Review of heroin dependence

JAMA has a Clinician's Corner review on heroin dependence. It's a chatty, narrative review which covers the history of heroin abuse in the US, its epidemiology, the history of and research supporting methadone therapy, buprenorphine and naltrexone treatment, as well as a Q&A at the end which addresses some of the language used:

When I was on the American Psychiatric Association DSM III-R...committee, the problem that we had when we were designing a diagnostic classification scheme was that we were trying to come up with a scheme that applied to all drugs of abuse. So that meant nicotine, alcohol, cocaine, heroin, and so forth. People who work primarily with alcoholics don't like to use the word "addiction" regarding alcohol. But it absolutely fits. All of the drugs of abuse activate the reward system, but through different mechanisms. The reward activation produces learning, which results in long-term behavioral effects that increase the probability of relapse. The major problem with terminology is the tendency to stigmatize. However, as more public figures have admitted to addiction problems, we see that it can happen to anyone. I think it is better if addiction is dealt with as an illness instead of as something that implies bad character. Addiction is just another medical problem. I think the stigma is a holdover from the time when addiction was thought of as weakness of will or bad character or criminal activity. Addiction is a chronic disease of the brain with strong heredity components, and it ought to be approached as a medical illness.

TD buprenorphine for everything and everyone

European Journal of Pain has a review of transdermal buprenorphine for pain. It's an interesting article and makes some dizzyingly impressive claims on behalf of the drug, which I note below.

Buprenorphine is a partial mu-opioid agonist and a kappa-opioid receptor antagonist. The article states that despite being a partial agonist no ceiling effect of analgesia has been observed in humans, and that it acts like a full mu agonist when used at 'analgesic doses.' On the other hand they present data that there is a ceiling effect to buprenorphine's respiratory depression effects (meaning that it's theoretically safer than other opioids regarding that toxicity; they note that dangerous respiratory depression is nearly unheard of with buprenorphine unless other CNS depressing drugs are being used). The article notes that buprenorphine not only does not induce mu-opioid receptor internalization (one of the mechanisms for opioid tolerance seen in other opioids) but that it actually increased cell surface density of mu-receptors, which may be an explanation for the impression that less analgesic tolerance is seen with buprenorphine than other opioids. It has an anti-hyperalgesic effect (as opposed to the hyperalgesic effects seen with other opioids). It has been demonstrated to have fewer side effects in head to head studies with morphine. It can be taken safely with other opioids with additive analgesic effects. In placebo controlled trials rates of nausea, dizziness, and tiredness were no worse with TD buprenorphine than with placebo. It's less constipating than morphine or fentanyl. At least one patch formulation can be cut to decrease the dose. It's had decent studies in both cancer and non-cancer pain. Theoretically people are less likely to have problems with psychologic dependence on it.

Whew. Reading this article leaves one with the feeling that TD buprenorphine is (in the parlance of my former residency program) liquid Jesus (i.e. good for just about pretty much anything - we would use it to describe drugs like aztreonam, etc.). Let's see: better analgesic with less side effects/tolerance/hyperalgesia which is nearly impossible to OD on? It seems almost too good to be true (there is no mention of who sponsored the article) and I sat here reading this saying to myself if all of this is true then why hasn't this revolutionized opioid pain management and why hasn't TD buprenorphine become the opioid of choice for chronic pain? It raises the skeptic bug in me, but perhaps this is simply because we're behind the times here in the US.

Transdermal buprenorphine is not available in the US (or Canada?), but sublingual buprenorphine is (it's approved for opioid maintence therapy in opioid dependent patients). I'm told that one can prescribe it for pain without a special license however I'm not entirely sure if that's true (this seems to contradict what I was told).

My questions are: 1) is anyone using this or seen sublingual buprenorphine used for pain in the US, 2) does anyone know if transdermal or sublingual buprenorphine are being evaluated for approval (for pain treatment) in the US?, and 3) are any of our European readers using this and if so is it good as this article tells us?

Methadone, methadone, methadone

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.

2008 ASCO: methadone, genetics, modafinil

The 2008 American Society of Clinical Oncology meeting was last month. Every year the palliative care, supportive care, and end-of-life care abstracts are worth browsing (abstracts here).

I wanted to particularly point out 3:

1. First is a case series about one center's experience with initiating and rotating to methadone in outpatients. Very little has been published about rotating to methadone in the outpatient setting despite it being a relatively common practice (that's my sense at least) - most of the publications about methadone rotations have been in inpatients. The data presented here suggest it's safe (no one falling over dead from torsades) and has salutary effects on pain.
2. Second is one looking at genetic polymorphisms (of cytokine genes) and their associations with pain and opioid dose (certain polymorphisms in this lung cancer population were associated both with pain and opioid dose). I'm probably prematurely excited about the growing trickle of research (in actual real live humans in pain) into the genetic basis of the variable response to opioids, but there you go.
3. Third, outcome data from a randomized, placebo controlled trial of modafinil for cancer-related fatigue was presented. Patients were all initiating chemotherapy, and those who reported severe fatigue (but not mild or moderate) seemed to benefit from modafinil over placebo. The magnitude of the benefit, while statistically significant, is unclear from the abstract. I've used modafinil occasionally, with (of course) mixed results; these are the first placebo controlled data I've seen on it in our population. I'm curious as to readers' experience with it.
   

Opioid vs Narcotic; ABCs of Medicine; Hyperalgesia; Required Reading

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.

2]
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.”

3]
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.

4]
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.

Making Sh*t Happen: Methylnaltrexone

Methylnatrexone has hit the big time with a very timely publication of a industry funded double-blinded RCT in the New England Journal of Medicine. If you have been in palliative care for the past few years, methylnatrexone has been one of the drugs with some 'buzz' around it at conferences and in publications. We have touched on MNTX a few times here at Pallimed before.

This new study does not add much to previous knowledge about the medicine, but the study is the largest and most comprehensive one to date. Other double-blinded RCT's have already been published (JPSM 2008, Clin Pharm Ther 2000, J Pharmacol Exp Ther 2002, JAMA 2000) showing efficacy versus placebo without affecting analgesia from opioids. The patients were from nursing homes, hospices or palliative care centers and 60-70% were ECOG/WHO 3 or 4 (confined to bed more than 50%)

The participants were already on stable opioid doses, and stable laxative regimens with less then 3 reported BM's in the past week. More than 50% rated their 'constipation related distress' as moderate to severe. This seems to be a somewhat broad inclusion criteria. Constipation can be a very distressing symptom, but there are two types of distress from constipation: psychological distress of not 'being regular' and physical distress from GI discomfort. Many patients with advanced illness may have decreased number of stools for many reasons besides just opioid constipation, and I would propose that a regular number of stools for those with anorexia-cachexia syndrome and decreased functional status may be less then 3 per week. In assessing constipation related distress, managing expectations is part of good clinical care.

Interestingly less then 30% were on stool softeners, but most were on 2 laxatives of some category (stool softener, enema, bulk producer, contact laxative, or osmotic agent). I thought the percentage would be much higher in this population.

Of interest to some will be the oral morphine equivalent doses (OMED) these patients were on. I always find this interesting when seeing studies about hospice and palliative care patients, because opioids have a wide range of therapeutic dosing. The mean OMED was 339mg (+/-1214 )(placebo) and 417mg(+/-787)(MNTX) with a wide range in the study (9-10,160mg of morphine equivalents per day). For those readers who have not worked in palliative care you did read that number right. 10,160mg of morphine equivalents per day. If you ask anyone in palliative care they will probably tell you about the one or two patients they have seen up in that range. Now that would be a case-series to figure out how someone is tolerating those doses.

Sidebar:
As far as drug names go, I find 'Relistor' pretty uninspiring. Methylnaltrexone is fun to say, MNTX is easy to write, Relistor...eh. To me it sounds like a drug to get you back on a transplant list-> Re-listor=Re-lister. Or was Wyeth going for being 'realistic' about your constipation or advanced illness. Maybe they were trying to stay away from names that were too scatological or associated with OTC meds. Relistor just is uninspiring. (Sorry for the sidetrack, I find drug names fascinating.)

BTW the logo is pretty bland too. Come on now another circular logo? Are they trying to replicate the millions of hospice logos with 'embracing circles/hugs?' I would think something coming out of something else would be more representative. Any graphic designers or wordsmiths want to help Wyeth out?
(end sidebar)

I am sure many in palliative care are glad this medication is available and we will probably go through the next few months trying to figure out where it fits in the bowel toolbox. Thomas and the rest of the authors (and Progenics) should be commended for a well-designed research study in a hospice-oriented patient population. It would be a good article to review in a journal club to see how the study was designed and carried out, especially with so many institutions.

Overall the study is a good one, but it should be noted it was industry funded, which is notably very transparent in the article: "Progenics Pharmaceuticals designed the protocol and collected and analyzed the data." Is this part of the beginning of more pharmaceutical industry-palliative care/hospice collaborations? I would be interested to hear from Pallimed readers about their thoughts on the field's collaboration with industry. Is this a new source for funding and advancement of our field? Or is this a 'bogeyman' that is relatively absent from our small but growing field?

Of note there are two good editorials (here and here - sub required) in the issue regarding opioids and constipation.

(Disclaimer: I get nothing from Wyeth. Neither does Pallimed.)

(Advanced apology for the near-swear in the title for those who might be offended)

(Image from same issue of NEJM - not Opioid Induced Constipation)

(I like parentheses.)

Reference:

Thomas, J., Karver, S., Cooney, G.A., Chamberlin, B.H., Watt, C.K., Slatkin, N., Stambler, N., Kremer, A., Israel, R. (2008). Methylnaltrexone for Opioid-Induced Constipation in Advanced Illness. New England Journal of Medicine, 358(22), 2232-2343.

American Pain Society Meeting

I attended the first two days of the American Pain Society Annual Scientific Meeting in Tampa, Florida. It is a big affair, over 1300 people. I was quite impressed by the quality of the speakers--not just the the content of the presentations, but the speakers were, for the most part, good presenters.

The most prevalent recurring theme in the clinically oriented (as opposed to the basic science) presentations was the issue of prescription opioid abuse. It got a bit wearisome after awhile, perhaps because I presented on the same topic at the Nursing SIG session! Kinda reminded me of a recent cautionary comment by Kathy Foley at another meeting that pain management is being eclipsed by risk management. The most controversial session, on the Washington State opioid guidelines (see previous mention), was well managed and avoided descending into a shoving or shouting match. I'm still left unconvinced that the identified problem (an increase in opioid-related deaths in workman's comp patients) will be solved with the institution of the guidelines. They have been identified as a pilot and an educational endeavor, but one person from the audience said that he had been denied insurance payment for a patient on opioid doses greater than 120 mg unless additional justification was provided (perhaps an inevitable and predictable but unintended consequence). The "education" is being provided by the medical director for the department that handles workman's comp. He was obviously well-meaning and very concerned about safety issues, but he is not a pain specialist, and as far as I could tell, had no special training or experience in pain management.

The exhibit hall also had it's share of substance abuse-related products and give-aways. There were several urine toxicology companies there and multiple free "risk-reduction" education pieces, all sponsored by pharmaceutical companies.

There was an entire session (which I did not attend) on new tamper-resistant formulations of opioids.

Other new products and products in clinical trails of interest to this readership: Subcutaneous methylnaltrexone (Relistor) for opioid bowel dysfunction (see previous post); an oral form is just entering phase 2 trials; a pegylated oral form of naloxone is just entering human trials; an oxycodone-morphine combination tablet has just completed its first phase 3 trial; a sustained-release hydrocodone-acetaminophen tablet has completed a phase 3 trial; a cannabinoid is approaching clinical trials. Most of you are probably aware that there are new dosage strengths of OxyContin (15, 30, & 60 mg), and that all of the generic CR oxycodone products are off the market. There are also new dosage strengths of oxymorphone ER (Opana ER; 7.5, 15, & 30 mg).

There was a lot of exciting new basic science regarding pathways, receptors, neurotransmitters, and other cool stuff that was mostly over my head, but by implication provided new therapeutic targets.

One of the most interesting sessions was on rational approaches to multidrug treatment of neuropathic pain. It's all about patient assessment and pharmacokinetics.

On to the nursing (American Society for Pain Management Nursing) pain meeting in the fall!

Evidence and palliative care; hydration reviewed, sort of; opioid antagonists for OBD

1)

Over here at Pallimed we’ve been having an off-line conversation about “evidence” for palliative care-related practices, and decided to bring it to our readers. The impetus for the discussion is the publication of two new Cochrane reviews, one on medical hydration in advanced illness and the other on mu-opioid antagonists for opioid-induced bowel dysfunction.

Regular readers of Pallimed will know that the three of us are strong proponents of increasing and improving the evidence base for palliative care. We are also very much aware of the difficulty of doing so, especially using the stricter definitions and methods of evidence-based medicine (EBM).

I will disclose that I am not a regular devotee of the Cochrane reviews, but “medically assisted hydration” caught my eye. I was disheartened, however to see that only 5 papers made the cut to be reviewed, and that the conclusion was “There are insufficient good quality studies to make any recommendations for practice with regard to the use of medically assisted hydration in palliative care patients.” It reminded me of a conversation a couple of years ago with a well-known pain physician and researcher. He told me that he doesn't even read Cochrane reviews anymore. "They all end with the same conclusion: there is insufficient evidence to make a recommendation about . . . " I don't think that is necessarily a bad thing, but they are super-strict in their criteria for selection. That makes it particularly difficult in palliative care, where doing the type of research one might do for approving a hypertension agent is almost impossible. The issue, of course, is that the assumed “highest” level of evidence is the randomized controlled trial (RCT). Some have argued that RCTs are not only difficult to design and conduct, but may be unethical in interventions for people with advanced disease where comfort, not cure or control, is the therapeutic goal. Others criticize the misuse of EBM, either attempting to apply broadly the results from a trial in a subset if patients, or conversely denying payment for a successful intervention for a specific individual because the RCT “proves” that the intervention doesn’t work. Fragile patients with advanced disease are usually excluded from RCTs, yet that is precisely the population most in need of evidence-based palliative interventions.

The phrase “perfect is the enemy of good” springs to mind. But the RCT is unlikely to ever be the “perfect” tool for symptom management, population-based or public health studies, and other complex beyond-the-physiology questions.

Carr, an early proponent, points out that EBM continues to evolve, has limits, and can easily be misused. Where applicable, the RCT should be used, but with the results interpreted judiciously for specific populations and individuals. Hallenbeck, Carr (specifically for pain medicine), Aoun & Kristjanson, and Devery are among those who have made reasoned criticisms of EBM, and suggested “other ways” of using EBM or of gaining knowledge. These include an “Equity-based evidence framework” (Aoun & Kristjanson), “narrative-based” evidence (Devery), or recognition that “lower” (not necessarily less rigorous) levels of evidence apply quite well to palliative care.

We’d like to hear how our readers use and interpret “evidence” in their practice of palliative care.

2)

Getting back to the Cochrane reviews:
Hydration: there was only one “high quality” study (2 RCTs) but over a very short duration (2 days) and very underpowered. Overall, results of the 5 studies reviewed were somewhat contradictory, but showed suggestions of improvement in sedation and myoclonus. Negative effects cited were fluid retention leading to peripheral edema, ascites, and pleural effusion. In their conclusion, the authors acknowledge the difficulty of conducting clinical research in the palliative care population. They also comment “the issue of medically assisted hydration in palliative care patients causes such divergent views, yet there are so few studies to guide clinical practice properly. As well as looking at further RCTs in this area, the evidence base will be improved with at least more prospective controlled trials.” It should be noted that the "best" study had quite a few patients with reasonably good performance status, especially in the intervention group. It was not really helpful, therefore, in answering the question: "is medically assisted hydration a helpful intervention in patients in the last days of life?" One of the included studies, a prospective controlled trial, attempted to mimic real world decision-making by allowing physician preference in allocating to the intervention arm. This introduces bias,of course, but downgrading the score on the study design because of it may make some clinicians grind their teeth. The whole point in reading a study is to find help in making real world decisions, isn't it? That raises questions for a future conversation.

Opioid antagonists for opioid-induced bowel dysfunction (OBD):
Naloxone, nalbuphine, methylnaltrexone, and alvimopan were reviewed. There was only one study of nalbuphine. All studies were placebo-controlled RCTs (which makes sense in this case; active-controlled studies would also be welcome). Some studies of the newer agents (methylnaltrexone & alvimopan) were in healthy volunteers. The authors report that their task was made more difficult by use of various opioids in trials, and by inconsistent definitions of postoperative ileus. In general, though, they found (in a limited number of studies with small numbers) that methylnaltrexone and alvimopan were sufficiently safe and effective (increased transit time/decreased constipation) to be labeled “promising.” It should be noted that methylnaltrexone was administered parenterally in these trials, and that oral methylnaltrexone has yet to be reviewed. Alvimopan trials were interrupted because of excess cardiac events. The current target indication for alvimopan (not yet approved) is postoperative ileus.

.

Just as an aside, the last author on this review is Dan Carr, cited above in the EBM discussion.

There is another recent review here.

A just-published RCT was not part of either review. Subcutaneous methylnaltrexone (Relistor) was approved by the FDA last week for patients in late-stage advanced illness and should be available next month.

.

So, who among our readers is waiting impatiently for methylnaltrexone to become available? Given the route, cost, and limited research, are you eager to give it a try? In general, are we adequately treating opioid-induced constipation, but need this for backup? How will you determine which patients receive it? How many other interventions do you need to go through before you determine that constipation is refractory to more conventional treatment? Oh, and do any of you actually use the newly minted term 'opioid bowel dysfunction' (OBD)? The Comments link awaits you.

"I Wanna Be A DNR" and other Goodness from the Web

Since it is Friday, let's have a little fun. Here are some palliative care related links and highlights from the web.

A ICU Nurse and some colleagues rewrote the lyrics to the popular Nickelback song "Rockstar" to emphasize how some patients may feel in the ICU. The video itself is just the lyrics. Here is hoping she puts together more song parodies and maybe a video or two. (Hat Tip: KPW)

If you cannot see the You Tube video, then click on the post title to hear the song on the original post.


If you go to the original You Tube page, make sure to read the comments for insight on how some medical professionals feel about this song and subject.

BMJ has selected palliative care as a focus for "Making a Difference" project. This project will focus on higlighting palliative care in BMJ Journals for the next year. Hooray, more to blog about! Thanks to all that voted. (HT: JP Pinzon)

Dr. Wes comments on the general unhelpful nature of point and click electronic medical records systems for nursing notes. I don't think this is limited to just nurses, as I have seen some doctor's notes look the same regardless of the patient. Why must EMR's have so much data that is worthless? Many of the EMR's I have seen are good for data in, but not for data out. Anybody have a solution? (Thx: Kevin MD)

Psychology Today rails against the 'stages of grief' model being misconstrued again and again as a road map for how you are supposed to grieve. The article has some good points, but without some structure for beginning to tease apart such a complex phenomena and without a basic roadmap, it is that much more difficult to identify complicated grief, and figure out how best to support those experiencing it. A real Catch-22. (Thx: HFA Blog)

Also check out HFA's blog for locally oriented coverage of the Dartmouth Atlas Study. Great post!

Hospice Guy is starting to post more...Hooray! And this time he bares his soul about the Hospice Cap. Don't know about the hospice cap. Well Pallimed has not really commented on it yet, but may soon.

The anonymous Angry Pharmacist has a few choice (not safe for work (NSFW) or sensitive ears) words about the DEA and controlled substance regulation between his pharmacy and his wholesaler. Some interesting points I did not know about pharmacies hidden in the ranting.

Dan Savage, the outspoken sex-advice columnist, eulogized his mother in his column. A profound look at emotions and grief and how one single curse word can convey so much.

At the Hospice and Nursing Homes Blog, Frances Shani Parker has a great poem about the "loss" of our senses and abilities Here is a tiny excerpt:

Handfuls of August clouds
whisk you to a picnic,
hint at mashed potatoes.

Have a good weekend all! I will be off-blog for two weeks in Australia (to give a talk on the clinician's estimate of survival and meet with my CPC mentor).

I have dutifully prepared a few posts ahead of time for Drew to post for me so I don't appear to be a slacker. I am excited to leave, but also excited to come back because Pallimed has some big surprises coming up in mid-May! Any guesses?
Photo courtesy of flick.com user Vermin Inc