Tweet

Thank goodness I get The Pain Medicine News.  I used to think of it as a throwaway industry newspaper but lately it has been a great source of information about the FDA's plans toward the future of opioid prescribing and the Risk Evaluation and Mitigation Strategy (REMS) plans that are coming down the pipeline.  This week's issue discusses the Pain Medicine communities trepidation towards the REMS for Onsolis. (article behind membership wall)

Some background first: If you have not heard about Onsolis yet, it is a film containing fentanyl applied to the buccal (inside cheek) surface to dissolve for immediate pain relief.  If you are thinking "Haven't I heard of something like that before?" you may be recalling it with:

Fentora - Fentanyl buccal tablet made by Cephalon
Actiq - Oral transmucosal fentanyl citrate (on a stick but don't call it a lollipop!) made by Cephalon

Onsolis is made by BDSI and in the Summer of 2009 received FDA approval.  And it got a parting gift from the FDA, the first opioid to be subject to REMS.  I won't spend this post talking about the relative merits or risks of prescribing Onsolis but instead will focus on the REMS as it has a huge potential to affect good pain relief.

So here is the REMS process for Onsolis called FOCUS:

• Each patient, prescriber, distributor, and pharmacy enrolls in FOCUS
• Prescriber faxes the initial prescription information to FOCUS
• Prescriber sends the original, hardcopy prescription to a FOCUS pharmacy via courier using the supplied shipping label
• Patient receives a counseling call
  
• While the hardcopy prescription is in transit the FOCUS pharmacy confirms that the patient and prescriber are active in the FOCUS Program database, the patient counseling call has been successfully completed and schedules Onsolis delivery to the patient.
• Upon receipt of the original, hardcopy prescription, the FOCUS pharmacy dispenses Onsolis and delivers the medication directly to the patient via a secure, traceable courier (with adult signature required) (Apparently within 24 hours, and at most 5 business days)
  

So we can now add bureaucracy to the possible barriers to prescribing opioids.  I am not sure how these steps reduce any risk with opioids with overdose and diversion being the two big ones I would assume the FDA is trying to reduce.  I think the goal is laudable and one I think the hospice and palliative care community has not given the full attention I think it deserves, but the method to me just seems to add red tape without effect.  Has the FDA tested this in opioids in a RCT to see if it reduces any risks?  It would be nice to see an evidence based approach to this important problem.  Thank goodness the law that gave the FDA this power also stipulates review of the REMS program for each drug at 18 months, 3 years and 7 years.

But if the FDA trials it with one drug, I doubt anyone is going to prescribe it when there are viable non-REMS options for immediate relief pain control.  The Pain Medicine News article quotes BDSI staff diminishing the REMS effect on sales, but I think the REMS provide a really tough barrier to prescribing unless you have really run out of other options.  The American Pain Society president wrote the FDA a letter stating they were "surprised and disappointed" the Onsolis REMS were "in stark contrast to many of the stakeholder suggestions made."  The article also highlighted the special needs of the hospice and palliative medicine community although I do not know if anyone in our community was directly involved in any of these discussions.


The FDA has a pretty detailed FAQ on the Onsolis FOCUS REMS program here.  The FDA does not expect the Onsolis REMS will be the REMS for long acting opioids. Here is a list of opioids they expect to fall under REMS in the future.  The InVivo Blog has some more info on the FDA's strategy towards REMS.  And here is BDSI's slide deck about Onsolis which I may tease apart more in the future.

And the cost of the medication is unknown at this time.  I knew you were thinking that.  Are you planning on enrolling in the FOCUS program?  I will ask to enroll if only to tell you all about it.

Tweet

We don't typically endorse products, webinars, conferences, job listings or much of anything else here at Pallimed, but when we do know about a resource that can impact your everyday palliative care work we want you to know about it.

Such is the case with the Hospice and Palliative Care Formulary USA ($75/$65 for AAHPM members) now being published in the 2nd edition from the founders of PalliativeDrugs.com, Robert Twycross and Andrew Wilcox.  I wanted to write in more detail about why I access this book more often than any other palliative care book since I just ordered 6 of them for the teams I work with.

The first edition was printed in 2006 and my copy is dog-eared from carrying it around, showing it to hospice team members, lending out to fellows, residents, nurse case managers, copying a page for a pharmacist, referencing it for numerous presentations, etc.

Any other medication reference book (nursing or medical) has so many warnings/misinformation about the medications we commonly prescribe and administer in palliative care settings that general pharmaceutical reference books are essentially useless.  I often find nurses and physician trainees who read some of those freebie/cheap Nursing/Medical Drug Guides begin to contradict basic palliative care understanding.

For some poor examples from referencing other drug guides...

"We can't give more than 5mg of morphine...the book says she might have respiratory depression."
"Octreotide? I don't see anything about small bowel obstruction but it does treat a VIPoma."
"Constipation? How about we try more fiber?"

Here is why I find HPCF-USA so useful:

• Detailed palliative care oriented medication information
• Extremely well referenced drug monographs - Awesome for talks
  
• FDA Approved indications clearly listed as well as likely palliative care uses
• Cost information (in actual dollars not some crappy $-$$$$ scale)
• Candid discussion about alternate route dosing/administration for many medications
• Detailed pharmacologic information in tables to compare different meds within a class
• A treatment monograph on 'Oxygen'  - When was the last time you read 4 detailed pages about the ins and outs of oxygen therapy? Wonderful!
• Monographs on related but not primary palliative care meds - A whole section on antifibrinolytic drugs! Bronchodilators! Diabetes meds! Potassium! Magnesium!  You get the point.
  
• Super helpful chapters covering meds in a meta-approach - Opioids and Fitness to Drive; Continuous Subcutaneous Infusions; Drugs Administered via Enteral Tubes
• Designed for use in the USA (as opposed to the UK version with UK only meds like diamorphine)

Here are the things I wish were included/changed/fixed:

• Better binding - it seems to be fragile after a lot of use, and my book gets used
• Not much info on fentanyl IV compared to transdermal and buccal routes
• The 2nd edition cover is a little boring compared to the Red, White and Poppy motif on the 1st edition.
  

If you are an AAHPM member you can get a 20% discount via the AAHPM website.  Also you could access it online via PalliativeDrugs.com but I find the book very useful and a rapid access to have at my desk.  And now with the extra copies I purchased it will be at almost all of my clinical sites.

Do you use HPCF-USA?  Tell me what you like best about it.

Disclaimer: No kickbacks given to any Pallimed author because of this post.  We did give away a HPCF-USA free edition back in 2007 for our winter contest.  And it was pretty cool when I met Robert Twycross in Austin and he recognized my name from Pallimed and told me he was a big fan of Pallimed.  But that is not why I wrote this.  Obviously I think this is a super awesome book.

Tweet

So-super-briefly you won't believe it.

1)
JAMA has a paper looking at some aspects of the 'natural history' of LVADs (see recent post). The paper adds some further detail to the review I blogged about before - complication rates, etc. One question it answered for me is that how many patients 'get off' LVAD therapy without heart transplantation (the answer is just a few percent at one year - the rest died or continued on the LVAD). Notably, this study confirms patients who receive LVADs after a cardiac surgery do a lot worse than those who don't (presumably these patients suffered major complications post-operatively). Annual cost ~$150,000. This is the future of medicine, unless our economy and health care system really does collapse this time, all of us in palliative care will be caring for more and more of patients before (hopefully) and after LVAD implantation.

2)
Tapendatol is a new oral analgesic just approved by the FDA for moderate to severe acute pain (Medscape article here - sorry you need a free log-on sometimes and I couldn't find a better freer source). Apparently both a mu-opioid receptor agonist, with some other properties like norepinephrine reuptake inhibition - smells somewhat tramadol-ish to me. Anyone know anything about this? Or of research in cancer pain populations?

3)
Archives has a paper looking at rate of GFR decline and mortality in older adults (only for the prognosis completists) as well as a prospective study looking at depression and antidepressant use in CHF patients suggesting that it's the depression itself and not antidepressant use which accounts for increased mortality. Hooray.

4)
The depression and physician assisted suicide fist-fight (which one could cartoonishly characterize as the depression-doesn't-matter-in-PAS vs. screen-'em-all-fools debate) continues in letters to the editor in BMJ recently. Letters here, here, and here; blog post about original article here.

BMJ also has a letter arguing with the cancer pain guidelines I blogged about here: the letter makes a not-completely-crazy argument that buccal/transmucosal fentanyl should be considered the breakthrough med of choice at least for some types of 'breakthrough' pain.

Tweet

It's August, it's hot, I'm jealous of Tom Quinn who has seemed to be on an endless vacation (please give us the details when you get back), my little boy is about to take his first steps, I know all the secrets of the Harry Potter series, and my wee brain isn't working well, so I'm just going to touch on the interesting items cluttering my inbox this week.

1)
The latest issue of the Journal of Supportive Oncology has several notable articles (table of contents here; JSO is always available free online). There's a review on endoscopic procedures for malignant bowel obstructions (both small and large), particularly focusing on the use of self-expanding metal stents. It contains, among other things, a narrative review of the research surrounding SEMS use, and makes a good place to start for those who aren't familiar with their use. Two associated editorials are here & here.

The other article I wanted to mention was another trial looking at fentanyl buccal tablets for breakthrough cancer pain. It was an industry funded placebo controlled trial of opioid tolerant patients (median daily oral morphine equivalent dose of 180mg) which found, shockingly, that FBT provided more pain relief than placebo! What was interesting was that this trial provided further evidence that, at least with buccal fentanyl, baseline opioid dose does not correlate well with effective FBT breakthrough dose (i.e. the more opioids one is on at baseline does not mean one will need a higher breakthrough dose) and all patients need to go through a dose titration phase to find the right dose. Previous posts looking at the same question are here.

Oh and there's also a letter/case series on inhaled lidocaine for intractable cough; not a ringing endorsement of the practice.

2)
The American Journal of Health System Pharmacy has a review on long term trends in long-acting opioid prescribing in hospitalized cancer patients. It's from MD Anderson and, among other things, examines trends before & after their palliative care team was established in 1999. Basically what they found was that after the palliative care team was established, patients were prescribed more long acting opioids, but most of this increase was due to increased methadone prescribing, and overall costs went down because methadone is dirt cheap.

3)
JAGS has a study looking at the natural history of 'frailty' in older men. It is data from a large, multicenter, prospective study which followed ~6000 elderly community dwelling men (mostly in their 70's and 80's). Frailty was defined as: "A man was considered frail if three or more of the following five criteria were present: shrinking/sarcopenia, low activity, weakness, slowness, or low energy...." These criteria were each defined more objectively. 4% of the subjects were frail at baseline and these individuals had a strikingly different course than the 'robust' men: got sicker and died more. By the end of the study (mean follow up 4.7 years) 42% of the frail men had died compared to only 7% of the robust men and frailty was a very strong predictor of mortality (hazard ratio 2.05). Sounds like a perfect target population for early, palliative-care oriented, interventions.

4)
Nature and many news outlets have been reporting about the man in a minimally conscious state who has shown dramatic improvements after implantation of a thalamic stimulator (Nature article - actually it's a letter, Nature news story 1, Nature news story 2, NY Times story). The patient was 38 year old man who had been in a MCS for over 6 years after a traumatic head injury; he occasionally showed some awareness and attempts to communicate but was mostly stuporous. He is now alert much of the time, can verbalize appropriately at times, and can eat orally. He appears to have anterograde amnesia. There's a lot of neuro/MRI chatter in the case report that is too technical for me but it seems he showed imaging evidence of functioning cortex but his arousal system (including the thalamus) was not functioning - thus the apparent success of electrically stimulating his thalamus.

This is just one patient and the wider applicability of this technology may be be small, not to mention how unclear the long term outcomes are at this point. However it seems reasonable to assume we're moving into an era in which long term cognitive impairment (e.g. post strokes and anoxic and traumatic brain injuries) may be treatable (i.e. at least partially reversible with medical interventions other than supportive care & waiting to see if people get better with time which has been pretty much the only available options until now). This may make prognostic uncertainty even more difficult for these patients which will be a challenge and one for which we should be prepared as a profession. Talking through options, weighing uncertainties, identifying values and goals and hopes and helping people make decisions in light of them - these are our strengths in palliative care and as 'disease-modifying' options proliferate for even the sickest of patients these skills will become even more valuable. I hope.

(Image from the Cleveland Clinic's deep brain stimulation patient page.)

Tweet

1)
Neurology has an important article looking at prognosis in intracerebral hemmorrhage which finds that early treatment limitations are independently associated with mortality (related editorial here. ) The data come from a large, regional study of ICH outcomes in Texas, and the researchers reviewed charts looking for 'care'-limitations (DNR orders, decisions to not escalate care, withdrawal of life-prolonging treatments) in non-brain dead patients. Long-term mortality was also followed - median length of follow-up was 417 days. They looked at 270 ICH events total: of those, 93 had early (<24h of admission) treatment limitations vs. 177 who did not. Those with early TL's were older (77 vs 70 years), sicker (lower Glasgow Coma Score, larger ICH volume, more likely to come from a NH), and had much higher in-hospital mortality (75% vs 25%). Long-term survival was also very different (~65% survival at 3 years without TL vs 20% survival at 3 years with TL); all the difference in survival however occurred immediately (survival curves are identical - nearly flat - once past the initial event). None of this is surprising - the patients with TL were much sicker. What is notable is that after controlling for age, gender, ethnicity, initial coma score, ICH volume, extent and site of hemorrhage, early treatment limitations were still significantly associated with in-hospital and short & long-term mortality. Implication: the TL patients were in fact considerably sicker (but in a way that wasn't controlled for in the multivariate analysis...for instance medical comorbidity wasn't accounted for at all) or many of the TL patients would have lived much longer without those treatment limitations. Probably both of these are true; withholding or withdrawal of life-prolonging care is just that. The authors conclude: [E]arly predictions of poor prognosis and subsequent reductions in care could result in withholding care from individuals with the potential for meaningful recovery. Physicians may therefore wish to exercise caution prior to recommending limitations in the aggressiveness of care in the initial hours after ICH presentation.

Translation: don't withdraw/limit life-prolonging care immediately because you may be wrong. Those recommendations, then, are the real challenge of the study. What is missing from them though is that while TL may lead to earlier death that may very well be consistent with the patient's values - not have their life prolonged after such an insult if their quality of life afterwards was not going to be acceptable to them. Predicting that is, of course, difficult and weighing out the chances of that happening with a patient's desire not to have potentially burdensome care is the real trick and this research is not designed to speak to that. They mention 'potential for meaningful recovery' but this wasn't measured here - just survival - although if you're dead you don't of course have that 'potential.' To me, it seems like survival is the wrong outcome to measure in these situations. It's an easy outcome to measure to be sure, but what most patients want to know is their likelihood of being restored to health (to an acceptable level of health and function) and not their chances of solely being kept alive. My thinking that that should be the relevant outcome doesn't make it possible to define or measure well or 'operationalize' but one can still think it.

There are some patients who would have recovered well but don't due to treatment limitations, just as there are some who would have not wanted their lives prolonged who nevertheless received full life-prolonging care. Without perfect knowledge (or even much better knowledge than we have now) these 'mistakes' will be made. But are these 'mistakes'? Is that even the right way of thinking about it? Assuming we will never have perfect knowledge, if we (medical professionals) honestly and with humility talk with patients/families about both the limits of our knowledge to predict and the limits of our ability to heal, earnestly try to understand a patient's values and goals and limits, and then make the best decision possible - that is good medical care and not a 'mistake.' Holding ourselves to perfectly informed decisions is a positivist folly.

So, do treatment limitations in ICH increase your chance of dying? Yes - but that's not the right question.

2)
The British Journal of Cancer has an article comparing buccal fentanyl with IV morphine in a prospective, randomized, non-blinded trial for breakthrough pain in cancer. Despite involving only 25 patients (inpatients in a palliative unit) this was an astonishing complicated trial & results and I'm not quite sure what to make of them. I'm more mentioning this for those of you with a particular interest in transmucosal fentanyl. The major question it is addressed is whether it's safe to start buccal fentanyl in a patient using a dose which is a percentage of their overall opioid dose (many of us choose a starting breakthrough dose of ~10% of the daily opioid dose) as opposed to using the lowest buccal fentanyl dose and titrating up (this latter practice has been proposed because in other trials of buccal fentanyl the effective breakthrough dose seemed to have no relation to the prior opioid dose). In this study they chose 200mcg of fentanyl per 60mg of oral morphine equivalents daily dose as their breakthrough dose and it seemed to work and be safe and effective. That is, for someone on 180mg of oral morphine equivalents daily their data suggest 600mcg is a safe breakthrough dose of buccal fentanyl.

3)
And finally, courtesy of alert reader Dr. Steve Rommelfanger, The Onion once again has an offensive and funny 'end of life' related piece: " I've got some bad news, and I've got some hilarious news." Also note this fake headline from 2002 .

Tweet

2 from the Clinical Journal of Pain

1)
First is a randomized, placebo-controlled trial of a buccal fentanyl tablet** for breakthrough pain in cancer patients. It looked at ~80 cancer patients who had at least 4 breakthrough pain episodes daily. They went through an open label dose-finding titration phase where they used higher doses of the fentanyl tablet until they found a dose that was effective (up to 800mcg at a time). Those that found an effective dose then were blindly given either fentanyl or placebo for subsequent episodes of breakthrough pain (patients could use their prior rescue analgesia med if they didn't receive adequate analgesia with this). They found that the fentanyl tablet provided better analgesia than the placebo and was pretty well tolerated.

A couple things about this. The study seems like it was more or less done to generate data for FDA approval of the drug, and is not very helpful clinically. I'm not knocking this, these studies have to be done, and there are still some clinically relevant aspects to this article. The patients initially went through an open-label phase to see if they found the fentanyl tablet efficacious and tolerable. Those patients who didn't find the tablet efficacious or tolerable weren't included in the placebo controlled part of this trial (these patients constituted a quarter of the initial subject population), so it's no surprise that the placebo-controlled trial found the fentanyl tablet to be, well, efficacious and tolerable. FDA-wise this is helpful: the new drug seems to be safe and it certainly works for some patients. It doesn't however help us clinicians to have a good sense of: what to expect when we start our patients on this, who to start it on, what a reasonable adverse event rate is, etc. One would like to see head-to-head trials of this (or, for that matter, Actiq) with oral short-acting opioids for breakthrough pain (I'm being hopeful here and not suggesting that the authors should have done this in this particular study).

A secondary finding of the study is that, as with Actiq (the transbuccal fentanyl lollipop), the initial breakthrough dose of the fentanyl tablet (as defined through the open label dose-finding phase) seems to have no relationship with a patient's pre-existing opioid requirement. That is, the "your breakthrough dose should be approximately 10% of your total oral opioid dose" rule doesn't seem to apply with these drugs. This could be for two reasons: one is that there's something different about transbuccal fentanyl than oral opioids. The other is that appropriate breakthrough dosing of oral opioids has never really been studied (the ~10% rule is based on expert opinion) and maybe we should be going through a formal dose-finding on all our patients. (Of course, many of us do this, albeit not necessarily formally...I assume many of us out there have patients whose breakthrough dosing varies greatly from the dose the ~10% rule suggests).

**Per the article: "The fentanyl buccal tablet (FBT) incorporates a novel drug delivery platform, OraVescent technology, which employs an effervescence reaction to enhance fentanyl absorption through the buccal mucosa...." While I'm sure this is a swell new drug delivery method "OraVescent" sounds like it should describe some sort of new breath-freshener, mouthwash, or toothpaste and not an opioid delivery system. One wonders if the Freshtastic OraVescence of this product will preclude its blinded comparison with other opioids.

2)
Second is a prospective look at opioid rotation to long-acting hydromorphone in cancer patients. I've already blogged enough for one day so I'll keep this short.

i) They rotated ~50 patients at a morphine to hydromorphone ratio of 5:1 then decreased the dose by another 1/3 presumably for incomplete cross-tolerance.
ii) Speaking of breakthrough pain...they used long-acting hydromorphone for breakthrough pain (they didn't mention telling the patients to crush/chew it so one has to assume the patients were indeed taking an intact long-acting opioid for breakthrough).
iii) This seemed to be safe and well-tolerated overall, but across the group there weren't consistent improvements in pain or side effects (but clearly some patients did benefit).

Conclusion: if you're a student of the opioid-rotation literature this is an interesting study to think about, otherwise...I guess it's got me thinking about MS Contin as a breakthrough analgesic (ha ha).