THE EMERGENCY DEPARTMENT (ED) setting is an area that is well known for exploring alternative routes of medication administration (i.e., intramuscular, intranasal), and in many cases these routes have been shown to be not only viable but also advantageous routes of administration by reducing needlestick injuries and reducing the time to drug administration (Bailey et al., 2017). Aerosolized drug delivery is another modality of administration that is frequently utilized in the ED, traditionally for primary respiratory diseases such as asthma, but that also has the ability to treat a variety of both local and systemic diseases (Labiris & Dolovich, 2003). Providing medication delivery directly to the large, highly permeable, surface area of the lungs allows for not only the ability to provide pharmacotherapy directly to the site of action but also achieve a rapid therapeutic response at a reduced dose.

As opioids are one of the most commonly used medications in the ED, it naturally follows that the potential to nebulize opioids has been explored for the treatment of a wide variety of acute pain presentations from abdominal pain to the treatment of dyspnea due to terminal illness (Cohen et al., 2015; Cordell et al., 2002). The intent of this review is to explore the supporting literature behind the use of nebulized opioids, most specifically fentanyl, hydromorphone, and morphine, in the ED for the treatment of acute pain presentations and provide the most up-to-date guidance for practitioners.

FENTANYL

Because of its rapid onset, and short duration, of action compared with other opioids, fentanyl is commonly used for the treatment of acute pain in the ED. The rapid onset facilitates the completion of a diagnostic workup with a lower incidence of hemodynamic side effects while allowing for rapid clinical reevaluation (Chudnofsky, Wright, Dronen, Borron, & Wright, 1989; Peng & Sandler, 1999). Hence, nebulized fentanyl has been one of the most commonly evaluated opioids for the treatment of acute pain in the ED including for the treatment of abdominal pain, acute limb pain, and renal colic (Bartfield, Flint, McErlean, & Broderick, 2003; Deaton, Auten, & Darracq, 2015; Farahmand et al., 2014; Furyk, Grabowski, & Black, 2009; Imamoglu et al., 2017; Maleki Verki, Mozafari, Tirandaz, Motamed, & Khazaeli, 2019; Rezaei, Salimi, Kalantari, & Astaraki, 2021; Thompson & Thompson, 2016). The doses of fentanyl studied via nebulization range from the most commonly used doses via the intravenous (IV) route (1-2 mcg/kg) given via nebulization. Some practitioners have advocated for higher doses of opioids given via the nebulization route (up to 5 mcg/kg) as there may be variable absorption and bioavailability barriers; however, the published literature suggests that similar IV doses given via nebulization are safe and efficacious (Furyk et al., 2009).

One randomized, double-blind, double-placebo-controlled trial compared nebulized and IV fentanyl for the relief of abdominal pain in 50 patients (see Table 1; Bartfield et al., 2003). The primary outcome was a change in pain at 30 min from baseline following treatment. Patients were randomized to receive 1.5 mcg/kg of either IV or nebulized fentanyl for more than 5-10 min. The investigators used a breath-activated nebulizer, which ensures that no solution is lost during nebulization. There was a statistically significant difference in pain scores at 15 min favoring the IV fentanyl group; however, this endpoint was not found to be significant by 30 min posttreatment. The groups were not different with respect to need for rescue medication (50% for IV fentanyl vs. 69% in nebulized fentanyl, p = 0.25). The authors concluded that nebulized fentanyl provides comparable analgesia to that of IV fentanyl (Bartfield et al., 2003). Another study compared nebulized fentanyl at a dose of 2 mcg/kg with IV morphine 0.1 mg/kg for the alleviation of acute and undifferentiated abdominal pain (Deaton et al., 2015). In addition, they also evaluated patient and provider satisfaction with nebulized fentanyl. The fentanyl group was noted to experience more rapid pain relief and more sustained and clinically significant pain relief over the study. There were no adverse effects and both patient and physician satisfaction scores were higher in the fentanyl group. The authors concluded that fentanyl at 2 mcg/kg appears to be a feasible and safe alternative to IV morphine at 0.1 mg/kg in the treatment of acute abdominal pain (Deaton et al., 2015).

Table 1. Nebulized opioids

Multiple studies have been conducted on the use of nebulized fentanyl for the treatment of acute pain including acute limb pain (Farahmand et al., 2014; Furyk et al., 2009; Miner, Kletti, Herold, Hubbard, & Biros, 2007). One study compared 4 mcg/kg of nebulized fentanyl with 0.1 mg/kg IV morphine in 90 ED patients. The authors found that pain scores at 5, 10, and 15 min were similar between groups (p = 0.72; Farahmand et al., 2014). Another study enrolled 77 patients to evaluate fentanyl 4 mcg/kg nebulized compared with 0.1 mg/kg IV morphine in pediatric patients with limb fractures. They noted that decreases in pain scores for both groups were statistically significant (p < 0.0001). There was no significant change in any vital signs or serious adverse events in either group, and the authors concluded that nebulized fentanyl was an appropriate alternative for analgesia in this population (Furyk et al., 2009). Farahmand et al. (2014) compared 4 mcg/kg nebulized fentanyl with 0.1 mg/kg IV morphine. They concluded that pain relief in both groups after 5 and 10 min was similar (p = 0.72), patient satisfaction in both groups was similar, and there were no adverse effects (Farahmand et al., 2014). Miner et al. (2007) evaluated 1.5 mcg/kg IV fentanyl compared with 3 mcg/kg nebulized fentanyl for the treatment of acute pain in 41 pediatric patients aged 6 months to 17 years. The pain treatment was described as adequate by the treating physician and there was no statistical difference between the two groups and no adverse events were reported (Miner et al., 2007).

The use of nebulized fentanyl for acute pain secondary to renal colic has also been evaluated (Imamoglu et al., 2017; Rezaei et al., 2021). One study compared IV fentanyl (1.5 mcg/kg) with nebulized fentanyl (3 mcg/kg) in 115 patients randomized between these two groups. Nebulized fentanyl was administered for more than 15 min and they evaluated a change in pain scores from baseline. Patients receiving IV fentanyl had lower rescue analgesia requirements (37.1% vs. 54.7%), but adverse effects were more frequent in the IV fentanyl group (22.1% vs. 9.4%), although neither difference was statistically significant (Imamoglu et al., 2017). Another study of pediatric and adult patients with renal colic (n = 186) compared 0.9 mg/kg IV ketorolac with 3 mcg/kg nebulized fentanyl (Rezaei et al., 2021). They evaluated pain scores and found that although fentanyl was safe, IV ketorolac was statistically significantly better at achieving complete pain relief at 2 hr after the intervention than fentanyl (Rezaei et al., 2021).

There have been numerous studies evaluating various nebulized opioids for treatment of dyspnea (Bausewein & Simon, 2014; Charles, Reymond, & Israel, 2008; Coyne, Viswanathan, & Smith, 2002; Farncombe, Chater, & Gillin, 1994). The exact mechanism behind which opioids improve dyspnea is not completely understood. Systemic opioids have been a long-term mainstay for acute pain and treatment of dyspnea in and out of the ED (Afolabi, Nahata, & Pai, 2017; LeGrand, Khawam, Walsh, & Rivera, 2003; Parshall et al., 2012). When treating dyspnea, it is important to remember when using these agents that the aim with using nebulized opioids in the course of treatment of end-stage lung conditions may not necessarily be to improve ventilation but to improve patient's perception of shortness of breath. Subjective improvement in dyspnea may be more common in patients with malignancies rather than other chronic respiratory diseases. Dyspnea in these patients may be more difficult to manage due to excessive production of secretions, narrowing of the airways, or irreversible physiological destruction of lung tissue (Afolabi et al., 2017; Boyden et al., 2015; Foral, Malesker, Huerta, & Hilleman, 2004). Coyne et al. (2002) evaluated the use of nebulized fentanyl in 35 patients for acute dyspnea related to cancer-related disease. Twenty-six of 32 (81%) patients reported improvement in breathing and the oxygen saturation improved from 94.6% at baseline to 96.8% at 5 min and 96.7% at 60 min (p = 0.0069 compared with baseline). Respiratory rates improved from a baseline of 28.4 breaths/min to 25.9 breaths/min at 5 min and 24.1 breaths/min at 60 min (p = 0.025) and no side effects were observed. The authors concluded that inhaled nebulized fentanyl significantly improved patient's perception of breathing, respiratory rate, and oxygen saturation (Coyne et al., 2002). Fentanyl is the most investigated agent with the largest volume of evidence suggesting efficacy similar to IV administration.

HYDROMORPHONE

Hydromorphone is another commonly used IV opioid in the ED. It has a longer duration of action than fentanyl but a faster onset of analgesia than morphine (Charles et al., 2008). A retrospective chart review involved 54 patients in the terminal stage of their illness (both malignant and nonmalignant lung diseases), 17 of whom received nebulized hydromorphone at a dose of 1 mg every 4 hr for relief of dyspnea (Farncombe et al., 1994). While nine of these patients required further titration, one of the nine patients required a maximum of 20 mg nebulized every 4 hr but was already receiving this dose IV prior to transitioning to a nebulized route of administration. If patients experienced fewer than 4 hr of relief from dyspnea, the dose was increased by 25%-30% to achieve at least 4 hr of comfort between doses (Farncombe et al., 1994; Foral et al., 2004). One placebo-controlled, crossover study compared the effects of 5 mg nebulized hydromorphone with IV hydromorphone and with 3-ml nebulized 0.9% sodium chloride in 20 patients with advanced cancer (Charles et al., 2008). Patients were given a test dose of 2 mg of hydromorphone in 2-ml sterile water under supervision prior to randomization. All treatments showed a significant improvement in pain scores and respiratory rate at 10 min posttreatment (p < 0.05; Charles et al., 2008). Although the data are far less robust with hydromorphone than with fentanyl, there is evidence to suggest that hydromorphone is a viable alternative via this route.

MORPHINE

One study evaluated the safety and efficacy of a single dose of 0.2 mg/kg of nebulized morphine to 28 patients experiencing severe acute pain (Bounes et al., 2009). Although no adverse effects were noted, no patients experience pain relief at 10 min after the end of the nebulization. The authors concluded that nebulized morphine was not effective in managing acute pain in the ED. A systematic review of the literature assessed the use of nebulized morphine for the relief of dyspnea due to chronic lung disease (Brown, Eichner, & Jones, 2005). The authors concluded that the results of the limited studies available do not support the use of nebulized morphine for the treatment of dyspnea.

However, not all available data are discouraging. One prospective, randomized controlled trial of 300 patients with severe trauma pain compared the use of one nebulization of 10 mg of morphine and one nebulization of 20 mg of morphine with 2 mg of IV morphine (Grissa et al., 2015). The authors concluded that nebulized morphine boluses of 10 mg have similar efficacy and better safety than IV morphine and that increasing the doses to 20 mg increases effectiveness without increasing side effects. There was a significantly lower time to resolution of pain in the 20-mg nebulization group with an average of 20 min. Overall, 18.4% of the IV group and 5% of the 20-mg nebulization group experienced side effects, with the most frequent side effect being dizziness. Overall, comparatively less data are available regarding the use of nebulized morphine for acute pain in the ED, and the data that are available are far less encouraging, making it a much less desirable agent to administer via this route.

IMPLEMENTATION CONSIDERATIONS OF NEBULIZED DRUG DELIVERY

Unlike other modalities of medication administration in the ED, aerosolized drug delivery requires quite a bit more in terms of equipment (e.g., nebulizer, compressor), time, and expertise (Kuhn, 2002). Furthermore, additional manipulations of the pharmacologic agent itself may be necessary to help ensure optimal and predictable drug delivery (Kuhn, 2002). The type of nebulizer may affect the efficacy of nebulized opioids, given it impacts particle size, rate of nebulization, and amount of drug deposited (Afolabi et al., 2017; Boyden et al., 2015). In certain conditions drugs need to be delivered by different types of nebulizers to ensure appropriate disposition in the bronchial tree.

Unfortunately, this is not a viable route for all medications and there are multiple medication characteristics that can influence the efficacy of the aerosolized delivery of medications (Kuhn, 2002). The size of the particles themselves can influence efficacy as small particles (less than 1 microm) may be exhaled and not deposited, whereas large particles (less than 5 microm) may be deposited in the upper airway and subsequently swallowed (Kuhn, 2002). Furthermore, the lipophilicity of the agents can also greatly impact their absorption across physiologic membranes. For example, the absorption of morphine is relatively limited across membranes as it is more hydrophilic than some other agents (Chrubasik, Wust, Friedrich, & Geller, 1988). Conversely, fentanyl and hydromorphone are more lipophilic and have the potential to be more easily administered via intranasal or nebulization routes (Bausewein & Simon, 2014).

The tonicity of the nebulized solution will also impact efficacy. Hypotonic or hypertonic solutions may induce bronchial irritation or bronchospasms, thus decreasing the effectiveness of nebulized opioids. The preferred carrier fluids in most studies were 0.9% sodium chloride or sterile water (Boyden et al., 2015). Fentanyl doses can be prepared using a standard 50 mcg/ml solution diluted in 2 ml of saline for nebulization (Coyne et al., 2002). Farncombe et al. (1994) prepared preservative free hydromorphone 1 mg in 2-ml sterile water for injection. This was nebulized with compressed air or compressed oxygen at 5-6 L/min until gone (usually after 7-10 min; Farncombe et al., 1994). For either fentanyl or hydromorphone, it would be reasonable to use 0.9% saline or sterile water as a vehicle with a volume not to exceed 4 ml for either medication. Increasing the fill volume of the nebulizer may also decrease the amount of drug that remains in the delivery system, something that becomes increasingly important at smaller doses (Gardenhire, Burnett, Strickland, & Myers, 2017; Hess, Fisher, Williams, Pooler, & Kacmarek, 1996).

Opioids administered via nebulization appear to have a bioavailability approaching 20% of the typical IV dose, although substantial interpatient variability can exist (Alexander-Williams & Rowbotham, 1998; Chrubasik et al., 1988; Furyk et al., 2009). It would be reasonable to initiate hydromorphone at doses of 1 mg or fentanyl at doses of 1-3 mcg/kg, followed by a reevaluation of the duration of effect and patient/provider perceptions of comfort. If patients have previously received IV doses, it would also be reasonable to transition patients receiving IV opioids to nebulized opioids at similar doses. Fentanyl has extensive first-pass sequestration in the pulmonary vasculature, which translates to these absorption variabilities and therefore a slightly delayed onset of analgesic effect compared with IV doses (up to 10 min compared with 2-4 min; Roerig et al., 1987; Thompson & Thompson, 2016). Analgesic effects or relief from dyspnea can be expected to be rapid and occur within 10-15 min from treatment with fentanyl or hydromorphone and persist for up to 4 hr or more depending on dose and prior opioid tolerance (Charles et al., 2008; Farncombe et al., 1994).

Claustrophobia and discomfort from the mask (if used) are commonly cited adverse events from nebulized therapy. Additional adverse events specific to nebulizing opioids include bronchospasm, bitter or metallic taste, and dry mouth (Afolabi et al., 2017). Morphine and hydromorphone (to a lesser extent than morphine) cause histamine release from mast cells. This can result in systemic side effects including hypotension, itching, and bronchospasms. When nebulized, the incidence of hypotension or itching is typically lower than when administered via the IV route.

CONCLUSION

The use of inhaled opioid therapy for the treatment of acute pain in the ED is a viable alternative to more traditional routes of administration and may confer potential advantages. Fentanyl is the most investigated agent with the largest volume of evidence suggesting efficacy similar to IV administration. Although the data are far less robust, there is evidence to suggest that hydromorphone is a viable alternative as well. Currently, there is limited evidence to suggest that morphine can be effectively administered via this route. The lack of efficacy seems to be founded in its pharmacodynamic differences from the other opioids. The efficacy of any nebulized medication can be impacted by the type of nebulizer utilized and the diluent volume. Therefore, it is recommended that practitioners work closely with respiratory therapists to ensure optimal medication administration.

REFERENCES