morphine  both conducted in COPD patients were published. In addition, a retrospective chart review on the intranasal application of fentanyl in dying newborn babies was published .
The feasibility study by Jensen et al.[27▪] did not show a demonstrable effect on either the intensity or unpleasantness of perceived dyspnea at isotime or at peak exercise, but the rate of increase in dyspnea intensity and unpleasantness ratings between isotime and peak exercise was less after treatment with fentanyl citrate than placebo. In addition, significant improvements in exercise endurance time were indicated. As this was a feasibility study, no firm conclusions can be drawn from the results as they need to be confirmed in a fully powered RCT. However, an increase in the exercise tolerance could be an important achievement as many patients suffering from breathlessness live in social isolation as their exercise capacity is markedly reduced.
The results by Shohrati's study  are somehow surprising as a single dose of 1 mg inhaled morphine had a measurable benefit on breathlessness in patients suffering from COPD and bronchiolitis obliterans up to 8 h. As the disrupted lung parenchyma was a consequence of exposure to sulfur mustard in Iraq rather than the typical risk factors for COPD, these patients have no evidence of emphysema . This was one explanation of the authors for the effectiveness shown in their study. However, the study has some limitations. No sample size calculation was provided and the randomization process is not described at all. Therefore, the study has a high risk of bias which affects the interpretation of the results.
The only publication reporting the use of intranasal fentanyl described the use in a small cohort of newborn infants up to 6 months dying from lethal fetal anomalies and suffering from respiratory distress . As measurement of breathlessness has its limitations in this patient group, the authors used surrogate parameter such as tachypnea, nasal flaring, grunting, use of accessory muscles, chest wall retractions, and signs of distress (restlessness, irritability, and crying) to assess the effect of intranasal fentanyl. Quality of reporting about the effect on breathlessness varied as this was not a research study but a retrospective chart review of clinical notes. Therefore, the authors concluded that in most cases, the distress of the babies which presented as labored breathing and restlessness settled after medication . It could be questioned to include this study in the review because of the patient group and the lack of subjective measurement of breathlessness. However, we have decided to mention it as it gives an important indication and is the only study published recently on the intranasal application of opioids.
Although a number of case studies using intranasal or nebulized fentanyl were published in the recent years, sound evidence from robust RCTs is missing. Conducting RCTs in a palliative care population is challenging, especially in patients suffering from breathlessness because of advanced disease. Therefore, it is not surprising that the two recent RCTs were conducted in COPD patients and not in cancer patients. Most studies assessing the effectiveness of breathlessness in advanced disease included predominantly COPD patients and only a small number of cancer patients [1,35]. Furthermore, some drug regulators such as the European Medicines Agency (EMA) demand that for safety reasons patients who are receiving nebulized or intranasal opioids need to be opioid tolerant. For example, with fentanyl, patients need to receive regular opioids with a morphine equivalent of 60 mg per 24 h. This makes research in this area challenging as many patients need much lower doses for the relief of breathlessness . However, in pain management, first studies are testing nasal opioids in opioid-naïve patients . Nevertheless, three studies are currently registered on clinicaltrials.gov, with two studies testing inhaled fentanyl and one testing intranasal fentanyl.
As there are a number of medication delivery systems available, the question needs to be considered which one is the best option. Is it inhalation or intranasal or sublingual or buccal or oral application? Only patients can judge their preference and what is acceptable to them. One hundred and nineteen patients suffering from breathlessness because of advanced malignant and nonmalignant disease have been asked about their preferences for six application forms (oral, inhaled, sublingual, intranasal, buccal, and transmucosal). The inhaled route was the most acceptable and preferred route of application, but no route seemed to be acceptable to all patients [37▪]. In order to offer patients evidence-based therapies in relation to their personal preferences, we need to urgently test the effectiveness of these applications.
Opioids play a central role in the pharmacological management of breathlessness. During the recent years, new modes of delivery such as inhaled nebulized and intranasal application have been tested for pain management. These are also attractive for the management of acute episodes of breathlessness because of the short onset of action and ease of use. Although a number of case and before-and-after studies have been published during the recent years, there is still little evidence to support the use of inhaled nebulized and intranasal opioids for the relief of breathlessness. Therefore, more robust studies are needed before these modes of application can be recommended for routine use in the management of breathlessness.
C.B. receives research funding from the German Federal Ministry of Education and Research.
S.T.S. received research funding for a clinical trial (IIT) evaluation of buccal fentanyl for episodic breathlessness from TEVA Ltd.
Disclosure of funding received for this work: none for C.B.
Conflicts of interest
There are no conflicts of interest.
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