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by Tom Quinn

In case you didn’t notice, the US Centers for Disease Control published their long-awaited (dreaded?) “CDC Guideline for Prescribing Opioids for Chronic Pain.” It made a pretty big splash: Five editorials plus the full Guideline in the online Mar 15 JAMA, front page New York Times feature article, the first hour on NPR’s “Diane Rehm Show,” (Mar 17) and multiple others. It is specifically aimed at primary care prescribers, who write about half of the scripts for opioids in the US. It is intended to “support clinicians caring for patients outside the context of active cancer care or palliative or end-of-life care.” The Guideline was published in the Mar 15 Weekly Morbidity and Mortality Report and is the first US Government guideline to address treatment of chronic pain; it is 52 pages long. A good “Cliff Notes” version of the Guideline is the JAMA piece by CDC Director Thomas Frieden, MD and Debra Houry, MD.

I should point out that the document was prepared by the CDC’s Division of Unintentional Injury Prevention. The Guideline is intended to address the epidemic of opioid-related deaths, not the pandemic of chronic pain. On its face, the Guideline promotes good, standard prescribing practices, especially for potentially high-risk agents: history and diagnosis of the painful disorder, prognosis of the painful state, history of prior interventions, establishing clear treatment goals, careful selection and implementation of treatments based on patient informed consent and risk-benefit discussion, and close follow-up with scheduled re-evaluation of the condition and effects of the intervention. Appropriately, the Guideline states that “nonpharmacologic therapy and nonopioid pharmacologic therapy are preferred for chronic pain.” The Guideline focuses on chronic pain, but points out that many prescriptions begin for acute pain. For acute pain, the lowest effective doses of opioids for the shortest possible course (3 days or less; “more than 7 days will rarely be needed”) should be used.

Additional risk-management strategies for opioids include: using short-acting opioids at the commencement of treatment; avoid concurrent benzodiazepine prescribing; evaluate patient history of substance misuse; use the state prescription drug monitoring program (PDMP); do initial and periodic urine drug screening.

“Higher” opioid doses are defined as those greater than or equal to 50 morphine milligram equivalents (MME) per day, and the prescriber should “carefully justify” any increases to ¬> 90 MME/day. The discussion states that the 50 and 90 MME levels were chosen because of epidemiologic data showing increasing risk of overdose as the prescribed dose increases.

So, what are the implications of all of this? 

1. I’ll start with the positives:
   a. The Guideline highlights a major public health issue, namely a dramatic increase in the past 20 years in opioid prescribing and a corresponding increase in opioid overdoses and deaths, especially in the past 10 years.
   b. About half of all opioid prescriptions are written by nonspecialists, many of whom have asked for a guideline for treating chronic pain with opioids; this Guideline responds to that need.
   c. Prescribing practices for potentially high-risk medications are reinforced. One hopes that more thoughtful prescribing will reduce the habitual writing of 30-day prescriptions when 7 or 15 days is more appropriate (this assumes a 1 or 2-week, not one-month, follow-up)
   d. Chronic pain is often a complex treatment dilemma—prescribers are reminded that multimodality intervention is the preferred treatment

2. The Guideline does nothing to address (and may make worse) insufficient capacity in our healthcare infrastructure for
   a. Nonpharmacologic treatments such as physical and occupational therapy
   b. Care by pain management specialists, some of whom limit the number of patients they see for medication management
   c. Treatment for substance use disorder including methadone and buprenorphine programs

3. Capacity aside, some insurance will pay for pills but not for physical therapy

4. Many insurance plans will not cover so-called alternative interventions such as therapeutic massage. [I acknowledge a major burden on insurance plans to start covering everything in the “alternative” realm. How could they possibly evaluate them all? Perhaps plans could consider an ‘allowance’ for alternative interventions: massage, acupuncture, yoga, tai chi, etc. The PCP and patient could choose which approach seems most appropriate to the individual situation].

5. Not only is it quick and easy to write a prescription (with some serious attendant risks), but analgesics generally work much faster than other interventions. Sometimes analgesics make it possible for patients to participate in other interventions, such as physical therapy. I fear that some clinicians will interpret the Guideline as requiring physical therapy prior to using “strong analgesics” such as opioids.

6. Alternative analgesics may not be as effective and may has their own serious side effects and contraindications. NSAIDs are an obvious example of those with serious side effects, especially in elders. Acetaminophen has recently been shown to be no more effective than placebo for osteoarthritis patients in a clinical trial.

7. Because of DEA practices it is already difficult for pharmacies to maintain sufficient stock of opioids, so patients commonly must do monthly “pharmacy shopping” to fill their prescriptions. Do prescribers “get” this when the PDMP shows their patient getting their meds at a different pharmacy 4 months in a row?

8. It is easy to conjecture that insurance companies will use the Guideline to reinforce pill count limits

9. Some prescribers, already nervous about the DEA and medical and pharmacy boards looking over their shoulders, may stop prescribing opioids or limit them to no more than 50 MME/day (Morphine Milligram Equivalent)

10. The Guideline stresses screening and follow-up practices that are very time consuming. Many medical systems (and insurance companies) will not be supportive

11. The Guideline has the potential to reinforce prejudice against opioids and opioid-users that is already extensive in medicine, nursing, and pharmacy.

12. Despite language that encourages individualizing treatment plans, the barriers to complex plans are not addressed. Nor is individual patient response. “Start low, go slow” is almost always appropriate, but therapeutic limits to dosing based on epidemiologic data is not entirely rational. The patient in front of me is always an anecdote. But every anecdote falls someplace on a normal curve. We don’t know, especially when initiating treatment, where the patient will ultimately fall on the curve.

13. The Guideline discussion acknowledges that data on the effectiveness of opioids for long-term use is sparse, but lends a lot of weight to research that could be interpreted to suggest that opioids “don’t work” for chronic pain. But the research base is very, very thin.

14. There are many research questions to be addressed, some of which we really haven’t figured out how to ask, much less design an adequate study around. And who will pay for and who will do long-term studies?
   a. What are the biological differences between those who become “addicted” vs those who don’t? Is there a continuum? If so, might an individual move in both directions on the continuum?
   b. What is the impact of rate of metabolism for certain opioids on safety and effectiveness of pharmacologic treatments? What is the prevalence of the so-called ultrarapid metabolizers vs poor metabolizers?
   c. What does “opioids for chronic pain don’t work” really mean? [This clause does not come from the Guideline but is similar to statements made by groups who advocated for the Guideline as a way to reduce opioid prescribing].
   d. There seems to be a subset of people who are very functional on long-term opioids—what differentiates them from the “opioids don’t work” population?
   e. There has been some interesting work showing persistent changes in the brain after opioids have been discontinued. What is the extent of these changes over large populations? Are there predictors for which changes and what their behavioral effects are?
   f. So, really, what is the risk of becoming “addicted?” The varying finding of 0 to 50% just isn’t helpful, and neither the upper nor lower percent seem very credible. How is a clinician to determine, and explain to a patient, what is the risk of addiction?
   g. Can we develop better tools for stratifying risk for misuse?
   h. Does “high risk” have to translate to “don’t treat?” We need evidence-based models for treating chronic pain in those with a history of and those with current substance use disorder.
   i. How effective is urine toxicology monitoring in managing patients? [Will insurance companies cover this cost?]. If the Guideline writers really think urine testing has significant value, the Guideline is weak—“at least annually.”

15. What happens with all the patients who are currently on opioids for chronic pain when their prescriber (or insurance or health system or risk management department) decides that they need to reduce doses based on this Guideline? (This was happening already, even before the CDC Guideline came out)

16. The Guideline specifically does not include care of patients undergoing active cancer treatment and for those in palliative care settings. It remains to be seen what unintended impact the Guideline will have when pain may be part of a serious advanced illness, or may be part of one of several comorbidities.

17. Will professional organizations review their own guidelines, in response to the CDC Guideline? (the American Pain Society and the American Geriatrics Society both published revised guidelines in 2009)

18. Will professional organizations increase pain and chronic pain-related offerings at their annual meetings?

19. Will medical, nursing, dental and pharmacy schools start teaching more about “pain management” rather than just pharmacology and pathophysiology?

20. A major question has to be: can the efficacy and effectiveness of this Guideline be determined on a scale and in a time frame that benefits the most patients and society at large sooner rather than later? Does the government have a commitment beyond issuing a Guideline? Perhaps the CDC and collaborating NIH institutes can work with a couple of major health systems and major insurance companies to implement the Guideline in a study of a comprehensive approach to chronic pain management. The study would have to last a minimum of 2 years. It may make the most sense to start with new patients, not try to cram existing patients into the Guideline (that would be a separate study).

This Guideline puts the prestige of the CDC and US Government behind an approach to prescribing opioids that is intended to help derail the epidemic of opioid-related deaths. CDC-monitored overdose deaths from all classes of drugs (in aggregate and by class) looked like they were leveling off in 2012 and 2013, but spiked again in 2014 (the most recent national data available). The Guideline is an appropriate step, but certainly inadequate to address the enormity, much less the complexity of the issue. In addition, the inadequacies of practice and the knowledge base for treatment of chronic pain remain unaddressed.

Thomas E Quinn, APRN-CNS, AOCN is an oncology and palliative care advanced practice nurse. He has recently accepted a clinical position at Jewish Social Services Hospice in Montgomery County, MD, which will really cut into his pickleball playing at the senior center.

Photo Credit: "lego_head-pain" by Flickr user Mr. Pony via CC 
Photo Credit: "Pain!" by Flickr user Harald via CC 
Photo Credit: "pain" by Flickr user wallsdontlie via CC 

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Last year an article by Thoonsen et al noted that early (they use the term 'proactive') palliative care "has hardly been addressed in the scientific literature."  In 2012 there have been over a dozen papers (by my very informal and quick count) on this topic in both specialty (palliative care and oncology) and general medical journals.  Both European and US-based journals are represented.  They are an eclectic group, including retrospective studies, clinical trials, case studies, secondary analyses, and reviews.  Some form of the term 'integration' (integrated, integrative) is commonly used as an adjective.  Others seen are proactive, as noted above; concurrent; early or early access; prospective; comprehensive; and holistic.  The focus varies:  specific diagnoses (breast and lung cancer) vs general "advanced cancer;" specific symptoms (peripheral neuropathy and depression); outcomes (costs and hospice referrals); and comparisons of symptom burden in various ethnic groups.  A few of the papers noted that integrated palliative care benefits healthcare providers as well as patients and families.  Most papers cited Temel et al's 2010 NEJM study comparing standard care of newly diagnosed metastatic nonsmall cell lung cancer with standard care plus palliative care starting at diagnosis.  Most also cited culture change, resources, widespread misunderstandings about palliatiuve care, and a small evidence base as barriers to integration.

Last month I attended the excellent Eighth Annual Chicago Supportive Oncology Conference.  The overall theme of the first day was integrating palliative care with standard/usual cancer treatment.  Highlights for me included:

• Deborah Dudgeon, MD, of Cancer Care Ontario (CCO) discussing the effort to both integrate palliative care and coordinate across multiple institutions.  A basic element is the use of computer kiosks in oncology waiting rooms in which patients enter their current symptom status using the Edmonton Symptom Assessment Scale.  Cancer Care Ontario has also developed symptom management and palliative care tools to encourage standardized approaches to care.
• Toby Campbell, MD, is a medical oncologist and palliative care physician.  Wearing his palliative care hat, he sees patients jointly with thoracic oncologists.
• Marie Bakitas, DNSc, of Norris Cotton Cancer Center (Dartmouth), discussed findings from the ENABLE series of studies of concurrent palliative care.  These studies have confirmed that early/concurrent palliative care does not shorten survival.  Among other things, they are also exploring what is in the "palliative care syringe:"  components and doses.
• Ralph Hauke, MD, of Nebraska Cancer Specialists, discussed the ASCO Leadership Development Program in Palliative Care, identifying palliative care as "an integral component of oncology care and is underutilized throughout the continuum of care."  He described a Palliative Care Service Model that uses some of the same approaches and tools as CCO.
• Tom Smith, MD, of Johns Hopkins, discussed the economics of integrated palliative care.  He advocated a palliative care approach as a way to "bend the cost curve" of exponentially increasing cancer care costs.
• Susan Block, MD of Dana Farber, discussed the poorly-designed electronic medical record as a barrier to quality care, using the example of searching for an advance directive in a record that wasn't designed to note it, store it, or track it.  She went on to describe how Dana Farber redesigned part of the medical record to support patient and family communication and consistent recording of advance care planning.

One thought that came to me is that palliative care programs that are in the early stages of development should have integration as a high policy and structural priority--much easier than retrofitting.

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The FDA has opened a comment period, closing December 7, on it's just-released draft "Blueprint for Prescriber Continuing Education Program." The accompanying request-for-comment states that "The central component of the Opioid REMS program is an education program for prescribers and patients." If you've missed the previous discussion of opioid REMS, see Drew's blogs here and here and especially Stew Leavitt's extensive analysis last April.

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I started to blog about two new reports from the Institute of Medicine (IOM). Both relate to patient-centered care, a major area of interest for the IOM in the past decade. But then I got distracted by some headlines that seem somehow related: The first was a New York Times piece, "The Downside of Doctors Who Feel Your Pain." The article, written by a young physician who considers herself to be empathetic and likable, wonders aloud if the current emphasis on improving the doctor-patient relationship is just a fad. Furthermore, she wonders if the adage her father introduced to her, "competence is inversely proportional to how much patients like" the physician, might have some truth to it. Appropriately, she questions how one measures the impact of improved interpersonal skills in overall healthcare quality and cost. Of course, palliative care was a little ahead of the curve in emphasizing interpersonal skills. Billings & Block at Harvard; Tulsky's pioneering research; Back, Arnold, Tulsky & company's Oncotalk training; ELNEC and EPEC (and EPEC-O); and family meeting as a bedrock "procedure" of palliative care are all examples.

"The Virtual Nurse Will See You Now" and "Friending Your Doctor Online" are recent offerings in the online newspaper, Technology Review. I was surprised to read that patients found the virtual nurse, "Elizabeth," a computer simulation, was likeable and effective. Patients are reported to resonate with the empathic responses of Elizabeth and to respond well to her instructions and coaching. [I wonder how well she would get along with Siri?] A physician-prescribed social network designed by a startup called Wellaho is in clinical trials in San Diego. It differs from other health-related social networks by including clinicians and by being integrated with the electronic health record. Might this improve coordination across disciples and care sites? Could it reduce hospital readmissions through improved monitoring and communication?

Back to the IOM: Patient-Clinician Communication: Basic Principles and Expectations is the inaugural IOM Discussion Paper, a new IOM series. Patient-Centered Cancer Treatment Planning: Improving the Quality of Oncology Care is the report of a workshop (Feb 28 – Mar 1, 2011) jointly sponsored by the National Coalition for Cancer Survivorship and IOM. Both of these publications grew out of the IOM emphasis on patient-centered care that was highlighted in the 2001 consensus report, Crossing the Quality Chasm: A New Health System for the 21st Century. In that report patient-centeredness was identified as one of six key characteristics of quality care.


Patients are the “ultimate stakeholders” in an increasingly complex delivery system, often with poor coordination and unclear roles. “The effectiveness of patient-clinician communication can be as important as that of a diagnostic or treatment tool.” Basic principles of patient-clinician communication are enumerated: mutual respect, harmonized goals, a supportive environment, appropriate decision partners, the right information, transparency and full disclosure, and continuous learning. In cancer care the last point might be illustrated by the follow-up/reassessment visit before the next in a series of treatments, the transition visit between treatment modalities or at the end of treatment, or the reassessment following a family meeting or after introducing a treatment for a bothersome symptom.

"Patient-Clinician Communication" is short, pretty straightforward, and appropriate for use in an introductory education offering in improving communication skills. It is, after all, a discussion paper, and is likely to spark substantive discussion in classroom and workshop settings.

Applying these principles to cancer treatment planning is a challenge. 80% of cancer patients are treated in the community where fragmentation of services is inherent, but even academic medical centers are subject to communication hurdles (I know many of your are astounded to read that). The average cancer patient sees three specialists who may each be in a different location and has multiple treatments across time and space. Imaging and blood tests might also be in different locations. Each setting and even different departments within an institution may have documentation systems that don’t link with each other. Tumor Boards, designed to improve multidisciplinary care, may not insert their conclusions into the patient record and don’t include the patient in the discussion of treatment recommendations. Meanwhile, patients may access information from friends or the Internet that adds further complexity and confusion, despite the availability of high-quality Web sites. Many patients lose touch with their primary care practitioner during the acute treatment phase.

The major recommendations of the conference were that a shared decision-making model be used and that each patient be given a written treatment plan. Shared decision-making includes an active partnership between patient and physician in which shared treatment goals are agreed, risks and benefits of various alternatives are discussed, and the values and preferences of each are honored. A written treatment plan includes collaborative input from each discipline and specialty involved, incorporates patient preferences, and identifies the responsible clinician(s) for each phase of care. The treatment plan is organic and may need to be revised as the patient progresses through treatment. The treatment plan then becomes the basis for the treatment summary and survivorship care plan, documents advocated by a previous influential IOM report, From Cancer Patient to Cancer Survivor: Lost in Transition. A good summary of the treatment planning publication can be found in the Oct 10 issue of Oncology Times.

The cancer treatment planning conference did not limit itself to the acute treatment phase of care. It also covered advance care planning, survivorship planning, and planning care for advanced disease. Despite the splash made by Jennifer Temel's early palliative care study in late 2010, it was mentioned only once in this report, in the context of advanced care planning. Discussants included Tom Smith, Betty Ferrell, and others well-known to the palliative care community.

The cancer-planning document is not a peer-reviewed report, like "From Cancer Patient to Cancer Survivor." None-the-less, it is meaty and the discussants are all well-known and influential. I suspect (and hope) that it will become the basis for numerous discussions around the country about improving the process of treatment planning at all phases of cancer care.

[IOM products are available for purchase in hard copy, can be viewed free on the IOM web site, and many, including those mentioned here, can be downloaded in free in PDF format].

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An unusual and sobering study on the state of the “palliative oncology literature” has recently been published online. Searching 6 bibliographic databases, this group from M.D. Anderson undertook a massive review of the palliative oncology literature, comparing from 2004 and 2009 the number of articles, proportion of all oncology articles, topics, and study designs.

The paper begins by highlighting the familiar barriers to palliative care research: limited research funding, few personnel trained in palliative care research, difficulty in recruiting and retaining patients/subjects, methodologic issues. They also pointed out that there still isn’t a consensus taxonomy and classification system for palliative care literature (can you tell they had professional research librarians on the teams?). An issue in designing this study is the great complexity and diversity of the palliative care literature. Here’s a sentence I loved: “Unlike other disciplines, palliative care transects numerous domains.” Ever seen ‘transect’ in a palliative care paper? The number of clinical issues, populations (multiple subsets), disciplines involved, and something they didn’t mention, the diversity of publication titles, makes the task of reviewing the whole of the literature for a specific major disease class pretty overwhelming to contemplate. They admitted, in a bit of understatement, that it was a “labor intensive” project.

I’ll skip over the study methods and jump to the results. Combining the 2 periods,

• Of over 6000 articles screened 1213 were reviewed. A significant proportion of studies were excluded from this review because they involved topics such as palliative chemotherapy with survival as the primary endpoint
• 70% of papers were original studies
• 42% of the studies were published in palliative care journals while 19% appeared in oncology journals
• Over 400 journal titles had at least one palliative oncology paper.
• “The palliative oncology literature is flooded with descriptive studies when we urgently need more practice-changing analytic studies.”
• Physical symptoms, health services research and psychosocial issues were the most common topics. There were many “orphan” (under-studied) topics even under physical symptoms).
• Pediatric palliative care was “largely unexplored.”
• Providers and lay caregivers are under-studied
  

Over the 5-year study period:

• The proportion of palliative care articles in the oncology literature remained below 1% and even decreased slightly, despite an increase in absolute numbers of papers.
• There was a 47% increase in original studies.
• The percent of randomized controlled trials decreased from 7% to 5%

Overall, the results show a disappointing lack of improvement in the overall quality and quantity of the palliative care articles focused on the oncology population. This is inherently limiting in addressing the total palliative care literature, but it would be time and cost prohibitive to do the same analysis over that larger universe. The barriers to doing palliative care research, especially improving the evidence base for treatments, haven’t changed and, despite increases in overall numbers of papers, methodology remains weak. Perhaps this paper will help to focus attention on improving the science of palliative care research.

By the way, articles in The Oncologist have recently been made freely available (again) with registration to individuals.


Hui, D., Parsons, H., Damani, S., Fulton, S., Liu, J., Evans, A., De La Cruz, M., & Bruera, E. (2011). Quantity, Design, and Scope of the Palliative Oncology Literature The Oncologist DOI: 10.1634/theoncologist.2010-0397

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I’m not sure how it got there, but an article from the Milwaukee Journal Sentinel landed in my inbox last week. It described the foundations of a new documentary, Consider the Conversation, by two friends who had recently experienced losses; one of them is also affiliated with a hospice. The video examines contemporary dying in America from both personal and cultural/health systems perspectives. The personal approach is achieved through “person on the street” interviews and interviews with people dying of progressive diseases. There are also interviews with well-know palliative care experts such as Ira Byock and James Cleary and journalist/author Stephen Kiernan.

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I'm expecting a lot of discussion about this study in the current issue of JAMA, "Religious coping and use of intensive life-prolonging care near death in patients with advanced cancer." Religious coping is defined as "how a patient makes use of his or her religious beliefs to understand and adapt to stress." Previous studies have shown that people with high positive religious coping are more likely to have preferences for aggressive life-prolonging treatment and less likely to have advance directives. "Positive" religious coping employs reliance on faith to promote healthy adaptation. "Negative" religious coping tends to see illness as punishment and may indicate existential crisis. Positive and negative religious coping are not mutually exclusive, but negative coping is uncommon. This is the first study to look at actual outcomes in patients with high vs low religious coping.

The subjects in this study were enrolled in the Coping with Cancer Study, a multi-institutional, prospective, psychosocial study of patients with advanced cancer. The Coping study is funded by the National Cancer Institute and the National Institute of Mental Health. Data was collected in a 45-minute interview. Both English and Spanish-speaking subjects were enrolled. In addition to patients, caregivers completed separate questionnaires, although caregiver religiousity was not a focus of the current study. Caregivers were approached a few weeks after the patient's death for information about the death (post-mortem chart reviews were also done). The instrument used was the Brief RCOPE, a validated 14-item questionnaire that assesses religious coping. Seven positive and seven negative types of religious coping are included, answered with a 4-point Likert scale. 92% endorsed a least one positive coping scale item, while only 43% endorsed any negative item. Patients were designated as having either high or low religious coping depending on whether they scored above or below the median. In addition, the Structured Interview for DSM IV Axis I to identify patients with panic, anxiety, or posttraumatic stress disorders or depression. Finally patients were asked to characterize their health status and whether their religious/spiritual needs were being met by the medical system.

A total of 664 patients participated in the overall study. Data were available on 345 of the 385 patients who had died at the time of the analysis. Death came a median of 122 days after the patient interview. The primary findings were that "a high level of positive religious coping at baseline was significantly associated with receipt of mechanical ventilation compared to patients with a low level;" and with "intensive life prolonging care in the last week of life." Nonsignificant differences were found for CPR received, death in the ICU, and hospice enrollment. In addition, a high level of religious coping, compared to low, was associated with the following: use of negative religious coping, active coping, greater acknowledgement of terminal illness, greater support of spiritual needs, preference for heroic measures, less advance care planning in all forms.

The findings persist when adjustment for various psychosocial factors are included. "These results suggest that relying upon religion to cope with terminal cancer may contribute to receiving aggressive medical care near death." The authors characterize this as a possible negative outcome for religious copers "because aggressive end-of-life cancer care has been associated with poor quality of death and caregiver bereavement adjustment." This is a problematic statement for me. It seems to contradict a previous statement that these patients see themselves as "collaborating with God to overcome illness and positive transformation through suffering. Sensing a religious purpose to suffering may enable patients to endure more invasive and painful therapy at the end of life." In addition, some patients see prolonging life as an essential acknowledgement of the sacredness of life. It seems to me that the task of spiritual care with this population is to support, to the extent possible, the patient's expressed beliefs and values while maintaining informed decision-making and consent. It is also important for patients who belong to an organized religion to receive adequate teaching and counsel in the teachings of that religion in order to clear up misunderstandings and misconceptions that may impact their decision making.

The authors recommend earlier spiritual assessment and support and inclusion of clergy/chaplains in the care team. A follow up research recommendation is to study the "mechanisms by which religious coping might influence end-of-life care preferences, decision making, and ultimate care outcomes."

Andrea C. Phelps, Paul K. Maciejewski, Matthew Nilsson, Tracy A. Balboni, Alexi A. Wright, M. Elizabeth Paulk, Elizabeth Trice, Deborah Schrag, John R. Peteet, Susan D. Block, & Holly G. Prigerson (2009). Religious Coping and Use of Intensive Life-Prolonging Care Near Death in Patients With Advanced Cancer JAMA, 341 (11), 1140-1147

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A new study just published online in Cancer by the MD Anderson palliative care group asked this question of medical oncologists, nurse practitioners, and physician assistants at their institution in an anonymous web-based survey. Interestingly, there was a 70% response rate to the questionnaire among the 200 practitioners to whom it was sent.

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I'm guessing that most of our readers do not peruse Bone Marrow Transplantation every month, but you might want to check out this article. It was written by the BMT & palliative care folks at the Massey Cancer Center, Virginia Commonwealth University. Yes, that would include Tom Smith, well known oncologist & palliative care doc at VCU.

Significant inroads have been made in the historic emergency room and ICU resistance to palliative care and end-of-life care. BMT may be one of the last clinical areas to incorporate palliative care & end-of-life care into unit protocols and practice. Indeed, the authors of this paper believe that it is the first of its kind in the BMT literature.

Interestingly, the paper starts with a few epithets that hypothetical BMT and palliative care clinicians might launch at each other, demonstrating apparently radically different world-views.

The real message, of course, is not the least bit radical: BMT and palliative care were made for each other--unless either group chooses to over-emphasize the end-of-life care part of palliative care, which is very likely the crux of the perceived divide--one statement made is that "transplant physicians may not realize that PC is not the same as hospice care." Another recent article, a study at MD Anderson on which I will blog in a few days, suggests that large percentages of medical oncologists and mid-level providers confuse palliative care and hospice care. So we are hearing from two major cancer centers with well-known palliative care programs that the folks inside their own institution don't know what they do and represent.

Even if there are very different world views--the same is true of patients, too--there is plenty of room for overlap and collaboration. Despite the contention that "the two fields should be complementary" and "the fields should mesh well," there have been no significant attempts to explore the relationship. This is one group's attempt to do so. Stylistically and rhetorically, I wish they had used the following at the beginning of the paper rather than the end: "When and where to perform PC for BMT patients? This question can be answered, 'Well of course . . . all of the time and everywhere!'"

A very suprising statement (to me, anyway) is that there have been no published papers on the symptom experience of BMT patients since 1993. There has been considerable advancement in this specialty, including improvements in symptom management, since then. It would seem about time to get a good picture of symptoms and symptom management in "modern" BMT. They suggest that a systematic approach to symptom assessment and management, previously demonstrated at both Anderson & VCU in non-transplant patients, would be applicable in the BMT setting.

The next section of the paper reviews treatment approach for expected symptoms (e.g., mucositis, N/V, diarrhea, etc.). Then there is fairly extensive discussion of areas that may be less familiar to some in the transplant community: communication, especially regarding prognosis; family education and support; and transition to end-of-life care and hospice. A very interesting and too-short section addresses the problems specific to transplant patients that make hospice referral difficult. As an example, severe GVHD may well be more appropriately managed from a symptom perspective in an intensive care setting. Support for MICU staff as well as intensive palliative care for the patient and family are necessary in this circumstance.

There is little in this paper that will be new to most folks actively engaged in palliative care. However, the paper was written for the transplant audience. It may very well be the first introduction to palliative care as a concept and practice that many in this audience have had. As such it is a valuable & valiant foray into a relationship that will be new for those in both specialties.

Chung HM, Lyckholm LJ, Smith TJ. Palliative care in BMT. Bone Marrow Transplant. 2009 Feb;43(4):265-73. doi:10.1038/bmt.2008.436

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Patient Impact Assessments: A late entry in the category of Most Intriguing Ideas of 2008: require that the DEA conduct a “Patient Impact Assessment” (PIA), analogous to the Environmental Impact Assessment required prior to major building projects, before issuing new controlled-substance regulations. David Brushwood, a pharmacist and lawyer, has suggested this idea as a way for the DEA to make more informed and balanced decisions. The PIA would do the following:

• Describe purpose of proposed regulation, including the problem it is intended to address
• Alternatives that have been considered and found to be inferior to the proposed regulation
• Describe the patient population affected
• Describe adverse effects on access, if any, to necessary therapies, and health outcomes that could result from new restrictions
• Describe strategies to minimize adverse effects, including monitoring of effects
• Explain challenges of unknown aspects of the situation
  
  Brushwood DB. Should the DEA conduct a "Patient Impact Assessment" when promulgating new restrictions on controlled substance distribution? J Pain Palliat Care Pharmacother. 2008;22(4):322-326.

WHO Analgesic Ladder Reconsidered: In the ever-interesting guideline vs rule debate, two short essays from a European perspective question the ladder, especially Step 2, the so-called weak opioid step. Both authors credit the ladder with helping to improve cancer pain management over the past 20 years. They point out that the Ladder assumes a gradual progression of pain, starting with mild pain amenable to non-opioid analgesics. The second step has been criticized on a couple of points. Some researchers and clinicians see no advantage to using codeine, tramadol, or propoxyphene rather than low doses of “strong” opioids such as morphine and oxycodone. Codeine & propoxyphene, in particular, may have more problematic side effect profiles than the strong opioids. Neither author addresses the combination products oxycodone or hydrocodone plus acetaminophen, which appear as Step 2 drugs. They also complain that if a patient has rapidly escalating pain, strict adherence to the ladder forces a delay in getting to the strong opioids, because of the belief that the 2nd step must be exhausted before the 3rd step can be entered.

Also pointed out is that there is no provision for either psychological approaches nor invasive approaches at any step.

Personally, I think the ladder is a useful construct that, after all these years, seems so logical and straightforward that is needs little defending, nor should a lot of ink be spent on attacking its perceived inadequacies. It’s a guideline--not a rule. It was promulgated at a time when using opioids was controversial in most places. It remains a useful teaching tool for new clinicians or those new to cancer pain management. As with any other guideline, individual patient needs trump the guideline (because it is not a rule) and adequate measures need to be taken, including skipping steps one or two and using invasive interventions earlier rather than later, if necessary.
That said, I would not object to a major multinational, multidisciplinary study group being tasked with bringing the ladder up to date with the complexities of pain management as we now know it.

See the International Perspectives on Pain & Palliative Care section of J Pain Palliat Care Pharmacother. 2008;22(4):327-330.

Number needed to treat, Number needed to harm: "Number needed to treat" is an interesting construct intended to translate (primarily) pharmaceutical research findings into information that clinicians can use in decision-making about whether to recommend a particular treatment. The lower the NNT, the more likely it is to have the intended effect in patients in the target population. An excellent review of history, interpretation, and appropriate and inappropriate use of this measure is found in the Sept 2008 Canadian Medical Association Journal.

A logical extrapolation is the notion of the "number needed to harm" which followed close on the heels of NNT. An article describing the use of both numbers in clinical decision-making is Sierra (below).A recent appeal to apply NNH to palliative care appears in a short letter to the editor by a hospice medical director (Herbst, below) who wonders if it's application would result in better utilization of resources in large medical systems.

McAlister FA. The "number needed to treat" turns 20--and continues to be used and misused.
CMAJ. 2008 Sep 9;179(6):549-53. (Free full text)

Sierra F. Evidence-Based Medicine (EBM) in practice: applying number needed to treat and number needed to harm. Am J Gastroenterol. 2005 Aug;100(8):1661-3.

Herbst L. Number needed to harm. J Palliat Med. 2008 Dec;11(10):1291.

New agents: Two new unrelated agents for pain--tapentadol and milnacipran--use inhibition of reuptake of norepinepherine as the primary mechanism of action. Tapentadol is a cousin of tramadol, and like tramadol is also a weak mu receptor agonist. Milnacipran (trade name Savella) is a serotonin-norepinephrine re-uptake inhibitor (SNRI). As with the two previous SNRI's on the market, duloxetine and venlafaxine, it is approved for fibromyalgia. Unlike the other two (as far as I can tell) it has not been approved for major depression.

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My leading candidate for headline of the decade is "Are You Brain Dead? Depends on the Hospital." It is from a news article reporting on a study in Neurology (one of the few studies in the entire medical oeuve of 2008 that we have not blogged on). The study authors surveyed the "Top 50" neurology centers in the United States, as ranked by US News & World Reports, on their institutional guidelines for establishing brain death. Three of the 41 responding institutions do not have guidelines. Of the 38 that do, there was considerable variation in the criteria for determining brain death and more-than-expected variance from the guidelines established by the American Academy of Neurology in 1995 and reaffirmed as recently as 2007. It should be noted that 2008 is the 40th anniversary of the recommendation & criteria for using brain death in potential organ donor situations.

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In a short article in American Journal of Hospice and Palliative Medicine a palliative care team in India describe their observation that some patients who did not experience constipation while receiving IV morphine required laxatives for constipation when converted to oral morphine. They did a 5-month retrospective chart review and found 11 patients who did not experience constipation while on moderate doses of intravenous morphine. They had a pretty "clean" sample: opioid-naive patients admitted for severe pain, no malignant or comorbid GI pathology, not using laxatives prior to admission. When switched to equianalgesic doses of oral morphine, 7 of the 11 patients required laxatives for the remainder of their inpatient stay and were discharged on laxatives.

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There is an interesting pair of studies in Quality Management in Health Care on the use of a simple Microsoft Excel-based simulation tool for teaching medical residents to manage pain crisis in cancer inpatients. The authors had previously determined through surveys of residents and nurses that residents were unprepared for and uncomfortable with managing pain with opioids. Specifically, they were afraid of respiratory depression, especially with escalating doses and long-acting opioids, and had no preparation for converting to other routes or drugs. The informal practice was to manage all cancer pain with intermittent short-acting opioids. The result was that patients complained of uneven pain control marked by "peaks & valleys" and that average pain scores actually increased among hospitalized cancer patients. Not surprisingly, patients, residents and nurses were dissatisfied with pain management. Outcomes, by the way, were unchanged following standard educational interventions such as grand rounds presentations.

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A couple of weeks ago Drew blogged on a short essay/case report in Journal of Clinical Oncology that addressed a physician’s struggle in prescribing chemotherapy that he considered to be futile. The same day I got my latest issue of Oncology with an article (with 2 invited responses, here and here) on patient demands for chemotherapy that clinicians feel is futile. I believe this is the inaugural offering in the new feature, “Areas of confusion in oncology.”

The Oncology article is a fairly wide-ranging piece that begins by addressing what is meant by “futile care.” The authors point out that there is no common or consensus definition [I imagine that at least some of this is one of those “I know it when I see it” phenomena]. A recurring theme in this paper is discordance of perceptions and perspectives between patient and physician. Expert panels struggling over guidelines, a physician facing a desperate or resolute patient, children not willing to contemplate “giving up” on Mom, a patient with a religious belief that “everything” must be done, third-party payers—whether private or government, and John Q. Public (i.e., “society”) in the grip of a compelling drama may have varying and conflicting perspectives.

The authors quote a 1993 article in which the reader is advised to distinguish an effect from a benefit. That dovetails nicely with an observation later in the paper that some patients overestimate prognosis because they confuse response with cure.

Not surprisingly, a major cause of the disparate perceptions is assigned to inadequate communication between patient and physician. And not all the blame falls on the physician. When each is waiting for the other to bring up discussions of goals, values, quality of life, prognosis, end-of-life issues, etc., “misalignment of perceptions” can be expected. The physician may even have thought that s/he provided adequate information on prognosis. But if they provide too wide a range of outcomes, don’t periodically come back to the discussion, or don’t check in with the patient to see what was understood, the discrepant perceptions can grow ever wider. “Lack of patient-provider communication regarding prognosis, goals of therapy, and benefits of aggressive symptom management (hospice) all play a role in the delivery of futile chemotherapy.”

There are several interesting tidbits provided that may be helpful to both experienced clinicians and to students or junior clinicians who are trying to get their heads around the issues related to futility dilemmas.

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Three recent methadone-related reviews, two by the same group, are well worth the reading. The first two, on conversion ratios and drug-drug interactions, respectively, are the long-awaited published versions of presentations made at the AAHPM/HPNA conference in Salt Lake City in 2007. They are among the most thorough and well-organized reviews on any topic that I have read in recent years. The third is a consensus guideline on parenteral methadone in palliative care.

Methadone conversion ratios:
The authors reviewed clinical trials, retrospective analyses, case reports, and case series published from 1996 to 2006; reviews were excluded. A total of 41 papers (22 studies, 19 case reports; N = 730) were reviewed. None of the studies were deemed to be of high value. Not surprisingly, they identified the heterogeneity of studies as the biggest challenge in their analysis. Not only were different methods and populations used, as well as different descriptive statistics and outcome definitions, but different conversion values and tables for non-methadone opioids were used. While most suggested conversion procedures recommend converting all opioids to morphine equivalents, some use oral equivalents and some use parenteral equivalents. Rather than just throwing up their hands in frustration, the authors recalculated many of the formulas presented, using consistent values.

It should be well known by now that there is not a simple ratio of morphine to methadone that works at all dose levels. Most studies stratified patients according to the pre-rotation morphine-equivalent dose because of the “dynamic inverse potency relationship between methadone and other opioids.” The most common ratios reported were 4:1 and 10:1; the review authors estimate that 30% of all patients were converted using one of these ratios. However, the reported range was 4:1 to 37.5:1.

Using scatter plots, the authors sought to determine the correlation between prerotation morphine dose and the morphine: methadone ratio. They identify a “strong, positive linear relationship between the prerotation morphine dose and the postrotation methadone dose,” but the dose ratio is not constant in relation to the previous morphine dose. When attempting to apply these findings to individual patients, there is confounding due to large interindividual pharmacokinetics with methadone. They emphasize that the “care process” or conversion procedure as well as the calculation of dose ratios varies considerably across studies. “It may be less important to determine an exact opioid ratio . . . than to be sure that the patient is an appropriate candidate for methadone rotation, the switch is carried out over a time period consistent with the therapeutic goals, and that the patient is monitored closely by medical staff throughout the process.” They note that there is no consensus regarding the various published methods of conversion, but that the majority of patients are successfully rotated in all settings regardless of method employed and ratio used.

There is also acknowledgement that conversion ratios are not bidirectional and that there is almost no guidance in the literature for conversion from methadone to another opioid.

Finally, there is a long discussion of the deficits in the research literature and suggestions for the future direction of research.

I’m not sure that anyone already experienced in methadone conversions will change his/her clinical practice because of this paper, but it may well provide rationales for teaching and encouragement for reseach.

Weschules DJ, Bain KT. A Systematic Review of Opioid Conversion Ratios Used with Methadone for the Treatment of Pain. Pain Med. 2008 Jun 18. [Epub ahead of print] DOI:10.1111/j.1526-4637.2006.00289.x


Methadone drug-drug interactions:
This is an advanced primer in the clinical science of managing patients on multiple drugs, especially when one of them is methadone. It should be in everyone’s teaching and reference files. The paper includes:

• Eye-opening dissertation on just how complex methadone metabolism is
• Good description of the cytochrome-P 450 (CYP450) enzyme system in drug metabolism
• Other mechanisms—including some that are pretty esoteric—that can affect how methadone is absorbed, metabolized or eliminated, including the effect of changes in urine pH
• The important effect of the order in which drugs are added—or removed—from a regimen
• Theoretical vs clinically observed interactions
• Class-by-class descriptions of actual or potential interactions
• Limitations of the evidence base
• The fact that pharmacy drug-drug interaction checkers can pick up an interaction when a drug is added but not when it is removed from a regimen

Weschules DJ, Bain KT, Richeimer S. Actual and potential drug interactions associated with methadone. Pain Med. 2008 Apr;9(3):315-44. DOI:10.1111/j.1526-4637.2008.00461.x

Parenteral methadone use:
The consensus panel are almost all very well-known pain and/or palliative care clinicians. They review the very limited literature specific to parenteral methadone, then suggest clinical approaches to optimize it’s use. The paper includes a pretty extensive discussion of the implications for QTc interval changes and the risk of torsades de pointes. This paper doesn’t compare in thoroughness to the other two, but it is a useful review and probably unique in its focus specifically on parenteral methadone.


Shaiova L, Berger A, Blinderman CD, Bruera E, Davis MP, Derby S, Inturrisi C, Kalman J, Mehta D, Pappagallo M, Perlov E. Consensus guideline on parenteral methadone use in pain and palliative care. Palliat Support Care. 2008 Jun;6(2):165-76.

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1]
Several times in this blog we have discussed our preference for the term ‘opioid’ rather than ‘narcotic’ when referring to the substances (natural, synthetic, endogenous, exogenous) that occupy the mu receptor. See here and here for a couple of examples. Note the comments, as well. An interesting small, simple, and direct study from the Pittsburgh Veterans Administration Hospital has addressed the important issue of what patients understand when they hear the terms ‘opioid’ and ‘narcotic.’ One of our readers previously commented that using ‘narcotic’ makes sense since that’s the term patients (and other lay people) use and understand. On the basis of this study’s findings, she’s right. The researchers asked 4 (almost) identical questions of 100 people in a clinic waiting room. The “almost” part means that half the patients were asked about the term opioid and half about the term narcotic. The questions: “What is a narcotic/opioid?” “Give an example of a narcotic/opioid.” “Why does someone take a narcotic/opioid?” “What happens when someone takes a narcotic/opioid for a long time?”

The findings are both surprising and not. 83% of the patients in the opioid group did not know what it means; only 10% did not know what narcotic means. Actually both numbers sound high to me. Strikes me as nearly impossible to get well into the adult years without knowing what a narcotic is. I guess its more disappointing than surprising that so many patients don’t recognize the term opioid. Subjects in this study were recruited from outpatient primary care and surgical clinics. There was no breakdown of answers by clinic reported. Of the patients who recognized either term, only half in each group associated it with pain management in their definition and again when asked why someone would take an opioid/narcotic. Again, that is disappointing, but in my somewhat jaded view that may well be higher than the results you’d get polling reporters, DEA agents, politicians, politically-inclined prosecutors, and maybe some strata of the general population.

One of the major concerns expressed by those of us who worry about the negative legal and addiction associations of “narcotic” when applied to pain management was confirmed, but the numbers weren’t too bad, considering. 19 of 50 respondents associated abuse and illegal drugs with the term narcotic. The bad news is that 90% of the people who answered the question on what happens when someone takes an opioid/narcotic for a long time referenced addiction or an adverse outcome and the vast majority of those specified addiction.

The bottom line is that, if these results are generalizable, we have a lot of educating to do, at all levels and via all media.

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This must be VA day at Pallimed. Paul Rousseau, a well-known palliative care doc at the Phoenix, AZ VA hospital wrote a short essay for The Left Atrium column in the Canadian Medical Association Journal called ABCs of Medicine. Seemed like the kind of piece you might write after a long day—or week—of tiredly swimming against the continually rising tide of depersonalization that “the System” has become. The trigger is an admission note that begins: “62-year-old male admitted for hospice placement with the diagnoses of HIV, DVT, PTSD, GERD, BPH and PUD.” Digging a bit, he is able to conclude that the patient is a “pleasant and alphabetized man who is dying, no longer smokes, and lives with his wife.” He muses on the various reasons for the “psychosocial silence in this chart.”

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One more from the VA: this is a short review of opioid-induced hyperalgesia. It’s not very meaty and it is not a how-to article, but it succinctly lays out the prevailing theories/models of opioid-induced hyperalgesia and the three thus-far-identified interventions: opioid rotation (enough evidence to recommend it as a first line intervention); addition of an NMDA receptor antagonist such as ketamine or dextromethorphan (evidence not very strong and not recommended); addition of an ultra-low dose of an opioid antagonist (again, evidence noy very strong and not recommended). The authors point out that there is an investigational agent (Oxytrex) currently in clinical trials that combines oxycodone and naltrexone for pain management.

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Check out this title: “A matter of definition—key elements identified in a discourse analysis of definitions of palliative care.” Sounds terribly dry, but it turns out to be surprisingly readable and so well put together that I will make it required reading of my students next semester. The article is fascinating from an historical, etymological, sociological, and cross-cultural perspective. The authors are all palliative medicine physicians (turns out there is no translation for palliative care other than ‘palliativmedezin’ in Germany) affiliated with German universities. They searched for definitions of ‘palliative care’ and ‘palliative medicine’ in Google and in textbooks, finding a total of 35 definitions in English and 26 in German. They then used discursive practice—“a process by which cultural meanings are produced and understood”—to analyze the definitions.

Key elements identified were target groups, structure, tasks, expertise, theoretical principles, and goals of palliative care.

Among the conclusions:

• The term palliative care is a pleonasm (a new word for me—means redundant) since both palliative and care are concerned with the issue of protection.
• Palliative care/medicine is unlike any other specialty since it doesn’t have a specific object of study nor define itself by the age of its patients
• In fact, it has a hard time defining its population of focus at all. Protection of the patient “means a comprehensive and at the same time diffuse orientation.”
• Only a very few definitions explicitly describe the philosophy of palliative care.
• Having the family and patient as both the unit of care and as members of the care team creates some inherent role difficulties
• There is no consensus on the meaning of the terms multidisciplinary and interdisciplinary
• There is an emphasis on symptom control, but Kearny is quoted as warning against becoming a ‘symptomatologist,’ as symptom management is only the beginning of palliative care therapy.
• In that context, the human being is the focus of care, the goals address suffering and quality of life, and emphasizing wholeness through a respect for autonomy and dignity is a defining value.
• Interestingly, the current American definitions are seen to de-emphasize death and dying as compared to historical and some European definitions.
  

There is much more and I can’t do it justice in this space. This is a great journal club article, and can be grist for both introductory discussion and reflection on practice and meaning for veterans and their teams.

References:
Mangione MP, Crowley-Matoka M. Improving Pain Management Communication: How Patients Understand the Terms "Opioid" and "Narcotic." J Gen Intern Med. 2008 May 31. [Epub ahead of print]

Rousseau P. ABCs of medicine. CMAJ. 2008 Jun 3;178(12):1580-1581.

Leonard R, Kourlas H. Too much of a good thing? Treating the emerging syndrome of opioid-induced hyperalgesia. J. P-harm Pract 2008;21(2):165-168.

Pastrana T, Jünger S, Ostgathe C, Elsner F, Radbruch L. A matter of definition - key elements identified in a discourse analysis of definitions of palliative care. Palliat Med. 2008 Apr;22(3):222-32.