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Case

CH is a 56-year-old woman with metastatic breast cancer to bone, liver and brain. She is admitted to the hospital with increasing lethargy and a marked decrease in her oral intake. She has also not had a bowel movement for 10 days. Further interview reveals that she has been on a fentanyl patch 75 mcg for months, senna and colace, and hydrochlorothiazide. Her diuretic is stopped and she is placed on intravenous fluids. Except for dehydration, a metabolic work up is unremarkable. Her exam reveals hypoactive bowel sounds, a scaphoid abdomen with palpable mobile masses, and soft stool in the rectal vault. She is disimpacted. No active bowel movement follows despite suppositories. She is also not able to retain enemas. She has increasing nausea and anorexia. Given her inadequate response to a bowel regimen from below and inability to tolerate an oral regimen, she is dosed with methylnaltrexone subcutaneously x1. She has a large formed bowel movement 2 hours later.

Discussion

Constipation is a well recognized side effect from opioids. Tolerance does not occur. In fact, the dose that can cause constipation is ¼ of an analgesic dose. Opioids exert their constipating effects by decreasing GI motility, gastric emptying, increasing ileocecal valve tone, increasing fluid resorbtion, and decreasing the reflex to defecate.

Methylnaltrexone (MNTX) is a mu receptor antagonist that unlike naloxone does not cross the blood brain barrier as it is a quaternary amine. Naloxone has been used in the past for opioid induced constipation. However, this use has also been associated with opioid withdrawal and decreased pain relief. MNTX was approved for the treatment of opioid induced constipation by the FDA last year. Given its expense, many institutions have tried to limit its use. Our institution has made a Palliative Care consult one of three consultation services that can approve dosing.

The phase three clinical trials that led to approval of MNTX involved patients either enrolled in hospice or as part of a palliative care program, and opioids were thought to be the primary cause of the constipation. They must have been receiving opioids for two weeks and on a stable opioid and laxative regimen for three days.

Enrolled patients had had no bowel movement in greater than 48 hours or had had less than 3 bowel movements the week prior. Bowel obstruction, fecal impaction or other acute abdominal processes were ruled out. In addition, patients with peritoneal dialysis catheters and fecal ostomy bags were excluded. While 80 percent of the patient population had cancer, patients with cardiovascular disease, AIDS, dementia, and COPD were also included. MNTX is administered subcutaneously based on the patient’s weight. After administration of MNTX, greater than or equal to 50% of the study group had a bowel movement within 4 hours. Most patients had a bowel movement within 30-70 minutes. As compared to placebo, the most frequent side effects were abdominal cramping, nausea, dizziness, increased body temperature and flatulence. However, the number of patients who discontinued therapy secondary to side effects was similar to that in the placebo group. No decrease in pain control or signs of opioid withdrawal were noted as compared to the placebo group.

There are many medications and dosage forms that are available for opioid induced constipation. Previously, routes of administration have been oral and rectal. Dysphagia, nausea or decreased mental status can greatly hinder an adequate regimen by mouth. Rectal routes of suppositories and enemas can also be tried. Inability of the patient to participate can limit effectiveness of enemas. In properly selected patients, MNTX may be able to aid in relief of opioid constipation without adversely affecting pain control

References:

1. Thomas, Jay et. al. Methylnaltrexone for Opioid Induced Constipation in Advanced Illness. 2008. NEJM 358 (22): 2332-2343.

2. Yuan, Chun-Su. Methylnaltrexone Mechanisms of Action and Effects on Opioid Bowel Dysfuction and Other Opioid Adverse Side Effects. The Annals of Pharmacotherapy, 2007. 41: 984- 993

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Case:

Mrs. Smith is a 52-year-old woman with metastatic lung cancer diagnosed two months ago when she developed chest wall and right arm pain. Since then she has seen her primary care physician, an oncologist, and a palliative medicine physician. Her opiate dose was escalated from nothing to 200 micrograms of fentanyl without any pain relief. She was admitted to the hospital two days ago for uncontrolled pain and placed on a hydromorphone PCA. She is currently using 10mg/hr (continuous and bolus), still rates her pain as a 10 out of 10, and has developed nausea.

She describes her pain as a throbbing of the right chest wall and numbness, burning, and tingling down her right arm. Her physical exam is consistent with a lower brachial plexopathy. Her radiographic studies reveal metastases to the sternum and ribs and a right upper lobe mass invading the brachial plexus.

Given the patient is currently using almost 5 grams of oral morphine equivalents a day with no relief and probable opioid induced nausea, what is the next step?

Discussion:

While cancer pain can be relieved in 80-90% of patients using the WHO analgesic ladder, this case raises the question of what should be done when a patient’s pain is uncontrolled even on very high opiate doses. In this discussion, we will assume the pain is caused by tumor rather than distress from psychological causes (delirium, anxiety, addiction) or spiritual/existential suffering.

A key question is whether the patient has ever been responsive to opiates for this condition. If the answer is yes, the increased pain should lead to a search for a worsening of the underlying disease or a new cause of pain. Prior to concluding that a patient’s pain is not opioid responsive, one needs to make sure that the patient has had an adequate trial. The dose should be increased until the patient has pain relief or unacceptable toxicities develop. Aggressively treating the opiate’s side effects may improve the analgesic window. Control of the patient’s vomiting, hyperalgesia, myoclonus, delirium or drowsiness may make it possible to increase the opiate dose to an effective level. In addition, a Cochrane review suggests that rotating from one opiate to another may help decrease side effects and widen the therapeutic window. In addition, recent studies have shown that for patients with opioid responsive pain and uncontrolled side effects, an epidural pump leads to better pain management and is cost-effective.

If analgesia is still ineffective, one can add a drug that produces independent analgesic effects. For example, this patient seems to have both bone and neuropathic pain syndromes. The former may respond to steroids, non-steroidals, or biphosphonates, the latter to topical lidocaine, antidepressant, or antiepileptic drugs. While the strongest evidence supports tri-cyclic antidepressants, gabapentin, and serotonergic neuroepinephrine reuptake inhibitors for the treatment of neuropathic pain, one may have to try five or six agents (including agents such as clonidine, intravenous lidocaine, or mexelitine) to get a significant decrease in pain. A combination of these may also be needed. One should systematically add a co-analgesic and increase the dose until the maximal dose, pain relief, or intolerable side effects occur. A medication should be continued if it results in at least a 50% decrease in pain.

One should also consider non-pharmacological analgesic interventions. Acupuncture and behavioral interventions have been shown to help with pain syndromes. Radiation to the patient’s sternum and ribs may help with bone related pain, while a regional nerve block may help the neuropathic component. In addition radiopharmaceuticals such as samarium, can be considered in patients with pain secondary to diffuse bone metastases.

In very difficult cases, one may need to try and enhance the opiate’s analgesic effect. Drugs that antagonize the NMDA receptor, for example, have both direct analgesic effects or may reverse opiate tolerance, resulting in better pain management. The three drugs that are most commonly used are ketamine, methadone, and dextromethorphan. The use of these drugs should only be done with a pain or palliative care consultation.

While opiate unresponsive pain is not that common, it is very frustrating. Systematically approaching the problem will ensure that one develops the best treatment plan.

References:

1. Mercadante S, Portenoy RK. Opiate Poorly Responsive Cancer Pain Parts 1-3 Journal of Pain and Symptom Management 2001 Vol. 21 #1 page 144-150; Vol. 21 #2 page 255-264; Vol. 21(4) #3 page 338-354.

2. Smith, TJ, Staats, PS., Deer, T., et al. (2002). "Randomized clinical trial of an implantable drug delivery system compared with comprehensive medical management for refractory cancer pain: impact on pain, drug related toxicity, and survival." J Clin Oncol 20(19): 4040-9.

3. Fallon, M. (2008). "When morphine does not work." Support Care Cancer 2008: 16(7):771-5.

Acknowledgments: We appreciate input from David Weissman who helped us think through and provide part of the algorithm for this article.

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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.