Did The FDA Forget About America's First Amphetamine Epidemic?

That was the first thought I had when I read through the FDA release on the approval of Vyvanse for "binge-eating disorder".  I thought of the rotation I did on the Eating Disorder service at the University of Minnesota with some of the top experts in anorexia nervosa and bulimia.  In those days the residents admitted the patients and also rotated through the outpatient clinic where they saw new cases of eating disorders and developed treatment plans with the supervision of the attendings.  We talked about a lot of binge eating, since binge eating was a critical aspect of bulimic behavior.  ""Do you ever consume an amount of food large enough that it might be embarrassing if someone else found out?" and getting the details of that specific behavior was one of my standard interview questions.  It was clear that the binge eating of bulimia was a volume and rate task.  I would hear about large amounts of diet soda and popcorn being consumed in order to complete the cycle.

In the intervening 2 decades the only real changes was the addition of bulimia nervosa a composite of bulimic and anorexic behaviors.  That is until the advent of Binge-Eating Disorder in DSM-5.  In addition to a binge definition not much different from the one I used in 1984 eating an amount of food that is "definitely larger than what most people would ingest in the same period and similar circumstances" there is loss of control, and behavioral specifiers for rapidity, physical sensations, appetite, and psychological reactions to the binge eating.  Marked distress needs to occur and it cannot be part of another eating disorder.  The time specifier is that it needs to occur at least once a week for 3 months.  A summary of the FDA release about the indication states:

 “Binge eating can cause serious health problems and difficulties with work, home, and social life,” said Mitchell Mathis, M.D., director of the Division of Psychiatry Products in the FDA’s Center for Drug Evaluation and Research. “The approval of Vyvanse provides physicians and patients with an effective option to help curb episodes of binge eating."   

The DSM-5 has a point prevalence estimate of 1-1.5% in women with a peak in late adolescence and early adulthood.  That same section in the DSM-5 suggests that the course is variable:

"However, over longer-term follow-up, the symptoms of many individuals appear to diminish with or without treatment, although treatment clearly impacts outcome. Periods of remission longer than 1 year are associated with better long-term outcome." (DSM-5 p 351-352)

As far as I can tell, the evidence supporting the fast tracked application for Vyvanse is a typical 8 week clinical trial that looked at remission and reduction in binge eating rates in a multicenter study of 255 individuals (1).  Both the 50 and 70 mg doses were effective.  The publication of the research coincides fairly closely with the FDA release.  Searching through the FDA web site reveals no information about the opinion of a Scientific Committee and whether there was any consensus on the decision or concerns about the addictive potential of the drug.  

The pharmacology of the Vyvanse is interesting.  It is a prodrug - lisdexamfetamine that is a conjugate of lysine and amphetamine.  After it is absorbed into the circulation it is hydrolyzed to lysine and amphetamine.  There has always been some debate about whether this prodrug approach confers a decreased likelihood that the compound can be abused or used in an addictive manner.  Most addiction psychiatrists will tell you that it can and  the FDA approved package insert confirms the fact that it has significant abuse potential.   It is a Schedule II drug according to the DEA.

The lesson of the first amphetamine epidemic is that these drugs will be prescribed, to the point that there is very high demand and production of the drug.  Widespread health consequences were noted from overprescribing stimulants for questionable indications (weight loss, nasal congestion, depression, anxiety, psychosomatic complaints).  During the peak of this epidemic (1969) the total number of 10 mg amphetamine doses was about 25 million.  This was not exceeded until about 2005 and then only as a combination of amphetamine and methylphenidate.  As a psychiatry resident in the 1980s, I was still seeing obese people who had not lost a pound using very high doses of amphetamines.  The weight loss indication was subsequently banned in order to establish some limits on the overprescription of these compounds.  In other words, they were taking the drug because of an addiction rather than using it for any therapeutic effect.  It is clear that the prescription of controlled substances for diagnoses that are based on subjective findings is a recipe for epidemics of addictive drugs both in terms of total prescriptions, escalating use, and diversion.  Stimulant medications have the additional allure as possible performance enhancing drugs and are widely diverted for that purpose.

In that context, it would seem that the FDA would need to come up with a clear rationale for using a Schedule II drug to treat what may be a time limited disorder or a disorder that responds to non-medical therapies.  The complex nature of medications that have addictive potential needs to be recognized.  The prescription of these compounds takes more than rote knowledge. At the minimum there needs to be strict pharmacosurveillance on how this drug is prescribed and flags need to be in place for trends indicating that the prescriptions are starting to exceed the known prevalence of the disorder or the dose ranges are higher than recommended and/or combined with short acting stimulants.  These are all common problems seen in the overprescription of controlled substances.

Passive post marketing surveillance can no longer be considered a viable option for stopping the overprescription of controlled substances.   Waiting for intervention by law enforcement when problems have already begun is an approach from the 1960s.  In an era when data mining is commonplace, the FDA can do a lot more than get drugs out into the marketplace and wait to see what happens.         

George Dawson, MD, DFAPA

1: McElroy SL, Hudson JI, Mitchell JE, Wilfley D, Ferreira-Cornwell MC, Gao J, Wang J, Whitaker T, Jonas J, Gasior M. Efficacy and Safety of Lisdexamfetamine for Treatment of Adults With Moderate to Severe Binge-Eating Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2015 Jan 14. doi: 10.1001/jamapsychiatry.2014.2162. [Epub ahead of print] PubMed PMID: 25587645.

2: Nutt, David, Leslie A King, William Saulsbury, Colin Blakemore. Development of a rational scale to assess the harm of drugs of potential misuse. The Lancet 2007; 369:1047-1053. PMID 17382831;doi:10.1016/S0140-6736(07)60464-4

Supplementary 1:  The following graph is from Wikimedia Commons and it is public domain.  It is a derivative work of reference 2 above and a complete description is available at this link.  I could find no author to cite.

Supplementary 2:  Almost on cue I noticed the first banner ads for Binge-Eating Disorder today (2/12/2015).  It is advertised as a "real medical disorder" and is a brief informational film.  It has a spokesperson who talks about her experience with the disorder and refers the interested viewer to the company web site at BingeEatingDisorder.com.  It carefully coaches people in how to talk with their doctor.  The pharmaceutical company and manufacturer is listed at the bottom on the page.  The graphic of a pizza slice over a drawing of a brain varies in different views.  I don't know exactly what that means.  It suggests psychological therapies for B.E.D. and does not mention Vyvanse.  But let's face it - when people read there is a pill for their eating problem and it is an amphetamine - how many people will be asking for the psychological therapies?

The Increasing High Cost of Generic Drugs

With all of the drama about high pharmaceutical drug prices, the marketing behavior of the Big Pharma biz, and the medicalization of American society - there has been very little said about the generic drug business.  I discussed it in this piece about the DSM-5 and an absurdly high anti-depressant profit attributed to the pharmaceutical industry.  One of the highlights was how inexpensive some of the most well researched and recommended  antidepressant drugs were.  Then just this weekend I got a call from a friend who was taking an antidepressant who told me that his cost went up by 25% on the medication he was taking on the same insurance plan.  As any psychiatrist knows it is practically impossible to advise a patient on what they will end up paying for an extended release version of venlafaxine, even though it has been generic for a while.  Any attempt to find out online results in a confusing blend of American and Canadian prices.  Some of the Canadian prices on the same list exceed what would be paid in the US.

I caught an article by Hirst, reproduced in my local paper this weekend.  She describes a patient who was taking generic carbamazepine.  Carbamazepine has been generic for years.  I can recall prescribing the generic 15 - 20 years ago for patients with bipolar disorder.  This patient had been taking the medication for epilepsy and getting the drug through Walgreen's Prescription Savings Club.  He was paying $20 for a three month supply, but recently the price increased to $100.  That forced him to buy it on a month to month basis.  My drug information suggests at least 5 generic manufacturers and the original name brand along with a sustained release patented version are all on the current market.  Senator Bernie Sanders (I-Vt) is quoted:  "....We wanted to know if there was a rational economic reason as to why patients saw these price increases or whether it was simply a question of greed?"  The federal government tightly regulates health care with special attention from the Department of Justice - how could dramatic price increases in the face of ample competition be a matter of greed?  Wouldn't there need to be a cooperative effort on the part of all competitors to drive up the prices that fast?  The article cites "raw material shortages, consolidation in the industry and medical advances that make replicating brand name drugs more expensive".  I don't accept that explanation any more than greed.  One of the most expensive medications to manufacture in recent times was atorvastatin.  When it first came out, I spoke to a scientists involved in the production and he told me what it cost per pill to manufacture.  That cost was a small fraction of the overall prescription price.  That leads me to believe that even a $4/month prescription for ranitidine can lead to profits for a generic manufacturer.

The Hirst article quotes a pharmacy benefit manager as saying that average cost of a generic drug prescription has increased from $14.21 in 2005 to $41.88 in 2009 and that 1/3 of available generics cost more than $100 per prescription.  Another consultant suggested that acquisition costs of pharmacies have increased 17,700% in the past year.

A more academic article is available from the New England Journal of Medicine by Alpern, et al.  Those authors look at the specific example of albendazole, a broad spectrum anti-parasitic with a long expired patent.  In 2010, the average wholesale price (AWP) for a single day dose was $5.92.  By 2013 it was $119.58.  The authors look at the National Drug Acquisition Costs file and cite a number of significant price increases in widely known generic drugs including captopril, clomipramine, digoxin, and doxycyline.  They have produced an excellent graphic that looks at the number of prescriptions and global Medicaid budget for mobendazole and albendazole and the factors that led to the significant price increases for the latter.  In this case it seems like a lack of competition as being the limiting factor and the authors cite that "drug shortages, supply disruptions, and consolidations within the generic drug industry" are all factors that decrease competition and therefore may increase prices.  They also described the generic drug approval process as slowing down competition especially in a market where a delay in implementation of the generic can cost additional tens to hundreds of millions of dollars.

Both the NEJM article and the Chicago tribune article have a supply side emphasis.  Adequate competition and innovation in a free market increasing supply and driving prices lower while maintaining high value to the consumers.  But there is another story.  Demand for pharmaceuticals is relatively inelastic.  That means that if there are price increases buyers cannot postpone their purchases for a better day without the risk of significant and in some cases life-threatening consequences.  That inelasticity is compounded by several recent factors that lead the further complications.   The first is the advent of high deductible health insurance plans.  The majority of employers use these plans largely because managed care has failed to contain costs and costs to their employees are generally shifted to that risk pool in the subsequent year.  This puts anyone with high deductibles at significant risk for out-of-pocket costs until that deductible is satisfied.  Any drug manufacturer can expect to receive significant out-of-pocket payments while the deductible applies.  The second is the advent of "tiered' coverage based on the insurance plan.  This usually involves a steeper copay for an insurance plan that covers less.  The real risk is that the patient may decide to simply forgo the prescription, but until that point is reached there is a good chance that they will pay significantly more than the lowest generic price in the drug class.  The current system of government sanctioned managed care and inelastic pharmaceutical demand places all Americans at financial risk since it is essentially a tax and in many ways an entitlement to health care companies including generic drug manufacturers.

The other obvious factor that none of the authors comment on is that some pharmaceuticals remain top selling drugs despite the fact that they are now generics.  In some cases like Advair Diskus, the drug is in a unique delivery system that is also patented.  Anyone using Advair is very likely to want to continue to use this delivery system whether or not it is a generic drug or not and the price remains high.  In another example from asthma care, numerous metered dose inhalers underwent a regulatory change in propellants from chlorofluorcarbons (CFCs) to hydrofluoralkanes (HFAs).  That was accompanies by a patent and an immediate and significant price hike to anyone using these inhalers.

I think that this trend is instructive for a number of reasons.  First, it illustrates that when it come to pricing of any pharmaceutical product it is more complex than just monopoly power.   There are clearly market forces in play that will escalate the prices of drugs that have been around well past the patent expiration date.  Conversely, there are many medications that have no pricing power and to the concern of patients and physicians they are just no longer manufactured.  It is easy to understand why generic drug manufacturers are unwilling to maintain a large inventory just so Wal-Mart and Walgreens can have a $4 per month formulary.  Second, it shows that there is a potential for significant distortion of markets being introduced by managed care  companies and their government counterparts.  Rather than the idealized "cost effectiveness" some of the arrangements out there are anything but cost effective and my example of how saving pharmacy costs can explode the cost of care in another direction is a case in point.

Most significantly, we have gone through a period of blaming the name brand pharmaceutical industry (otherwise known as Big Pharma) for a number of problems.  They have been blamed inadequate disclosure of clinical trials data, distortion of clinical trials data, ghost writing articles for physicians, and misleading marketing practices.  Critics also have the usual complaints about efficacy and side effects but seem to miss the regulatory goal of getting a relatively safe and effective (but not perfect) drug into the market for use.  They seem to get a pass  on their influence at the FDA and in fact, some critics seem to think that they can create an idealized regulatory agency that is free from political influence.  These critics seem to suspend the reality that pharmaceutical companies are businesses and that the people on the science end of those businesses in all likelihood have no idea about what is going on at the business end.  The explicit motivation according to the critics is money - the fuel of all businesses.  The generic drug industry (Little Pharma?) has a much smaller marketing infrastructure.  Research and development costs are much less.   They aren't detailing physicians. Until recently they were viewed as the saviors of the patient with little resources and a definite positive for every managed care company looking to enhance their bottom line by lower pharmacy costs.  They were the antidote to Big Pharma.  Despite all of the positive spin there has been a 300% price increase in 5 years for generic drugs.  I don't think I am going too far out on a limb here to say that generic albendazole may be one of the most profitable medications ever made.  Politicians are starting to make noise.  Can physicians be implicated like they were in the Big Pharma scandals? I don't see how, but nothing coming out of Washington would surprise me.

But the real silence here seems to be all of the Big Pharma critics.  We have a generic drug industry with no real explanation for huge price increases at least nothing we can easily attribute it to.  Instead of saying that Big Pharma unconsciously influences physicians into prescribing their expensive drugs, we have hundreds of thousands of physicians consciously trying to prescribe the least expensive drugs for their patients and they are now failing to do that on a regular basis.  Maybe the appearance of conflict of interest isn't quite the theory it was cracked up to be?

Where are the Pharmascolds with their theories?    


George Dawson, MD, DFAPA

Refs:

1.  Ellen Jean Hirst.  Generic drug prices skyrocket in past year:  They were supposed top be cheaper but market forces have intervened.  Chicago Tribune  11, 30, 2014.

2.  Alpern JD, Stauffer WM, Kesselheim AS. High-cost generic drugs--implicationsfor patients and policymakers. N Engl J Med. 2014 Nov 13;371(20):1859-62. doi: 10.1056/NEJMp1408376. PubMed PMID: 25390739.

3.  National Drug Acquisition Costs.  Page with multiple files.  This is a large document with over 600 pages and 20,000 medications listed by NDC number.  For a sample click on the graphic below and discover why aripiprazole (Abilify) is such an expensive medication.

The Antidepressant Black Box Warning - A Better Solution

There were two opinion pieces in the New England Journal of Medicine this week on the antidepressant black box warning.  Richard A. Friedman, MD contends that the warning had an adverse effect on antidepressant prescriptions, a decreased rates of new depression diagnoses, increase in psychotropic drug poisoning (as a proxy measure for suicide attempts)  and that is reflected in an increase in the rate of completed suicides in people from 10-34 years of age between 1999 and 2010.  He argues for removing the warning entirely.  Marc B. Stone, MD points out that there is contradictory data showing that an increase in suicide rates and no good correlation with an increase in rate and the year of the boxed warning.   He discusses other factors that can result in fluctuating levels of depression diagnosis and treatment, including a change in antidepressant marketing because many antidepressant were becoming generic at the time and how that may have affected the prescription rates.  He cites CDC data on the rate of intentional versus non-intentional overdose as a more appropriate metric and points out that rate was lower both before and after the warning.  He concludes that despite many efforts there is no real correlation between the warning and suicide rates.  Disclosure forms will be available when the article becomes available online but for now Dr. Friedman appears to be affiliated with the Department of Psychiatry, Weill Medical College of Cornell University and Dr. Stone is affiliated with the FDA.

One of the central problems with the debate is the problem of looking at statistical significance in low rates on a longitudinal basis.  In all of the studies I have seen and in these debates, the longitudinal data is almost always interpreted as correlational (we seem to never be able to determine causality) and there appear to be endless number of correlations - and none of them are mathematical.  In these articles alone the authors looked at drug company marketing and sales strategies, the impact of the original warning, the impact of the revised warning,  the impact of the discussion in the media as opposed to the warning, the diagnostic patterns of physician, the impact of managed care and pharmacy benefit managers, and the prescribing patterns of physician (broad versus narrow) as possible correlates.  All of this is analyzed at a qualitative level and apparently not by anyone who is an expert in the analysis of longitudinal data.  The debate becomes a series of true or false statements based on snapshots.  That to me is essentially a political analysis of the data and it seems to lead nowhere.  It can be a question of "my data being better than your data" but it is not the kind a probabilistic analysis that physicians are trained to do.  The central question here is whether the original FDA meta-analysis of clinical trials showing a 4% to 2% ratio of "suicidality" in the treated versus placebo group is valid and what should be done about it, keeping in mind that suicidality did not confer any increased risk of completed suicide.  In this case Dr. Friedman agreed that something should be done based on that meta-analysis so both authors would agree that finding is significant.

They differ on what existing data mean and what should be done.  As a clinical psychiatrist  who deals with side effects at least as much as symptoms of depression and anxiety, I think a lot could be done to improve the awareness of side effects and improve treatment.  The solution is a lot less drastic but more comprehensive than a Black Box Warning.   After all, it is highly likely that most people are going to encounter more common and potentially problematic side effects than intrusive suicidal thoughts  or suicide attempts.   That is probably as true for medications without a black box warning as medications with a black box warning.  Even considering another class of medications with a warning about suicidal ideation - anticonvulsants, says nothing about whether a patient is more likely to experience those thoughts with the anticonvulsant or the antidepressant.  Depression is a common problem in people with epilepsy, what about people needing to take both an anticonvulsant and an antidepressant?

My recommended approach to the problem would resolve a couple of issues.  It would emphasize to the public that a choice to take a medication is not without risk and is not a guarantee of a cure.  That one cannot assume that an FDA approved medication is totally benign and will be completely effective for their problems.  The FDA is unique in terms of the efficacy, side effects, and pharmacosurveillance data that they collect.  They are also not transparent with it.  In that context they expect physicians to make sense out of what is presented to patients in the risk-benefit discussion of whether or not to take a medication.  That leaves the benefit discussion full of unnecessary guesswork about what does and what does not need to be discussed.  In that context a black box warning is just another rare cloud on the horizon.  Using the Back Box warning as a standard, a doubling of suicidality from 2% to 4% with no completed suicides with antidepressants is on par with a 1-6/10,000 chance of Stevens-Johnson's syndrome from carbamazepine.

The solution here is an FDA attachment to the package insert of what needs to be discussed with the patient to give them a better idea of the risks and benefits of a particular medication.  It makes no sense at all to feel forced into a discussion of suicidality from taking a medication when far more patients will experience fatigue, headaches, diarrhea, and discontinuation symptoms.  I have attached a sample of a general outline of what needs to be covered.  I think that Medline plus medication handouts could also be considered.  The FDA can specify what these points are for every medication.  If the psychiatric profession has not set a standard, it is time for the regulators to do more than issue confusing black box warnings and back it up with all of the data in an accessible format on their very confusing web site.  You can bet that the managed care industry does not want their psychiatrists spending an extra few minutes with a patient to have this discussion.  The regulator in this case has a unique opportunity to set a uniform standard for side effect discussions based on the priorities they establish from both clinical trials and pharmacosurveillance.   The solution to the debate of the toxic or non-toxic black box warning is as simple as that.

Most importantly the physicians having the discussion with the patient can document "The FDA recommended risk/benefit discussion for this medication was completed with the patient."

George Dawson, MD, DFAPA    


Friedman RA.  Antidepressants' black box warning 10 years later.  N. Engl J Med 2014;317;18: 1666-1668.

Stone MA.  The FDA warning on antidepressants and suicidality - why the controversy?   N. Engl J Med 2014;317;18: 1666-1668.

Peter Diggle, Patrick Heagerty, Kung-Yee Liang, Scott L. Zeger.  Analysis of Longitudinal Data.  Oxford University Press.  Oxford.  Second Edition 2002.

Life Is Not A Randomized Double Blind Controlled Clinical Trial

Or  what is wrong with placebo controlled clinical trials and transparency?

I was in an imaginary meeting with a bunch of Internists and Psychiatrists.  We were debating the available and meager literature on the use of trazodone for sleep.  We got into one of my favorite topics - the double blind placebo controlled trial and that catch all "Evidence based medicine."  The dialogue went something like this:

Internist:  "The evidence from double blind placebo controlled trials is weak for trazodone....."

Me:  "Do I need a double blind placebo controlled trial to tell me to prescribe trazodone for sleep?"

Internist: "Are you saying you don't need evidence.  Oh wait, I was at a conference where the head of the society stood up and and gave evidence that clinical trials have their limitations.  Like they are subsequently proven to not be true...."

Me:  "That is not what I am talking about.  I am talking about all of the hype out there that only 40% of people recover from antidepressants or that they are no better than placebo........"

Internist: "But you do have the algorithmic approaches that show...."

Me:  "Yada, yada, yada - for every algorithm, there is somebody with a meta-analysis to show it is wrong.  No I am talking about the ridiculous notion that psychiatrists could stay in business or want to stay in business if only 40% of the people they treat got better.  If that was true I would have become a recluse 20 years ago and just walked away."

General laughter

Internist: "I would kill for a 40% response rate for some of the problems that I treat."

And so on........

This informal conversation among colleagues is illustrative of the recent arguments that focus on physicians and generally psychiatrists more than other physicians that treatments are ineffective.  They are based on an oversimplified view of placebo controlled clinical trials and conflict of interest.  Many times there are no clear points of demarcation between what is a scientific issue (the technical aspects of the clinical trial) and the ethical issue (conflict of interest issues that may compromise the scientific results).   You can read all about current technical problems with clinical trials, like the common observation that there is a lack of generalizability to clinical populations compared with the highly selected and trial sample that in the case of psychiatry generally has much milder forms of the illness being studied.  Here are a few of the concerns that I don't see being discussed anywhere, especially when it comes to clinical trials of psychiatric interventions:

1.  The crude state of clinical trials:  Clinical trials in psychiatry are tremendously unsophisticated. The trial result generally depends on rating scale or clinician global rating scale results that grossly oversimplify the condition and measure parameters that are irrelevant in clinical settings.  The best example I can think of is depression rating scales that list DSM criteria for depression and then apply a Likert dimension to those symptoms.  In clinical practice it is common to see hundreds of patients with the same score on this scale who have a full spectrum of disability from absolutely none to totally disabled.  Which population might be more likely to exhibit an antidepressant effect?  It is also common to see medically ill patients with insomnia who may score as mildly to moderately depressed who are physically ill and not depressed at all.   The same problems exist with clinical trials of schizophrenia, anxiety and Alzheimer's disease.   When this weak technology is combined with a selection process that eliminates clinical populations with the most severe illness, it should not be surprising that any treatment being studied has a weak effect.

2.  A weak clinical trials data base:  One of the clarion calls of so-called evidence based medicine is the Cochrane Collaboration.  I have looked up hundreds of their reviews and the majority of those reviews of both medical and psychiatric studies is: "insufficient results and methodologically unsound".  I suppose it is good to have somebody make that statement, but if you have proclaimed that you are an evidence based physician - you have nothing to go on.  In fact, at some point you stop going to Cochrane because the results are fairly predictable.   Even in the case where you have a result does it apply to the patient you are seeing?  I don't see many Cochrane studies depressed patients that have right bundle branch block, ventricular premature contractions, or complex atrial fibrillation - all common patients seen in clinical practice.  How many more research papers do I have to read that conclude that "more research is needed" while continued inadequate trials are being published and analyzed by Cochrane?  From the current trends and political correctness of evidence based medicine this will go on forever.  The practical aspects are the very large costs of trials.  That is the real reason that pharmaceutical companies (Big Pharma) sponsor these trials.  The political system in the US has decided to farm out clinical trials to private for-profit companies in the exact manner that the US government has farmed out management of the entire health care system.  In these systems Big Pharma absorbs a disproportionate amount of criticism relative to managed care companies.  Managed care has equated "medically necessary" care with care that can be provided in the form of a pill.

3.  The politicalization of clinical trials:  No clinical trials of psychiatric medications can be done these days without an eye to the politically relevant dimensions.  A new antidepressant needs to get as many FDA approved indications as possible in order to beat the political restrictions of utilization review by managed care companies.   That would include indications not only for depression, anxiety, panic, and social anxiety but also chronic pain and possibly attention deficit-hyperactivity disorder (ADHD).  The best way to beat utilization review is to have the only FDA approved indication in the class.  That is also applied to atypical antipsychotics and that fact seems to escape the critics who focus on the number of prescriptions and what that implies.  Physicians are pawns in a game when there are no suitable tolerated medications for bipolar disorder depression and there are atypical antipsychotics for that indication.  These current political factors in clinical trials preclude a focus on cognition, functional capacity, and endophenotypes - all potentially much more valuable than a focus on diagnostic criteria or rating scales based on those criteria.

4.  A characterization that the average physician is ignorant - at best:  Any political movement is associated with ugly rhetoric.   There has clearly been an effort to stampede any physicians with reservations about evidence based medicine into a Neanderthal category.  The irony is that the criticism often comes from sources like managed care companies, medical certification authorities and the press (bloggers) - all entities with their own high levels of conflict of interest.  Common rhetoric used against psychiatrists has been: "You just don't want to be measured".  If the criticism originates from a government, managed care company or administrative authority there is often the attached explicit threat: "Those  days are over!".  The obvious implicit observation is that medicine and psychiatry is now being run by people who don't know anything at all about medicine and there is plenty of evidence on this blog to back that up.

Many critics seem to get a lot of mileage out of the position that they seem to be particularly anointed to criticize the field.   That seems especially true if they happen to be a physician as in: "My colleagues certainly seem to be a bunch of chumps and therfore can be rejected on a wholesale basis or of course listen to me for enlightenment".  I have never witnessed that level of incompetence in any group of physicians where I have practiced across multiple settings.

5.  The use of statistics for rhetorical purposes:  At this stage after reading research for that past 35 years, I am convinced that you can come up with a meta-analysis that will show whatever you want it to show.  Several years ago in the New England Journal of Medicine there was a study that looked at how well meta-analyses predict the results of available large scale clinical trials.  That study showed 2/3 times.  It is common to see a result and then see a meta-analysis that "disproves" the clinical trials result.  Nobody seems very interested in looking in detail at how sound that meta-analysis was.

Today we have a large number of questionably valuable clinical indicators or quality care markers that are often based on the political rhetoric of the government and managed care organizations.   They may be invalid on the face of it, but there is a second equally important aspect.   These same organizations have no valid approach to looking at the statistics of longitudinal data.  They will look at clinic results or even results from the same physician and convert them all to a numerator and a denominator.  Whether that fraction means anything or not is anybody's guess, but there is an administrator somewhere who will be happy to tell you all about it.

6.  False assumptions about the expertise of physicians:  Much of the rhetoric above is focused on physicians.   Psychiatrists as the most politically disenfranchised group are a frequent target.  In the past years we have endured the ideas that medical treatments being prescribed are ineffective and overprescribed.  That brings us full circle to the opening imaginary conversation.  Physicians are trained to focus on several goals including acute treatment, treatment of chronic problems, and providing care for the dying.  The psychiatrists and physicians that I have had the pleasure of working with have been highly effective is achieving those goals.  When I look at the modest results of poorly designed clinical trials all I can do is shake my head.  I would have quit a long time ago if my diagnostic or treatment capabilities were accurately described in clinical trials and most physicians would have.  Informed clinical treatment is a series of often rapid changes in course, rejecting poorly tolerated treatments and looking for things that work better along the way.  I can change the course of treatment depicted in a clinical trial in one day.  In the trial that result is carried to the end as a failure.  How is it that a clinical trial or this evidence would predict my treatment results by mean?  If a treatment is ineffective or not tolerated in my practice, I don't stop treatment and call that person an unsuccessful intent-to-treat subject.  I work with them to establish effective treatment - often in the same time frame as a clinical trial.  Is it quite literally absurd to suggest that clinical trials accurately describe what will happen in clinical practice and yet that is the state of discourse.

7.  The false promise of transparency:  Anyone who followed politics knows that disclosing potential conflicts of interest  is meaningless in the case of politicians.  The general idea is that politicians would refrain from either accepting money from sources where they are involved politically or just not be involved in that area of legislation.  In reality that does not happen.  Sometimes the politicians involved will speak out against any suggestion that there is a connection between the money they receive and their legislative record even when their activities are consistent with a financial conflict of interest.  The sunlight of transparency that many of the critics talk about simply legitimizes ongoing involvement in areas of potential conflict of interest.   Disclosure is a stamp of approval for involvement.  All of that can be researched on Congressional watchdog sites.   The new CMS web site that posts payments to doctors is hyped as a way to appease all of the critics who seem clueless about transparency.  For an eye opener take a look at their decision point on conflict of interest.  CMS seems much more charitable than the typical blogger, politician or journalist with this disclaimer:

"Sharing information about financial relationships alone is not enough to decide whether they’re beneficial or improper.  Just because there are financial ties doesn’t mean that anyone is doing anything wrong.  Transparency will shed light on the nature and extent of these financial relationships and will hopefully discourage the development of inappropriate relationships.  Given the complexity of disclosure and the importance of discouraging inappropriate relationships without harming beneficial ones, CMS has worked closely with stakeholders to better understand the current scope of the interactions between physicians, teaching hospitals, and industry manufacturers."

8.  A lack of appreciation of the regulatory environment:  In the rush to condemn Big Pharma and anyone associated with them, critics often have an idealized version of regulation in their minds.  If only they had access to all of the clinical trials data to analyze for themselves.  They would personally be able to hold Big Pharma's feet to the fire and only allow drugs to be approved that they deemed to be safe and effective.   They are smarter and more ethical than anyone doing the actual trials and certainly smarter than the regulators.  This is at the minimum a failure to recognize that pharmaceutical regulation is after all a political process.  Like all politically directed regulation there are broad goals of safety and efficacy but they are relative and the regulatory mandate takes that into account.  On this blog I have pointed out several cases of medications that not only I,  but the Scientific Committee employed by the FDA recommended against based on safety considerations, but that were approved by the FDA.   Many drugs that I approved as a member of a Pharmacy and Therapeutics Committee (P&T) were expensive but had minimal efficacy.  We approved it based on political considerations (small but vocal advocacy group and untreatable illness) rather than pure efficacy or safety considerations.  The regulatory environment is currently designed to get promising agents into the hands of clinicians for clinical use.  The limited exposure of patients in clinical trials means that rare but serious side effects will not be recognized until post marketing surveillance occurs.  Every person taking an FDA approved medication should realize that.  The regulatory process is not designed to provide perfect medications because there are none.

There is a lot more to say about this subject like a detailed analysis of how the politicalized version about how physicians work and think has nothing to do with the way physicians actually work and think.  But for today I am stopping here.

Life is not a randomized double blind controlled clinical trial and that is generally a good thing.

George Dawson, MD, DFAPA

Paroxetine For Hot Flashes - A Potential Problem

This opinion piece caught my eye in the New England Journal of Medicine this week for a number of reasons.  First off, it involves my least favorite antidepressant, so I am always interested in why there may be broadened indications.  I stopped prescribing paroxetine well over 20 years ago because of what I considered to be an unfavorable pharmacokinetic and side effect profile.  In this case there is a potential interaction that could decrease the efficacy of tamoxifen - a medication used to treat breast cancer.  In my capacity as a consultant, I frequently encounter people who are already on paroxetine and will continue it if that is their preference.  I do encounter people with side effects and either transition them off of the medication or onto something else depending on the clinical scenario.  Second, FDA decision-making is always interesting to follow and that is also true in this case.  Like the recent Zohydro decision, the FDA decided to go against the recommendation of its scientific committee and approve the specified name brand product for hot flashes.  Third, the remarketing for generics as brand name drugs with slightly different formulations is another interesting aspect of FDA regulation and in this case that is also true.  The product in this case is Brisdelle, a 7.5 mg tablet of paroxetine.  Paroxetine is currently available as a generic drug as 10, 20 , 30 and 40 mg immediate release tablets and 12.5, 25 and 37.5 mg controlled release preparations.    Some of the 10 mg tablets are scored allowing for an approximation of the approved product.  Another interesting pint is that this action is apparently over a year old according to this FDA release.

The scientific evidence comes down to two randomized, double-blind, placebo controlled trials of 1184 women.  Baseline moderate to severe hot flashes were occurring at a rate of about 10 per day.  The effects observed during the trial were described as modest with an overall decrease in these hot flashes by about 0.9 per day by week 12 in one study and 1.7 per day in the other.  Despite that slight effect, the women on active drug reported a meaningful difference at the end of the study and again at 6 months.

In balancing the risk rewards of this study and the regulatory decision, the FDA Reproductive Health Drugs Advisory Committee voted 10-4 against approving Brisdelle.  The authors speculate that modest efficacy and existing warnings about suicidality swayed the Advisory Committee in this vote.  I thought it was interesting that the authors consider the safety profile of paroxetine to be well established.  Paroxetine seems to be one of the most complained about medications on the Internet and a favorite of critics who consider themselves as watchdogs of the pharmaceutical industry.  In the case of Brisdelle, the formulation had side effects that did not exceed placebo.  Anyone used to prescribing selective serotonin reuptake inhibitor (SSRI) type antidepressants is aware of a possible significant discontinuation syndrome.  The authors suggest that Brisdelle does not need to be tapered if discontinued but the package insert from the web site suggests potential problems including potential discontinuation symptoms and symptoms in neonates exposed to the medication.

The authors discuss the importance of a non-hormonal agent to treat hot flashes, especially give the impact on lifestyle and risks of stroke, coronary artery disease, thromboembolism, and breast cancer.  The only current FDA approved treatment is hormonal therapy in the form of estrogen or estrogen-progestin.  The problem is that using SSRIs or SNRIs for hot flashes is already a fairly widespread practice and it is backed up to some degree by double blind controlled trials where approval by the FDA was not the goal of the study.  I did a Medline search of controlled clinical trials for hot flashes and came up with this rough collection.  If you look up the specific studies you will find some positive and some negative.  I did not look for meta-analyses.  The most interesting opinion was naturally the one that matched mine and I found it in this study.  In this study the authors correctly conclude that potent CYP2D6 inhibitors should be avoided in women taking tamoxifen and the recommendation to avoid paroxetine is being ignored.  Using a database from the Netherlands paroxetine remains a widely prescribed antidepressant.

The last reference reflects my opinion on paroxetine in general and certainly for this specific problem.  It is also an example of how the FDA could consciously avoid problems rather than sending them out into the free market and waiting for the post marketing surveillance.  That is acceptable in the case of serious conditions with no current therapies.  But this is a case of alternate therapies with scientific backing being readily available and experts in the field recommending not to use paroxetine.  I also have a concern about the impact that remarketing a generic drug with an unusual dose on the generic drug market in general.  I am thinking about the precedent of generic doxepin being remarketed as Silenor in unique dosages of 3 and 6 mg.  Most pharmacies have generic doxepin 10 mg tablets as the smallest available dose size with a liquid form that can be ordered for additional dose adjustments.  My impression is that the prescribing of doxepin in low doses has increased in general with the recognition that low doses can be used for insomnia.  Doxepin is primarily a substrate for CYP enzymes, but at some point could probably accumulate with higher doses.  If the same thing happens with paroxetine it may result in standard antidepressant doses being prescribed for hot flashes.  That could lead to more complications and potentially more drug interactions.

George Dawson, MD, DFAPA

1:  Ronald J. Orleans, M.D., Li Li, Ph.D., Myong-Jin Kim, Pharm.D., Jia Guo, Ph.D., Mahboob Sobhan, Ph.D., Lisa Soule, M.D., and Hylton V. Joffe, M.D., M.M.Sc.  FDA Approval of Paroxetine for Menopausal Hot Flashes.  N Engl J Med 2014; 370:1777-1779.

2:  Binkhorst L, Mathijssen RH, van Herk-Sukel MP, Bannink M, Jager A, Wiemer EA, van Gelder T. Unjustified prescribing of CYP2D6 inhibiting SSRIs in women treated with tamoxifen. Breast Cancer Res Treat. 2013 Jun;139(3):923-9. doi: 10.1007/s10549-013-2585-z. Epub 2013 Jun 13. PubMed PMID: 23760858.

Dangerous Medication - Part 3 - A Risk-Averse Approach To Prescribing Bupropion

Bupropion is a widely prescribed antidepressant.  It is a safe and effective medication according to the FDA.  It can be safely prescribed with a high level of success.  It is probably more widely prescribed with the advent of guidelines suggesting that it is an augmenting agent for situations where antidepressant monotherapy is ineffective.  It may also end up being used with another antidepressant if a patient is interested in using it for smoking cessation and in an off label manner for attention deficit hyperactivity disorder and to treat sexual dysfunction associated with SSRI type antidepressants.  Bupropion does have a unique position in antidepressant pharmacotherapy.  With the increased focus on electrocardiogram abnormalities, it is probably the antidepressant that  is least likely to affect the QTc interval.

Bupropion is generally well tolerated, but there are some people who develop increased anxiety, agitation and insomnia.  This people generally need to stop taking the medication or reduce the dose.  A small number of people will develop mild to moderate hypertension and depending on the situation, the medication should be discontinued or the hypertension treated.  The largest problem I see with this medication is deciding when to stop and start it based on its contraindications.  The FDA package insert (from the FDA website using the brand name) on the matter is clear:

CONTRAINDICATIONS
WELLBUTRIN is contraindicated in patients with a seizure disorder. 
 WELLBUTRIN is contraindicated in patients treated with ZYBAN® 13 (bupropion hydrochloride) Sustained-Release Tablets, or any other medications that contain bupropion because the incidence of seizure is dose dependent. 
WELLBUTRIN is also contraindicated in patients with a current or prior diagnosis of bulimia or anorexia nervosa because of a higher incidence of seizures noted in such patients treated with WELLBUTRIN. 
WELLBUTRIN is contraindicated in patients undergoing abrupt discontinuation of alcohol or sedatives (including benzodiazepines). 
The concurrent administration of WELLBUTRIN and a monoamine oxidase (MAO) inhibitor is contraindicated. At least 14 days should elapse between discontinuation of an MAO inhibitor and initiation of treatment with WELLBUTRIN. 
WELLBUTRIN is contraindicated in patients who have shown an allergic response to 
bupropion or the other ingredients that make up WELLBUTRIN Tablets

The package insert goes into some of the evidence for these contraindications, but the details seem fairly clear to me.  So why is it that the following happens?

1.  Patients who are not aware of the fact that bupropion can cause seizures.
2.  Patients who are prescribed this medication in spite of the contraindications.
3.  Patients with a past history or an active eating disorder taking this medication.
4.  Patients who are regularly drinking alcohol +/- sedative hypnotics taking this medication.
5.  Patients who have had generalized tonic clonic seizures taking this medication and the medicine is still prescribed.

I could go into much greater detail about some of the most extreme situations where this occurs, but I think it would be more instructive if I just cut to a few basic recommendations for the safe use of this medication:

1.  Do not prescribe it in the presence of contraindications.
2.  Do not prescribe it to anyone who has a known problem with alcohol or sedative abuse problems.  In fact, obtain a new history for those disorders at the time you are obtaining informed consent for the prescription and revisit the contraindications every time you increase the dose since the seizure risk increases with dose increases.
3.  Discontinue bupropion immediately if you are treating the patient for alcohol or sedative hypnotic withdrawal.  Have a serious conversation with that person about seizure risk an the FDA contraindications before restarting it.  People provided with that information quickly reassess the need for the medication and whether or not it has been helpful.
4. Discuss the warnings with the patient if they have medical comorbidity that is flagged in the package insert such as:

Hepatic Impairment: WELLBUTRIN should be used with extreme caution in patients with severe hepatic cirrhosis. In these patients a reduced dose and/or frequency is required, as peak bupropion, as well as AUC, levels are substantially increased and accumulation is likely to occur in such patients to a greater extent than usual. The dose should not exceed 75 mg once a day in these patients.

and:

The risk of seizure is also related to patient factors, clinical situations, and concomitant 
medications, which must be considered in selection of patients for therapy with WELLBUTRIN. 
Patient factors: Predisposing factors that may increase the risk of seizure with bupropion use include history of head trauma or prior seizure, CNS tumor, the presence of severe hepatic cirrhosis, and concomitant medications that lower seizure threshold. 
Clinical situations: Circumstances associated with an increased seizure risk include, among others, excessive use of alcohol or sedatives (including benzodiazepines); addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; and diabetes treated with oral hypoglycemics or insulin. 
Concomitant medications: Many medications (e.g., antipsychotics, antidepressants, theophylline, systemic steroids) are known to lower seizure threshold. 

5.  Seriously weigh the seizure risk of adding any medication that might lower the seizure threshold to any person who is stable on bupropion and keep that person involved of the possible seizure risk.  Do a detailed and individualized risk assessment for prescribing medications to any patients.
6.  Document the vital signs of any patient on bupropion and the trend.
7.  Do not prescribe bupropion again to anyone who has had a seizure while taking it.

I have seen bupropion prescribed in the context of all of the contraindications and warnings without seizures or other complications.  Risking a low frequency but serious complication is not the optimal way to prescribe it.  The other consideration is that the risk assessment needs to be done on an individualized basis.  A general number quoted as an average side effects from clinical trials obviously would not apply to a patient with multiple risk factors or a patient who reliably gets side effects every time he or she takes the drug.  Population based care sounds good when it is promoted by managed care companies or government agencies, but this is a good example of where that concept fails.  As I think about all of the high risk ways I have seen bupropion prescribed, I go back to the recent post on overprescriber biases and how that influences the process.  No physician trained in psychopharmacology would have these deficits on a purely cognitive level, but in the case of treatment resistant depression and a contraindication the situation may become higher risk.

That is an ideal time for consultation or referral rather than taking a chance.

If you are reading this from the patient perspective, I encourage reading the Medline Plus handout on any medication that you are taking. The FDA approved package insert is usually available on the Internet, even in the case of most generics.  I would exercise caution if you decide to study it.  In a previous post, I point out that a lot of people really don't want to know about detailed side effects in advance because they fear developing them by mere suggestion or they might avoid taking a useful medication entirely.  Some package inserts have specific "Information to the patient" that is usually designed to communicate important information.

George Dawson, MD, DFAPA

Dangerous Medications - Part One

Some of the most common rhetoric used against psychiatrists is that the drugs that psychiatrists prescribe are somehow more dangerous than other drugs.  There are numerous problems with the argument including the fact that psychiatrists don't really influence what medications are approved by regulators and the majority of the so-called psychotropic medications (up to 80%) are prescribed by primary care physicians.  There are the associated arguments that they are overprescribed and ineffective and I will address those at another time.  What is the evidence about dangerousness?  I have previously commented on the issue of whether or not the medications used by our field cause a person to become homicidal.  I will restrict this post just to the issue of medication complications and whether or not regulatory action needs to be taken against a medication.

The areas of pharmacovigilance and  pharmacoepidemiology offer some insights into the area of drug dangerousness, but at this point there are few good studies available in public access formats.  One study done in Wales showed that over a 5 year period there were about 100,000 incident reports related to medications or about 9.7% of all patient safety incidents.  The incidents resulted in severe harm or death in 822 patients (0.9%) of the medication related incidents.  The majority of reports were skewed toward reports from hospitals (75%) as opposed to primary care clinics.  Looking only at the severe and fatal outcomes by drug class (Table 8) 2/13 drugs could be classified as medications used to treat mental illness.  Benzodiazepines and antipsychotics were ranked 6th and 12th respectively.  The top 5 drugs starting with number one were opioids,  antibiotics, warfarin, heparin, and insulin.  Any physician working on hospital safety committees is aware of the number of complications due to anticoagulation.  To add further context the total population of Wales in 2011 was about 3 million people, but the total prescriptions per drug class or the critical denominator to determine any true complication rate is unknown.

Unfortunately in the US, we have no complete systems for pharmacovigilance.  We have a long standing data base that has been around for decades that was used primarily to monitor physicians prescribing practices for pharmaceutical companies.  Pharmaceutical representatives would detail physicians (introduce product information) and this company would sell the information about whether the detailing resulted in increased prescriptions of that product.  Occasionally data from this large data base makes it out into the medical literature, but there is a serious question about how well marketing information works for pharmacovigilance.  There is publicly available data from the Centers for Disease Control (CDC) indicating that there are about 50,000 deaths per year attributable to medications.  The majority of these deaths are accidental and intentional overdoses and there is no granularity to look at common severe side effects like anaphylaxis.  A third source of data is proprietary databases from health care companies, hospitals, and government agencies.  Those sources often lead to questions about the generalizability of the conclusions from those studies.

A potentially useful regulatory measure is the number of medications that have been identified as problematic in post marketing surveillance and removed from the market for safety reasons.  The best review I could find on that topic is reference 2.  The paper looks at market withdrawals of new molecular entities (NMEs) approved by the FDA between the years 1980 and 2009.  Of a total of 740 NMEs during that period, 118 (15.9%) were discontinued.  Twenty six drugs out of 118 were withdrawn due to safety reasons or a total of 3.5% of the original approvals.  Nervous system drugs represented a total 104/740 approved drugs and a total of 6.7% of the discontinuations as a percentage of the approvals.  Safety withdrawals were a total of 3 drugs or 2.9% of the total approvals in this therapeutic class.  The bottom line is that a total of 1 drug used for psychiatric indications out of 740 NMEs in the last 3 decades was a medication was withdrawn for safety reasons.

The authors go on to provide a high degree of granularity with a complete list of all NMEs that were withdrawn for safety reasons and they are listed in Table 3.  The three nervous system drugs listed are nomifensine (an antidepressant), levomethadyl acetate ( a drug used to treat opioid dependence), and pergolide mesylate (a drug used to treat Parkinson's Disease and restless leg syndrome).  The  study apparently does not look at the issue of drugs where the manufacturer voluntarily discontinued sales.  As an example, Bristol Myers Squibb discontinued sales of Serzone (nefazodone) in 2003 due to a low incidence of hepatotoxicity with serious outcomes like liver failure and the need for transplantation.   The conclusion of this article is that the majority of of drug discontinuations are due to commercial reasons and not safety.  They noted a trend for decreasing NMEs over time and an associated decrease in drug discontinuations.

Part of the problem with the perception of drug dangerousness, especially with medications used for psychiatric indications seems to be the idea that they should be devoid of side effects.  That is certainly the ideal scenario, but that is not the approach taken by regulatory bodies like the FDA.  Like any regulatory body that depends on politicians for funding there will always be a variety of political influences.  In some cases the bureaucratic structure may be prioritized over scientific review.  The paper by Qureshi, et al is a good example of a certain threshold of severe side effects that may lead to drug discontinuations for those reasons, but any inspection of current approved medications and their rare but serious side effects shows that there are plenty of concerns out there for commonly prescribed drugs in all classes.  The regulatory concern is that many of these medications are useful for the people who really need them.  When any medication is applied over a population of people, there is a likelihood of rare but very serious side effects.  That is not a reason to call the drug dangerous, especially if there are people who benefit from taking it.  There is also a likelihood of common side effects that are less dangerous but adversely impact quality of life.  It is also easy to see the problem politically.  In other words there is some kind of conspiracy driving the prescription of some medications as opposed to others.

The reality is that the patient has a decision to make and as I have pointed out before, I have really never encountered a person (including myself as a patient) who takes that decision lightly.  There are additional interpersonal and psychological factors.  My personal bias as a physician is that the primary goal of treatment is minimal to no side effects and that tolerating side effects is a decision made by the patient but informed by the physician.  It always needs to be balanced against any therapeutic effect of the medication.  


George Dawson, MD, DFAPA:

1:  Cousins DH, Gerrett D, Warner B. A review of medication incidents reported to the National Reporting and Learning System in England and Wales over 6 years (2005-2010). Br J Clin Pharmacol. 2012 Oct;74(4):597-604. doi:10.1111/j.1365-2125.2011.04166.x. Review. PubMed PMID: 22188210; PubMed Central PMCID: PMC3477327.

2:  Qureshi ZP, Seoane-Vazquez E, Rodriguez-Monguio R, Stevenson KB, Szeinbach SL.  Market withdrawal of new molecular entities approved in the United States from  1980 to 2009. Pharmacoepidemiol Drug Saf. 2011 Jul;20(7):772-7. doi: 10.1002/pds.2155. Epub 2011 May 14. PubMed PMID: 21574210      

Why Has Suboxone Turned Into A Problem?

The short answer is that it is like very other drug and there was always the potential for a problem.  Any practicing physician realizes that when a drug is approved by the FDA for general release to the public there are all kinds of unintended consequences that are possible.  That is the basis of post marketing surveillance by the FDA.  There is invariably a lot of hype associated with the release of a drug, but as I have previously pointed out the FDAs approval process is not in place to guarantee a drug that is safe for everyone.  It is focused on a releasing a drug that is a potential tool for responsible practitioners.  That means any drug can potentially cause a small number of serious unexpected reactions (liver failure, cardiac arrhythmia)  that even the most experienced practitioners will not be able to predict.  There is also an implicit understanding that the practitioners prescribing the drug have a thorough understanding of its pharmacology, indications and contraindications.  Many practitioners advise against trying out a product that has just been released but that advice is tempered by the severity of individual circumstances and the hope of relief and also the general bias that new drugs are somehow better than the old ones.  That bias has been repeatedly disproven.

Suboxone prescribers have to take a special course in order to get a prescriber number in addition to their usual DEA number.  I took the Suboxone prescriber course about 7 years ago.  It was a total of 8 hours of lectures given in a convention center room in a hotel.  It was jointly sponsored by state medical association.  The morning sessions were largely a review of the pharmacology of the drug and the scope of the opioid addiction problem at the time.  The afternoon session focused on vignettes of patients with addictions of varying complexities and the exercise was to determine of Suboxone should be prescribed to that person and how the induction would be done.  That was the first suggestion that something was problematic.  There apparently were no contraindications to Suboxone.  The clear message was that it should be given to anyone with an opioid addiction no matter what their social circumstances or comorbid psychiatric diagnoses and addictions.  There was a definite implication that this was a drug that would revolutionize the treatment of opioid addiction.

 
Suboxone is a combination of buprenorphine and naloxone.  Buprenorphine is the active ingredient in terms of treating addiction.  In this post I will use Suboxone and buprenorphine interchangeably.  The pharmacological properties of buprenorphine that were interesting in terms of potential use for addiction included the fact that it was a opioid mu receptor partial agonist and antagonist at the kappa receptor.  The partial agonist effects relevant for addiction such as euphoria and sedation occur at the lower doses and the antagonist effects occur at higher doses.  The antagonist effects like preventing respiratory depression were thought to put a ceiling effect on this side effects and make it safer than pure mu receptor agonists that would produce dose related toxicities.  In the Suboxone course the mixed agonist/antagonist effects were described as producing less toxicity and less risk of abuse.  The naloxone component of Suboxone is a pure mu receptor antagonist.  In the course I took, the explanation for the combination of buprenorphine and naloxone was that it reduced the risk of intravenous drug use and that this had occurred in Europe and it resulted in several deaths.  The company also sold Subutex which was buprenorphine only and indicated for use in pregnant women.

The pharmacodynamics and pharmacokinetics in real life can differ quite a bit from the idealized cases that the initial marketing and advertising was based upon.  Like many medications it can be a life changing drug.  People can recover and break the cycle of addiction, recovery and relapse and go on to productive lives.  It is the outliers that physicians need to be most concerned about.  In real life there are always going to be people who get significant side effects even at low doses and cannot tolerate the drug.  There are also people who tolerate the drug at high doses and do not experience the ceiling effect of mu receptor antagonism.  The people are probably very low in number but they are significant because they are not protected by the ceiling effect that is supposed to be there from the drug.  Drug addiction always attracts or produces a significant number of people who become amateur pharmacologists and use the drug to facilitate their addiction.  The word gets out and suddenly buprenorphine has street value (about $1,000 for a 1 month prescription) and opioid addicts can use it when they run out of heroin or oxycodone.  In a few people it is their preferred opioid because it has a longer half life.

The politics of Suboxone are as complicated as you will find in the pharmaceutical industry.  There are plenty of conflicts of interest in terms of how the drug was initially marketed and plenty of crossover between regulators and the company who developed, marketed and sold it - Reckitt-Benckiser.  According to a New York Times article last fall, the company was granted a period of exclusive sales that ended in 2009.  After that they went on the offensive to suggest that their new product - a Suboxone film was superior to the generic tablets especially in the area of child safety.  They stopped selling the Suboxone tablets at that point.  Insurance companies can work any controversy to their advantage and people on buprenorphine maintenance have been cut off based solely on the amount of time they have been taking the drug.  There are no scientific guidelines for how long a person should take buprenorphine and like most drugs used for maintenance therapy there will never be a study that looks at that question due to the expense.  Most experts would agree that if you have a severe addiction and have recovered based on buprenorphine there is no reason why you would be cut off.  In fact discontinuing buprenorphine seems to present a more significant problem as dose is tapered to 2 mg and  lower.   We also have a familiar political theme in the issue of opioids with the government seeming to create the problems in the first place and now saying: "Trust us we have the solution."  That may have explained the desperation in the descriptions of how public health officials were trying to increase Suboxone prescribers to address a public health opioid epidemic that was a likely result of government initiatives to improve the treatment of pain.

Suboxone has become a problem for the same reason that every other drug becomes a problem - unrealistic expectations, conflicts of interest, and a knowledge deficit on the part of the practitioners.  The title of the New York Times article illustrates how the press can look at the dual nature of drugs and imply that there is a larger problem.  I don't know of two many drugs that do not have a "Dark Side".  The negative trends in buprenorphine use can be reversed but it will take more than the suggested strategy in the NY Times article.  Here are a few ideas:

1.  The CDC needs to get involved and look at Suboxone/buprenorphine related deaths and study it in the same manner that they studied methadone.  It would be very instructive to see exactly where Suboxone/buprenorphine falls on the spectrum of deaths/100 kg MME (milligram morphine equivalents).  The expectation of some in the article is that it is much safer, I would prefer to see the numbers.  Only the CDC has access to the detailed data to look at this issue.  I would take it a step farther and suggest that the CDC recalculate this table on an annual basis as a key metric in reversing the significant public health problem of accidental opioid overdose deaths.

2.  The physicians prescribing the buprenorphine need to be highly motivated and well versed in prescribing medications to individuals with addictions.  The NY Times article suggests that there are many who take an entrepreneurial approach to the prescription of buprenorphine with cash only practices that vary from $100 - $250 a visit.  I have no problem with cash only practices if there is a quality approach.  By definition that involves a lot more than handing someone a prescription in 5 minutes.  The problem is the rest of what happens during that time is poorly defined.  The original prescribing information said that the physician needed to refer the patient to counseling services.  In many presentations of research that I have seen there is a clear movement to illustrate that - counseling adds little to nothing to outcomes when buprenorphine is prescribed.  There are problems drawing that conclusion about this research given the modest outcomes of the buprenorphine treatment.

3.  At least part of the interview of any patient recovering from the severe addiction that occurs with opioids is assessing their functional capacity.  What are they doing on a day to day basis and is that routine consistent with both recovery and a lack of cognitive side effects from the buprenorphine?  Being able to corroborate that improvement with a third party makes it even more reliable.

4.  A big part of the unconscious aspects of addiction is the behaviors that are present to continue the addiction despite the best conscious efforts of the person affected.  Good examples include craving, lying, and hiding use from others.  That requires prescribing physicians to engage their patients at this level and not develop a law enforcement transference.  A lot of physicians don't know how to respond to an accusation of: "You don't trust me!" when there is a question of the need for a toxicology screen or a discussion of a positive toxicology.  The interpersonal aspect of treatment is very important and it received no attention in the standard Suboxone prescribing course.

5.  Continued work on a model of treatment looking at all of the potential positive factors is needed.  There is nothing worse in medicine than to treat a scientific topic like a political one and not have a rational approach to the person with the problem.  Like the original course I took, there are  people out there who say that buprenorphine prescribed out of a physicians office is all that is needed.  Is that the case when you have a person who takes two to three times the prescribed amount to get high?  Or the person who is crushing it and snorting or injecting it?  Or the person who is selling it on the street to get purchase heroin?  Or the person who can't function due to cognitive problems at 2 mg a day?  Or the person who is hospitalized for recurrent bowel obstructions due to severe constipation?  As the prescribing physician - are  you confident that you can accurately screen for these problems?  What about competing approaches like the long acting mu antagonist naltrexone injections?  Where does 12-step recovery like Narcotics Anonymous fit in?  Where do sober housing and residential treatment fit in?  And finally - where can a person get detoxified and should anyone be forced to go through acute opioid withdrawal when they are incarcerated?

All of these questions are currently unanswered.  But like most treatments in medicine, the solution is typically a lot more than a pill.  Drugs with addictive potential always add the complication of significant financial gain from a captive audience.        

George Dawson, MD, DFAPA

Deborah Sontag.  Addiction Treatment With A Dark Side.  New York Times. November 16, 2013.

SAMHSA.  Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction.  A Treatment Improvement Protocol.  TIP 40.

NICE.  Naltrexone for the management of opioid dependence. 2010.

NICE.  Methadone and buprenorphine for the management of opioid dependence.  2010.

The Great Unconscious - Why REMS Are Bound To Fail

REMS is an acronym for Risk Evaluation and Mitigation Strategy.  It is an FDA initiative to deal with the risks associated with certain medications.  I first encountered this new concept because one of my lectures is on the current opioid epidemic and looking at the potential risks of opioids.  The FDA has an REMS section on their web site including a list of all currently approved REMS.  For the purpose of this post I am going to focus on the REMS for Extended Release and Long Acting Opioids.  The actual document is 42 pages long.  I read it twice and really cannot see anything in the document that would detect the major problems with opioids or potentially prevent those problems.  It suggests a thorough evaluation of the type than many primary care physicians no longer have the time to do.  The basic elements of a complete history and physical exam, pain diagnosis and examination for addiction and psychiatric comorbidity needs to be taken in the context that substantial numbers of patients with psychiatric diagnoses are now diagnosed by a symptom checklist that is checked off in about 2 minutes.  If there is any take home message from this REMs it should be that chronic pain requiring opioid therapy should be referred to a specialty center where they have the time and staff to do the required assessment.

The biggest misconception here seems to be that patients are accurate reporters and they have no unconscious agenda.  It leads me to question whether the FDA employs any psychiatrists.  It also highlights a naive approach to medicine that suggests physicians and patients are automatons who are basically reading and completing checklists.  The complete checklist suggests the diagnosis.  On what planet does this happen?  With regard to the population of patients with an addiction seeking treatment of chronic pain with opioids, the following graphic may apply.

The data represented in the above diagram are from the National Survey on Drug Use and Health.  The sample size is 70,000 persons, but the conclusions in the diagram are all drawn from the survey and have the usual limitations.  What the diagram shows is that most people who believe they need treatment for an addiction do not make an effort to get it.  The NSDUH looks at detailed information across a number of treatment settings and reasons for not accessing treatment.

I use the above diagram when I am taking with primary care physicians or residents about the situation where they are trying to determine whether or not it is safe to prescribed opioids for chronic pain.  I point out that the people they are seeing in their office probably resemble the sample participants from the NSDUH.  How would those evaluations of themselves affect their response to questions about addiction during their assessment?  By the  time people see me and they have an entirely different frame of reference.  They may have had one (or several) near death experiences from overdosing on opioids.  They may have become homeless and lost the support of their friends and family.  They may have encountered a number of situations making the drug use problem very difficult to deny.  The people receiving the REMS evaluation from their physicians will almost always be similar to the NSDUH sample.  The implication is that these folks won't be "honest" with their physician, but the problem is much more than an honesty problem.  Anyone with an addiction has lost their capacity to fully recognize the nature and severity of the problem.  Their responses are based on a number of biased decision-making processes that continue the addiction.  The primary care physician is in the impossible position of needing to be a lie detector with a person who may not feel like they are lying.  It is another operation of the great unconscious but in this case one that is unrecognizably biased by addiction.

The response to opioids is the first clue that there may be a problem.  People disposed to addiction have a striking response to opioids.  The described an intense euphorigenic effect.  In contrast to the usual ideas that opioids are sedating many will feel much more energetic and productive.  A distinct feeling that a hoped for potential has finally been realized with the expected boost in confidence is often a third feature that is extremely reinforcing.  These are generally the opioid response features that place a person at high risk for opioid addiction.  

The unconscious aspects of drug addiction are described in a number of ways.  Sellman describes it as compulsive drug seeking being initiated outside of consciousness.  Koob talks about the process going from an initial process of an impulse control disorder involving positive reinforcement to compulsive activity that is driven by the negative reinforcement of avoiding withdrawal phenomena.  Most people are not conscious of that process unless it it reviewed with them in detail.  Another unconscious aspect of addiction is cravings.  Cravings can vary from a spontaneous intense urge to use a drug to an urge associated with sensory phenomena that occurs after exposure to a drug cue like seeing people use the  drug on television.  Whether the craving is cue-induced or spontaneous they represent a drug induced change in a person's conscious state that can be present long after there has been exposure to a drug.

A risk management strategy to identify problems with opioid prescriptions needs to incorporate a strategy that takes these features into account.  Information about limiting access to prescription opioids and destroying unused opioids is certainly a useful public health strategy but it does nothing for a person who has a strongly reinforcing reaction to the drug.  At the minimum there needs to be education that the response to the drug is a key feature to identify addiction risk.  Patients need to be educated about that as well as addictive behaviors and those anchor points need to be revisited at every physician visit where response to pain, addictive behavior, psychiatric comorbidity and functional capacity needs to be assessed.  These are also the areas where the bulk of physician education needs to occur.  There is also the issue of whether teaching primary care physicians is the best strategy to limit opioid overprescription.  It may ultimately be the best strategy because the lessons learned could be applied to the overprescription of many drugs with similar dynamics like antibiotics, benzodiazepines, and stimulants.  There is also the model of specialty referral to reduce the burden on primary care clinic.  This model was popular in many states prior to the more widespread practice of prescribing opioids for chronic noncancer pain and it is the basis of the guideline for treating chronic neuropathic pain by the National Institute for Health and Care Excellence (NICE).

George Dawson, MD, DFAPA          

Latest Bad Ideas From the FDA - Zohydro and Adasuve

Like them or not the FDA is the critical agency in terms of pharmaceutical regulation and the politics of pharmaceuticals.  It is easy to confuse the politics of drugs with pharmaceutical science.  Clear examples include special interest groups lobbying the FDA and members of Congress for rapid access to medications that have not been approved for specific indications.  Some of those medications have significant side effects and very low therapeutic efficacy.  At the same time, the FDA is criticized for approving medications that add nothing to the existing pharmacopeia or that have marginal evidence for efficacy.  If you view medications as tools that need to be applied in various on and off label ways by practicing physicians, that is by definition a lower threshold for regulatory approval than the standard that a medication must be very effective and very safe.  It turns out that there are very few medications with that profile.  Some problems and inconsistencies are more glaring than others.

I was surprised to get a recent warning letter from the FDA on an inhaled preparation of loxapine called Adasuve.  Loxapine is an antipsychotic drug of medium potency.  Back in the late 1980s we had a drug trial of loxapine versus haloperidol on one of the inpatient units I was running at the time.  It was a fairly effective drug for acute symptoms of psychosis and was less potent than haloperidol so it has fewer neurological side effects.  It never seemed like a very popular medication with psychiatrists.  There was some recurrent interest around the issue of first and second generation antipsychotics with some authors suggesting that it had a receptor profile that was more similar to second generation or atypical antipsychotics.  During the initial period when it was approved and marketed under the brand name Loxitane it was available in both oral and injectable forms.

I could only locate one study at PubMed on the Adasuve in the current medical literature searching on the brand name.  There were 20 studies at clinicaltrials.gov web site but unfortunately no results were posted.  Some of them appear to be very interesting including one that looks at the QTc interval effects of inhaled loxapine.  A review of the Adasuve web site shows that bronchospasm is a black box warning and that there is a Risk Evaluation and Mitigation Strategy (REMS) to assess prior to prescribing and monitoring the patient after each administered dose. It looks like it can only be given in a registered health care facility by personnel who can assess and manage any pulmonary complications.  Although the pulmonary conditions that contraindicate use seem fairly straightforward (asthma, COPD, any pulmonary diagnosis associated with bronchospasm) the actual diagnoses are probably more complex due to a number of factors including smoking status, body weight, and the complexity of the underlying pulmonary syndromes.  Staff administering this medication should assess the patient for pulmonary problems at every episode and not depend on historical diagnoses.

From a philosophical standpoint, there needs to be an active debate about new patents or patent extensions on medications that are currently generic drugs like loxapine.  During the time it was primarily used it certainly did not demonstrate any superior efficacy or side effect profile relative to other typical or atypical antipsychotics.  Loxapine is metabolized to amoxapine, an FDA approved antidepressant that has been used on a limited basis in psychiatric practice and is generally not considered a first or second line antidepressant.  The metabolic relationship led some authors to speculate that the combination may be effective in psychotic depression but that application was never realized.   So in this case we have a drug with limited applications that has been repackaged in a riskier dosage form.  That seems like several steps in the wrong direction.    The details about the pharmacokinetics are available in the package insert.  Looking at this data, the main advantage appears to be the short time is takes to reach maximum plasma concentration (1-2 minutes).  A useful study here would have looked at a subgroup of patients taking parenteral loxapine and similar pharmacokinetic measures.  In the study I alluded to from the 1980s loxapine was compared directly to haloperidol for acute agitation in schizophrenia or bipolar disorder. 

With this medication released into practice, if I was still working on an acute inpatient unit I would be very skeptical of using this medication for acute agitation.  Use is limited to a single dose in a 24 hour period.  The people who need this medication are generally medically complex, may still have street drugs in their system, are generally cigarette smokers and their pulmonary and in many cases their cardiac status may be unknown.  If the initial dose is not effective, the question becomes - now what?   Patient preference may be an issue since some patients request a fast acting medication but they do not want parenteral injections.  Patients with an addiction history may have used drugs by insufflation, inhalation, and intravenous injection and that may be a factor in their decision making.  All other factors considered there have been studies of patient preference for specific medications to treat acute agitation and of the antipsychotic class of medications only olanzapine is highly rated.  Besides the degree of acceptance, post marketing surveillance will be important in terms of medication side effects.  The current approval was based on pooled data from three studies looking at a total of 259 patients getting the active medication and 263 patient receiving placebo.  That is not many doses of this medication.

Zohydro probably requires less discussion.  Zohydro is advertised as the only acetaminophen free, extended release form of hydrocodone available in the United States.  It is available in dosage forms ranging from 10 mg to  50 mg intended as a twice-a-day dose schedule.  Zohydro comes with the following black box warning:

The interesting part of this approval process was that the scientific advisory panel, for the FDA voted overwhelmingly against approving this medication, but it was approved anyway.  We are currently in the midst of an opioid epidemic based on a number of metrics including emergency department visits for complications, deaths from accidental overdose, per capita consumption of opioids relative to the rest of the world, and the increasing number of people addicted to opioids.  We are also entering a period of increased policing of physicians by numerous agencies for opioid prescribing practices.  There is fairly good evidence that the "opioid epidemic" started with a pain treatment initiative suggesting that physicians were not treating pain aggressively enough.  The pendulum has swung to the point where there will be clear blame for at least some physicians who are using opioids to treat chronic pain. 

There are a couple of additional problems with the FDA approved package insert for Zohydro.  The first is the Indication or reason the FDA approved this drug in the first place.  The indication for Zohydro is: ".....the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment for which alternative treatment options are inadequate."  That is a shockingly inadequate description of a pain syndrome.  In keeping with a medication as a tool model for regulatory approval this is acceptable.  But any physician prescribing this medication should have a more specific pain diagnosis that specifically addresses the chronicity of the pain and why this might be an acceptable approach. 

The second problem on my first read through of the package insert is the following graphic of the efficacy of this medication.  It plots the results of an study of Zohydro versus placebo in 510 subjects who were already on chronic opioid therapy for chronic back pain. 

I think that these examples highlight the fact that the FDA does not seem to have any guiding philosophy when it comes to some new drug approvals of repackaged generics other a Darwinian free market approach.  Since the original drug passed the safety and efficacy standards why wouldn't the repackaged generic?  Physicians should demand a more specific regulatory approach.  At the minimum there needs to be clearer evidence of an advance in pharmacotherapy in terms of increased efficacy or a better side effect profile.  Repackaging generic drugs without that kind of guidance and obvious risks seems like a mistake to me.   There also needs to be a better approach to chronic pain and drugs that are clearly addictive and a more uniform methodology for measuring efficacy.  Most studies looking at opioid use in chronic pain show modest pain relief at best.  In clinical practice, the relief is generally on the order of what is expected with non-opioids on population wide comparisons.  There should be an easy way to operationalize that knowledge and instruct pharmaceutical manufacturers on the appropriate design of clinical trials to answer these questions.  There is also the issue of conflict of interest and the need for complete disclosure of who is advocating for the use of the medications in question.

From an addiction standpoint, hydrocodone and acetaminophen compounds are some of the most frequently diverted and abused compounds.  It is not uncommon to get a history of people taking amounts that are the equivalent of chronic overdoses with the acetaminophen component.  Many if not most of the people with this addiction are aware of the risks of the acetaminophen component but when the chronic phase of the addiction develops they will continue to use it and ignore that danger.   Patient preferences can be a factor in the decision to prescribe an opioid.  Hydrocodone combination medications are in high demand on the street indicating to me that is is a preferred product to many addicts.  The package insert contains remarkably little useful practical information on abuse, dependence, and addiction.   We are told that there is a REMS strategy and that the FDA is requiring manufacturers of newly approved long acting opioids to conduct long term follow up studies to look at the "serious risks of long term use."

I think it would be a lot easier if FDA regulators just looked at the current data on the CDC web site about the addiction risk of opioids and answer the question: "Why would Zohydro be any different?"

George Dawson, MD, DFAPA


FDA.  Adasuve Full Prescribing Information. (Click on appropriate link).

European Medicines Agency.  Adasuve EPAR (European Public Assessment Report).

Additional Clinical Note 1:  On 1/14/2014 the FDA issued a recommendation that health professionals stop using combination products that contain more than 325 mg acetaminophen.  That same page has a link to a letter that will be sent to manufacturers that these dose strengths be withdrawn over the next three years.  Based on their rationale (no increased efficacy with acetaminophen and risk for hepatotoxicity), I don't know why 325 mg acetaminophen is the magic number.  The addiction experience with combination products suggest that people will routinely use potentially toxic doses as part of their addiction, even when they know that there is a potential problem with the amount of acetaminophen.  This new rule may increase increase the amount of opioids prescribed.