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Case:

Mr. R is a 65-year-old man who retired as a high-level executive at a large business. He had been hospitalized with worsening pulmonary fibrosis and had ultimately received a double lung transplant. Following transplant, Mr. R suffered multiple complications over a period of three months. In these months, Mr. R was a participant in his own care during times of relative medical improvement. Yet his primary team noticed at the present admission that, he seemed to be withdrawn and was not engaging well with physical or occupational therapy. The team also noted that he had more difficulty concentrating when they went into the room to see him. The team expressed concern that the stress of a prolonged hospitalization was getting to him and/or that Mr. R might be suffering from depression.

The team requested a palliative care consult and, as the psychiatrist on the service, I was asked to see Mr. R. When I first examined him, I indeed found him to be quiet and withdrawn and not at all the "go-getter" that his wife described. When the palliative care doctor had initially seen the patient, she was concerned that he appeared to be confused at times, and my examination bore this out. Mr. R was lethargic and would drift in and out of sleep while we talked. With a little prodding, he revealed that he had noticed a "problem" with his thinking and frequently found himself to be unsure of where he was and why people were coming in and out of his room. He denied any hallucinations or paranoia.

Discussion:

It is very common for doctors to identify hyperactive delirium in patients. Hyperactive delirium is the disturbance in thinking that results from physical illness, medications, or various other etiologies and is characterized by a previously stable individual becoming disoriented, agitated, paranoid, and hallucinatory. It frequently results in a disturbance on the medical unit, and is therefore usually diagnosed. Far more common, but less frequently noticed (estimates run from 32-66% missed) is the condition known as hypoactive delirium. Hypoactive delirium is also a disturbance of consciousness wherein the patient's mental status waxes and wanes, but it frequently manifests with symptoms more like those observed in Mr. R: patients become withdrawn, display less motivation, have lower energy, and are quietly confused.

It is not uncommon for patients with this symptom set to be mistaken for depressed or even as simply lacking the motivation to improve medically. The incidence of delirium among hospitalized patients has been estimated at around 10%. Among patients nearing the end of life, these numbers increase to approximately 60%. It is known that untreated delirium results in increased morbidity and mortality in the 6 months following a hospitalization. Identifying and treating hypoactive delirium is therefore an important component of improved quality and length of life for palliative care patients.

The treatment for both hyperactive and hypoactive delirium is the same: identification and treatment of the underlying cause, and short-term use of antipsychotic medications to reduce disruptive symptoms. Mr. R was started on risperidone 0.25mg twice a day with additional doses available as needed. Within two days of starting this regimen, he was interacting more with his providers, reengaging in rehab, and having conversations with his wife that both of them found to be more successful. Mr. R. never endorsed symptoms that would suggest depression. He was better able to communicate his needs and participate in his care.

References:

1. Casarett D, et al. Diagnosis and management of delirium near the end of life. Ann Int Med 2001; 135 (1): 32-40. (open access pdf)

2. Rea RS, et al. Atypical antipsychotics versus haloperidol for treatment of delirium in acutely ill patients. Pharmacotherapy 2007; 24 (4): 588-94.(no open access pdf)

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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.