Extended and Sustained Release Opioids

To assess the effect of regularly administered extended-release morphine for dyspnea in patients receiving standard hospice care

• Regular administration of extended-release oral morphine 10 mg twice daily or 30% dose increase for those already on morphine
• Patients received 15 mg twice-daily metoclopramide for the first five days and a laxative.

• N = 15 (13 completed 48-hour assessment, 9 completed final assessment)
• MEAN AGE = 73 years
• MALES: 7, FEMALES: 8
• KEY DISEASE CHARACTERISTICS: Patients with cancer in hospice; mixed diagnoses—mostly lung primary or lung metastases, but four also had chronic obstructive pulmonary disease; patients with dyspnea from irreversible causes
• OTHER KEY SAMPLE CHARACTERISTICS: 13 were opioid-naive, and 2 were opioid-tolerant

• Eight patients were at home, and seven were hospice inpatients.

• Open, nonrandomized, uncontrolled

• Dyspnea visual analog scale (VAS)
• Support Team Assessment Schedule
• Borg Scale
• Respiratory rate
• Sedation VAS
• State-Trait Anxiety Inventory
• Pain (0–10)
• Assessments at baseline, 48 hours, and 7–10 days

Decline in dyspnea VAS scores for six patients was not statistically significant (p = 0.06). No clinically significant decline was found in respiratory function. No change was seen in anxiety, but actual scores were not reported. The authors stated that the high incidence of sedation and dizziness was of concern and indicated a need to monitor patients carefully. The authors also stated that the use of immediate-release morphine on an as-needed basis might be effective and cause less sedation.

Although the authors claimed that morphine should be trialed in patients, the evidence from this study does not support that. The problem may be the use of modified-release morphine 10 mg opposed to immediate release.

• The study had a small sample size with attrition.
• Three patients died, and three asked to withdraw because of side effects.
• Sedation at 48 hours was the main problem.
• Two patients who withdrew and two who died reported excessive drowsiness.

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 this study was to evaluate the efficacy of injectable form of oxycodone on pain and dyspnea in terminally ill patients with cancer.

• Medical records of patients who received continuous subcutaneous oxycodone for pain relief were analyzed. 
• Patients' verbal ratings that were documented were used for analysis. 
• Changes in ratings and use of rescue doses were analyzed.

• The study reported on a sample of 95 patients.
• The mean age was 71.7 years, with a range of 47–92 years.
• Of the sample, 56% were males and 44% were females.
• Tumor types varied; the most common were lung and colon.
• All patients were in inpatient hospice care.

This single-site study was conducted in an inpatient setting in Japan.

• Patients were receiving end-of-life care.
• The study has clinical applicability for palliative care.

The study was a retrospective, descriptive trial.

A three-point symptom severity verbal rating was used.

• The most frequent reason for initiating subcutaneous oxycodone was patient difficulty taking oral medication. 
• Duration of administration ranged from 2.08–111.2 days, with an average of 14.4 days. 
• Initial base dosages used ranged from 4.8–84.6 mg per day, and final base doses averaged 61.8 mg per day, with a range of 3.8–192 mg per day. 
• Most patients were previously receiving parenteral morphine, oral oxycodone, or transdermal fentanyl.
• Effect on pain was rated as moderate in 50% of patients and as high in 41.7%.
• Effect on dyspnea was moderate in 36.5% and high in 4.2%. 
• The most common side effect was drowsiness/somnolence.

Subcutaneous oxycodone administration was effective for reduction of pain and dyspnea in some patients.

• The study had a small sample size of less than 100 patients.
• The study had a risk of bias (no control group, no blinding, and no random assignment).
• Measurement validity/reliability is questionable.
• Data were extracted retrospectively from medical records.

• This study describes the experience of one group in using subcutaneous oxycodone in end-of-life palliative care. 
• The study has many limitations, so the strength of this evidence is low. 
• Subcutaneous oxycodone administration may be a useful alternative for pain and dyspnea management in some patients.

• 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.