Nebulized opioids are a formulation of the drug that is diluted and provided in a form that can be inhaled. Nebulized opioids have been evaluated in patients for the management of dyspnea.
Ben-Aharon, I., Gafter-Gvili, A., Paul, M., Leibovici, L., & Stemmer, S.M. (2008). Interventions for alleviating cancer-related dyspnea: A systematic review. Journal of Clinical Oncology, 26(14), 2396-2404.
The objective of this study was to systematically review the evidence for the efficacy of pharmacologic and nonpharmacologic treatments in alleviating dyspnea in patients with terminal cancer.
Databases searched were Cochrane Library up to 2007, MEDLINE (PubMed) (1966–2007), American Society of Clinical Oncology conference proceedings, and references of all included documents. In addition to databases, the search included the reference lists of key studies, the reference lists of 16 review articles on the topic, reference lists from 16 textbooks, and seven websites. Authors (15) of main investigations were contacted, and all members of the Association of Palliative Care and users of the www.palliativedrugs.com bulletin board were contacted for additional information and unpublished data.
Search keywords were opiate, opioid, morphine, benzodiazepine, furosemide, steroids, corticosteroids, oxygen, nonpharmacological, acupuncture, nursing, cancer, carcinoma, malignancy, dyspnea and breathlessness.
Studies were included in the review if they were a randomized controlled trial assessing dyspnea in patients with terminal cancer in which any intervention for dyspnea relief was compared with no intervention, placebo, or another intervention.
Studies were excluded if they were nonrandomized studies or trials in which only a minority of the patients had a cancer diagnosis.
Literature evaluated included 37 studies, plus one abstract initially reviewed. A final set of 18 studies was included; 7 assessed opioids, 6 assessed oxygen- or helium-enriched air, 1 assessed furosemide, and 4 assessed nonpharmacologic interventions. Meta-analysis was not completed due to the paucity of studies and heterogeneous outcome measures.
Sample Size Across Studies:
Sample Range Across Studies:
With respect to gender, age, and diagnosis within the sample, the opioids subgroup included both genders. The median age range was 56–73 years. The majority had primary lung cancer, and both opioid-tolerant and opioid-naïve participants were included.
The oxygen or helium subgroup included both genders. The median age range was 64–72 years. The majority had primary lung cancer.
No comment was available on gender or age for the nonpharmacologic subgroup, but the primary diagnosis was lung cancer.
The primary outcome was subjective dyspnea relief according to the visual analog scale (VAS) or dyspnea intensity according to the modified Borg scale. The secondary outcome was oxygen saturation and adverse effects.
Opioid Intervention:
Oxygen Intervention:
Furosemide Intervention:
Nonpharmacologic Interventions:
Acknowledging the paucity of evidence from randomized controlled trials to support the interventions is important.
Limitations of this review were
A major research opportunity exists to further document outcomes from nurse-led dyspnea interventions.
Jennings, A.L., Davies, A.N., Higgins, J.P., Gibbs, J.S., & Broadley, K.E. (2002). A systematic review of the use of opioids in the management of dyspnoea. Thorax, 57(11), 939–944.
This systematic review included trials of opioids for the treatment of dyspnea secondary to any cause.
Eighteen randomized, double-blind, placebo-controlled crossover trials were evaluated. Meta-analyses were performed on all included studies and on various subgroups (e.g., nebulized opioids).
Patient populations were mixed, with 2 of the 18 trials including patients with a cancer diagnosis only and one of the 18 trials including patients with cancer with other advanced diseases.
A strong effect of non-nebulized opioids relative to placebo in reducing breathlessness was found. The subgroup analysis failed to show a positive effect of nebulized opioids on the sensation of breathlessness. Evidence supports the use of oral and parenteral opioids to treat dyspnea and argues against the use of nebulized opioids.
All but one study had a small sample size (n = 6–18 subjects); cancer-related dyspnea was included but was not a main focus of the research.
Viola, R., Kiteley, C., Lloyd, N.S., Mackay, J.A., Wilson, J., Wong, R.K., & Supportive Care Guidelines Group of the Cancer Care Ontario Program in Evidence-Based Care. (2008). The management of dyspnea in cancer patients: A systematic review. Supportive Care in Cancer, 16(4), 329-337.
The objective of this study was to evaluate the effectiveness of four drug classes: opioids, phenothiazines, benzodiazepines, and systemic.
Databases searched were HealthSTAR, MEDLINE, CINAHL, EMBASE, Cochrane Library and Database of Abstracts and Reviews of Effects Issue 2, American Society of Clinical Oncology conference proceedings (1995-2006), Canadian Medical Association Infobase, and National Guidelines Clearing House. Reference lists from relevant articles were searched for additional trials
Search keywords were dyspnea, breathlessness, shortness of breath, respiratory distress, breath and shortness, and breath and difficult combined with terms for pharmacologic agnets, study designs, and publication types.
Inclusion criteria included
• Systematic reviews
• Meta-analyses
• Evidence-based practice guidelines
• Fully published or abstract reports of randomized or nonrandomized controlled studies of opioids, phenothiazines, or benzodiazepines administered by any route involving adult patients with dyspnea
• Subjects with any advanced disease
• Studies involving corticosteroids, only if the primary advanced disease was cancer
• Studies in which one of the outcomes reported was dyspnea, measured by a patient-reported scale.
Exclusion criteria included
• Studies in languages other than English
• Stuides eported in letters or editorials.
The total sample across 29 trials was 600 patients, with individual sample sizes ranging from 4-101. Trials included involved
Bruera, E., Sala, R., Spruyt, O., Palmer, J. L., Zhang, T., & Willey, J. (2005). Nebulized versus subcutaneous morphine for patients with cancer dyspnea: a preliminary study. Journal of Pain and Symptom Management, 29, 613–618.
To compare subcutaneous (SC) injection versus nebulized morphine (median dose of 45 mg, equal to half of the scheduled equivalent opioid dose) on two separate days; because nebulized morphine is thought to have rapid onset of action and low systemic absorption, adverse effects may be avoided.
The study used a double-blind, randomized crossover trial design.
Significant improvement occurred in dyspnea scores from baseline to 60 minutes measured at 15-minute intervals for both SC (dyspnea score decreased from 5 to 3; p = 0.025) and nebulized morphine (dyspnea score decreased from 4 to 2; p = 0.007). No significant difference was found between SC and nebulized morphine for each time period. Bronchospasm was not observed in the nebulized treatment group.
Both routes were effective in this sample. The number of patients was insufficient to determine a difference between the routes.
Charles, M. A., Reymond, L., & Israel, F. (2008). Relief of incident dyspnea in palliative cancer patients: a pilot, randomized, controlled trial comparing nebulized hydromorphone, systemic hydromorphone, and nebulized saline. Journal of Pain and Symptom Management, 36, 29–38.
To compare the efficacy of nebulized hydromorphone, systemic hydromorphone, and nebulized saline for incident dyspnea in patients with advanced cancer.
On three occasions when patients requested treatment for incident breathlessness, they randomly received one of the following:
If patients felt the intervention was not effective, they could ask for additional pharmaceutical interventions. Patients scored breathlessness at 10, 20, 30, and 60 minutes from completion of treatment. Treatment order was randomized.
Patients were undergoing the palliative and end of life phases of care.
The study was a pilot, double-blind, randomized, crossover, controlled trial.
There were no differences between treatments in improvement scores. Improvement in breathlessness at 10 minutes post intervention completion was seen in each of the treatment conditions. Improvement considered to be clinically significant (≥1 cm on the VAS) was only seen with the nebulized hydromorphone. Respiratory rate improved over time from 10 to 60 minutes (p < 0.05), with no difference between treatments. There were no clear, consistent preferences among patients for any particular intervention.
The results suggest that nebulized saline provides relief of incident breathlessness; its effect is ongoing and does not differ significantly from the effects of nebulized opioid treatments.
Coyne, P. J., Viswanathan, R., & Smith, T. J. (2002). Nebulized fentanyl citrate improves patients’ perception of breathing, respiratory rate, and oxygen saturation in dyspnea. Journal of Pain and Symptom Management, 23, 157–160.
To test the theory: \"Inhaled opioids usually are ineffective with report of respiratory depression; however, fentanyl may be more readily absorbed with less bronchospasm and thus relieve dyspnea.\"
Patients were given 25 mcg of fentanyl with 2 mL of saline via a nebulizer.
The study used a convenience sample, uncontrolled design.
Fentanyl improved all three measures and may offer substantial relief of dyspnea. No significant side effects were reported.
Clinical questions about repeated dosing and method of administration (mask or mouthpiece) remain.
Quigley, C., Joel, S., Patel, N., Baksh, A., & Slevin, M. (2002). A phase I/II study of nebulized morphine-6-glucuronide in patients with cancer-related breathlessness. Journal of Pain and Symptom Management, 23, 7–9.
A single dose of nebulized morphine-6-glucuronide (M6G) (the active metabolite of morphine) was given to patients with cancer who had breathlessness. Three dose levels were studied: 5, 10, and 20 mg of M6G. The single dose of morphine was inhaled using an Acorn Porta-Neb jet nebulizer over 15 minutes.
This was an open, uncontrolled study that randomized patients to one of three dose levels.
All patients reported a subjective improvement in breathlessness by the VAS and the Borg scale. A significant difference (p = 0.023) in dyspnea VAS was observed with time across all time points. No significant difference existed among the three treatment groups across all time points (p = 0.176), suggesting no difference among the three doses. A significant difference in dyspnea was found between patients. No significant changes existed in anxiety VAS and effort of breathing VAS with time or with dose. Minimal adverse effects were noted.
Nebulized M6G was relatively safe and possibly therapeutic in patients with cancer-related breathlessness.
A randomized study is planned.
Tanaka, K., Shima, Y., Kakinuma, R., Kubota, K., Ohe, Y., Hojo, F., . . . Nishiwaka, Y. (1999). Effect of nebulized morphine in cancer patients with dyspnea: a pilot study. Japanese Journal of Clinical Oncology, 29, 600–603.
To test the theory that the local benefit of opioids is related to opioid binding sites in peripheral bronchus.
Patients were given 20 mg of morphine dissolved in 5 mL of normal saline administered through an ultranebulizer. If no subjective relief resulted, the dose was increased to 40 mg and was tried again after four hours.
Inpatient hospital in Japan
This was a pilot, open-label, nonrandomized, uncontrolled study.
Significant decrease occurred in VAS after nebulization (p = 0.005). Eight of 15 patients evaluated treatment effective and requested continuation. No significant change occurred in RR or oxygenation. A not statistically significance tendency was found for patients on systemic opioids to benefit more compared to nonopioid patients.
Zeppetella, G. (1997). Nebulized morphine in the palliation of dyspnoea. Palliative Medicine, 11, 267–275.
Nebulized morphine 20 mg mixed with 2 mL of saline was administered using a face mask every four hours for 48 hours.
Unknown but assumed to be in a hospital
The study used an open, uncontrolled, nonrandomized design.
The Dyspnea Assessment Questionnaire (DAQ) and a recalled 24-hour visual analog scale (VAS) were used. Three subscales of the DAQ—Total Severity Score, Percentage Total Severity Score (PTSS), and Dyspnea Quality-Quantity Score (DQQS)—were also analyzed. DQQS was the primary outcome measure. Measurements were taken at baseline (one hour before the first dose of nebulized medication) and were repeated at 24 and 48 hours.
Sixteen patients (94%) reported significantly lower (p = 0.0005) DQQS scores at 24 hours. The four opioid-naïve patients showed no significant benefit from the nebulized treatment. (The theory is that the prevalence of binding receptors in airways is influenced by systemic use of opioids.) Improvement appeared greater in the qualitative aspect of dyspnea as shown by PTTS versus VAS. Benefits were noted at 24 hours and did not improve from there. Change in DQQS scores from 24 to 48 hours was not significant (p-value not given).
Qualitative aspects of dyspnea improved more than quantitative aspects.
Parshall, M.B., Schwartzstein, R.M., Adams, L., Banzett, R.B., Manning, H.L., Bourbeau, J., . . . American Thoracic Society Committee on Dyspnea. (2012). An official American Thoracic Society statement: Update on the mechanisms, assessment, and management of dyspnea. American Journal of Respiratory and Critical Care Medicine, 185(4), 435-452.
A multidisciplinary group of international experts determined the overall scope of these guidelines according to group consensus. This was followed by evidence reviews in key topic areas conducted by committee members with relevant expertise, and all group members agreed on final content.
Databases searched were PubMed and CINAHL (1999- 2009).
Search keywords were dyspnea, breathlessness, and respiratory sensation, with additional keywords according to specific sections. Reference lists of the articles were hand-searched.
Included were
The exclusion criteria were not clearly described.
These consensus guidelines from a respected professional organization fill an important void in the literature by describing the pathobiology and measurement instruments for dyspnea. The brief review of treatment options provides information for clinicians to consider for patients with refractory dyspnea.