Immediate Release Opioids (Systemic)

STUDY PURPOSE: To evaluate the effectiveness of opioids in relieving the symptom of dyspnea in people with advanced disease

TYPE OF STUDY: Meta-analysis and systematic review

• FINAL NUMBER STUDIES INCLUDED = 26 in review, 18 in meta-analysis 
• TOTAL PATIENTS INCLUDED IN REVIEW = 276 in meta-analysis
• SAMPLE RANGE ACROSS STUDIES: 6–25
• KEY SAMPLE CHARACTERISTICS: Cancer, chronic obstructive pulmonary disease (COPD), and heart disease were included.

PHASE OF CARE: End-of-life care
 
APPLICATIONS: Palliative care

Based on change in dyspnea from baseline, no statistically significant difference existed with opioids across seven studies. This evidence showed high heterogeneity and low overall quality. A comparison of post-treatment dyspnea scores in 11 studies showed significant benefit with opioids (standard mean difference [SMD] = –0.28, 95% confidence interval [CI] [–0.5, –0.05], p = 0.02). No significant effects (two studies) existed for nebulized opioids. Six studies were of patients with cancer. A few studies evaluated breathlessness in terms of exercise tolerance only.

The findings show that oral opioids have some benefit for the relief of dyspnea and may have some benefit for short-term improvement in exercise capacity.

• Mostly low quality/high risk of bias studies
• High heterogeneity
• Low sample sizes
• No subgroup quantitative analysis; differences for various patient subgroups were not analyzed.

Oral opioids are of benefit for reducing dyspnea. Nebulized opioids were not shown to be effective.

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Palliative Care and users of the www.palliativedrugs.com bulletin board were contacted for additional information and unpublished data.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:

• Opioid intervention = 256 patients
• Oxygen or helium = 148 patients
• Furosemide intervention = 7 patients
• Nonpharmacologic intervention = 403 patients

Sample Range Across Studies:

• Opioids = 9–101 patients
• Oxygen or helium = 12–51 patients
• Nonpharmacologic = 34–203 patients

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:

• The administration of subcutaneous morphine resulted in significant reduction in dyspnea according to the VAS compared with placebo.
• Nebulized morphine versus placebo failed to demonstrate a significant effect of nebulized morphine. No difference in dyspnea VAS score was observed in one trial when nebulized morphine was compared with subcutaneous morphine, although patients preferred the nebulized route.
• In one trial, the addition of benzodiazepines (midazolam) to morphine was significantly more effective than morphine alone, without additional adverse effects.

Oxygen Intervention:

• Oxygen was not superior to medical air for alleviating dyspnea, except for patients with hypoxemia.

Furosemide Intervention:

• One small trial assessed the use of nebulized furosemide with a trend toward worsening dyspnea.

Nonpharmacologic Interventions:

• Nurse-led interventions improved breathlessness.
• Acupuncture was not beneficial.
• Nurse-led interventions encompassed routine follow-up by nurses performing methods of counseling and relaxation and teaching coping strategies.
• The nurse-led breathlessness rehabilitation techniques and education and advice regarding coping with the psychological aspects of the symptoms assessed the primary outcome of dyspnea relief after weeks.
• All nurse-led interventions proved to be beneficial, improving breathlessness and quality of life in terms of physical, psychological, and emotional aspects.

• No evidence supports subcutaneous morphine as effective in treating dyspnea in patients with advanced cancer.
• Use of oxygen to alleviate dyspnea in nonhypoxic patients with cancer cannot be recommended. Supplemental oxygen is expensive and can restrict mobility with possible decrease in quality of life. Use of medical air (78.9% nitrogen, 21.1% oxygen) was shown to be effective in reducing the sensation of dyspnea. However, this intervention is not used routinely in care settings.
• This review recommended integration of pharmacologic and nonpharmacologic interventions, such as those used in nurse-led programs to relieve dyspnea.

Acknowledging the paucity of evidence from randomized controlled trials to support the interventions is important.

Limitations of this review were

• Few randomized controlled trials
• Small studies
• Short follow-up in opioid studies
• Lack of consistency regarding opioid doses.

A major research opportunity exists to further document outcomes from nurse-led dyspnea interventions.

The objective of this meta-analysis and systematic review was to evaluate the role of different interventions to alleviate dyspnea.

• Databases used were CENTRAL, EMBASE and PubMed.
• Search keywords were opiate, benzodiazepine, furosemide, steroids, oxygen, or pharmacological and dyspnea or breathlessness.
• Studies were included if they were randomized controlled trials assessing patients with terminal cancer with dyspnea in which an intervention was compared with no intervention, placebo, or an alternative intervention.
• No exclusion critera were stated.

A total of 829 references were retrieved. The specific method of evaluation was not described, but the small sample size of most studies was noted.

• The final number of studies included was 18.
• Of the specifics included, sample sizes ranged from 9–38.
• All studies involved patients with end-stage disease.

Patients were undergoing end-of-life care.

• Meta-analysis of three trials comparing opiods with placebo yielded a weighted mean difference of -1.31 (95% CI, -2.49, -0.13), showing a statistically significant benefit with opioids. 
• Studies tended to show better results with nebulized opiods rather than subcutaneous administration. 
• Analysis of six trials of oxygen showed lack of benefit. 
• Standard mean difference was -0.3 (95% CI, 1.06, 0.47).
• Two studies compared midazolam to morphine and the combination of both drugs.
• One study showed that addition of midazolam to morphine improved results.
• Two small studies concluded that furosemide did not improve dyspnea.

• Opioids are effective in reducing dyspnea and may work better if nebulized. 
• The addition of midazolam to opioid may improve results. 
• Oxygen and furosemide were not effective in reducing dyspnea.

• Relatively few studies used each intervention. 
• Opioid trials were limited by lack of dosage information and various types of opioids used. 
• In studies evaluating oxygen, hypoxemia was not routinely evaluated. 
• Method of measuring dyspnea varied across studies.

Findings provide guidance regarding effectiveness of interventions for dyspnea in patients with cancer. These results demonstrate the effectiveness of opioids. Findings also confirm those of others that palliative oxygen is of no benefit for this symptom. Some reviews continue to suggest the use of palliative oxygen. This is not supported by evidence, and home oxygen therapy is generally not covered by insurance for patients who do not have hypoxemia. Unnecessary use can be costly to the patient. Evidence is limited regarding the effects of the addition of hypnotics to opioids in managing dyspnea. This is an area that could benefit from additional research.

The objective of this study was to discuss the evidence for our present understanding of the symptom of dyspnea and unanswered questions regarding the genesis and management of cancer-related breathlessness.

Databases searched were MEDLINE, CINAHL, and EMBASE (1966-2006). 

Search keywords were breathlessness, cancer, lung cancer, cancer, dyspnea/dyspnoea, intervention, management, and nonpharmacological.

Studies were included in the review if they were double-blind, randomized, randomized- controlled, or placebo-controlled trials, case reports, or uncontrolled trials that

• Defined the experience of breathlessness
• Assessed the effectiveness of pharmacologic and nonpharmacologic management to relieve breathlessness in patients with advanced cancer.

Older reviews were excluded.

Volume of studies retrieved, methods of study evaluation, and specific information about studies retrieved were not provided. Authors reviewed articles they deemed important to the science of dyspnea in patients with cancer and its management from the perspective of content experts.

The sample characteristics were not described.

• Listening to the patient and caregiver’s experience with dyspnea and creating an individualized breathlessness plan may be helpful in alleviating anxiety-related dyspnea.
• A fan directed at the face is inexpensive and showed efficacy in one study and may be ideal to manage a breathlessness crisis.
• Relaxation and diaphragmatic breathing techniques may aid in breathlessness and anxiety.
• Noninvasive ventilation may have a role in dyspnea symptom control in select patients but has been ill-defined.
• Safety of using opioids across populations of breathless patients with cancer needs to be tested by adequately powered epidemiologic studies.
• No controlled trials support use of phenothiazines or benzodiazepines for management of breathlessness, but authors suggest use of these agents as adjuncts to other therapies or when symptoms are refractory to other therapies.
• A fully powered multi-center randomized controlled international study is underway to test the efficacy of oxygen in reducing dyspnea.
• Heliox is best used after therapies have been rigorously applied and failed to elicit reduction in dyspnea.
• The use of antidepressants or inhaled furosemide for breathlessness in patients with advanced cancer requires systematic investigation.

Progression of the science of understanding breathlessness in patients with cancer requires collaboration between the research and clinical practice of cardiology, oncology, palliative medicine, social sciences, and physiology. Because dyspnea is a dynamic process that may manifest differently in unique populations and situations, possible variables should be well delineated and interventions should be varied to learn the most information about management of this complex symptom.

This review provides a summary of the evidence in multiple interventions, but the report is limited due to lack of provision of study sample characteristics and information regarding the search strategy and methods of evaluation of the strength of the evidence. These limit the level of confidence in findings and conclusions.

The first step to managing breathlessness is careful assessment of the patient and investigation of potential correctable etiologies of breathlessness. The interview should include a patient and caregiver accounting the dyspnea and its triggers, intensity, aggravating factors, alleviating factors, and response to pharmacologic and nonpharmacologic interventions.

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.

STUDY PURPOSE: To review evidence regarding the use of opioids for dyspnea and associated risks of respiratory depression

• DATABASES USED: MEDLINE, TRIP database, Cochrane Collaboration 
• KEYWORDS: MESH terms for morphine; respiratory insufficiency or respiratory function; and opioid. Search terms provided in the article
• EXCLUSION CRITERIA: Studies in pediatric patients

TOTAL REFERENCES RETRIEVED: 47

• FINAL NUMBER STUDIES INCLUDED = 8 
• TOTAL PATIENTS INCLUDED IN REVIEW = 118
• SAMPLE RANGE ACROSS STUDIES: 9–31 patients
• KEY SAMPLE CHARACTERISTICS: Various disease types, including cancer

PHASE OF CARE: End-of-life care
 
APPLICATIONS: Palliative care

In studies measuring dyspnea, opioids were consistently shown to significantly reduce dyspnea and respiratory effort. A few studies described minor changes in respiratory rate and PaCO₂, but they were not clinically significant.

Findings support the safety and effectiveness of opioids for the management of dyspnea in patients with advanced disease.

• Limited number of studies
• Small samples

This review provides additional support for the effectiveness of opioids to reduce dyspnea, and provides some evidence that this does not cause significant respiratory depression.

STUDY PURPOSE: Evaluate the four most commonly used pharmacologic therapy options for the management of breathlessness in patients with advanced cancer and non-cancerous diagnosis

TYPE OF STUDY: Meta-analysis and systematic review

DATABASES USED: Ovid, PubMed, Medline, Cochrane

YEARS INCLUDED: (Overall for all databases) 1950 to 2012

INCLUSION CRITERIA: Randomized controlled trials, controlled clinical trials, and systematic literature reviews and meta-analyses that were published in German or English of patients who experienced continued breathlessness despite treatment for the underlying disease including cancer, COPD, chronic heart failure, ALS, MS, and HIV/AIDS, and received pharmacologic treatment with opioids, benzodiazepines, corticosteroids, or oxygen which the intensity of breathlessness could be measured. 

EXCLUSION CRITERIA: Studies with the use of nebulized or oral steroids as a basic treatment for COPD and studies including oxygen for patients with hypoxic COPD.

TOTAL REFERENCES RETRIEVED: 2,029

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Database search yielded 2,559 reviews; after review for duplicates, the references were 2,029. Two reviewers independently searched and analyzed the title, abstract, and study for inclusion criteria, which left 65 references. The reviewers then conducted a full-text review, leaving seven references which made up the final inclusion along with eight references from experts. The final number of studies included 5 systematic reviews and 10 randomized controlled trials.

FINAL NUMBER STUDIES INCLUDED: 15

TOTAL PATIENTS INCLUDED IN REVIEW: 2,125

SAMPLE RANGE ACROSS STUDIES: Patients with advanced cancer, cancer, CHF, COPD

KEY SAMPLE CHARACTERISTICS: Included nine studies, one systematic review and eight RCT/CCT, on efficacy of opioids. Two studies, one systematic review, and one RCT/CCT on efficacy of benzodiazepines. Four studies (three systematic reviews and one RCT) on efficacy of oxygen.

PHASE OF CARE: Multiple phases of care     

APPLICATIONS: Elder care, palliative care

Results are categorized in three medication groups and oxygen. No results are available for corticosteroids because there were no studies identified. Two reviews for benzodiazepines were conducted. A systematic review of seven studies, including 200 patients in which 6 of the 7 studies did not show efficacy for the use of benzodiazepines for breathlessness (effect size = -0.32 with 95% CI [-0.89, -0.24]). The second review was a RCT comparing temazepam to placebo with no difference in relief of breathlessness between the two groups. The strongest evidence is from the nine reviews (one systematic literature review and eight RCT) for studies using opioids. Significant efficacy was reported from the systematic literature review of 18 RCT and 293 patients with oral/parenteral morphine (effect size = -0.4 with 95%CI [-0.63, 0.17], p = 0.0006). All eight reviews of RCT were positive, with three showing morphine significantly better than placebo and five showing relief of breathlessness. There were four reviews (three systematic reviews and one RCT) for the efficacy of oxygen identified. The three systematic reviews all compared oxygen to room air. Two did not show significant improvement, however, in one study of 702 non-hypoxemic COPD patients, oxygen showed significant improvement of breathlessness (effect size = -0.37 with 95% CI [-0.5, -0.24]). The RCT compared oxygen to room air in 239 patients. Breathlessness was improved in both the morning and evening by 0.9 and 0.7 points, however, there was no significant difference between the two groups.

The review emphasizes the treatment of breathlessness is still a challenge with evidence varying and partly limited. However, opioids are recommended as a first choice for the treatment of breathlessness for patients with cancerous and non-cancerous advanced diseases. Benzodiazepines are recommended as a second choice for the co-existing management of panic symptoms, anxiety, and breathlessness. Oxygen is not proven to be effective in the non-hypoxic patient with cancer and the use of hand-held fans should be offered.

• Limited search
• Limited number of studies included
• The search strategy was not specific, including only studies written in English or German, excluding studies in other languages. Studies with uncontrolled study designs were also excluded.

Findings show that only opioids offer benefit to patients experiencing breathlessness and should be considered as first-line therapy. However, there are several other nursing implications provided by this review. A smaller dose of opioid is effective in relieving breathlessness and, whenever possible, should be started low and go slow. The fear of respiratory depression with the use of opioids is not warranted based on results of several studies. This finding should be communicated to nurses with education provided to patients and families. Although benzodiazepines are commonly used for breathlessness, efficacy has not been established. However, nurses must recognize the benefit of reducing anxiety and possibly allowing for lower doses of opioids. Lastly, the use of hand-held fans producing an air stream across the patient’s midface and over the nasal mucosa is an intervention nurses may easily use to reduce breathlessness.

STUDY PURPOSE: To review the evidence for opioids in the treatment of dyspnea in patients with cancer

TYPE OF STUDY: Systematic review

• FINAL NUMBER STUDIES INCLUDED = 14 
• TOTAL PATIENTS INCLUDED IN REVIEW = 247
• SAMPLE RANGE ACROSS STUDIES: 9–70
• KEY SAMPLE CHARACTERISTICS: Lung and breast cancer were the most common. Other tumor types were included.

PHASE OF CARE: Not specified or not applicable
 
APPLICATIONS: Palliative care

• Morphine was examined in nine studies. All showed positive effects of morphine on dyspnea at rest or exercise, given by oral or subcutaneous routes.
• Hydromorphone was examined in five studies. Most were nonrandomized studies, and all showed benefit in opioid-naïve and opioid-treated patients.
• Fentanyl was examined in three studies. Mixed results were reported.
• No respiratory depression episodes were reported with the use of opioids.

Overall, opioids were seen to be beneficial in reducing dyspnea.

• Limited search
• Limited number of studies included
• Low sample sizes

This review adds to the body of evidence regarding the efficacy of opioids for the management of dyspnea in patients with cancer. Morphine is the most frequently studied opioid.

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 search identified two practice guidelines, three systematic reviews, 23 published randomized controlled trials (RCTs), two abstracts of RCTs, and three published nonrandomized trials, for a total of 33 references.
• The review did not identify the number of excluded items from the initial search. 
• Study quality was evaluated formally using the Jadad scale.

The total sample across  29 trials was 600 patients, with individual sample sizes ranging from 4-101. Trials included involved

• 6 trials of opiods in only patients with cancer
• 10 trials of systemic opioids including patients who did not have cancer
• 7 trials of nebulized opioids including patients with and without cancer
• 4 trials of benzodiazepines
• 2 trials of phenothiazines.
   

• Search sources and criteria were not reported in either of the two practice guidelines. One indicated that both corticosteroids and opioids were options for managing dyspnea but that the evidence was poor. The other, a Finnish guideline, recommended opioids, steroids, and benzodiazepines, but evidence was only cited for opiods.
• Opioids studied included morphine orally, subcutaneously, or via nebulizer; dihydrocodeine; diamorphine; and promethazine with morphine. All but three studies examined the effects of a single dose on dyspnea via use of a visual analogue scale or exercise tolerance.
• In opioid trials involving only patients with cancer, four examined systemic opioids, one used nebulized opiods, and one included both systemic and nebulized administration. One trial used a combination of morphine and midazolam. Systemic opioid studies tended to show significant decrement in mean dyspnea and respiratory rate with morphine. In the trial that included midazolam, more patients on the combined regimen reported relief from dyspnea at 24 and 48 hours and had fewer episodes of breakthrough dyspnea. However, no differences were seen in mean dyspnea scores and exercise tolerance between groups overall.
• Nebulized opioids did not show significant differences compared to systemic morphine in one trial.
• One benzodiazepine trial involved patients with cancer. In trials with other patients, none of the studies demonstrated a significant reduction in dyspnea when compared to placebo.
• No trials were on phenothiazines in patients with cancer. One study showed a benefit with promethazine compared to placebo on dyspnea and exercise tolerance.
• Adverse effects reported across trials included drowsiness, nausea and vomiting, and constipation in opioid trials. Results of opioids on oxygen level were mixed.
• Results of benzodiazepines and phenothiazines on oxygen and carbon dioxide levels were mixed. Drowsiness was the most frequent adverse effect reported with benzodiazepine.

• Overall evidence favors a beneficial effect of systemic opioids on dyspnea and exercise tolerance.
• None of the studies comparing nebulized morphine with placebo or systemic opioids found it to be beneficial. 
• Whether studies with opioids indicate a drug class effect is not clear because only a few drugs have been studied.
• Studies of benzodiazepines did not suggest any benefit.
• Studies of phenothiazines gave conflicting results.
• Overall evidence in this area demonstrate conflicting results, and this systematic review also gives conflicting results and conclusions within the article.
• Most studies had very small sample sizes, and doses, dose schedules, routes, and outcome measures varied greatly, making overall conclusions difficult.
• While the stated purpose of the review was to determine effects within a cancer population, most of the research reviewed was not in this population.
• While use of opioids may be of benefit for patients with cancer in reducing the sensation of dyspnea, this effect needs to be balanced with the adverse effects that can be expected with such treatment, including symptoms of constipation, drowsiness, and nausea and vomiting. Interventions to prevent or manage these effects would also be essential.

The objective of this study was to compare the efficacy of supplemental, oral, and parenteral opioid doses consisting of either 25% or 50% of the equivalent 4-hour opioid dose (i.e., total 24-hour opioid dose divided into 4-hour portions) in patients already receiving opioids on a regular basis.

The study reported on a sample of 33 terminally ill patients with cancer and dyspnea at rest who already were receiving opioids.

The study was conducted in three separate palliative care centers in Quebec, Canada.

The study was a randomized, double-blind, continuous sequential controlled trial.

Dyspnea intensity on the visual analog scale and respiratory rate were measured at baseline, 30, 60, 120, 180, and 240 minutes after dose.

The overall treatment effect, as measured by dyspnea intensity and respiratory frequency, was not significantly different for 25% or 50% of the equivalent four-hour opioid dose. A significant (p < 0.0001) decrease was found in pre- and post-dyspnea intensity. Dyspnea decrease was inverse to baseline dyspnea intensity (i.e., low dyspnea at baseline had greater decrease in dyspnea intensity whereas high dyspnea at baseline had less decrease).

• Authors reported that the sample required one more pair to offer definitive preference in favor of 25% of the four-hour dose.
• The finding was restricted to those already receiving regular opioids.
• The study was properly designed and conducted at multiple sites; however, the sample was limited.

Because 25% and 50% doses had the same effect, a supplementary dose of 25% of the equivalent four-hour opioid dose is recommended to reduce dyspnea for as long as four hours.

The objective of this study was to assess the effect of one dose of subcutaneous (SC) morphine on dyspnea in patients with terminal cancer.

Patients were given 2.5 times their regular dose of morphine, administered at the time of their scheduled analgesic dose. In five patients who were not receiving opioids, the dose was 5 mg of morphine. The average dose administered was 22–28 mg.

The study reported on a sample of 20 consecutive patients with terminal cancer; all patients had severe dyspnea at rest because of restrictive respiratory failure.

The study was conducted on a palliative care unit.

The study was an open, uncontrolled trial.

• Dyspnea visual analog scale (VAS) and pain VAS were measured before the dose and every 15 minutes for 150 minutes.
• Respiratory rate, respiratory effort, arterial oxygen saturation (SO₂), and end-tidal arterial carbon dioxide pressure (PaCO₂) were determined before and 45 minutes after SC morphine.

• A statistically significant improvement in dyspnea was seen without any significant change in respiratory rate, respiratory effort, oxygen saturation, or PaCO₂.
• In patients with pain, the effect of morphine on dyspnea had a shorter duration than the analgesic effect.
• Toxicity was minimal and consisted of nausea.
• Of 20 patients, 19 reported improved dyspnea after SC morphine and continued to receive the same dose for dyspnea on an as-needed basis with continued relief.
• Authors suggest the need for confirmation with a double-blind study.

The study had a small sample size.

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:

• 5 mg of nebulized hydromorphone
• A systemic breakthrough dose of hydromorphone
• 3 mL of nebulized saline and an agent to maintain double blinding.

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.

• The sample was comprised of 20 patients (11 men, 9 women) receiving palliative care.
• Mean age was 69 years (range 48–83). 
• Diagnoses included primary lung cancer or secondary lung pathology, including lung metastases, pleural effusion, or pulmonary emboli.
• To be eligible, patients had to have Mini Mental State Exam (MMSE) results of at least 24 out of 30.
• Thirteen patients were on continuous oxygen.
• Mean baseline total opioid dose in morphine equivalent mg was 82 (range 10–540).

• Inpatient- and community-based hospice service in Brisbane, Australia
• Single site

Patients were undergoing the palliative and end of life phases of care.

The study was a pilot, double-blind, randomized, crossover, controlled trial.

• Perceived intensity of breathlessness was measured on a vertical 100-mm visual analog scale (VAS).
• Pulse rate and peripheral oxygen saturation were measured with a pulse oximeter.
• Respiratory rate was counted by the research nurse over two 30-second intervals.

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.

• The study was appropriately powered to answer the study questions, but the study had a small sample size.
• A change of 1 cm on the VAS was used as a clinically significant symptom change, in concert with the work of others.
• Further research to define clinically significant differences in patient perception would be beneficial.
• It is not clear if higher doses of hydromorphone might yield differences across groups.
• The authors suggested that improvements in respiratory rates and peripheral oxygen over time likely represent Type I error in this study because the patients had a background of irreversible baseline dyspnea.
• The presence of the research nurse, to specifically administer this protocol, may have had an effect in terms of reassuring patients and confounded the overall results. Similar research having patients self-administer treatments might address this aspect.
• It is unclear if findings represent placebo effects.

The objective of this study was

• To assess whether, and/or in which way, symptomatic treatment of dyspnea with opioids is associated with respiratory depression
• To verify whether nasal water insufflations and opioid administration respectively lead to decrease in dyspnea.

One opioid dose of morphine (mean dose 9.4 mg [SD = 8.8 mg]) or hydromorphone (morphine equivalent dose of 10.8 mg [SD = 3.8 mg])

The sample was comprised of 11 patients with dyspnea (5 severe, 4 moderate, and 2 mild), 8 patients with lung cancer, 2 patients with breast cancer, and 1 patient with acute lymphoblastic leukemia. None of the patients had a history of chronic obstructive pulmonary disease.Two patients were pretreated with opioids for pain control.

The study was conducted on an inpatient palliative care unit.

The study was a prospective, nonrandomized, uncontrolled trial.

• Numerical rating scale (NRS) 0-10 severity of dyspnea
• NRS 0-10 anxiety
• Arterial pressure of carbon dioxide (pCO₂)
• Oxygen saturation %
• Pulse rate

After opioid administration

• No significant change in oxygen saturation (pCO₂) or pulse rate was observed.
• A significant (p = 0.003) decrease in respirations from 41 (SD = 4.7) to 26.5 (SD = 5.3) was noted.
• A significant decrease in dyspnea score (p = 0.003) at rest from 5.4 (SD = 2.5) on admission to study to 0.9 (SD = 0.8) at 120 minutes and dyspnea on exertion from 7.5 (SD = 2.7) to 2.9 (SD = 1.5) at 120 minutes was noted.
• A significant decrease in anxiety also was observed (p = 0.003).

Patients’ ratings showed no significant decrease in dyspnea intensity with nasal oxygen.

Decreased respiratory rate and decreased dyspnea scores with opioid dose were evident.

• Respiratory depression with therapeutic doses of strong opioids was excluded.
• Study limitations are small sample size and uncontrolled, nonrandomized design.
• A possible contamination is that patients also were offered psychological, spiritual, and nonpharmacologic therapy (e.g., breathing therapy, relaxation exercise) as part of routine palliative care.

The objective of this study was to assess the safety and effectiveness of hydromorphone for the improvement of ventilation and intensity of dyspnea in palliative care patients.

Baseline intensity of dyspnea was recorded at rest and during exertion during a light physical activity. Baseline data, including arterial pressure of carbon dioxide (tcPaCO₂), peripheral oxygen saturation (SaO₂), and pulse frequency (PF) were measured continuously via a noninvasive calibrated digital sensor (i.e., the SenTec Digital Monitor) attached to the patients’ earlobe. They then were initiated on orally administered hydromorphone every four hours and titrated to at least 50% dyspnea reduction. Rescue doses of one-sixth of the calculated daily dose were made available for relief of breakthrough dyspnea.

• The sample was comprised of 14 patients.
• The patients ranged in age from 40–84 years.
• The median age was 64 years.
• Six of the patients were female, and eight of the patients were male.
• The diagnosis documented was advanced terminal cancer.
• Admission diagnoses included lung (7), breast (3), pancreatic (1), colorectal (2), and ovarian (1) carcinoma.
• At admission, all participants reported moderate to severe dyspnea (as indicated by self-reported scores of greater than 3 out of 10 on a numeric rating scale), recorded at rest and on exertion during performance of light physical activity.
• Seven of the 14 patients were not opiate naïve.

The single-site study was conducted in an inpatient setting on a palliative care unit at the Center for Palliative Medicine in Germany.

Patients were undergoing end-of-life and palliative care.

The study was a prospective, nonrandomized trial.

• Respiratory rate
• Subjective rating on intensity of dyspnea numeric rating scale where 0 indicates no dyspnea, 1–3 indicates mild dyspnea, 4–7 indicates moderate dyspnea, and greater than 7 indicates severe dyspnea
• Peripheral oxygen saturation (SaO₂)
• Transcutaneous arterial pressure of carbon dioxide (tcaCO₂)
• Pulse frequency

• Oral hydromorphone was found to significantly decrease dyspnea 120 minutes after use (p < 0.001).
• No increase in tcaCO₂ or decrease in SaO₂ were observed that would suggest respiratory depression.
• Mean respiratory rate decreased from 38.8 breaths (SD = 4.9 breaths) per minute to 34.6 breaths (SD = 4.2 breaths) per minute after 30 minutes and 29 breaths (SD = 3.1 breaths) per minute by 120 minutes.

Use of oral hydromorphone potentially could reduce dyspnea with minimal risk of respiratory depression to patients with advanced or terminal cancer.

• The study had a small sample size, with less than 30 participants.
• This was done for only 120 minutes at a single point in time–longer term efficacy is not clear.
• The level of significance for time to symptom relief was not reported, but effects on severity of dyspnea were apparent as early as 30 minutes after beginning treatment.

Use of hydromorphone in the palliative care setting may serve as an effective treatment alternative for patients with renal impairment or intolerance to morphine in the management of dyspnea and work of ventilation. Hydromorphone may reduce dyspnea even in patients who already are receiving opiates for other symptoms.

The objective of the study is to compare the effects of oxygen application and use of opioid treatment on ventilation and palliation of chronic dyspnea in hypoxic and non-hypoxic palliative care patients.

Four liters per minute of oxygen were given via nasal cannula. After 60 minutes, patients rated dyspnea, and respiratory parameters were recorded for comparison to baseline. Patients initially received immediate release opioids every four hours and rescue doses as required for breakthrough dyspnea. Patients who had been pre-treated with opioids were switched to oral morphine equivalent doses, and the opioid dose was titrated to achieve a tolerable and stable level of symptoms. When stable, patients were changed to sustained release opioids.

The study reported on a sample of 46 patients. The median age was 66.5 years, with a range of 40-90 years, for hypoxic patients and a median age of 70.5 years, with a range of 40-86 years, for non-hypoxic patients. Twenty-three patients were females; 9 were hypoxic, and 14 were non-hypoxic. Twenty-three patients were males; 9 were hypoxic, and 14 were non-hypoxic. In the hypoxic group, participants were diagnosed with end-stage cancer of multiple types. Participants were included if they experienced dyspnea at rest, had a hemoglobin level of greater than or equal to 10 g/dl measured within 2 weeks, and had normal cognitive function. Of the participants included, 18 were noted to have been pre-treated with opioids for pain control, while 28 were opioid naive. In addition, four participants were noted to have a medical history of chronic obstructive lung disease. Seventeen patients reported intermittent pre-treatment with oxygen therapy (2-6 L/min).

The single-site study was conducted on a palliative care unit in Germany.

Patients were undergoing end-of-life and palliative care.

Prospective non-randomized study

• Numeric rating scale (NRS) of intensity of dyspnea (scale of 0-10)
• Karnofsky Performance Status Score to assess baseline level of function
• Transcutaneous measurement of carbon dioxide partial pressure, oxygen saturation, and pulse rate via an earlobe sensor

During 60-minute oxygen insufflation with the 4 L/min nasal cannula, no decrease in dyspnea was noted among the hypoxic and non-hypoxic patients. No significant correlation was seen between intensity of dyspnea and oxygen saturation. A significant increase was seen in SaO₂ in hypoxic patients after opioid application (P < 0.0001), and a significant decrease was seen in respiratory rate in both groups. In non-hypoxic patients, respirations in the opioid naïve ranged from 38 (SD = 5.6) per minute to 27 (SD = 4) per minute (P = <0.0001) after 120 minutes, while patients who were pre-treated with opioids ranged from 37 (SD = 4.5) per minute to 27 (SD = 3.4) per minute (P = 0.003) after 120 minutes.

• Use of opioids for the reduction of dyspnea was more effective than oxygen insufflation, even in hypoxic patients.
• Oxygen did not reduce dyspnea.
• Opioids appeared to reduce dyspnea both in opioid-naïve patients and those who had previous medication with opioids.

The study had a small sample of less than 100. Baseline measurement of dyspnea intensity, SaO₂, PaCO₂, and tcpaCo₂ during 60-minute oxygen administration obtained from the 17 participants who were known to have used as much as 6 L/min nasal cannula at home calls into question the accuracy of comparative data because study intervention used only 4 L/min nasal cannula. The results only pertain to patients experiencing “chronic” dyspnea and do not relay or compare the effects of increasing oxygen concentration or modes of oxygen delivery (i.e., greater than 4 L/min, face mask, FiO₂, etc.) in management of acute, chronic, or breakthrough dyspnea in hypoxic and non-hypoxic patients.

Oxygen therapy for the management of chronic dyspnea in patients with cancer with advanced disease may not be a cost-effective intervention and has no established long-term benefits for symptomatic relief of work of breathing. Intermittent use of opioids for the safe improvement of symptomatic dyspnea may be a better alternative with minimal likelihood of resulting respiratory depression.

To compare the effectiveness of orally administered red morphine drops (RMD) and subcutaneous morphine (SCM) in patients with advanced lung cancer

Patients were randomized to two groups. Group 1 received oral RMD and a subcutaneous injection of isotonic saline. Group 2 received a placebo oral RMD and a subcutaneous injection of morphine. All injections were given in the leg in a location without edema. Patients were instructed to hold the RMD or placebo RMD solution in their mouths as long as possible before swallowing. The study preparations included a) morphine hydrochloride at 2 g, ethanol 96% at 5 g, cochenille tincture PhD.48 10 g, purified water up to 100 g (one drop corresponded to 0.6 mg morphine), b) ethanol 96% at 5 g, cochenille tincture PhD.48 10 g and purified water up to 100 g, c) injectable morphine 20 mg/ml, and d) isotonic saline. Measurements were taken at baseline and five, 10, 15, 20, 30, and 60 minutes after medication administration. Patients were not allowed to take any opioid within four hours prior to the experiment.

• N = 20  
• MEAN AGE = 69 years (range = 42–84 years)
• MALES: 10%, FEMALES: 90%
• KEY DISEASE CHARACTERISTICS: Lung cancer
• OTHER KEY SAMPLE CHARACTERISTICS: Terminally ill patients receiving opioids for pain; resting dyspnea of at least 3 on 0–10 Visual Analog Scale at rest

• SITE: Single site    
• SETTING TYPE: Not specified  
• LOCATION: Denmark

• PHASE OF CARE: End-of-life care
• APPLICATIONS: Palliative care 

Double-dummy randomized, controlled trial

• Visual Analog Scale (VAS) 0–10 to assess the severity of dyspnea
• Respiratory rate
• Oxygen saturation
• Pulse rate

There was no significant difference in dyspnea between the two groups. Both RMD and SCM showed a significant decrease in dyspnea (time p = 0.0451, and treatment p < 0.0001). In addition, RMD and SCM were associated with significant decreases in pulse rate (p = 0.0410). Although it was not statistically significant, patients receiving SCM showed a more rapid decline in dyspnea. Patients in the RMD group received 3.3%–8.6% of their total 24-hour opioid dose. Patients in the SCM group received 1.5%–5.5% of their total 24-hour opioid dose.

Both RMD and SCM improved dyspnea in terminally ill patients.

• Small sample (< 30)
• Baseline sample/group differences of import
• Risk of bias (no blinding)
• Key sample group differences that could influence results
• Other limitations/explanation: Primarily women in the sample; baseline dyspnea was 1 higher in the RMD group

RMD is a reasonable alternative to SCM and should be considered as part of patient preference at the end of life. Subcutaneous administration may provide more rapid relief. It is noteworthy that opioid use relieves dyspnea for patients receiving regular opioids for pain management. The most effective dosage of RMD is not yet known. Additional research to understand the pharmacokinetics of RMD is needed.

To describe the management of moderate to severe dyspnea in patients receiving palliative care

A retrospective study was conducted using the records of patients who were consulted by a palliative care service over a five-year period. Information about medications prescribed was collected for patients who self-reported moderate to severe dyspnea at their initial evaluations by the palliative care service. Follow-up assessments of dyspnea were conducted by the palliative care service within 24 hours of the initial assessment. Data extraction was completed by a physician.

• N = 115  
• MEAN AGE = 64 years (SD = 17 years)
• MALES: 51% (n = 59), FEMALES: 49% (n = 56)
• KEY DISEASE CHARACTERISTICS: Primary diagnoses were cancer (64%, n = 59), heart failure (8%, n = 9), and chronic obstructive pulmonary disease (5%, n = 6). 
• OTHER KEY SAMPLE CHARACTERISTICS: Half of the sample was Caucasian (54%, n = 62). Pneumonia was diagnosed in 34% of patients (n = 39), and 30% of patients (n = 35) had a pleural or pericardial effusion. 

• SITE: Single site  
• SETTING TYPE: Inpatient  
• LOCATION: Urban medical center

• APPLICATIONS: Palliative care

Retrospective chart review of patients with moderate or severe dyspnea

• Charleston Comorbidity Index (CCI) to assess the severity of illness through the classification of comorbidities to predict short- and long-term mortality
• Dosages of opioids were converted into milligrams of oral morphine per day by equianalgesic dosing.
• Plonk’s equation was used to convert methadone to morphine. 
• Dyspnea, pain, and anxiety were measured using a four-point categorical scale based on patient self-reports.
• Data from the chart review included the frequency and dose of opioids and benzodiazepines, age, sex, race, comorbidities, the presence of pneumonia, and pleural or pericardial effusion. 

Most patients reported an improvement in dyspnea within of 24 hours after palliative care service consultation. Most patients with dyspnea received opioids but only the combination of benzodiazepines and opioids was independently associated to improve dyspnea.

• Baseline sample/group differences of import
• Risk of bias (no control group) 
• Risk of bias (no random assignment) 
• Risk of bias (no appropriate attentional control condition)  
• Other limitations/explanation: The results were from a retrospective chart review. Conclusions cannot be drawn about the effectiveness of treatment or the causal relationships between medication and improvements in in dyspnea symptoms due to the study’s design. The study acknowledges potential confounding factors including patient factors, procedures, and psychological care that may impact the study’s findings. The results are reflective of the practices of one institution, which may limit generalizability. The population studied may not be generalizable to the broader palliative care population.

Because dyspnea is a common symptom in patients receiving palliative care, the authors conducted a study that reviewed the records of patients with moderate or severe dyspnea. The study found that opioids given with benzodiazepines were associated with improvements in dyspnea. Additional research to determine whether the use of benzodiazepines alone or in combination with opioids is more effective is necessary to to lead to improvements in dyspnea treatments.

Subcutaneous (SC) morphine 5 mg or placebo in opioid-naïve patients and regular oral morphine dose plus half of the every-four-hour (q4h) dose given SC in patients on regularly scheduled opioids

• The sample was comprised of nine patients (seven opioid naïve and two opioid tolerant).
• Mean patient age was 73 years.
• The sample included four women with advanced cancer and dyspnea resulting from lung involvement.
• All patients had normal Mini-Mental Status Examinations (MMSEs).

The study was conducted in an inpatient geriatric hospital.

The study was a double-blind, placebo controlled, randomized, cross-over trial.

• Dyspnea visual analogue scale (VAS) (100 mm) and Borg scale obtained at baseline and 45 minutes after SC study dose and repeated until 240 minutes
• VAS for pain, somnolence, and anxiety
• Respiratory effort, including rate, cyanosis, and use of accessory muscles
• Pulse oximetry

• Mean change of VAS (–25, p < 0.01) and Borg scale (–1.20, p = 0.03) scores were significantly decreased with morphine compared to placebo.
• Respiratory effort (p = 0.05) and rate (p = 0.02) scores were significantly improved after morphine compared to placebo.
• No significant changes in pain, somnolence, anxiety, or oxygen percent saturation were found.

Intermittent injections of morphine at the doses used reduce cancer-related dyspnea. The changes in respiratory effort and rate but not anxiety support the theory that the benefit of morphine is unlikely related to somnolence or an effect on anxiety.

• This is a well-designed randomized, controlled study with the major limitation of sample size.
• The study points out the difficulty in conducting pharmacologic studies in patients with cancer and dyspnea.

The objective was to investigate and compare emergency medical treatment of acute dyspnea in palliative care patients with advanced-stage cancer on the basis of several emergency medical therapy schemes.

The study consisted of a retrospective evaluation of emergency medical treatment initiated in response to palliative client complaints of “acute dyspnea” over a 24-month period. Data collected were based on the emergency service protocol of four different German emergency medical services. Patients were categorized into five groups based on the intervention utilized by emergency physicians in the management of their dyspnea. Group 1 used therapy with morphine IV and oxygen; Group 2 used morphine IV, bronchodilator-effective drugs (IV and per inhalation), and oxygen; Group 3 used bronchodilator therapy (IV and per inhalation); Group 4 used oxygen therapy only; and Group 5 utilized no therapy. The extent to which the symptom was relieved was measured by patients’ numeric rating of intensity of dyspnea compared to extent of “vital sign normalization” on the basis of patients’ arterial oxygen saturation and respiratory rate.

• The sample was comprised of 116 patients.
• Patients ranged in age from 49–91.
• The median patient age in Group 1 was 77 years, Group 2 was 69 years, Group 3 was 73 years, Group 4 was 74 years, and Group 5 was 71 years.
• Of the 116 patients, 47 were females and 69 were males.
• Only patients diagnosed with advanced stage of disease (i.e., palliative stage with no feasible curative therapy alternative) were included in the current study.
• Multiple cancer types were included.
• Patients with advanced non-cancer disease and non-cancer related dyspnea (e.g., COPD) were excluded.
• All 116 patients were pre-treated with opioids according to WHO III standards for symptomatic pain control. Fifty-six patients (48%) were also pre-treated with rescue opioid medication for breakthrough symptoms of acute dyspnea (estimated as 1/6 of pain opioid dose rate).

The study was conducted during multiple out-of-hospital emergency response/home visits by four emergency medical services in Germany.

This was a retrospective, descriptive study.

• Numeric Rating Scale (NRS) to subjectively measure intensity of dyspnea (0 = very bad, 6 = very good)
• Arterial oxygen saturation
• Respiratory rate
• Phone interview and directed survey of emergency physicians regarding expertise in emergency medical care and palliative medicine

Based on improvement in respiratory rate, arterial oxygen saturation, and patient’s numeric rating of dyspnea, 47 patients (41%) experienced relief of dyspnea from emergency medical treatment. Dyspnea was relieved in 14 Group 1 patients (67%), 15 Group 2 patients (52%), 8 Group 3 patients (22%), 5 Group 4 patients (18%), and 5 Group 5 patients (71%). Though no significant differences regarding relief of dyspnea were noted between Groups 1 and 2 and between Groups 3 and 4 (P > 0.05), a statistically significant difference was noted when Groups 1 and 2 were compared to Groups 3 and 4 (P <  0.001), indicating a higher success among the two groups that utilized opioid therapy in the management of dyspnea. Only Group 5 experienced a correlation between subjective dyspnea ratings and objective measurements (i.e., oxygen saturation and respiratory rate). The high success rate in dyspnea alleviation observed in Group 5 (no medical treatment) was achieved by the transfer of a tracheostomy tube, which was the noted cause of dyspnea in five patients. Morphine was the only medication used during opioid therapy, and no respiratory sedation was noted by emergency physicians.

Significant relief of acute dyspnea was observed when IV opioid therapy was used as opposed to oxygen and bronchodilator therapy alone.

The study was purely descriptive, with no structured study protocol with measures for comparison or randomization of subjects. Thoroughness and accuracy of each documented encounter analyzed is also questionable. The investigation was carried out on the basis of a German system of emergency/pre-hospital treatment options that are not wholly generalizable to the American paramedic emergency response system.

IV opioid therapy for the management of acute dyspnea in out-of-hospital encounters for palliative care patients appears to be more beneficial than use of oxygen therapy and bronchodilator (IV and per inhalation) alone. Integration of a palliative care team (preferably with 24-hour accessibility) in the subsequent alleviation of dyspnea in out-of-hospital emergency palliative encounters may prove beneficial. This study raises the question of how dyspnea among palliative care patients may be managed by pre-hospital services in the United States and pre-hospital service staff knowledge of symptom management for this group of patients.

RESOURCE TYPE: Consensus-based guideline

PROCESS OF DEVELOPMENT: Relevant literature was selected by the authors; not based on a systematic review

Not specified

• Oxygen is not recommended for routine use. It can alleviate dyspnea in patients with hypoxia.
• Opioids are identified as the only pharmacologic agents with sufficient evidence for effectiveness.
• Benzodiazepines can be used in cases of insufficient response to opioids, either alone or in combination with opioids.
• Little evidence for nonpharmacologic interventions exists.
• In assessment, it is important to differentiate between continuous, episodic, breakthrough, or crisis breathlessness and determine exacerbating and relieving factors.
• Treatment of reversible causes should be considered before starting symptomatic treatment.

• No specified systematic review
• Written as mainly consensus-based

Provides very basic recommendations for dyspnea management in patients with advanced disease.

RESOURCE TYPE: Consensus-based guideline

PROCESS OF DEVELOPMENT: Guidelines were developed by a panel

These guidelines did not provide a specific search strategy or information about literature search results.

• Dyspnea: Use fans, cooler temperatures, stress management, and relaxation therapy; use morphine if the patient is opioid-naïve, and add benzodiazepines symptoms are not relieved by opioids; give oxygen for subjective relief; reduce excessive secretions with scopolamine, atropine ophthalmic solution, or glcopyrrolate.
• Anorexia: Consider an appetite stimulant such as megestrol acetate, olanzapine, dexamethasone, or a cannabinoid.
• Constipation: Use senna with or without docusate; add other laxatives as needed; consider methylnaltrexone for opioid-induced constipation.
• Diarrhea: Administer loperamide; recommend the Bananas, Rice, Applesauce and Toast (BRAT) diet; consider atropine, corticosteroids, infliximab, or octreotide.

These recommendations were made mainly by consensus, and the guidelines provided no information about literature search results and appeared to use only one database for searching. All suggestions were based on low-level evidence and uniform consensus.

These guidelines provided numerous suggestions for the management of various symptoms, but they were not truly evidence-based. In those aspects for which there was no research evidence, the guidelines provided expert opinion suggestions for management.

• The objective was to update the 1999 ATS consensus statement on dyspnea based upon new knowledge of neurophysiology and increasing interest in dyspnea as a patient-reported outcome.
• Included were patients who experience dyspnea from any etiology.

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

• Mechanisms underlying dyspnea
• Instruments used to measure dyspnea
• The clinical approach to patients who complain of dyspnea
• The treatment of dyspnea that persists despite maximal treatment of underlying pathologic processes responsible for breathing discomfort
• Topics that should be in the focus of future research.

The exclusion criteria were not clearly described.

• Patients were undergoing multiple phases of care.
• The guidelines have clinical applicability for elder care and palliative care.

• Results were not clearly defined.
• Literature was summarized in a general fashion with strong referencing, but levels and strength of evidence were not noted.

• Evidence describing the pathophysiology and measurement of dyspnea was comprehensive and well referenced.
• Management of refractory dyspnea despite aggressive assessment and attempts to control the etiology was the focus of the treatment section of the document.
• Therapies with strong evidence to support use include opiates, but adverse effects may interfere with acceptance.
• Therapies with limited evidence to support use include oxygen therapy, nebulized morphine, nebulized furosemide, heliox, anxiolytics, pulmonary rehabilitation, inspiratory respiratory muscle training, chest wall vibration, cool air movement on the face, noninvasive ventilation, acupuncture, and acupressure.

• The consensus document does not use systematic review techniques.
• Although dated 2012, key high-level evidence articles used in the ONS PEP review process (Cochrane Reviews) were not included in the references.
• In these guidelines is limited reference to patients with cancer.

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.

Objectives were to

• Present evidence that will contribute to the improvement of palliative care at the end of life.
• Answer questions regarding critical elements.
• Identify patients who could benefit from palliative approaches.
• Identify treatment strategies that work for pain, dyspnea, and depression.
• Identify elements important in advance care planning, collaboration and consultation, and assessment and support aspects helpful to caregivers.

Included were patients with any disabling or symptomatic condition at the end of life.

The guideline was based on a systematic evidence review, done by others, in an Agency for Healthcare Research and Quality evidence report. The guideline does not address nutritional support, complementary and alternative therapies, or spiritual support because evidence related to these areas does not often appear in the literature. Specific procedures for grading the evidence and recommendations are not described.

The guideline was developed for the Clinical Efficacy Assessment Subcommittee of the American College of Physicians. Evidence and recommendations were graded using the clinical practice guidelines grading system (GRADE).

Databases searched were MEDLINE and the Database of Abstract Reviews of Effects (January 1990–November 2005); citations from the review by the National Consensus Project for Quality Palliative Care (2003) also were searched.

Search keywords were cancer, congestive heart failure, and dementia. The full description of search terms is published elsewhere.

The guideline outlines the strength of GRADE recommendations and includes a brief description of the supporting evidence for each recommendation.

Critical Elements for End-of-Life Care: Elements identified are preventing and treating pain and other symptoms; supporting families and caregivers; ensuring continuity of care; ensuring respect for patients as people and informed decision making; ensuring well-being, including consideration of existential and spiritual concerns; and supporting function and duration of survival.

Identifying Patients Who Could Benefit From Palliation: No evidence tools have been validated or effectively shown to predict optimal timing. Decisions should be based on each patient's symptoms and preferences.

Treatment Strategies:

• Pain
  • Evidence is strong in support of the use of nonsteroidal anti-inflammatory drugs, opioids, bisphosphonates, and radiotherapy or radiopharmaceuticals for pain, with bisphosphonates used for bone pain specifically.
  • Insufficient evidence exists to evaluate the usefulness of acupuncture or exercise for pain control.
  • Palliative care teams may be moderately beneficial in providing pain management.
• Dyspnea
  • Evidence shows a valuable effect of morphine.
  • Nebulized opioids show no additional benefit over oral opioids.
  • Evidence regarding the use of oxygen is equivocal.
  • Studies that evaluated facilitated communication or palliative care consultation showed no effect.
• Depression
  • Evidence suggests that long-term use of tricyclic antidepressants, selective serotonin reuptake inhibitors, and psychosocial interventions are beneficial for patients with cancer who are depressed.
  • Evidence is mixed regarding the benefit of guided imagery and exercise in the defined patient population.
  • Evidence showed that care coordination had no effect.

Important Elements for Advance Care Planning: Evidence shows that extensive multicomponent interventions, goal-oriented interviews with palliative care providers, and proactive communication involving skilled discussants can reduce unnecessary services, without causing harm, and increase the use of advance directives.

Collaboration and Consultation: Use and patient-centered outcomes improve when multidisciplinary teams include nurses and social services providers, address care coordination, and use facilitated communication.

Supporting Caregivers: Evidence regarding the effects of palliative care teams for caregivers is mixed.

The following were graded as strong recommendations with moderate quality of evidence.

• Patients with serious illness at the end of life should be regularly assessed for pain, dyspnea, and depression.
• For patients with cancer, clinicians should use therapies with proven effectiveness to manage pain. These therapies include nonsteroidal anti-inflammatory drugs, opioids, and bisphosphonates.
• Clinicians should use therapies with proven effectiveness to manage dypsnea. These therapies include opioids (for unrelieved dyspnea) and oxygen (for the relief of short-term hypoxemia).
• Clinicians should use therapies with proven effectiveness to manage depression in patients with cancer. These therapies include tricyclic antidepressants, selective serotonin reuptake inhibitors, and psychosocial interventions.
• Clinicians should ensure that advance care planning occurs for all patients with serious illness. Such planning includes the preparation of advance directives.

• Several authors had grants from the Agency for Healthcare Research and Quality or pharmaceutical companies.
• Financial support for this guideline was entirely from the American College of Physicians.

The guideline provides clear guidance in several areas of end-of-life care and symptom management and identifies the relevant evidence and strength of the evidence. The guideline may not apply to all patients and is not intended to override clinical judgment. In addition to recommending medication interventions for depression, the guideline recommends psychosocial interventions.

RESOURCE TYPE: Evidence-based guideline, as well as expert consensus

No information was provided on the volume of evidence. The grading system developed by the Medical Information Network Distribution Service (MINDS) was used to evaluate the level of evidence, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to evaluate the strengths of the recommendations.

• Oxygen therapy is recommended in patients with hypoxemia and not recommended in patients without hypoxemia.
• Noninvasive positive pressure ventilation (NPPV) suggested to be used in patients with hypoxemia and hypercapnia
• High-flow nasal cannula oxygen therapy suggested in patients with hypoxemia refractory to standard oxygen therapy

• Systemic morphine is recommended.
• Systemic codeine/dihydrocodeine is recommended.
• Nebulized morphine is not recommended.
• Systemic fentanyl is not recommended.

• Benzodiazepines are not recommended to be used alone.
• Benzodiazepines are recommended to be used in combination with opioids.

• Nebulized furosemide is not recommended.

• Caution against routine use of systemic corticosteroids without the consideration of the cause of dyspnea
• Corticosteroids recommended for patients with lymphangitis carcinomatosa, superior vena cava syndrome, or major airway obstruction

The authors declared that, because of the lack of rigorous evidence, most recommendations statements were based on level of evidence and mostly on expert consensus. Some evidence reviewed were not wholly based on patients with cancer. The authors were unable to find adequate information on treatment effect on quality of life and pharmaco-economic outcomes.

The low level of evidence on which these recommendations are based point to a need for stronger studies on the management of dyspnea in patients with cancer. More research is also needed to investigate the effect of recommended interventions for dyspnea on patient quality of life, as well as cost-effectiveness.