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Case:

Mr CC is a 67-year-old with NSCLC (non-small cell lung cancer) and metastatic disease to his mediastinum and left chest. He was admitted to the hospital for increasing right sternal chest pain over the past month. Pain is described as burning and non-radiating. There are no exacerbating or relieving factors. The pain is so bad that he has anorexia. The month prior to admission, he was started on Oxycontin, and his dose was titrated up 160 mg twice a day with Dilaudid 8 mg every 3 hours PRN (as needed). Despite dose escalation, his pain was unchanged. While in the hospital, a fentanyl patch and a dilaudid PCA (patient controlled analgesia pump) were added to the original regimen. However, no increased analgesia occurred.

A palliative care consult was obtained. His regimen was simplified to a Dilaudid continuous intravenous infusion (CI) and PCA. Doses were escalated to 4 mg/hour CI and 4 mg PCA with 8 mg RN dose q1 hour. He reported no change in his pain. Co-analgesics of NSAIDS, Tylenol, dexamethasone, and a TCA (tricyclyic anti-depressant) were tried. Radiation oncology was consulted and saw no lesions to irradiate. The patient began to complain of worsening pain. As he continued to complain of 7-10/10 pain, the patient was changed to morphine and titrated to 10 mg continuous infusion and 10 mg PCA dose. Marked analgesia was noted. Attempts to transition to methadone were unsuccessful, as his need for morphine PCA doses remained unchanged. Despite initial complaints of sedation on morphine, the patient’s pain scores decreased to 3/10. As such, he was continued on morphine and discharged from the hospital on a PCA.

Discussion:

Opioid rotation, or trial of an alternative opioid, is commonly practiced when a patient’s pain responds poorly to one opioid or intolerable side effects develop. These intolerable side effects may include nausea, vomiting, sedation, or even hyperalgesia. Although rotation is a common practice, a Cochrane review in 2004 found that evidence to support the practice for opioid rotation was anecdotal and in non-controlled studies. Randomized trials were suggested. Since that time, several prospective studies have been performed where opioid analgesic effect was inadequate or side effects to the opioid were intolerable. Studies by both Narabayashi et al. and Wiraz et al. investigated rotation to an alternative long acting opioid, dilaudid or oxycodone. In addition, patients had increased analgesia compared to the prior regimen. Often the effective equianalgesic dose in these studies was greater than the prior dose, suggesting that prior side effects may have been dose limiting. More is being learned about the pharmacokinetics and pharmacodynamics behind opioid metabolism. It is clear that there is variability between individuals. Some of this may be secondary to disease states (i.e. renal or hepatic impairment), or the effect on metabolism by other drugs. Other differences are due to genetic variations.

Inherited differences in opioid receptors, channels, and metabolism to active and inactive compounds have been found. These differences may extend to transporters effecting bioavailability from the GI tract to even penetration of the blood brain barrier. This variability may account for differences in effectiveness and side effects from one patient to another. For example, “non analgesic responders” to methadone were found to have lower blood levels of the drug when compared to the same dose with “responders.” This suggests that the “nonresponders” may actually just clear methadone faster. It is frequently cited that 5-10% of the Caucasian population has the inability to convert codeine to its active metabolite, making it an ineffective medication in those individuals. Differences in metabolism have also been found with tramadol and oxycodone. In trying to obtain adequate analgesia with these medications, large doses may be tried with the development of side effects.

When switching to a different opioid, it is recommended to decrease the dose by 25-50% and even greater when switching to methadone. The rationale behind this has been “incomplete cross tolerance” and the concern that a patient may be more sensitive to the side effects of the second opioid, especially sedation. Understanding possible individual genetic variability, gives this practice even more credence.

Mr. CC was tolerating 20 mg IV dilaudid /hour without analgesia. His basal rate of 4 mg/hour dilaudid may be equianalgesic to 20-30 mg IV morphine hour. Given his profound tolerance to IV dilaudid and oral oxycodone, a conservative CI of 7 mg morphine/hour was started with frequent PCA doses available. Even with sub-equianalgesic dosing, he noted marked analgesia.

When doses of an opioid are escalated without apparent benefit and/or with side effects, opioid rotation should be considered. An individual’s biochemistry may determine if a particular opioid regimen will be successful and tolerated.

References:

1. Smith, Howard S. “Variations in Opioid Responsiveness.” Pain Physician 11:237-248, 2008. (free pdf available)

2. Narabayashi, Masaru et al. “Opioid Rotation from Oral Morphine to Oral Oxycodone in Cancer Patients with Intolerable Adverse Effects: An Open- Label Trial.” Japanese Journal of Clinical Oncology 38: (4)296-304. 2008

3. Quigley C. Opioid switching to improve pain relief and drug tolerability. “Cochrane Database of Systematic Review 2004”, Issue 3. Art. No.: CD004847 DOI: 10.1002/14651858.CD004847.

*Slight editorial changes were made for readability.

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Case:

Jane (not her real name), a 66 year-old woman with advanced COPD, has been hospitalized 5 times in the last six months for shortness of breath. During the current admission, she has been anxious, tearful, and stated to her nurse “I don’t know if it’s worth it anymore.” Nursing staff suggested a palliative care consultation to assist with managing Jane’s symptoms.

During her initial meeting with the palliative care team, Jane reported that she sees herself “going down hill” and is frightened of dying, specifically of suffocating. The palliative care team reviewed Jane’s recent clinical course and current medical regimen with her primary team and the other consulting teams. Given her persistent symptoms despite maximal therapy for her COPD, the palliative care team suggested a trial of opioids and benzodiazepines to manage her persistent dyspnea and associated anxiety.

Jane began taking:

oxycodone 5 mg every 4 hrs RTC (round the clock) for dyspnea
oxycodone 5mg q2 hr prn (as needed) for dyspnea
lorazepam 0.5 mg every 6hr for anxiety

and noted significant improvement. A fan was placed in her room and she continued on supplemental oxygen. A behavioral medicine specialist met with Jane and taught her relaxation techniques to use when her breathing was bothersome. With improvement in her shortness of breath, anxiety, and mood, Jane began to work with members of the palliative care team and her primary physician, as well as with representatives from social work and pastoral care, to clarify her overall goals and plans for the future.

Discussion:

Dyspnea is a commonly feared symptom in patients with advanced diseases affecting the lungs. Careful assessment, based on the patient’s subjective symptoms, and a thorough history and physical examination, guide management. Identifying and treating the underlying cause of the shortness of breath (pulmonary edema, bronchospasm, pleural effusion, etc.) generally provides the most effective relief. If treating the underlying cause is not possible or practical, efforts to manage the symptom itself are essential.

Oxygen, opioids, and benzodiazepines, as well as non-pharmacological interventions, represent the main strategies for controlling dyspnea. Opioids, often in lower doses than used for pain, reliably relieve dyspnea. All opioids are effective for managing dyspnea, though morphine is often used because of its low cost and ease of titration. Clinicians often fear respiratory depression when using opioids to control dyspnea, but they can be used safely and effectively when titrated carefully and followed closely. Sedation occurs well before respiratory depression and can signal a need for dose adjustment or more cautious titration.

Benzodiazepines can be safely added to opioid therapy to manage co-existing anxiety, starting at low doses and titrating to effect. Simple relaxation techniques can be easily mastered by patients and can provide a sense of control over distressing symptoms. Fresh air from an open window or fan can also provide significant relief. Patients and families should be reassured that dyspnea can be effectively controlled with the modalities discussed above.

References:

1. Luce J, Luce J. Management of dyspnea in patients with far-advanced lung disease: “Once I lose it, it’s kind of hard to catch it…” JAMA 2001: 185:1331- 1337. doi:10.1001/jama.285.10.1331

2. Emanuel L, von Gunten C, Ferris F. Education for Physicians on End-of-Life Care (EPEC) Module 10: Common Physical Symptoms. American Medical Association, Chicago: 1999.

*Historical Cases are presented intermittently to allow for twice monthly publication on the blog.
**Slight editorial changes were made for improved readability.