Making medicines safer for all of us

Adverse drug events are now the fourth leading cause of death in hospitals.

It’s a reasonable bet they are an even greater cause of death in non-hospital settings where there is no one to monitor things going wrong and no one to intervene to save a life. In mental health, for instance, drug-induced problems are the leading cause of death — and these deaths happen in community rather than hospital settings.

There is also another drug crisis — we are failing to discover new drugs. [Read more...]

Archive for May 2012

Once is Never

This is the second of 3 posts laying out the philosophical basis for RxISK.org which will be live in the next few weeks. The others are Cri de Coeur & the Unbearable lightness of being.

In Cri de Coeur, I outlined a scenario in which a treatment that causes suicide when put into good trials without any manipulation of the data, any statistical artifice, or any ghostwriting might give rise to a relative risk of suicide that is less than 1.0.

Companies know exactly how to use RCTs to hide risks without any fraud at all

This poses a real problem for anyone who thinks RCTs provide evidence of cause and effect in general or that RCTs are the way to investigate adverse effects. How could a drug that does one thing in real life do exactly the opposite in an RCT?

Given what we now know about antidepressants and suicide, we can construct studies to make suicide on antidepressants appear or disappear. We could produce almost any relative risk between 0.1 and 10.0 (see Heads we win, tails you lose, Psychotic doubt, Cri de coeur).

Companies know exactly how to use RCTs to hide risks without any fraud at all. The surprise is that they got caught out in the case of antidepressants and suicide. There may be other risks they have worked out how to conceal for ever.

We can map out the dynamics in the case of antidepressants and suicide because this problem is now well understood. Comparable scenarios can be constructed for some arrhythmias on some anti-arrhythmics, or respiratory problems following beta agonists given for asthma, and of course everyone believes certain vaccines can cause brain damage but that controlled studies would show a lower incidence of brain damage in the vaccinated group.

Hide deliberately or hide accidentally

In principle companies can deliberately use RCTs to hide problems in every case in which both an illness and its treatment give rise to at least superficially similar problems. Where the problems are not understood the way the antidepressant and suicide issues are, RCTs risk accidentally becoming a means to hide rather than reveal the problem.

Impossible to have confidence, despite any number of confidence intervals

If the adverse event is not well understood, RCT results are impossible to interpret with confidence, despite any number of confidence intervals. We should only say that these are the data that emerged from this particular assay. We should also say that for adverse events it may be a serious mistake to give RCT data primacy over other data.

With adverse events that stem from both an illness and its treatment, the question is what weight to put on observations from controlled trials that have not been designed to investigate the issue versus good observations from clinicians staring the problem in the face, who have an opportunity to investigate the link by means of challenge, dechallenge and rechallenge (CDR) relationships, along with evidence of dose-responsiveness, and reversal by antidote.

We might discount a report from one doctor reporting a patient develop an adverse event on treatment who because of CDR, dose response and other relationships links a drug to the problem. But if a thousand doctors make the link (and even more so if each knows there are 999 other reports) the field will believe the outcome.

Where do we cross the credibility threshold for believing clinical reports like these? The antidepressants and suicide offer a good test case because so few people naturally believe this could happen. It is now clear that the original set of 6 cases from Teicher, Glod and Cole were spot on the mark. The later addition of reports from 5 further centers provided powerful corroboration regardless of what the RCT data might have shown. FDA and everyone else should have gone with these reports as evidence of cause and effect.

But it’s not just FDA who have dug themselves a hole on this one (see Cri de Coeur).

I wrote a version of this post for the Lancet 12 years ago. Before I got the reviews back I had feedback that the Lancet would “buckle” and the article would not be accepted for “political” reasons. (I put the article and its reviews on Healyprozac.com a decade ago).

“completely bizarre” and lacking in “any statistical sense”

The reviews of my paper were in fact longer than the paper itself. The clearest point at which a reviewer lost their cool was when the statistical reviewer was faced with the suggestion that a relative risk greater than 0.5 for a problem in a trial that could stem from both an illness and its treatment might be grounds for concern. He went into orbit, branding this as “completely bizarre” and lacking in “any statistical sense”.

He went on to say that it would be completely unethical to run a trial designed to look at the issue of suicide – or by implication any other hazard. In fact FDA and Lilly had designed just such a trial but dropped it when the public relations heat cooled down.

It is this attitude that delivers Evidence Based Medicine straight into a drug company’s pocket.

Using exactly the same thinking, GlaxoSmithKline’s Ian Hudson argued that even though in scores of cases company employees had categorized a suicide or other problem as caused by their drug, because there was no statistically significant RCT data showing an increased relative risk on the drug these judgments were meaningless (Psychotic doubt).

Our drug killed people retrospectively

In 2006, when GlaxoSmithKline’s data for suicidal acts became statistically significant, did these prior judgments of causality in individual cases magically change from wrong to right?

Now is a time for those supporters of Evidence Based Medicine who spend their time bravely challenging the charlatans of complementary medicine to step up to the plate and sort out this critical problem within orthodox medicine.

They need to say that a relative risk of 1.0 or less can be consistent with a drug causing a problem, or else explain why this is wrong.

The acknowledgement needs to be as specific as this. There are lots of generic statements to this effect in books like Rothman’s Modern Epidemiology but generic statements cut little mustard with the lawyers working for pharmaceutical companies or with doctors in general.

RCTs are not a sacrament

Why would anyone with good intentions fail to step up to the plate?

Well here’s the dilemma. Saying that RCT data from a drug that causes a problem might show a relative risk less than 1.0 concedes that RCTs are not some sacrament that purifies but are rather an assay system and that the results may have little meaning outside the assay. It also entirely undercuts FDA’s current position (see Cri de coeur).

Conceding this point concedes that the results of an RCT may be deeply misleading for variables other than the primary outcome measure (and even on this score may mislead).

There is a way forward even for secondary outcome measures that embraces RCTs – it would call for all RCTs conducted in healthy volunteers to be registered with the data made fully available (see Mystery in Leeds).

Anyone who accepts the overall argument here about the role of RCTs in determining adverse events but remains silent becomes to some extent party to drug induced deaths in people who do not deserve to die, to suicides, violence and inappropriate incarcerations on psychotropic drugs. This happens because your silence is being used every week of the year by drug companies to deny plaintiffs justice and by doctors every day of the year to deny patients recognition.

With SSRIs the suicide data says the risks outweigh the benefits – no one is saved by not warning

There is a second linked problem here. The relative risk of a suicidal act on an SSRI compared to placebo is in fact 2.0 or thereabouts. If this doesn’t mean that SSRIs cause suicide, what does it mean?

The only thing it can mean is that when it comes to suicidal acts the risk of harm in these studies exceeds the likelihood of a benefit. Regulators, doctors and others are reluctant to warn about the risks of antidepressants on the basis that the adverse publicity will mean that some who might benefit from treatment will be deterred from seeking treatment (See Pills and the man).

Regulators and others “feel” that somehow there are more people benefitting from antidepressants than being harmed. This is not an evidence based position.

Good Germans?

Before stepping up to the plate, anyone faced with this dilemma can ask two questions, the first of which is how did we get it so badly wrong?

As Daniel Kahneman and others have shown over the years, the simple repetition of mantras like RCTs are the gold standard and case reports are just anecdotes, and “once is never”, produces a sense of familiarity that induces agreement. The Golden Rule of propaganda is that once is never – repetition is all.

It takes a critical effort to pull ourselves out of the hypnosis, to wake up, to stop being good Germans. Academics who cannot recognize propaganda are like salt that has lost its flavor. Proper science should be the antithesis of propaganda, with a Golden Rule when you hear the words the Gold Standard… wake up!

The second question is if RCTs are not the Gold Standard for determining whether a drug causes an adverse event or not, is there an evidence-based alternative?

See The unbearable lightness of being.

Cri de Coeur

This is the first of 3 posts laying out the philosophical basis for RxISK.org which will be live in the next few weeks. The others are Once is Never & the Unbearable lightness of being.

“[I suggest] a meeting with yourself and your reviewers. I have spoken in public on these issues and offered to speak on any platform. I’ve visited the MHRA [British equivalent of FDA]. Part of my motivation has stemmed from a willingness, indeed almost a desire to be proven wrong, as the consequences of not being proven wrong are in many respects horrific. If you have a reviewer who can point out the error of my ways I will take any steps that might be called for in the light of any conversion”.

The consequences of not being proven wrong are horrific

This cri de coeur (cry from the heart) is from a letter I sent to Richard Horton, the editor of the Lancet, in 2000, when his journal was reviewing an article I had submitted (see Healyprozac.com). The Lancet didn’t hear my desperation or if they did didn’t take up my offer. I had been to and went again to the MHRA who listened to what I had to say, but never offered any evidence to make me change my view that SSRIs can cause suicide.

The point at the heart of the Lancet article that led to my offer to visit and be persuaded of the error of my ways remains unanswered to this day. It was not about whether antidepressants can cause suicide but about how we assess adverse events. Suicide on antidepressants provides the perfect natural experiment to bring out the problem.

Suicide on antidepressants the perfect natural experiment

In 1990 Martin Teicher, Carol Glod and Jonathan Cole triggered concerns about a suicide risk on Prozac. They outlined 6 cases in which patients became suicidal after treatment started, the problem cleared when treatment stopped and re-emerged when treatment was restarted. In a series of subsequent reports other groups found the emergence of suicidality could be blocked by an antidote.

These reports met all the standard judicial, clinical and scientific criteria for determining cause and effect (see Let Them Eat Prozac). Prozac caused suicide.

No-one was prepared to say RCTs were simply not the way to answer this problem

But Lilly’s response in 1990/1991 was that their clinical trial data showed no risk, and that reports of patients becoming suicidal were just anecdotes. Lilly took their trial data to FDA and published it in an article in the BMJ. In an Evidence Based Medicine era where randomized controlled trials (RCTs) are described as offering gold standard evidence and clinical experience is dismissed as anecdotal this argument worked extraordinarily well. No-one was prepared to say RCTs were simply not the way to answer this problem.

But RCTs are not the way to answer a problem like antidepressant induced suicidality. The repetition that RCTs are a gold standard for everything and good case reports are anecdotes is deliberate propaganda. It’s the effect of repetition that causes us to agree with something that in fact stands common sense on its head.

No-one stepped up to the plate

Evidence based medicine and RCTs are supposed to help us control the pharmaceutical industry. One might have expected some of the advocates of RCTs and EBM to step up to the plate and say that Lilly were misusing the clinical trial data – these trials were not designed to test whether SSRIs caused suicide.

No-one stepped up to the plate then. Will they flinch now?

We live in a world where EBM and RCTs have been effectively deployed as a means to silence people injured by treatment. Too many adherents of EBM acknowledge and bemoan this but say it is down to pharmaceutical company “fraud” – lack of publication, miscoding of data, lack of access to the data etc. If the fraud were eliminated RCTs would deliver the goods.

Trickery plays a part but… RCTs are not the answer

While such trickery undoubtedly plays a part, when it comes to adverse events, RCTs are simply not the answer to determining cause and effect.

In the case of SSRIs and suicide, we can now see that the anecdotes so called were from the start completely consistent with the trial data which in the case of Prozac showed a clear doubling (2.0) in the relative risk of suicidal acts on Prozac compared to placebo. The only company defence as of the 1990s was that the published data was not statistically significant (see Psychotic doubt).

Some 14 years later when a sufficiently large cohort of trials were assembled the relative risk of a suicidal act on SSRI antidepressants became statistically significant. At this point, FDA stated that this statistically significant doubling of the relative risk (2.0) of a suicidal act demonstrated a causal effect (where a close to statistically significant doubling of risk had not).

FDA being plain bizarre

The idea that adding a few more patients to the mix should transform our views from this drug doesn’t cause suicidal acts to this drug causes suicidal acts should strike anyone who thinks about it as plain bizarre.

But here is Russell Katz, the Director of the Central Nervous System division of FDA saying essentially this when discussing the doubling of the relative risk of a suicidal act on anticonvulsants compared to placebo:

“We are unequivocally comfortable with using the word, the “c” word, with saying that this establishes causality. Again, we have talked about this a fair amount. This is how we determine causality, this is how we base our findings of effectiveness for drugs.

We do randomized trials, we analyze them prospectively, we have an outcome measure, and if it’s statistically significantly different from placebo, we say the drug caused it, you know, once you rule out chance and fraud and bias and that sort of thing, which we think we have done here”

There is a far deeper problem here than challenging FDA claims that they have ruled out chance, fraud and bias in these company trials in which it’s openly known some patients didn’t exist.

1958 – where the story really starts

To see the bigger problem we have to step back in time to a meeting in Cambridge, England in 1959. This was one of the earliest meetings at which psychiatrists had a chance to talk about their clinical experience with the first tricyclic antidepressant, imipramine. Imipramine had been introduced in 1958. Several of those there stated on the basis of their clinical observations that imipramine could cause suicide.

ECT had previously also been linked to suicide. ECT it was said and is still said could mobilize stuperose and suicidal patients so that they were able to carry out their plans before those plans began to fade. The doctors in Cambridge were aware of this “rollback” theory about ECT indirectly leading to suicides. But they said something else was happening on imipramine. It could directly cause suicide by increasing agitation. No one disagreed.

Unlike the later SSRIs, the tricyclic antidepressants could also bring about dramatic improvements in severe depression (melancholia). When the SSRIs were first produced in the 1970s, they very nearly didn’t become antidepressants because they were of no use in severe depression. Several companies almost binned their SSRIs after a series of studies showed them to be less effective than older non-selective serotonin reuptake inhibitors like imipramine, clomipramine and amitriptyline.

The tricyclic antidepressants are therefore effective in a patient group at a substantially higher risk of suicide than the patients entered into SSRI trials. Because SSRIs were ineffective in severe depression, the SSRI studies were conducted in mild to moderately depressed patients where there was so little risk of suicide from the illness that the risks from the drugs stood out.

How to hide a rabbit in a hat

So let’s mount a thought experiment. To pull a rabbit out of a hat, the first thing you have to do is put the rabbit in the hat. If we were to undertake a large placebo controlled trial of imipramine in severe depression we would expect the rate of suicidal acts on imipramine to be lower than the rate of suicidal acts on placebo because imipramine reduces the suicide risk from the illness more than any risk that stems from the drug. The relative risk of a suicidal act on imipramine in such trials would be less than 1.0, perhaps as low as 0.5.

Where would this leave FDA? Given the corner they have painted themselves into with the SSRIs, they could not agree imipramine causes suicide on the basis of trial data like this.

They cannot concede that imipramine causes suicide on the basis of the challenge-dechallenge–rechallenge reports from the 1950s or 1960s even though these criteria are still embodied in standard adverse event causality metrics – because they didn’t concede that SSRIs cause suicide on the basis of even better reports.

FDA and the politics of suicide

But FDA has in fact labelled imipramine and other tricyclic antidepressants as causing suicide. They did so for political reasons. In 2004, they put a class-wide labelling for suicide risk on all antidepressants so that the makers of the latest drugs would not be disadvantaged. They had in fact offered to put a class-wide warning on all antidepressants as early as 1990.

It must be clear from this that we are about to descend into a morass. This sequence of events poses far more problems than might be immediately apparent.

To be continued.

The Day the Lyrics Lied

medicine liquid

This post was written by Dr Irene Campbell-Taylor, a former Clinical Neuroscientist and Assistant Professor of Medicine at the University of Toronto.

It is essential to read the marketing copy of pharmaceutical companies with care and attention for critical hidden details. It is rare to find an announcement with such obvious errors and dangerous suggestions up front as those contained in the latest media material on Pfizer’s Lyrica (pregabalin), an anticonvulsant drug used for neuropathic pain, partial seizures and generalized anxiety disorder.

In June 2007, Lyrica became the first medication approved by the U.S. Food and Drug Administration for the treatment of fibromyalgia. Sales reached a record $3.1 billion in 2010.

In 2009, Lyrica was one of four drugs, along with Bextra, Geodon and Zyvox, which a subsidiary of Pfizer pleaded guilty to misbranding “with the intent to defraud or mislead”. Pfizer agreed to pay $2.3 billion in settlement, and entered a corporate integrity agreement. The investigation was triggered by allegations made by six whistle-blowers.

“to put issues that diminish trust behind us”

A spokesperson for Pfizer said earlier this year that it would pay the fine “to put issues that diminish trust behind us”.

Now, in the EU, Pfizer announces that it is producing a liquid form of Lyrica for patients with dysphagia. This term applies to people who, usually as a result of neurological impairment, have difficulty swallowing. There are two types of dysphagia: oropharyngeal, caused by damage to the nerves and muscles of the mouth and throat and esophageal dysphagia in which there are problems passing food down the esophagus and into the stomach.

Pfizer appears to be directing its campaign toward oropharyngeal dysphagia but clearly has not consulted anyone with knowledge of the condition. Berkeley Phillips, Medical Director of Pfizer Ltd declared:

“By bringing pregabalin oral solution to the UK market, we can provide patients who are candidates for treatment but experience difficulty swallowing, with an alternative option. The difficulties associated with dysphagia for those who are required to take medicines orally are widely accepted. It is our hope that this new oral solution formulation will provide an appropriate alternative, which will be more convenient for these patients…..Dysphagia is linked to certain diseases and disorders, such as diabetes, epilepsy, multiple sclerosis (MS) and Parkinson’s disease (PD) and can also occur as a side effect to some types of medication. The risk of dysphagia increases with age and the condition can make it difficult for patients to swallow medications that are in solid form.”

American pie

This sounds American as apple pie – what could be wrong? The critically important detail is that these patients have difficulty swallowing liquids – not solids. Contrary to popular belief, the most difficult consistency to swallow is thin liquid because the damaged muscles within the mouth cannot control it and aspiration into the lungs becomes highly probable. Some companies such as Sandoz make millions selling “thickeners” for liquids to be ingested by people with dysphagia. Many of these products in fact do little other than cause dehydration.

But now we have Pfizer proposing that a medication be provided in a form that will increase the likelihood of its ending up in the lungs instead of the stomach.

The company goes on to state: “5% of over 79 year olds and 16% of those aged over 87 years are reported to suffer from symptoms of dysphagia. These figures rise to up to 60% amongst the elderly who live in nursing homes or sheltered accommodation. 24% of patients who are mildly impaired due to MS suffer from permanent dysphagia, however, the prevalence increases progressively together with rising disability, with 65% of severely disabled MS sufferers experiencing permanent dysphagia. According to estimates, almost 40% of patients who suffered a stroke also suffer from swallowing problems.….”

“According to research,” they continue, “patients who experience difficulty in swallowing pills have poorer health outcomes and higher health care costs.” After 25 years of treating dysphagic patients, I have no knowledge of any such research.

Martin Johnson, GP and RCGP Pain Champion explained:

“A wide range of patients with dysphagia will benefit from the introduction of the new oral formulation. The introduction of the oral solution will help us in our treatment of peripheral and central neuropathic pain in the elderly, those with epilepsy, diabetes, multiple sclerosis, stroke and Parkinson’s disease, and of course palliative patients as well.”

Breathless

This is such a potentially dangerous statement that it leaves me breathless.

“According to recommendations from the National Electronic Library for Medicine, doctors should wherever available administer licensed alternatives, like oral solutions to those patients who are unable to take medicines in solid oral dosage forms.”

The suggestion for dysphagic patients is to change to suppository, or topical (on the skin) format, or medications that melt on the tongue but never to oral solution.

The known adverse effects of Lyrica are frightening

Our story, however, gets worse. The known adverse effects of Lyrica are frightening. Remember that this drug is recommended for people who already have neurological disorders. The admitted adverse effects include:

  • Mood or behavior changes, depression, anxiety, agitation, hostility, restlessness, hyperactivity (mentally or physically), thoughts about suicide or self-harm.

Patients are advised to: “Call your doctor at once if you have any of these serious side effects”:

  • Muscle pain, weakness, or tenderness (especially if you also have a fever and feel tired); easy bruising or bleeding; or swelling in your hands or feet, rapid weight gain.

Less serious side effects may include:

  • Dizziness or drowsiness, anxiety, blurred vision, loss of balance or coordination, problems with memory or concentration, dry mouth, skin rash or itching, constipation, stomach pain; increased appetite; or joint or muscle pain.

What is the most important information I should know about pregabalin (Lyrica)?

“You may have thoughts about suicide while taking this medication. Your doctor will need to check you at regular visits. Do not miss any scheduled appointments. This is not a complete list of side effects and others may occur.”

A spoonful of liquid helps the medicine go down – in the most delightful way

The advertising so far has been aimed at adults and elderly patients. But the availability of a liquid formulation makes it easier to give a medication to people who don’t like pills. How long before we see it offered to infants and children as has happened with multiple other drugs never intended for paediatrics.

There appears to be no end to the number of dangers that the gullibility of both the public and physicians can enable companies to sell for enormous profits. For Pfizer a billion dollar fine is just the cost of doing business. A civilization earns the name by its readiness to protect and care for the vulnerable and the needy – by the quality of its healthcare. Sometimes it seems like the barbarians are at the gates.

Every Drink Spiked

This post is written anonymously.

I outlined how my daughter Petra came to take Cymbalta on this blog a few months ago (see Petra’s story; also see Symbolta of Sorts). This post tells of events that led to her coming off.

Petra is an enthusiast for motor sport events. She has been on track days, hill climbs and driver training events. She is a member of an Italian car club. She is a safe, smooth and confident driver, who has held a driver’s license since age 17 – for over six years now. She has had no disqualifications or accidents.

speedometer drunk

Cymbalta and alcohol affected her judgment

Shortly after starting Cymbalta, she noticed that alcohol seemed to affect her judgment while driving. So she stopped driving if she had had any drink. This was easy because at the time she would tend to drink quite heavily or not at all.

One afternoon she had two glasses of beer (8 oz each) while listening to music at a city venue. The event ran for most of the afternoon. She felt happy to drive home. On the way home she was stopped for a random breath test and to her horror recorded a 0.05 Blood Alcohol level on the police breathalyzer. Fortunately, the police officer decided that since the reading was exactly 0.05 and probably falling, she could wait in her car for a while and then continue home.

Close to disaster

This was very close to a disaster. In Australia a reading of 0.05 or higher means that your driver’s license may be suspended pending a court hearing, which is likely to result in a fine plus automatic license disqualification for a minimum of 3 months. The loss of independence and convenience and the loss of something that she takes pride in would have been a real blow.

I purchased an alcometer. A standard drink for Australian purposes is one that contains 10 gm (about 12.5 ml) of alcohol. One such standard drink can be expected to raise Blood Alcohol Content (BAC) by about 0.025 grams per 100ml of blood. BAC levels are commonly thought to fall at the rate of about 0.02 per hour.

We confirmed on several tests that Petra would return a reading of 0.04 per 375 ml of beer (this was 1.4 standard drinks). This was the first problem. The second was that the reading didn’t fall at the expected 0.02 per hour and her BAC would consistently show 0.08 for 2 beers and 0.12 for 3 beers consumed over 2-3 hours.

Her blood alcohol levels were a shock

Petra’s friends, brother and myself all had much lower readings. The consistency of the tests was good. I also tested our device against a police roadside check and obtained the same result as the police device. Finding that Petra returned readings in excess of 0.2 after the consumption of several alcoholic beverages over quite long periods of time was a shock and a big concern. Clearly alcohol was going to be a serious problem for her under these circumstances.

Just girls!

Petra raised this with her doctor, whose response was dismissive – your device was ‘probably inaccurate’. A local pharmacist observed that some young women return much higher readings than expected and that this was probably ‘normal for them’. Our solicitor said that ‘Magistrates are not interested in young women who claim to have only had 2 drinks’.

Petra has now stopped Cymbalta. She says that alcohol does not now seem to affect her anywhere near as much.

So we ran the test again, with the same device as before. This time she returned a reading of 0.03 soon after the consumption of 2 x 375 mls beers, where the figure was 0.08 for the same drinks while taking Cymbalta. This is almost the same as her brother’s reading of 0.02 for the same consumption.

She then had one 375 ml drink with lunch and we checked how quickly her levels fell. She returned a reading of 0.00 1 hour and 35 mins after the start of lunch.

This has probably led to loss of life…

Conclusion: Cymbalta more than doubles the effect of alcohol for some people at least. This could lead to and probably has led to regrettable consequences including harm to self and others, loss of driving licenses, fines, and other losses.

Eli Lilly’s prescribing information for Cymbalta is as follows:

7.16 Alcohol

When Cymbalta and ethanol were administered several hours apart so that peak concentrations of each would coincide, Cymbalta did not increase the impairment of mental and motor skills caused by alcohol.

17.10 Alcohol

Although Cymbalta does not increase the impairment of mental and motor skills caused by alcohol, use of Cymbalta concomitantly with heavy alcohol intake may be associated with severe liver injury. For this reason, Cymbalta should not be prescribed for patients with substantial alcohol use

There is no mention of the risks Petra ran and others seem likely to be running.

DH comment

It is difficult to explain this finding but if valid there is no reason to think these risks are confined to Cymbalta. The testing that drugs undergo does not test for this possibility. There are routine drug and alcohol driving simulation tests which an hour after alcohol often show better performance on the combination of drug and alcohol than on alcohol alone – but no-one tests what might be happening several hours later.

Cymbalta and many other drugs can have an effect on liver function. At present this seems the likeliest way to explain this effect.

In the meantime, anyone on any medication who thinks they might have been affected should check themselves out. Anyone who has ever had a driving conviction may have a case to have their conviction overturned on the basis of company negligence. The same may apply to anyone who has ever lost a job or had an accident at work.

Anyone paying increased premiums on their insurance as a result of a drink driving accident or offence may have a case to reclaim their insurance payments.

There is an urgent need to establish the genetic bases behind effects like this. It is likely that not just Petra but others in her family would be similarly affected, and so it is not just the affected person who needs checking.

The implications for employers of possible accidents at work apparently linked to alcohol but not primarily caused by alcohol are immense.

The already high risks of birth defects and miscarriages in women of child-bearing years stemming from antidepressants, and possible mental handicap in their children, would be compounded in this case by additional increased risks from alcohol. A woman taking a single glass of wine, of which several a week should be harmless, might be exposing her child to riskier concentrations than she thought.

There are clearly issues here for health and other insurance companies covering occupational hazards at large corporations such as General Motors.

We are interested in every report we can get of people having problems that might be attributed to intoxication by alcohol and drugs as well as all possible reports of drug induced cravings for alcohol – See Out of my Mind: Driven to Drink. Please add your accounts to these posts to help get recognition for these issues.

A Symbolta of Sorts

facts and myths

In the early 1990s, Prozac was riding high but Lilly were planning its successor. The leading candidate was duloxetine – a dual inhibitor of both serotonin and norepinephrine reuptake as the older tricylic antidepressants (TCAs) had been. The company approached me in 1992 to recruit patients to a clinical trial of the new drug but before the trial could start duloxetine was pulled from development as an antidepressant. There were problems I was led to believe.

Some years later I heard duloxetine had been brought on the market in Europe as a bladder stabilizer. It is marketed as Yentreve.

To solve their successor to Prozac problem, Lilly turned instead to an isomer of Prozac. R-fluoxetine. This would emerge as Zalutria. The company was blazing a trail that Lundbeck (Forest) have followed since with Celexa becoming Lexapro, and Wyeth with Effexor becoming Pristiq and Astra Zeneca with Prilosec becoming Nexium.

Heart-stopping moments

But Zalutria ran into problems around 2000 when the data were sent to FDA. It interfered with cardiac QT interval on EKG tracings. When this happens those affected are at risk of simply dropping dead. If Zalutria does it badly enough to make it unmarketable, it has to be presumed Prozac does it also.

Since then other SSRIs such as Celexa and Lexapro have been reported to cause QT problems, and are running into problems for just this reason. In some cases companies appear to ‘discover’ QT interval problems in order to get some of their older drugs removed from the market. But while there were other reasons why they might have wanted to abandon it, in this case Zalutria’s interference with QT intervals was probably a major inconvenience for Lilly.

$3-4 billion per year is nothing to be sneezed at

Lilly turned back to duloxetine and turbocharged their clinical trial program. It was during this program that one healthy volunteer on duloxetine, Traci Johnson, committed suicide. Lilly submitted an application to FDA to bring the drug on the US market for both depression as Cymbalta and for bladder stabilization. The FDA were not prepared to license it for bladder stabilization – there had been too many suicidal acts of women on duloxetine in bladder stabilization trials. But Cymbalta was let on the market for depression.

So how would a drug that the company at one point had abandoned, that had significant side effects – such as marked urinary retention, suicidality along with physical dependence – do in a market where the parent company were also trying to persuade doctors that many of their cases of depression were in fact bipolar disordered and should be prescribed Zyprexa. Well $3-4 billion per year is nothing to be sneezed at. Doctors from Alaska to Australia (see Petra’s story) rushed to prescribe it.

Why do doctors roll over in the face of good marketing?

How does a company manage to turn a drug they had written off into a blockbuster? Why do doctors roll over in the face of good marketing? It all hinges on good stories. In the case of Cymbalta, the story was that this was helpful for pain. There was nothing about Cymbalta to recommend it for pain beyond other antidepressants. The marketing campaign might have even been worked out for Zalutria and just seamlessly transferred to Cymbalta. It makes little difference what the drug does. Companies listen to what doctors say they want and this is what they give them pretty well whether there is anything significant about the drug that would support these claims or not.

In this case Lilly were lucky, this story emerged just when the pain-killer Vioxx ran into trouble, and doctors were looking around for another new drug to help with one of the commonest problems in clinical practice – chronic pain syndromes. But it’s the listening to doctors and repeating back to them what they say they want that works every time. These are soothing not challenging stories.

I feel it in my waters

Cymbalta brings out another story that doctors have been totally sold on for 40 years – a perfect symbol of modern biobabble. From early on the first of the tricyclic antidepressants, imipramine, was used to stop bed-wetting in children. The tricyclics got a reputation as bladder stabilizers – sometimes too much so as they could cause urinary retention.

How did tricylics stabilize bladders? Well in the 1960s the story emerged that the antidepressants fixed the lowering of norepinephrine that was at the heart of depression. If this was what they did to treat depression, something else they did must lead to urinary retention. The field settled on the anticholinergic actions of the tricyclics as the culprit. Every single text on antidepressants trots this out. This led to the marketing copy for the SSRIs, 20 years later, the new kids on the block that didn’t have the nasty anticholinergic side effects of the tricylics.

It was and still is almost impossible to find a psychiatrist to say anything other than this even though all of them prescribe much more potently anticholinergic drugs than the tricylics to patients within the mental health system to stop some of the side effects of antipsychotics, but these potent anticholinergics rarely if ever cause urinary retention.

The mismatch between what the books say and what the drugs do is extraordinary

Imipramine and duloxetine in fact cause urinary retention because they act on the norepinephrine system. The mismatch between what the books say and what is going on here is extraordinary. The story that it’s the anticholinergic effects of antidepressants that cause urinary retention is a myth in service to another myth, the catecholamine hypothesis of depression, the source of all later myths about chemical imbalances.

In fact if a group of 10 healthy volunteers were given an SSRI, a norepinephrine reuptake inhibitor or an anticholinergic, we know that on the SSRI there is a good chance that 1 would be suicidal, most would have impaired sexual function and other problems. Those on the norepinephrine reuptake inhibitor would have erectile failure, bladder stabilization, constipation, chilblains and other problems. What would those on the anticholinergic have? If the dose was not too high, the answer is euphoria. Of the three groups of drugs, the anticholinergics have the highest street value.

Masturbation and myths

What’s the moral? You should believe little you hear about drugs and biology across medicine. What is peddled is for the most part a set of stories or myths. In the case of the antidepressants there is almost nothing but myths from chemical imbalances to lowered serotonin levels.

As with the myth that insanity was cause by masturbation, with mythologies in general the issue is whose interests are being served?

Shocking The Homeland

The thriller Homeland reached its denouement in the UK at the weekend – in an Electroconvulsive Therapy (ECT) scene. Claire Danes, a Homeland security agent supposedly taking Clozapine to contain her paranoia has to distinguish reality from psychosis to save the United States (see Homeland Security). Quite obviously to anyone who knows anything about Clozapine, she was not taking it. She is having ECT, which you are expected to think will wipe her memory, when she solves the plot. Quite obviously to anyone who knows anything about ECT, this is not a reliable way to wipe her memory – giving a benzodiazepine at the key moments would have been much more reliable.

A true story?

Homeland adds to a growing list of psychiatric treatments featured as characters in plots. While inaccurate it does not portray ECT as horrifically as Clint Eastwood’s The Changeling, which starts with a clip saying it is a true story – not just based on a true story. The Changeling portrays the horrors of psychiatry as they have been since One Flew over the Cuckoo’s Nest – through involuntary ECT – even though the heroine’s incarceration happened 10 years before ECT was invented.

The only explanation for getting the history so wrong in a “true” story is that ECT inflicted in this way clearly epitomizes fears about psychiatry. But forced treatment with ECT is vanishingly rare. In practice insiders, staff and patients, are more likely to fear forcible and indefinite medication with long-acting antipsychotic injections – a treatment that is more clearly brain damaging, memory disturbing and likely to turn a person into a zombie than ECT.

Pharmacological abuse

In terms of the greatest amount of damage done to the greatest number of people, the real abuses, the real dramas, lie in primary care treatment with prescription only drugs like the antidepressants, statins, asthma inhalers and other drugs. Where ECT given punitively, as has happened in the past, might be compared to rape, something closer to sexual abuse or sexual harassment happens with prescription drugs (see Pharmacological Abuse).

The psychiatric detention or treatment papers aren’t in evidence when we are prescribed a prescription drug. We are free to walk out the door after a consultation, and we think as a consequence that there is nothing to worry about.

But prescription links us inescapably to a prescriber. For most of us, going to the doctor is like going to the bank manager or the head teacher – we feel a few inches tall, absurdly grateful for the smallest signs of favor, and often completely forget what we had meant to say. If things begin to go wrong after treatment starts, the doctor may quickly seem like our only way out. We become ever more dependent on him, and grateful.

Stockholm syndrome

We head into a medical version of Stockholm syndrome – the puzzling state where hostages are often close to being in love with those who have taken them hostage. If the difficulties we develop are caused by the treatment and the doctor doesn’t recognise that what he is doing is wrong for us, we become hostages to fate.

It can be extraordinarily difficult to distinguish between the anxieties, insomnias, and morbid thoughts that treatments can cause even in healthy volunteers and the anxieties, insomnias and morbid thoughts stemming from the problem we took to the doctor in the first instance. It is effortless for the doctor to blame any worsening on our original problem, rather than his treatment. With much less going for them, surgeons blamed the victim faced with the evidence of memory problems after cardiac surgery, and psychiatrists routinely blame patients hooked on antidepressants or tranquilizers or who get diabetes from antipsychotics.

From stigma to reprisal

We can become isolated astonishingly quickly. If we approach someone for help in the case of an antidepressant, we have to risk the stigma of being seen to have a mental problem and then also risk being stigmatised as a loser. We risk incomprehension – even if we approach mental health professionals, none of whom are likely to side with us rather than the doctor. We risk having our next prescription increased to treat our illogical thinking. No one will call this a reprisal. If for some reason, we are listened to and treatment stops and we get worse, no-one is likely to counsel patience to help see us through what might well be a withdrawal syndrome.

Our questions will be put in the weighing scales… and found wanting

Our questions will be put in the weighing scales against the scientific answers and found wanting. There is no-one on our side who is likely to point out that the so-called scientific evidence has been carefully constructed by companies, who suppress trials that don’t suit their interests, and who selectively publish data from trials so that even a trial that has shown a drug fails to work and can trigger suicide can be transformed into a trial that shows unparalleled evidence of efficacy. No one to point out that pretty well all the trials published in even the best journals are likely to be ghostwritten. No-one to point out that lawyers and others looking after the interests of pharmaceutical companies regularly take advantage of medical innumeracy to hide even more dead bodies by constructing trials so the results will not be statistically significant.

As in other areas of abuse, if we wait for the abusers to recognise the problem we are likely to wait for ever. As in so many other areas from Enron to sexual abuse, it is likely to be women who will blow the whistle.

Dying for a cure

Rebekah Beddoe’s 2007 book Dying for a Cure does this. Following a post-partum depression, Beddoe outlines a drama of seduction, increasing personal confusion, family bewilderment and finally survival against the odds.

Dying for a Cure calls out for a movie to be made of it – but we are likely to be waiting a long time for Clint Eastwood or a future episode of Homeland to take on this challenge. What stops them? In contrast to The Changeling, the problems found in Dying for a Cure are ones in which we are all complicit.

If directors are not prepared to take on the challenge, as a matter of honor they should desist from making movies like The Changeling, which by picking out the wrong villain play a part in perpetuating the kinds of abuse that makes medicine induced death possibly the leading cause of death in the Western world today.

The Factories of Post-Modernism

In the 1960s revolution was afoot. Antipsychiatry was born. The new revolutionnaries targetted medicalization and claimed mental illnesses didn’t exist. Out of this cauldron, postmodernism was discovered. Postmodernism provided the basis for an ongoing guerilla war against capitalism and industrial society waged by social scientists, anthropologists and others trained in the humanities.

Science had led us to doubt the Bible, to doubt the stories of national identity and to doubt other stories that bound us together – and in so doing had led us into modernity. Now the message was that we should doubt science itself, which was after all just a bunch of stories – post-modernism. Just as science had once raised the question of whose interests our myths served, now post-modernism asked whose interests did the myths of science serve.

The 1990s saw the science wars

Finally in the 1990s science drew a line in the sand. The best account of this lies in the book Higher Superstitions. Perhaps to the surprise of most scientists – and why few people have heard of it – the Science Wars were over almost at the first engagement. When the bunkers in which the postmodernists had been hiding were examined, there was almost no-one there. The social scientists and others at whom these missiles were directed had apparently deserted the cause. One group were ironically seduced by a New Biology. In the 1990s, the Human Genome Project and developments in psychopharmacology catalyzed this New Biology. Academic social scientists, bioethicists and others rushed to be there at the birth of the New Man whose Star had arisen in the West. Another group vanished.

Reality is not a text than can be read one way today and another tomorrow

In the course of the Second World War, US Air Force planes flew into islands in the Pacific, disgorging all sorts of goods. Some of the islanders were so impressed by the appearance of these flying cornucopias that long after the military left they maintained the runways and control huts, beside which they continued to fly the American flag, in the apparent belief that the right appearances would lead to the right results. These were the Cargo Cults. For scientists reality is not a text that can be read one way today and another tomorrow. The ultimate defense of science has been that its planes fly. Science’s trump card against post-modernists is that having them in a laboratory would be the same as reproducing the airstrips and the US flag – we’d be left waiting forever for results.

What passes for evidence?

But what we have now in healthcare increasingly resembles a Cargo Cult. Today’s drugs are less effective than yesterdays, treatment is now in some areas of medicine the leading cause of death, and life expectancy in the US – the country that consumes the most of the latest on-patent blockbuster drugs – is now lower than Cuba’s. Have the post-modernists slipped in unnoticed and taken over the laboratories of science?

We have all the appearances of science – controlled trials, a relentless quantification, and a stupefying recourse to statistics. And in the front row, we have anthropologists, bioethicists and others who are singularly ill-equipped to deal with statistics and issues of causality. There is no critique of what passes for ‘evidence’, and little exploration of the growing threat to all of us.

Osteopenia, erectile dysfunction and pediatric bipolar disorder have appeared out of nowhere

Meanwhile, the marketing departments of pharmaceutical companies have achieved what the post-modernists of the 1980s could barely have dreamt of. They rewrite the text that is the human body from year to year with afflictions such as osteopenia, erectile dysfunction and pediatric bipolar disorder that appear out of nowhere, creations of ghostwriters who practice to deceive.

Take Donna, for example. In marketing Zyprexa for bipolar disorder, in 2002, Lilly produced Donna, “a single mom, in her mid-30s appearing in your office in drab clothing and seeming somewhat ill at ease. Her chief complaint is ‘I feel so anxious and irritable lately’. Today she says she has been sleeping more than usual and has trouble concentrating at work and at home. However, several appointments earlier she was talkative, elated, and reported little need for sleep. You have treated her with various medications including antidepressants with little success….You will be able to assure Donna that Zyprexa is safe and that it will help relieve the symptoms she is struggling with” [1].

Post-modernism – the new cargo cult

In the 1960s and 1970s Donna would have been seen as anxious, a poster case for treatment with Valium. In the 1990s, presenting with the same symptoms, she would have been seen as depressed, and in need of treatment with Prozac. Neither neuroscience nor any aspect of clinical science had moved forward by 2002 in a manner that might justify rediagnosing Donna as bipolar. But this doesn’t stop companies who are quite happy to read the vast majority of our problems one way today and quite another tomorrow.

The rules of science do not apply, and causality can never be proven

When it comes to the hazards of Zyprexa Donna may suffer from, just as with the hazards of the Lipitor she may have to take because Zyprexa has raised her cholesterol levels, or the Celebrex she may now be on because of arthritis linked to Zyprexa-induced weight gain, or the Avandia she needs because Zyprexa has caused diabetes, Donna and her doctor will find themselves up against a radical skepticism. When it comes to the hazards of a pharmaceutical company’s drug, the rules of science do not apply and causality, it seems, can never be proven. A more succinct definition of the post-modernist credo cannot be found than the phrase “doubt is our product.”

In the midst of the Industrial Revolution, the factories around cities like Sheffield were belching out so much smoke that the sun was blocked out and children famously developed rickets. The factories of industrial post-modernism are also belching out vast amounts of smoke and people are developing diseases from pediatric bipolar disorder to osteopenia as a result that will only clear when the smoke clears. These factories also contain a production line that turns out “North Koreans”, whose job it is to defend the system (see We’re all North Korean now). They have a department whose brief it is to work out new initiatives such as the colonization of May Fool’s Day (see May Fools’ Day).

We need to be able to recognize that little that glistens with statistical significance is therapeutic gold

In the face of this we need to recapture the ability to say that an increase in mortality is an increase in mortality. We need to be able to recognize that little that glistens with statistical significance is therapeutic gold, and refuse to allow companies, their experts and regulators to stand common sense on its head (see Psychotic Doubt). Speaking out would be a way for doctors and scientists to demonstrate the “right stuff” (see We need to talk about doctors).

We need our media studies and other university departments on the humanities side of the fence to deconstruct industry rhetoric. Where are they now when science needs them?

A small band of women clustered around Leonore Tiefer have responded – and derailed company efforts to industrialize female sexuality. Other women, mothers, wives and daughters have done more than any doctors to get recognition of drug-related hazards. 

They are up against the vanished post-modernists, who for the most part now have jobs in the marketing departments of pharmaceutical companies.

[1] Zyprexa. Primary Care Sales Force Resource Guide (2002). Zyprexa MDL 1596, Plaintiffs’ Exhibit 01926, page 7.

May Fools’ Day

jester hat

Following the long-standing tradition, dating back at least to Chaucer, of playing practical jokes on May 1, The Scientist clearly thought it would be a good idea to show the outside world that science doesn’t always have to be stuffy and picked the appropriate day to demonstrate the point (http://the-scientist.com/2012/05/01/data-diving/).

May Fools’ Day joke

Sadly, the joke has gone unnoticed, which defeats the point. Practical jokes of this type need to be celebrated. Hopefully this belated recognition will bring some comfort to the author and editors, and encourage them to continue bringing this important tradition into an arena that desperately needs it.

To celebrate May 1, the journal ran an article called Data Diving, ostensibly on a subject that is at the heart of healthcare debates today – access to clinical trial data. In the presence of full and unfettered access, scientific data will supposedly sing out clear and true (Chant clear – they might have said in Chaucer’s day). Without access, companies can claim their trials show whatever the company wants them to show. Without access, companies get to charge whatever they want for their products.

From Tamiflu to public citizen

Data Diving opens with the struggles of Peter Doshi, Tom Jefferson and colleagues to get access to the data on Roche’s Tamiflu. Several articles have appeared over the last 3 years mainly in the BMJ outlining what has now become a saga (see Pharmageddon). This story has recently been told by Doshi and Jefferson in a wonderful Op-Ed in the New York Times, outlining the billions of dollars lack of access has cost (see Drug Data Shouldn’t Be Secret).

The Tamiflu saga is one bookend to The Scientist’s May Fool’s Day joke. The other is the use of Sidney Wolfe of Public Citizen, Elizabeth Loder of the BMJ, and other distinguished activists on this issue.  These are names whose invocation leads all right thinking folk to agree with whatever is being said – in this case that pharmaceutical companies are leading the way toward the sunny uplands of an academic Arcadia.

Step forward Robert Gibbons – modest hero

The centerpiece of Data Diving, the joke, features the work of Robert Gibbons, who has supposedly had unfettered access to patient level data from the trials of Lilly’s Prozac and Wyeth’s Effexor (see Coincidence a fine thing). Just as Doshi and Jefferson’s access overturned a myth – that Tamiflu has a significant clinical effect, so also Gibbons’ access to the “data” seemingly has overturned myths. In this case, those pesky myths that antidepressants don’t really work and especially that they cause suicide. It was, it turns out, lack of access to the data in the first place that led us to these mistaken beliefs. Companies don’t engage in conspiracies, we are being told, they are masters of the cock-up, and if given a choice of feet to shoot themselves in will opt for both feet. It needs independent academics like Robert Gibbons to  wade in and put a stop to their self-injurious behavior.

The give away that this is a May Fool’s Day joke is that very few articles in recent years in the psychiatric or any other literature have received such withering critique as the Gibbons’ articles to which The Scientist refers – see for example the sequence from April 14 to 16 by boringoldman. The journal’s fact checkers would never have missed this, and by picking such an egregious piece are clearly letting us in on the joke.

High parody

There is high parody here in that of course Gibbons didn’t have access to anything the original authors of the Prozac papers didn’t already have access to, in that the original authors were all company people with presumably even fuller access than Gibbons was later given. Gibbons has also managed to avoid incorporating or otherwise handling data in the public domain that could be readily accessed anyway that show incontrovertibly that Prozac and Effexor can not only trigger suicide but that on balance the harms outweigh any benefits. By ignoring relevant accessible data in favor of data no-one else has access to, there is here an almost complete inversion of the standard access to data argument.

In the new spirit of openness and perhaps to continue the joke, The Scientist might consider asking Dr Gibbons to make his data fully available on the journal’s website. Or Dr Gibbons could be invited to chair an interview panel to recruit academics to whom companies would be prepared to make data available in the manner Lilly and Wyeth have done in this case.

Hey guys, get with it…

There may be an unexpected sequel to this joke. A scandal brewing over the Gibbons’ articles – some unreconstructed academics it seems just don’t “get it”. Not only are Gibbons’ data inaccessible they complain but it seems criticism of the Gibbons’ paper is out of bounds. The Archives of General Psychiatry has steadfastly refused to publish letters from a number of groups pointing out the lethal flaws in Gibbons papers.

Perhaps these critics should relax a little – it’s not as though much is at stake with data as old as these trials dating back in some cases to the 1980s – and entertain the possibility that following the lead of The Scientist, the Archives’ steadfastness may be a case of trying to draw the story out to have something ready for May 1, 2013. If all journals were to follow suit, May 1 could rapidly become the day most academics gear their year around.

What has the great scriptwriter in the sky in store next?

May Fool’s Day appears to have arisen out of a misreading of Chaucer. The tradition of practical jokes stemmed from his tale of how, even though he knew trusting foxes was not a good idea, the vain cock Chanticleer was tricked by a fox. Chaucer gave Chanticleer a second chance – let’s hope the great Scriptwriter in the Sky has written in a reprieve for the rest of us.