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Sleeping Pills Are Deadly? Says Who, Exactly?

March 1, 2012

As most readers know, we’re paying more attention than ever before to conflicts of interest in medicine.   If an individual physician, researcher, speaker, or author is known to have a financial relationship with a drug company, we publicize it.  It’s actually federal law now.  The idea is that doctors might be biased by drug companies who “pay” them (either directly—through gifts, meals, or cash—or indirectly, through research or educational grants) to say or write things that are favorable to their drug.

A recent article on the relationship between sedative/hypnotics and mortality, published this week in BMJ Open (the online version of the British Medical Journal) and widely publicized, raises additional questions about the conflicts and biases that individual researchers bring to their work.

Co-authors Daniel Kripke, of UC San Diego, and Robert Langer, of the Jackson Hole Center for Preventive Medicine, reviewed the electronic charts of over 30,000 patients in a rural Pennsylvania health plan.  Approximately 30% of those patients received at least one prescription for a hypnotic (a benzodiazepine like Klonopin or Restoril, or a sleeping agent like Lunesta or Ambien) during the five-year study period, and there was a strong relationship between hypnotics and risk of death.  The more prescriptions one received, the greater the likelihood that one would die during the study period.  There was also a specifically increased risk of cancer in groups receiving the largest number of hypnotic prescriptions.

The results have received wide media attention.  Mainstream media networks, major newspapers, popular websites, and other outlets have run with sensational headlines like “Higher Death Risk With Sleeping Pills” and “Sleeping Pills Can Bring On the Big Sleep.”

But the study has received widespread criticism, too.  Many critics have pointed out that concurrent psychiatric diagnoses were not addressed, so mortality may have been related more to suicide or substance abuse.  Others point out the likelihood of Berkson’s Bias—the fact that the cases (those who received hypnotic prescriptions) may have been far sicker than controls, despite attempts to match them.  The study also failed to report other medications patients received (like opioids, which can be dangerous when given with sedative/hypnotics) or to control for socioeconomic status.

What has not received a lot of attention, however, is the philosophical (and financial) bias of the authors.  Lead author Daniel Kripke has been, for many years, an outspoken critic of the sleeping pill industry.  He has also widely criticized the conventional wisdom that people need 8 or more hours of sleep per night.  He has written books about it, and was even featured on the popular Showtime TV show “Penn & Teller: Bullshit!” railing against drug companies (and doctors) who profit by prescribing sleep meds.  Kripke is also one of the pioneers of “bright light therapy” (using high-intensity light to affect circadian rhythms)—first in the area of depression, and, most recently, to improve sleep.  To the best of my knowledge, he has no financial ties to the makers of light boxes.  Then again, light boxes are technically not medical devices and, therefore, are not regulated by the FDA, so he may not be required to report any affiliation.  Nevertheless, he clearly has had a decades-long professional interest in promoting light therapy and demonizing sleeping pills.

Kripke’s co-author, Robert Langer, is an epidemiologist, a past site coordinator of the Women’s Health Initiative, and a staunch advocate of preventive medicine.  More importantly, though (and advertised prominently on his website), he is an expert witness in litigation involving hormone replacement therapy (HRT), and also in cancer malpractice cases.  Like Kripke, he has also found a place in the media spotlight; he will be featured in “Hot Flash Havoc,” a movie about HRT in menopausal women, to be released later this month.

[Interestingly, Kripke and Langer also collaborated on a 2011 study showing that sleep times >6.5 hrs or <5 hrs were associated with increased mortality.  One figure looked virtually identical to figure 1 in their BMJ paper (see below).  It would be interesting to know whether mortality in the current study is indeed due to sedative prescriptions or, if the results of their earlier paper are correct, simply due to the fact that the people requesting sedative prescriptions in the first place are the ones with compromised sleep and, therefore, increased mortality.  In other words, maybe the sedative is simply a marker for something else causing mortality—the same argument raised above.]

Do the authors’ backgrounds bias their results?  If Kripke and Langer were receiving grants and speakers’ fees from Forest Labs, and published an article extolling the benefits of Viibryd, Forest’s new antidepressant, how would we respond?  Might we dig a little deeper?  Approach the paper with more skepticism?  Is the media publicizing this study (largely uncritically) because its conclusion resonates with the “politically correct” idea that psychotropic medications are bad?  Michael Thase (a long-time pharma-sponsored researcher and U Penn professor) was put in the hot seat on “60 Minutes” a few weeks ago about whether antidepressants provide any benefit, but Kripke and Langer—two equally prominent researchers—seem to be getting a free ride, as far as the media are concerned.

I’m not trying to defend the drug industry, and I’m certainly not defending sedatives.  My own bias is that I prefer to minimize my use of hypnotics in my patients—although my opposition is not so much because of their cancer or mortality risk, but rather the risk of abuse, dependence, and their effect on other psychiatric and medical symptoms.  The bottom line is, I want to believe the BMJ study.  But more importantly, I want the medical literature to be objective, fair, and unbiased.

Unfortunately, it’s hard—if not impossible—to avoid bias, particularly when you’ve worked in a field for many years (like Kripke and Langer) and have a strong belief about why things are the way they are.  In such a case, it seems almost natural that you’d want to publish research providing evidence in support of your belief.  But when does a strongly held belief become a conflict of interest?  Does it contribute to a bias in the same way that a psychopharmacologist’s financial affiliation with a drug company might?

These are just a few questions that we’ll need to pay closer attention to, as we continue to disclose conflicts of interest among medical professionals.  Sometimes bias is obvious and driven by one’s pocketbook, other times it is more subtle and rooted in one’s beliefs and experience.  But we should always be wary of the ways in which it can compromise scientific objectivity or lead us to question what’s really true.

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The Power Of No

April 3, 2011

Why is it that when someone tells us we can’t have something, we just want it more?  Marketers (those masters of neuropsychology) use this to their great advantage.  “Call now!  Offer expires in ten minutes!”  “Only one more available at this price!”  “Limited edition—Act now!”  Talk about incentive salience!!!

This phenomenon is known as the Scarcity Effect—a psychological principle saying that individuals don’t want to be left alone without an item—particularly something they believe they cannot have.  We’ve all experienced this in our personal lives.  Tight budgets often invite wasteful expenditures.  Obsession over “forbidden foods” has ruined many a diet.  Saying “no” to a child is frequently a trigger for constant begs and pleas.

Given the apparent universality of this concept, it’s surprising that we fall victim to it in medicine as often as we do, particularly at times when we want to motivate behavior change.  Saying “no” to a patient usually doesn’t work—it’s human nature.  In fact, if anything, the outcome is usually the opposite.  Reciting the dangers of cigarette smoking or obesity, for example, or admonishing a patient for these behaviors, rarely eliminates them.  The patient instead experiences shame or guilt that, paradoxically, strengthens his resistance to change.

But if we understand the Scarcity Effect, we doctors can outsmart it and use it to our advantage.  This can be important when we prescribe medications which are likely to be misused or abused, like sleep medications or benzodiazepines (Valium, Xanax, and others).  These drugs are remarkably effective for management of insomnia and anxiety, but their overuse has led to great morbidity, mortality, and increased health costs.  Similarly, narcotic pain medications are also effective but may be used excessively, with unfortunate results.  We discourage excessive use of these drugs because of side effects, the development of physical dependence, and something I call “psychological dependence”: the self-defeating belief I see in many patients that taking a pill is absolutely necessary to do what the patient should be able to do by him- or herself.

If I give a patient a prescription and say something like “Here’s a script for 15 pills, but I’m not giving you a refill until next month,” I’m almost inviting failure.  Just as expected by the Scarcity Effect, the patient’s first thought is usually “but what if I need 16?”

(I’ve worked extensively in addiction medicine, and the same principle is at work here, too.  When an alcoholic in early recovery is told that he can never have a drink again, he immediately starts to crave one.  Now I know that most alcoholics in early recovery are not in the position to say “no” to a drink, but this is the ultimate goal.  Their ability and willingness to say “no” is far more effective for long-term sobriety than someone else saying “no” for them.)

So why exactly does inaccessibility lead to craving?  Because even when it’s clear that we cannot have something, our repeated efforts to get it sometimes pay off.  And here’s where another psychological principle—that of intermittent reinforcement—comes in to play.  People who play the lottery are victims of this.  They know (most of them!!) that the odds of their winning are vanishingly low.  Most people never win, and those who play regularly are almost always losers.  However, every once in a while they’ll get lucky and win a $5 scratcher (and see the news stories about the $80 million jackpot winner just like them!) and this is incredibly reinforcing.

Similarly, if a doctor tells a patient that she should use only 10 Ambien tablets in 30 days– and that no refills will be allowed– but she calls the doctor on day #12 and asks for a refill anyway, getting the refill is incredibly reinforcing.  In the drug and alcohol treatment center where I used to work, if someone’s withdrawal symptoms did not require an additional Valium according to a very clear detox protocol, he might beg to a nurse or staff member, and occasionally get one—precisely what we do not want to do to an addict trying to get clean.

The danger is not so much in the reinforcement per se, but in the fact that the patient is led to believe (for very therapeutic reasons) that there will be no reinforcement, and yet he or she receives it anyway.  This, in my view, potentially thwarts the whole therapeutic alliance.  It permits the patient’s unhealthy behaviors to prevail over the strict limits that were originally set, despite great efforts (by patient and doctor alike) to adhere to these limits.  As a result, the unhealthy behaviors override conscious, healthy decisions that the patient is often perfectly capable of making.

One solution is, paradoxically, to give more control back to the patient.  For example, prescribing 30 Ambien per month but encouraging the patient to use only 10.  If she uses 12 or 15, no big deal—but it’s fodder for discussion at the next visit.  Similarly, instead of making a statement that “no narcotic refills will be given,” we can give some rough guidelines in the beginning but let the patient know that requests will be evaluated if and when they occur.  Recovering addicts, too, need to know that relapses and craving are not only common, but expected, and instead of seeing them as failures of treatment (the big “no”), they are a natural part of recovery and worthy of discussion and understanding.

In medicine, as in all sciences dealing with human behavior, ambivalence is common.  Preserving and respecting the patient’s ability to make decisions, even those which might be unhealthy, may seem like giving in to weakness.  I disagree.  Instead, it teaches patients to make more thoughtful choices for themselves (both good and bad)—exactly what we want to encourage for optimal health.


Thank You, Somaxon Pharmaceuticals!

March 18, 2011

One year ago today, the pharmaceutical company Somaxon introduced Silenor, a new medication for the treatment of insomnia, and today I wish to say “thanks.”  Not because I think Silenor represented a bold new entry into the insomnia marketplace, but because Somaxon’s R&D and marketing departments have successfully re-introduced doctors to a cheap, old medication for a very common clinical complaint.

You see, Silenor is a branded version of a generic drug, doxepin, which has been around since the 1970s.  Doxepin is classified as a tricyclic antidepressant, even though it’s not used much for depression anymore because of its side effects, mainly sedation.  Of course, in psychiatry we sometimes exploit the side effects of certain drugs to treat entirely different conditions, so it’s not surprising that doxepin—which has been generic (i.e., cheap) for the last few decades—has been used occasionally for the treatment of insomnia.  However, this is an “off-label” use, and while that doesn’t prevent doctors from prescribing it, it may make us less likely to consider its use.

Somaxon spent several years, and millions of dollars, developing Silenor, a low-dose formulation of doxepin.  Stephen Stahl (paid by Somaxon) even publicized low-dose doxepin in his CNS Spectrums column.  Generic doxepin is currently available in comparatively high doses (10, 25, 50, 75, 100, and 150 mg), but Somaxon found that lower doses (6 and 3 mg, even 1 mg) can be used to treat insomnia.  Silenor is sold at 3 and 6 mg per tablet.

The obvious question here (to both expert and layman alike) is, what’s so special about the 3 or 6 mg dose?  Why can’t I just take a generic 10 mg pill and cut it in half (or thereabouts), for a homemade 5-mg dose?  Well, for one thing, the 10 mg dose is a capsule, so it can’t be split.  (There is a generic 10 mg/ml doxepin solution available, which would allow for very accurate dosing, but I’ll ignore that for now.)

Okay, so there’s the practical issue: pill vs. capsule.  But is 6 mg any better than 10 mg?  For any drug, there’s always variability in how people will respond.  The relative difference between 6 and 10 is large, but when you consider that people have been taking doses of up to 300 mg/day (the maximum approved dose for depression) for decades, it becomes relatively meaningless.  So what gives?

It’s natural to ask these questions.  Maybe Somaxon was hoping that doctors and patients simply assume that they’ve done all the necessary studies to prove that, no, doxepin is an entirely different drug at lower doses, and far more effective for sleep at 3 or 6 mg than at any other dose, even 10 mg.  Indeed, a few papers have been published (by authors affiliated with Somaxon) showing that 3 and 6 mg are both effective doses.  But they still don’t answer:  how are those different from higher doses?

I contacted the Medical Affairs department at Somaxon and asked this very question.  How is 3 or 6 mg different from 10 mg or higher?  The woman on the other end of the line, who (one would think) must have heard this question before, politely responded, “Doxepin’s not approved for insomnia at doses of 10 mg or higher, and the 3 and 6 mg doses are available in tablet form, not capsule.”

I knew that already; it’s on their web site.  I would like to think that no psychiatrist asking my question would settle for this answer.  So I asked if she had some additional information.  She sent me a six-page document entitled “Is the 10 mg Doxepin Capsule a Suitable Substitute for the Silenor® 6 mg tablet?”  (If you’re interested in reading it, please email me.)

After reading the document, my response to this question is, “well, yes, it probably is.”  The document explains that doxepin hasn’t been studied as an insomnia agent at higher doses (in other words, nobody has tried to get FDA approval for doxepin in insomnia), and the contents of the tablet are absorbed at a different rate than the capsule.

But what really caught my eye was the following figure, which traces plasma concentration of doxepin over a 12-hour period.  The lower curve is for 6 mg of Silenor.  The higher curve is for “estimated” 10 mg doxepin.

Huh?  “Estimated”?  Yes, that’s right, the upper curve was actually obtained by giving people 50 mg doxepin capsules and then “estimating” the plasma concentrations that would result if the person had actually been given 10 mg capsules.  (I know, I had to read it twice myself.)  I don’t know how they did the estimation.  Did they divide the plasma concentration by 5?  Use some other equation involving fancy things like logarithms or integrals?  I don’t know, and they don’t say.  Which only begs the question: why didn’t they just use 10 mg capsules for this study???

That seems a little fishy.  At any rate, their take-home message is the fact that with the lower dose, there’s less doxepin left over in the bloodstream after 8 hours, so there’s less of a “hangover” effect the next morning.  But this just raises even more questions for me.  If this is the case, then what about all those people who took 75-150 mg each day for depression?  Wouldn’t that result in a constant “hangover” effect?  I didn’t practice in the 1970s and 1980s, but I’m guessing that depressed people on doxepin weren’t in bed 24 hours a day, 7 days a week.  (I know, the serotonergic and noradrenergic effects “kick in” at higher doses, but the histamine and alpha-1 adrenergic receptors are already saturated.)  A related question is, what plasma concentration of doxepin is required to induce sleep anyway?  What plasma concentration accounts for a “hangover” effect?  0.5?  1.0?  2.0?  Does anyone know?

The Somaxon document states that “clinical trials demonstrated only a modest increase in mean sleep maintenance efficacy when the dose is increased from 3 mg to 6 mg.”  But according to the graph above, the 3 mg curve would be expected to look quite different, as it’s a 50% reduction in dose.  (And I can’t even begin to think what the 1 mg curve would look like, but that apparently works, too.)

We all know (or should know) that tables, charts, and graphs can be used to convey just about any message.  It’s important to look at which data are presented, but also which data are not presented, in order to draw any conclusions.  We must also ask what the data actually mean (i.e., the importance of a plasma concentration—what does it actually mean for a clinical effect?).  In the end, Somaxon’s “explanation” seems like a pretty flimsy explanation for using a very expensive name-brand drug.

That said, I do have to say “thank you” to Somaxon for reminding me of yet another medication that I can use to help treat insomnia.  Not Silenor, but low-dose generic doxepin (10 mg).  It’s a shame they had to spend the millions of dollars on R&D, clinical trials, and marketing, to convince me to prescribe the generic version of their drug, which costs only pennies a pill, but then again, you pays your money, you takes your chances.

(Postscript:  Speaking of money, Somaxon stock closed at $2.70/share today, down from a high of $10.01 on the day Silenor was approved, a loss of $258 million of market capitalization.  Imagine all the soft pillows, soothing music CDs, and OTC sleep aids that money could have bought…)


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