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BMJ has published evidence-based summary guidelines about the management of cancer pain. Nothing new of course. I found most interesting their recommendations for urgent needs for research:

• The relation between cancer pain and associated levels of psychological disability and distress
  
• Psychosocial interventions that are effective in reducing such disability and distress
  
• Standardisation of research methods into complementary therapies and the effect on pain of each individual intervention
  
• Determination of the benefits and harms of moving directly from step 1 to step 3 in the WHO ladder in patients with rapidly advancing pain who have never taken opioids before
  
• The effectiveness of different opioids and formulations in the management of breakthrough pain
  
• The method for determining the most effective dose of breakthrough analgesia for oral opioids such as morphine by comparing doses that are a fixed proportion of the daily regular opioid with a dose titrated to the individual patient or pain
  
• Determination of the effect of paracetamol on pain and wellbeing in patients already on a strong opioid regimen
  
• The role of ketamine as an adjuvant analgesic
  
• The role of topical analgesics, including opioids and topically applied local anaesthetics
  
• The value of opioid switching
  
• The role of cannabinoids in treating neuropathic pain.

My major response to this is that as much as I love more research as much as the next guy, I thought several of these topics had some good, at least observational data supporting them: opioid switching, breakthrough dose (ok, so it may not have been researched extensively, but lack of trial data telling me what breakthrough dose to start with is not a major clinical issue for me), skipping step 2 of the WHO ladder (does anyone dawdle with step 2 for patients in severe pain anyway?) - I can't remember off the top of my head but I'm sure in the last 5 years someone published research demonstrating that this is safe/fine/good.

I'm thinking through my counter-list of research I'd like to see for cancer-pain and it's something like this (please leave comments with your own, and please recognize this is a spontaneously improvised wish-list and nothing more):

• A controlled trial of ketamine as a co-analgesic alongside opioids for cancer pain (which involves oral ketamine and outpatients) with persistent moderate to severe pain or intolerable opioid side effects despite a couple weeks of opioid titration (or some similar inclusion criteria)
• A RCT of sublingual buprenorphine vs. oral morphine for cancer pain in a North American population
• Same for levorphanol
  
• Placebo controlled trials of methylphenidate and modafinil for persistent opioid-related sedation/fatigue
• A planned, prospective safety and efficacy trial with rigorous safety monitoring of outpatient opioid rotations to methadone in patients with relatively long prognoses (> 6 months)
• The big adjuvant smack-down pitting gabapentin, pregabalin, a TCA, and an SNRI (e.g. duloxetine) head to head for neuropathic cancer pain which looks at time to acceptable analgesia, safety/tolerance, and cost
• A large (for palliative care - you know - 50 patients or something) placebo controlled trial of systemic lidocaine for opioid refractory pain
• Same for mexiletine
  
• Long-term safety/efficacy trials for methylnaltrexone (at least monitoring trials) - these may already be going on
• Lidocaine 5% topical patch vs placebo patch for everything focal
  
• More trials defining with whom and when to use spinal opioids (e.g. intrathecal pumps)
  

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Journal of Clinical Oncology has a double-blind, placebo-controlled trial of depot octreotide for the prevention of radiation-induced diarrhea. (The context here is that octreotide has some good trial data supporting its use to treat radiation-induced diarrhea.) This study involved 125 patients receiving radiation involving the entire pelvis (for a variety of malignancies); they received 20mg depot octreotide or placebo at enrollment and after 29 days. The study was powered at 85% to detect a 1-grade difference in diarrhea severity between groups.

It didn't look very good for octreotide. Diarrhea outcomes were essentially identical (incidence and severity) and the octreotide group had more adverse events (no biliary toxicity, but symptoms of GI cramping and constipation-like symptoms). Incidence of moderate to severe diarrhea was in the 20-30% range overall.

This study was done well enough that it's pretty safe to conclude that depot ocreotide is, indeed, worthless to prevent acute radiation associated diarrhea, and has signficant side effects. Given that there are some ok data for short-acting octreotide to treat diarrhea once it starts, I'm unsure whether this is an effect of depot octreotide itself or (more likely) simply a matter that the incidence of acute radiation induced diarrhea is low enough that prophylaxing for it with a drug with significant toxicities is just not worth it. Or both. Severe enteritis from radiation, while relatively rare, can be such a devastating and morbid complication (fecal incontinence, hospitalizations for hypovolemia, disruption in cancer therapy) that it's disappointing this didn't pan out....

J. A. Martenson, M. Y. Halyard, J. A. Sloan, G. M. Proulx, R. C. Miller, R. L. Deming, S. J. Dick, H. A. Johnson, T.H. P. Tai, A. W. Zhu, J. Keit, K. J. Stien, P. J. Atherton (2008). Phase III, Double-Blind Study of Depot Octreotide Versus Placebo in the Prevention of Acute Diarrhea in Patients Receiving Pelvic Radiation Therapy: Results of North Central Cancer Treatment Group N00CA Journal of Clinical Oncology, 26 (32), 5248-5253 DOI: 10.1200/JCO.2008.17.1546

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Two more, briefly, from Journal of Clinical Oncology....

There is also a compelling editorial about the gap between patients' perceptions of the benefits of cancer therapies and reality (free full-text). It is a hard look at the language used in outcome reporting (in the scientific literature - not in the lay media - which is even more of a problem) and how that is often misleading (e.g. implying a statistically significant survival benefit represents a clinically significant benefit). It takes on 'progression-free survival' (suggesting instead 'progression-free interval') and asks the very relevant question If the death rate is reduced, how come everyone died? regarding trials involving incurable cancer and how reports of reduction in mortality can be interpreted as meaning some patients were cured.

In addition to this I'd add the mass-confusion patients have about 'response' and 'remission' and the constant touting in the lay media of 'exciting new breakthroughs' in cancer therapy. Sure, when a novel class of cancer therapies come available - or when a previously untreatable (at least with systemic therapy) cancer becomes 'treatable' (e.g. sunitnib for hepatocellular carcinoma) - that is a 'breakthrough,' and happy news. Our patients reading about that however usually aren't told (until their weary oncologist has to tell them) that it's unlikely to change the natural history of that disease for the vast majority of people who have it. Industry press-releases flooding 'consumer' news sites don't help, either.

Finally there's a letter (really an editorial) calling for more a more rigorous definition of 'best supportive care' in cancer trials.

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Nominee for best article title for 2008
Live Fast, Die Young, Leave a Good-Looking Corpse. David M. Burns, MD Arch Intern Med. 2008;168(18):1946-1947.
Winner for 2005
Palliative Trajectory Markers for End-Stage Heart Failure. Or "Oh Toto. This doesn't look like Kancerous!" Turris M, Rauscher C. Can J Cardiovasc Nurs. 2005;15(2):17-25.
(HT: A. Wollesen)

Feel free to email us any other good titles you find.

Medical Marijuana
Yesterday, Michigan voters approved Proposal 1 which allows medical marijuana to be prescribed for pain, nausea and other symptoms for any medical condition determined to be 'debilitating.' Two interesting quirks about the actual law. In the titles/subject headers marijuana is spelled with a 'j', in the body of the document the 'j' is replaced with an 'h.' I had never seen it spelled 'marihuana' before. But Wikipedia says it can be so there you go. The other quirk is that it lists 'nail patella' as a debilitating condition. I feel like a bad internist that I had to look this up, since I had never heard of it. I did not find a lot of information about intractable pain and NPS, but it is curiously prominently listed in the Michigan law.

Bonus Quiz
Can you name the 13 states that medical marijuna is legal in without resorting to Google? Give your best try in the comments section.

Medscape Interview of Pallimed Authors
For the Grand Rounds a few weeks ago we were interviewed by one of the coordinators. If you want to read about how Drew, Tom and I got into palliative medicine feel free to check it out, although you will need a user name and password to access it. (free)

More on Washington Death With Dignity Main Supporter
NY Times Magazine published an article in December 2007 on Booth Gardner, founder of the Washington State I-1000 initiative for Physician Assisted Suicide and some background into his motivation for proposing the legislation.

Freakonomics Blog Reviews the Economics of Managed Death
But curiously leaves out anything about the high quality, person-centered system wide cost-savings care found with hospice. The post is short and really more of a stem and a question for commenters to expound upon, which I would encourage you to read.

Kinda Creepy and Weird File
After giving up his euthanasia advocacy, Jack Kevorkian ran (and lost) as an independent for a House of Representative's seat in Michigan. This isn't really all that creepy or weird until you go to the Detroit News website to read the article and get 5 vignettes of Kevorkian's car, bedroom, kitchen, and bathroom. With bad puns on the vignette titles: "Driving with Dr. Death." [Groan] and the "I'm just hanging out with my slightly eccentric older friend" music, it just gives it this surreal aura. This was an interesting choice for web content by the newspaper.

Most interesting exchange:
Kevorkian: "Death is the enemy. Like hell it is! Death is natural! How can something natural be the enemy?
Reporter: "Yeah, but so are hemmorrhoids and I don't like those either."

Hopefully this will be the last of the medically hastened death news for a while. I need to get back to some of Pallimed's reguarly scheduled programming.

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After everyone wakes up from their political hangover all the other 'minor' political races will start getting sorted out. Senate seats, and House of Rep rearrangements and the local initiatives. Some got a lot of press like Colorado's personhood amendment and California's same sex marriage ban.

But I think a lot of people* across the US may be scratching their heads to wake up to another state** that has voted for the option of medically hastened death for terminally ill patients. Washington residents voted by a large margin (58 pro-42% opposed) to have a law endorsing physicians to prescribe medications with the intent of hastening a competent patient's death at their voluntary request. Much of the law is set up to look similar to Oregon's Death With Dignity Act that is now in it's 10th year since the Supreme Court appeals. I doubt Washington's will be appealed all the way to the Supreme Court again, but I would expect some legal opposition to hold up enactment of the law.

How this will affect hospice and palliative care programs in the area will be interesting to follow. Will they grow given the increased dialogue about end of life choices? Will some hospices assist with this practice and others not participate? Would this be an ethical marketing split?

If this gains traction in other states I could foresee medically hastened death may split the palliative medicine community. I wish end-of-life issues were talked about more openly in medicine and in public so that people could make informed opinions rather than strictly on hyperbole or emotional appeals of the moment. A boy can dream.

If any Pallimed readers from Oregon can share your on the ground experience in Oregon with how hospices dealt with this sensitive subject please feel free to add some info in the comments.

Would readers be interested in having occasional anonynmous polls here about topics such as this to generate further discussion? It is a feature we could implement fairly easily but we hav enot wanted it to be some sideshow gimmick.

*But not Pallimed readers, cause I harped on this so much in the last two weeks.
** Many people are still surprised to hear medically hastened death is legal in Oregon

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As much as we've enjoyed, um, politely complaining about the helpfulness of Cochrane reviews of palliative care-related topics, one was just released which got me a little worked-up.  It's a systematic review of antipsychotics for acute and chronic pain control.  They included randomized controlled trials of adult patients who were treated with an antipsychotics, in which the major outcome of interest was pain (any control was allowed - e.g. placebo, active, no treatment, etc. - and any duration or severity or type of pain was allowed).  All the typical Cochrane search and quality strategies were employed.  

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Some lighter fare for the weekend - two from the NY Times and one about veterinary palliative care (see subsequent post).

1)
First is a brief editorial from Thomas Lynch, the Michigan undertaker-poet-philosopher who I think of as a kind of Robert Bly of cadavers (see these posts here and here). It's about All Saints'/All Souls' Days and Americans' relationship to death. He's always an interesting read:

We humans are bound to and identified with the earth, the dirt, the humus out of which our histories and architectures rise — our monuments and memorials, cairns and catacombs, our shelters and cityscapes. This “ground sense,” to borrow William Carlos Williams’s idiom, is at the core of our humanity. And each stone on which we carve our names and dates is an effort to make a human statement about death, memory and belief. Our kind was here. They lived; they died; they made their difference. For the ancient and the modern, the grave is an essential station. But less so, lately, especially here in the United States, where we whistle past our graveyards and keep our dead at greater distance, consigned to oblivions we seldom visit, estranged and denatured, tidy and Disney-fied memorial parks with names like those of golf courses or megachurches.

2)
The second is a story about hospice chaplains in NYC. It talks about how that apparently hospice chaplaincy services are increasing in the US (up from 59% to 72% per the NHPCO) and presents that as a function of patient demand - something I was unaware of. The story is also discusses very positively the non-sectarian nature of the work, and implies, perhaps, the increase in demand is due to more and more patients not having pre-existing relationships with their own clergy.

Contrary to the above I'll point out Hospice Guy at Hospice Blog recently posted about his concerns hospice chaplains may be phased out in many hospices in the future.

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I've had an interesting email conversation with a veterinary radiation oncologist who is involved in the nascent pet hospice/palliative care movement, Dr. Lillian Duda. She was kind enough to say I could share some of her comments on the blog (slightly edited for flow):

Yes, there is a small but growing veterinary hospice/palliative care movement. There is even one pet hospice foundation that is an associate member of the National Hospice and Palliative Care Organization.

It is an interesting topic of discussion for several reasons. Obviously, euthanasia has always been a part of veterinary medicine and a mainstay of veterinary "palliative" therapy. However, as some pet owners demand ever increasing levels of high-tech medicine for their pets (pets that are often treated as nearly human members of the family), veterinary specialists have dealt increasingly with issues of futility and aggressive treatment efforts at the end of life. These efforts can be significant--specialty hospitals and tertiary care/academic centers have the capability of 24 hour ICU, ventilator support, hemodialysis, stereotactic radiosurgery, etc. etc. There are also a group of owners who decline euthanasia, and veterinarians must either provide palliative care (for which we have little training and some degree of ethical quandry) or leave owners to do what they can and watch and wait for their pets to die "naturally" at home.

There is talk about making palliative care a veterinary specialty (meaning board certification), although I think this is unlikely to happen any time soon. I serve as the veterinary editor for OncoLink. A veterinary page was started because a significant number of pet owners were contacting them with questions about cancer in their pets. There was a heated discussion amongst the editorial board early on, because a number of people protested vehemently against having information about animals on the same site as information about people. Some felt it was demeaning and insulting to so closely equate dogs and cats with people. The decision was to maintain a veterinary page, and an article was posted to help explain this decision. It can be found at: http://www.oncolink.com/types/article.cfm?c=22&s=69&ss=550&id=6003 if you are interested.

She recommends this site for further links as well: www.pethospice.org

If you're interested in the topic I suggest reading the oncolink page above - it's quite illuminating.

What struck me most about Lili's comments, and the reason I decided to post them, is just how familiar all those problems/concerns/tensions sound to us in the 'human medicine' world: all this technology which can prolong life but with major costs (both financially to be sure, but also emotionally, and to quality of life), providers struggling with ethical and professional dilemmas about if doing all this stuff makes sense and worrying about causing needless suffering for out patients, as well as providers feeling unprepared and poorly trained to deal with all this as well as to simply care for patients as they die. In addition, it's notable that access to euthanasia, and even broad cultural and professional acceptance of the practice, has not prevented this from becoming an issue - just as the practice in humans (in the Netherlands) has not at all slowed down or changed the acute need for palliative care-competent physicians and services there....

Thanks Lili.

While I'm here, and while we're posting lighter weekend fare, I'll tell my own story about pet hospice. One of the friends I did residency with was very much a pet-person (several dogs and cats). She told me that she got one of her cats from her vets office: it was dying, family had abandoned it, a lot of symptoms (I don't remember what was wrong with it or why it wasn't euthanized), and she agreed to take it in to care for it with the expectation it'd die within a few weeks. She took it home, fed it, gave it meds, and several years later the cat was alive and well and still with her. Another story familiar I'm sure to all of our readers who work in hospice!