Tuesday, November 20, 2007

Sativex for neuropathic pain; Research issues; VTE treatment in palliative care; Etc

Happy Thanksgiving to those of you who celebrate it - I won't be posting until after the holiday weekend.

Pain has a randomized, placebo controlled trial of a cannabinoid for neuropathic pain. The study involved using sativex (an oral-mucosal cannabinoid spray which uses THC-standardized botanical material from marijuana plants as its base). It involved ~120 patients (mean age 53 years; all had persistent pain for more than 6 months and most were on multiple other meds; mean pain ~7/10; most had focal neuropathic syndromes like post herpetic neurlagia, radiculopathies, or neuropathic pain involving a single limb) who were randomized to sativex or placebo (after a test dose, patients self-titrated their own sativex dose using a protocol) and followed for 5 weeks. Importantly, only ~20% of patients were prior cannabis users. Both active and placebo sprays were flavored with peppermint to prevent unmasking, and intention to treat analysis was used. It was an industry sponsored study.

Patients receiving sativex had a statistically significant decrease in pain at 5 weeks (and it took well over a week for the pain curves to diverge) - average decrease was 1.5/10 on the 0-10 scale (a 22% reduction) - placebo patients' pain didn't change significantly. They estimated a number needed to treat of ~8 to get a 50% pain reduction. 18% of sativex patients withdrew due to side effects (vs. 3% of placebo patients - damn that peppermint spray!) - the autonomic side effects appeared to be more prominent & disturbing to the patients than the psychiatric ones. Unblinding (patients deducing if they were receiving the active drug or not) was not measured.

My gloss on this is that it's evidence that sativex is a effective analgesic, although most patients get only a mild response (a NNT of 8 for a 50% pain reduction is not great compared to tricyclics or gabapentin which tend to be in the 3-6 range). While side effects were a problem here, it's encouraging that 80% of the patients were ostensibly cannabinoid naive suggesting that it can be effective even in patients not pre-selected to tolerate cannabinoids. Sativex however isn't available in the US, and is pharmacologically distinct from other cannabinoid products (like dronabinol). Any of our Canadian readers using it in their patients for pain?

Image is of cannabidiol (from Wikipedia).

There have been two recent journal issues devoted to research issues surrounding quality of life and symptoms in cancer patients.

Journal of Clinical Oncology has an issue looking at 'patient-reported outcomes' in cancer research. 'Patient reported outcomes' more or less mean symptoms and quality of life as reported by patients/research subjects. The issue contains a dozen summary articles from the National Cancer Institute's Patient Reported Outcomes Assessment in Cancer Trials (PROACT) conference from last fall. Most of the articles read like committee summaries (which they are), and I'm not going to belabor them here except to say it provides a snap-shot of the international research & funding issues about "PROs".

There is a certain sense of the orphan-nature of PROs in cancer research throughout, best put by the summary article:

"Yet, it is fair to say that questions about value added have been raised more frequently about PROs, and HRQOL specifically, than about any of the prominent biomedical outcomes. In part, this reflects the acknowledged importance of survival and disease-free survival as primary objectives of much cancer therapy. But it also reflects recurring concerns among some clinicians, regulators, and even cancer trialists about the meaning, technical quality, interpretability, and decision relevance of the PRO measures themselves. These issues are important because they challenge the validity, or at least the usefulness, of measuring cancer outcomes from the patient's own perspective. However, one of NCI's Strategic Objectives is "to ensure the best outcomes for all, including improving the quality of life for cancer patients, survivors, and their families." Thus, it would seem vitally important to measure the impact of cancer and its treatment on QOL from the perspective of those individuals living with and surviving cancer. For this objective to be realized, we need patient-reported measures of outcome that are valid, reliable, responsive, clearly interpretable, and decision relevant."

The other issue is from the Journal of the National Cancer Institute (Monographs) and is about quality of life and symptom research in cancer trials. These articles come from a symposium in 2005 about QOL measurement & meaning sponsored by the NCI's CCOP. It's more clinically oriented than the JCO issue, focusing more on the clinical relevance and use of QOL measurement in research.

It's mostly about health-related QOL, and avoids the perplexing philosophical questions about what QOL really means, but gives a few nods to 'global' QOL (excerpt is from this article):

"There is evidence that overall QOL is a distinct concept from the other components of the model of Wilson and Cleary, providing different information than symptoms, functioning, and perceived health status. In a study of 493 older patients, Covinsky etal. demonstrated a lack of concordance between patient ratings of health and their global QOL. They found that 43% of those with the worst physical functioning rated their global QOL as good or better. Conversely, of those with the best physical functioning, 15% thought their QOL was only fair or poor. They also found a lack of concordance for psychologic health and QOL. Of those with the fewest psychologic symptoms, 21% rated their QOL as only fair or poor. In addition, patients consider different aspects of life when rating QOL than when rating health status. Based on a meta-analysis of 12 studies in chronic disease, Smith et al. developed path models that demonstrated that patient ratings of their health and global QOL were influenced by different things. Perceived health status was most affected by physical functioning and to a lesser extent by emotional well being. On the other hand, global QOL was affected to the greatest extent by emotional well-being and less by physical functioning. A logical extension of these findings is that conclusions may differ depending on whether outcomes are measured in terms of health status or global QOL, particularly if there is lack of agreement between them. This provides an argument for the inclusion of overall QOL, in addition to measures of symptoms, functioning, and health status."

Together, the paper mentioned above, and this one here, make a good introduction to the measurement and meaning of QOL assessment in cancer research and would make good
articles for the teaching file (particularly for fellows - I wouldn't necessarily throw these at medical students).


Postgraduate Medical Journal has a review of managing thromboembolic disease in the 'palliative' setting. It's a general review of the topic, and makes some eyebrow raising statements. Notably it cites research to suggest that 25% of British oncologists were unaware of the elevated risk of thrombotic disease in cancer patients (looking at the study it cites about that it seems it was mostly about the increased thrombotic risk associated with tamoxifen and similar hormonal therapies). It also makes this statement:

"In the case series reported, most patients continued anticoagulation until they entered the last few days of life. These data, while shedding light on how long we should continue anticoagulation, also suggest that the majority of palliative care patients are appropriate for investigation and treatment of suspected VTE. Sometimes the biggest danger faced by the palliative care patient is not a complication of the disease process but rather the paternalistic nihilism inflicted on them by the attending clinician."

To be clear: there was a case series (lead-authored by the author of this review) which showed that one palliative service used anticoagulation until the final days of life - these descriptive data have now apparently morphed into normative data on what we should be doing, and, indeed, if we're not doing this, we are inflicting paternalistic nihilism on our patients.

What really gets me about this is that the sum of data we have on anticoagulating dying patients is a few RCT trials showing low molecular weight heparin is probably better than coumadin for VTE disease in advanced cancer patients; some descriptive data on what some centers are doing; and some tolerability data about LMWH shots (patients don't seem to mind them). What we don't have is any controlled data on actually anticoagulating patients with very short prognoses (less than a few months), and while one can reasonably argue that of course we should be anticoagulating these patients one could also reasonably argue that we don't know the risks of this and the benefits may not be great. We don't know - things that seem to make sense often don't turn out to be true in medicine - and because of that it seems lik
e intimating patient abuse ('inflicting nihilism') is a bit premature.

It is not yet time for mud-slinging. That said, I'm looking forward to the die when I don't have to argue with hospice agencies about low molecular weight heparin.

A couple e-pubs from Journal of the American Geriatrics Society.... One is a review of hypodermoclysis to treat dehydration. It's a straight-forward narrative review, mostly geared towards nursing home patients, but provides a good single source for the research base underlying the practice's safety and efficacy.

The second is about using cardiorespiratory fitness to predict mortality in the elderly long term. It shows that yes, long-term mortality (over a decade) is closely associated with CRF (in this case as measured on a treadmill test), but doesn't tell the average clinician much more, unless you're a prognosis junkie, as is one of the Pallimed contributors.

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