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Case: During a weekly Palliative Care Consult meeting, it was discussed that if D, 53-year-old woman with congestive heart failure, did not receive a heart transplant within several weeks to a few months at the most, she would probably die. I felt led to visit her, even though she was not on my normal unit rounds. On the initial visit, D was welcoming when I stopped by her room. After introducing myself as a Protestant staff chaplain, I inquired about her pain. D told me how uncomfortable she was and how she felt so limited by her physical condition. When I asked how she was coping with any other areas of suffering in her life, her lips quivered and her eyes filled with tears as she told of the burdens in her soul…deep, personal stresses in her life that continued to that very day. She had tearfully vented for about an hour, as I reflectively listened and reassured her that every word was confidential and I was there for her to listen, if nothing else.

After hearing her life’s trials, it was important to let her know, as a chaplain and pastor representing Christ’s church, that God could help not only with the treatment of the pain in her heart but also with the trauma of her suffering soul. I prayed for her and the medical team that would work with her and those behind the scenes to care for her, to harvest the new heart and skillfully transplant it into her body; as well as for the opportunity to deal with some of the issues of suffering that were plaguing her. Thankfully, the issues that she was suffering from began to be addressed within her family as the real possibility of D’s death triggered the process of reconciliation. As those issues began to be resolved and forgiveness and harmony blessed her life, hope and new meaning for her life made the anticipated pain of transplant more tolerable. D was sent home with a VAD long enough to appreciate how some of the stress that existed in the home before had dissipated. Within 48 hours D was back in for her heart transplant.

Surgery went very well, and D was out of the ICU with few complications. Yet, once D was on a step-down unit and dealing with post-operative pain in her body and the anxiety and depression that ensues after transplantation, she was troubled by her years of living as a sufferer. It was reassuring when she made her suffering known.

Thankfully, the issues were addressed by those that contributed to her suffering within her family, and positive changes brought meaning back into her life. D did embrace her new life with meaning and purpose, and as she healed from the pain of the transplant, it was made bearable by the liberation from suffering.

This was a process that was not resolved as in our modern media. It was assisted in by others in the Palliative Care Team, the Transplant Team, Unit Staff, Pastoral Care, Providence, and, of vital importance, D’s family members who realized D’s mortality and took ownership of her suffering and their contribution to the dysfunction in their household.

In many of the rooms of the hospital are laminated Comparative Pain Scales with 1 being expressed as :) demonstrating No Pain to 10 being Unbearable/Excruciating Pain. Modern technology addresses this pain well. Suffering of the soul, mind, psyche, what ever terminology you are comfortable with, also needs to be addressed with awareness and compassion. Everyone should participate. According to Thomas R. Egnew, “Suffering arises from perceptions of a threat to the integrity of personhood, relates to the meaning patients ascribe to their illness experience, and is conveyed as an intensely personal narrative.”

While the medical community has established procedures, protocols, and treatment plans that factor in typical emotional responses, suffering is personal, individual and commonly expressed as a narrative that needs the freedom and respect to be presented and the dignity to be acted on to reestablish meaning and significance. Pastoral Care is one piece of the solution, but by far, not the only piece in total patient care.

References:

1. Mayo Clinic on Chronic Pain; Mayo Foundation for Medical Education and Research. Kensington Publishing Corp., NY, NY. 1999

2. Egne, TR. Annals of Family Medicine; Suffering, Meaning and Healing: Challenges of Contemporary Medicine. LICSW. Volume 7 No 2. March/April 2009

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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.