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Case:

You are asked to see Mrs. RT, a 44-year old woman with end-stage COPD. She was admitted to inpatient hospice with increased anxiety, hopelessness, and pain “all over.” She says she is tired of being sick and exhausted, and wants to be “put to sleep.” She has heard about “terminal sedation” and is angry it hasn’t been offered. She lives with her husband and adult children who work full-time and is upset they can’t all stay home with her. She experiences dyspnea with activity, and uses a wheelchair, but can independently transfer to bed and toilet. Your exam reveals she is awake and alert, neither delirious by the confusion assessment score (CAM), nor suicidal. She is cachectic, tachypnic, and has generalized muscle atrophy. She lacks signs of infection or localized pain. You estimate her prognosis in months. She takes medications erratically for symptom control.

What is Palliative Sedation Therapy (PST)?

Patients and families sometimes have heard or been told about “terminal sedation,” but it is a frequently misunderstood term and therapy. The term “terminal sedation” suggests the goal of the therapy is hastening death for terminally ill patients, when in fact the goal is symptom relief. Therefore, the term “palliative sedation therapy (PST)” is much preferred since the goal of PST is relief from intolerable and untreatable symptoms, not shortening a patient’s life. An international panel of palliative care experts recently reviewed the medical literature on PST and published their recommendations for standardizing our understanding of this therapy1. They recommend the following definition: “Palliative sedation therapy is the use of specific sedative medications to relieve intolerable suffering from refractory symptoms by a reduction in patient consciousness.” They emphasize that palliative sedation is distinct from euthanasia while acknowledging lively debate on this issue.

The panel’s position is based on their assertion that hastening a terminally ill patient’s death is not the goal of PST. Other points of difference between PST and euthanasia are the principle of titration to comfort rather than to death, and PST’s reversibility.

What are refractory symptoms?

Refractory symptoms are considered symptoms for which all possible treatments have failed. A patient experiencing refractory symptoms must be differentiated from a patient who has symptoms that are difficult to treat. Refractory symptoms are symptoms that the palliative care physician and team determine cannot safely be relieved by invasive or noninvasive interventions. Expert panel members recommend Cherney’s definition of refractory symptoms: “Refractory symptoms are symptoms for which all possible treatment has failed, or it is estimated that no other therapies exist within the patient’s time-frame or tolerable risk-benefit ratio.”

When is PST considered?

PST is considered for patients with refractory symptoms only after discussions with the patient and/or family, the caregiving team, and the palliative care expert. The most frequent reasons for PST have been refractory delirium or restlessness, dyspnea, pain, and nausea/vomiting. The use of PST or psychological or existential distress is rare, and initiated only under exceptional circumstances. PST is considered only in the last hours to days of life.

Experts recommend a systematic and inclusive process to determine if PST appropriate, which includes the patient, if possible, designated surrogate and caregivers, and addresses the patient’s values, beliefs, and goals. If PST is chosen, then the specific intervention is discussed and reviewed, instituted, and carefully monitored. Decisions about nutrition and hydration are discussed separately from the decision to offer PST.

Medications used for PST include benzodiazepines (usually midazolam), except for delirious patients, phenobarbital, or propofol. Opioids are not recommended for PST because even high doses may not result in sedation.

Since the aim of PST is the relief of refractory symptoms, doses of sedatives are carefully chosen to relieve distress by reducing a patient’s level of consciousness and are not excessive. The degree of sedation can vary from superficial to deep sedation. Initial doses of sedatives should be small enough to allow a patient to communicate periodically.

Refractory symptoms may respond to temporary sedation, since a patient’s ability to tolerate symptoms may be improved following rest provided by sedation. Experts identify three levels of continuous sedation. With mild sedation, the patient is awake, but has a lowered level of consciousness. Moderate sedation results in stupor, so that the patient is asleep, but can be awakened to communicate briefly. With deep PST, the patient is unconscious and unresponsive. PST is frequently monitored and assessed, with attention to the needs and goals of both patient and family.

Back to the Case:

You convene a meeting with the patient, her family, and the palliative care team. After asking open-ended questions and listening to concerns, you offer information about PST but say that you think her symptoms can be treated. You offer medication changes including around the- clock rather than as needed opioids for relief of dyspnea and pain, and a comprehensive treatment plan for her anxiety and depression. Her family finds ways for her to be less isolated, and the hospice team offers additional services and frequent monitoring. Although she is skeptical, she is willing to consider these options as possibly improving the quality of her life.

References:
1. De Graeff A. Dean M: Palliative Sedation Therapy in the Last Weeks of Life: A Literature Review and Recommendation for Standards. Journal of Palliative Medicine 2007; Vol10 (1); 67-84.

2. Cherny NI. Portenoy RK: Sedation in the management of refractory symptoms: guidelines for evaluation and treatment. Journal of Palliative Care 1994;10;31-38.

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Case:

JD is a 66-year-old African-American female with cardiomyopathy and pulmonary hypertension who has been in and out of the hospital for the past two years. She had biventricular assist devices placed in August, 2007. Since then, she has experienced numerous setbacks and subsequently has been on and off the heart-lung transplant list. Most recently, she went to the OR to have her current LVAD replaced with a smaller unit. The procedure was aborted.

JD is divorced with no children. Prior to hospital admission, she lived alone, independently, in a one-story home. A supportive brother and sister live nearby. She is very sharp, speaks her mind, and has no patience for what she perceives as incompetence or “stupidity.” She expects staff to communicate with her directly and has no tolerance for ambiguity, mixed messages or superficiality. She has alienated several of the staff who don’t meet her expectations.

Over the past couple years, I have visited JD numerous times. In my first visit, she told me where to sit and told me to read certain passages of Scripture to her. (She has taught adult Bible study and has been very active in her church). I went along with her request (i.e., “order,”) and we actually had a stimulating theological discussion. Our visit ended with prayer. After this first visit, she no longer told me what to do. In subsequent visits, she shared her life story. I found that gently kidding around with her diffused her intensity. We spent many visits with her telling me about her life from childhood on, and we’ve shared much laughter. I enjoyed celebrating with her those memories that gave her joy.

In the last few months, her emotional ups and downs have become more pronounced. She was focused on getting a heart-lung transplant, which turned out not to be an option. She faced a surgery with a questionable predicted outcome, knowing she might die on the operating table. That surgery ended up being aborted. I have seen her at all-time emotional lows as well as in periods of bouncing back. Spiritually, she says she knows that God is with her; she has “no doubts” about that. She also says she must make all decisions, including life and death decisions, on her own – without God’s help.

Intervention:

The anchor in all my visits with her is prayer—prayer for guidance for her in decision making, prayer that lifts all her specific concerns and joys to God. We always hold hands in prayer, which she anticipates and appreciates. The healing aspects of this relationship are consistency and love. In the time we spend together, JD has shared precious, sometimes outrageously funny memories of her life. I have lifted up these memories to God in prayer with her, sometimes in a humorous way. My hope is that rather than compartmentalizing her spirituality she will allow God more and more into her decision making, that she will let God carry the weight of her burdens. This seems to be difficult for her, since she is so fiercely independent.

More and more, she seems now to be dealing with the prospect of her earthly life ending. While she remains trapped in a failing body with future prospects dim, she is now looking at her life with a sense of “well done, thou good and faithful servant” (Matthew 25:21) which is the ultimate healing.

Discussion:

Addressing quality of life is essential for patients with prolonged hospital stays. Patients on LVADS or BIVADS are physically restricted. While the body may be restrained, the mind is free to roam. Well-being must be viewed holistically, with emotional and spiritual needs being addressed. One researcher found that patient coping strategies include family support, religious convictions, and diversional activities, and that best way to support these patients is to establish a trusting relationship, foster independence and incorporate humor into their care. (Savage)

References:

1. Savage, Laura, RN, MSN (2003) Quality of Life among Patients with a Left Ventricular Assist Device: What is New? AACN Clinical Issues 2003 Feb. 14 (1) pp.64-72.

2. Savage, Laura, RN, MSN (1999) Life With a Left Ventricular Assist Device: The Patient’s Perspective American Journal of Critical Care Vol. 5, No. 5, pp. 340-343.

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Case:

Mr. L.O. was an elderly Russian immigrant to Canada, admitted to the Palliative Care Unit of a Canadian hospital with advanced rectal cancer. When L.O. was first presented to the multidisciplinary team, his major problems were identified as persistent rectal pain and anxiety. The initial workup of the pain suggested a neuropathic component, and adjustments were made to L.O.’s medications. His complaints of pain and anxiety persisted over the next several days.

L.O. then began to experience terrifying nightmares. Even during the day, when he was awake, he would have what he called “flashes” of frightening imagery, but the nightmares were the worst. L.O. was so fearful of them that he resisted falling asleep as much as he could. The images were horrific, often violent, with L.O. sometimes being the victim of the violence, sometimes the perpetrator. A CT scan was ordered to investigate the possibility of brain metastases as a contributing factor.

At the same time, the attending palliative care physician had a long interview with L.O., in which they explored the content of the nightmares in depth. L.O. was an amateur artist, and the physician suggested that he might sketch the images in his dreams, or, if not the exact images, some rendering of how they made him feel. L.O. did this. Subsequent conversations revealed that L.O. was estranged from his children; the main reason that he needed to be in the Palliative Care Unit was that none of his children cared enough about him to support him while he lived at home. L.O.’s sketches showed a small figure—himself—cowering at the bottom of a deep pit, with another figure standing far above, looking down.

The physician suggested that L.O., who had become physically well enough for a weekend pass, bring some of his previous paintings back with him to the Palliative Care Unit. Within a few days, the sound of hammering could be heard from L.O’s room. He was hanging his pictures, 15 or 20 in all. Most were landscapes, but there were also a portrait of a lovely young woman, and a winter scene, all in black and silvery white, of a snow- and ice-lined brook leading into a dark woods. The next morning L.O. reported that he had dreamed of eating a chicken dinner.

Discussion:

Two features of this case are striking. The first is the necessity of combining medical and psychosocial approaches to L.O.’s nightmares and overwhelming anxiety. Both the CT scan and several psychoactive medications were appropriate and helpful. But it was the in-depth exploration of the content of the imagery, and even more, the suggestion that L.O. use his art to capture his emotional state in drawings, that appeared to unlock the insights and emotions that lay beneath the anxiety and terror. The physician succeeded in helping L.O. find a language to express himself more effectively and concretely than he had been able to do at a purely verbal level. The physician found a form of expression that “fit” the patient, even though that form was somewhat unconventional.

The second feature concerns the possibility of creating a living space in the Palliative Care Unit where L.O. could work his way to a feeling of peace and safety, despite his estrangement. This use of the inpatient palliative care service would almost certainly be impossible in the United States, with our minimal lengths of stay and our restrictive utilization review requirements. L.O. died in this Canadian palliative care unit many days after his physical and emotional symptoms had been brought firmly under control. But the inpatient environment remained critical to his spiritual well-being. Even though the Canadian health care system faces some of the same economic pressures as that in the U.S., the possibility still exists there for more flexibility to respond to the broadest range of patient or family need, compared to the limits imposed by hospice and palliative care financing in the U.S.

References:

1. Pratt A, Wood M (eds). Art Therapy in Palliative Care. London: Routledge, 1998.

2. Lynn J. Serving patients who may die soon and their families: The role of hospice and other services. JAMA, 2001, 285:925-932. (No open access pdf)

3. Raphael C, Ahrens J, Fowler N. Financing end-of-life care in the USA. Journal of the Royal Society of Medicine, 2001, 94:458-461. (Open access PDF avail from Journal and PubMed Central)

(CS: Minor formatting edits for readability)

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Case:

Mr. C, a 68 year old widower with an implantable cardioverter-defibrillator (ICD) placed five years previously, was admitted to the hospital after his ICD discharged several times in one day. Each discharge was associated with severe pain, loss of consciousness, and heightened anxiety about experiencing future discharges. Evaluation of the ICD firing confirmed refractory ventricular tachyarrhythmias consistent with Mr. C.’s end-stage heart failure. Trials of anti-arrhythmic medications proved unsuccessful. The frequency of ICD discharges could not be reduced without deactivating the device (which would cause imminent death), yet leaving the ICD active would prolong Mr. C’s suffering.

When his primary medical team informed him about his medical condition and prognosis, Mr. C showed ambivalence about deactivating his ICD. He clearly stated to his health care team that he “did not want to live under these circumstances” and that “shutting off this pacemaker may be the best thing for me.” However, he did not like being left alone for fear his heart would stop and no one would be available to resuscitate him. His primary medical team consulted the Palliative Care Team (PCT) to discuss end-of-life options and goals with the patient and family. The PCT treated Mr. C’s anxiety with clonazepam and relaxation training, “supported” his ambivalence, and assisted with his discharge planning.

As the PCT continued working with Mr. C, it became apparent that Mr. C experienced tremendous remorse for “what I put my family through 20 years ago after my wife died.” Although his family openly stated that all was forgiven, Mr. C could not accept their reassurances – “I wish I could make it up to them.” The PCT initiated an intervention where Mr. C talked about his family members one at a time, and he described his happiest memory, what he appreciated, and what he loved about each one. His thoughts were written down, and the family was trained to continue the exercise until all family members were done. Mr. C was discharged with home hospice, and his family completed the PCT intervention at home. The day after Mr. C finished his individualized sentiments, he requested to have his ICD turned off. A representative from the ICD manufacturer came to Mr. C’s home and deactivated the ICD. Mr. C died two hours later in the comfort of his home and surrounded by his family.

Discussion:

ICDs are used to treat people at risk for sudden death due to ventricular tachycardia or ventricular fibrillation. They deliver an electrical charge to the myocardium during an arrhythmic event, and the “shock” allows the ventricle to resume a normal rhythm1. ICDs allow many people to enjoy a prolonged life without significant compromise to quality of life, but in cases of end-stage heart disease ICDs can cause significant physical suffering simply by doing their “job” - repeatedly normalizing arrhythmic events. Patient quality of life is further compromised by the severe anxiety associated with the fear of receiving a future shock2.

For patients with end-stage heart disease, deactivating the ICD can be a sound medical, ethical, and legal decision for them - albeit a difficult one. For Mr. C, his ambivalence about turning off his ICD was driven by his need for reconciliation with his family. Once this was achieved he calmly and peacefully made his decision to die. His case suggests that end-of-life decision making can be difficult for patients, and they may need time and guidance in completing their relationships with their loved ones before they can make the medical decision that is best for them.

ICDs can be deactivated in different ways depending on the urgency of the situation. In cases requiring immediate action (e.g., a patient is actively dying of end-stage cancer and his ICD fires causing the patient to go into convulsions), pacemaker magnets placed over the device deactivate it within seconds. In less urgent cases, the manufacturer and/or the electrophysiology service can assist with ICD deactivation. For patients at the end-of-life, turning off an ICD is similar to withdrawing a ventilator: the patient (or surrogate) has elected for comfort measures in lieu of aggressive medical care.

References:

1. Braun, TC, Hagen, NA, Hatfield, RE, Wyse, DG (1999). Cardiac pacemakers and implantable defibrillators in terminal care. Journal of Pain and Symptom Management, 18, 126-131. (No open access PDF)

2. Dunbar, SB, Warner, CD, Purcell, JA (1993). Internal cardioverter debrillator device discharge: Experiences of patients and family members. Heart Lung, 22, 494-501. (Open access PDF)

3. Quill, TE (1996). A midwife through the dying process: stories of healing and hard choices at the end of life. Baltimore, MD: Johns Hopkins University Press.

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Case:

Mary was a 58 year-old woman who was admitted to the hospital for management of a wound infection. Her past medical history included severe peripheral vascular disease, and she subsequently had bilateral, above-the-knee amputations. Her stumps were very necrotic, and did not respond well to antibiotic therapy. To further complicate her story, a routine imaging scan found suspicious lesions on both her lung and liver. This finding was highly suspicious for metastatic cancer since she also had a smoking history, significant weight loss and decreased appetite. Mary’s primary physician encouraged her to pursue a cancer workup, but she refused. She also decided that she did not want to pursue any other aggressive medical therapies that may prolong her life. Her only goal was to go back to her apartment where she could die in peace. The palliative care service was asked to become involved to help with discharge planning.

Since Mary previously lived alone, this was going to be a very difficult task. During her hospital stay, she became increasingly delirious, and it was clear that she would not be able to return home. We attempted to contact all of her relatives to recruit help. No one was able to take responsibility for her care at home, even with hospice assistance. So we attempted to make her hospital stay as pleasant as possible while these complicated issues were sorted out. We recruited a volunteer to sit with her several times per week to keep her company. Her delirium and agitation improved with the use of antipsychotics. Her pain had also improved after careful titration of her opiate and adjuvant medications. We also paid for a beautician to visit her here in the hospital. Mary was ultimately discharged to a local skilled nursing facility. To ensure continuity, our medical student on service wrote a letter to the attending physician there. We included some of the details of the care that we provided. We suggested that it would be very appropriate to provide Mary with some “luxuries” that would normally be contraindicated in her care such as milkshakes or ice cream.

Discussion:

Patients who do not have family or caregivers can create very challenging situations for hospital staff. Under usual conditions, palliative care extends the focus of care to family and friends of the dying patient. Family members are encouraged to create a home like environment in the hospital. Family photos, favorite music, or a blanket from home can make a hospital stay more pleasant. Patients that are alone often miss the comforts of home. According to Ferrell & Coyle, 2001, the discipline of palliative care provides physical, psychological, social and spiritual support to help the patient adapt to the anticipated decline, associated with advanced, progressive, incurable disease. Palliative care also alleviates isolation through a commitment to non-abandonment, ongoing communication, and sustaining relationships. The role of the volunteer and the medical student in this case was crucial. Volunteers are an integral part of the hospice and palliative care philosophy and approach. Beyond extending the available personnel, volunteers put a truly human, non-professionalized face on the provision of care.

References:

1. Ferrell, B.R., and Coyle, N. Textbook of Palliative Nursing. 2001. Oxford University Press, New York, 684.

2. Mount, B.M. Volunteer support services: A key component of palliative care. Journal of Palliative Care, 1992, 8(1):59-64. (no open access pdf)

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Have you ever wondered what other people might be saying about a particular subject you see on any of the three Pallimed blogs? But to actually remember to go back and check the post is something you never get around to doing?

Well for Pallimed readers who subscribe via RSS* we now have a Comments Only Feed that will keep you up on the latest conversations on the posts. Each Pallimed blog (Main, Arts, and Cases) has its own individual subscription link in the left hand column.

Pallimed: Main Comments Only Feed (About 5-10/week)

Pallimed: Arts Comments Only Feed (About 2-4/week)

Pallimed: Cases Comments Only Feed (About 1-2/month)

We rarely get spam comments 2-3/month and we delete them within 2-4 hours usually, so this should not be a big deterrent. The 'Comments Only' subscription is not available for email subscribers at this time, but if you would like an email subscription option then email me directly or post a comment.

This post will be cross-posted to all three Pallimed Blogs. My apologies in advance for readers who see it multiple times.

*Really Simple Syndication.

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Delay
Case Conferences are back after a month hiatus. Technically on a every 2 week schedule, only one post was skipped, but it just feels like a long time. So never fear, we are not leaving, there is still so much to post!

Scheduling
Case Conference posting will be moving to Thursday evenings to avoid crowding with Arts & Humanities (usually Monday evenings) and because the main Pallimed blog rarely posts on Thursday evenings. Still every two weeks for Case Conference posts.

Boards
The Case Conferences are a great tool for studying for the palliative medicine boards. I would encourage you to go to the UPMC Institute for Enhanced Palliative Care so you can get some of the archived cases.

Comments
We have a lot of readers but very few comments, so please feel free to add your two cents, anonymously or identified. And check out the new Comments Only subscription.

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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.

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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.