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...]

Author Archive for David Healy

Pandemrix and Narcolepsy

Editorial Note: In Pandemonium and Pandemrix the question was when and what basis is it possible to agree with an obviously smart women, as AM is, that there must be a link between the Pandemrix she was given and  the narcolepsy she ended up with.  No one really tackled this head on.

The answer has to be that if she and other smart people figure there is a link in their cases, there likely is. There are other factors that can be taken into account, such as whether anything else happening at the time might have played a part, but for the most part sensible people are largely right when it comes to adverse effects.

But rather than go with AM’s hunch, we turn to epidemiologists or other merchants of doubt to tell us whether there could be a link or not.  This post covers another way into the issue. 

In  a Guardian article two months back Dreaming of a Cure  Henry Nicholls wrote:

Sleeping on the Job

One of my first jobs was to keep a lookout for lions. There are some occupations that are not suitable for someone with untreated narcolepsy and this is probably one of them. I was 22, a recent zoology graduate studying meerkats in the Kalahari desert in South Africa. We worked in pairs, one of us on foot, walking with meerkats, the other in the jeep scanning the horizon for danger. On many occasions, I awoke with the imprint of the steering wheel on my forehead, realising that meerkats and colleague had wandered out of sight. I would look for signs of life and, as the panic grew, signs of death. I can tell this story now only because no one got eaten.

I have not always been like this. For the first 20 years of my life, I had a healthy relationship with sleep. Shortly after my 21st birthday, though, I began to experience symptoms of narcolepsy, a rare disorder thought to affect about one in every 2,500 people. If people know one thing about narcolepsy, it’s that it involves frequent bouts of uncontrollable sleepiness. This is true, but the condition is so much more disabling, often accompanied by cataplexy (where a strong emotion causes loss of muscle tone and a ragdoll-like collapse), trippy dreams, sleep paralysis, frightening hallucinations and, paradoxically, fractured night-time sleep. There is no cure. Yet.

A lot has changed in 20 years. There is now overwhelming evidence that by far the most common cause of narcolepsy is an autoimmune attack, where the body’s immune system mishandles an upper respiratory infection and mistakenly wipes out the estimated 30,000 neurons in the centre of the brain. In an organ of up to 100bn cells, this might not sound like too much to worry about. But these are no ordinary cells. They are found in the hypothalamus, a small, evolutionarily ancient and important structure that helps regulate many of the body’s basic operations, including the daily seesaw between wakefulness and sleep. The cells in question are also the only ones in the brain that produce orexins (also known as hypocretins).

The Doberman Guide to Narcolepsy

In April 1972, a  poodle in Canada produced a litter of four. One of them, a silver-grey female called Monique, soon developed what her owners described as “drop attacks” when she tried to play. These did not look like sleep; they were mostly partial paralyses: her hind legs would go weak, her bottom would slump to the floor and her eyes would become still and glass-like. At other times, particularly when fed, Monique would be struck by a full-blown attack.

When vets at the University of Saskatchewan observed Monique, they suspected these were bouts of cataplexy, and hence figured this might be a case of narcolepsy with accompanying cataplexy. As luck would have it, Monique’s diagnosis coincided with the arrival of a peculiar circular from William Dement, a sleep specialist at Stanford University in California. He was on the lookout for narcoleptic dogs. The Saskatchewan vets wrote back to him immediately.

“Monique is very likely to collapse when she’s eating something she especially likes, or when she smells a new flower outside, or romps around,” Dement’s colleague Merrill Mitler told the Associated Press for a story that ran in dozens of US newspapers. “We hope to discover exactly where in the brain the dysfunction occurs that causes narcolepsy,” Mitler said soon after Monique’s arrival at Stanford. “This could be the first step towards developing a cure.”

I ask Mitler if the story of the discovery of narcolepsy is really as good as it appears. “In a word, yes,” he says. “In the 70s, we didn’t know what we didn’t know about narcolepsy.” There is simply no way anyone could have anticipated how profitable the research into Monique and other dogs would turn out to be. The plan at that stage, he admits, was simply to use the animals to test new drugs that might improve treatment of the symptoms and to carry out autopsies in case there were some obvious physical changes to the brain.

Word began to spread, and soon Dement and Mitler were looking after Monique and several other narcoleptic dogs. The fact that narcolepsy appeared to be more common in some breeds than others suggested there could be some kind of genetic basis to the disorder. Then came the breakthrough: a litter of around seven Doberman puppies, all of them with narcolepsy and cataplexy. “Within 24 hours or less we saw the first of the litter and then the last of the litter all collapse,” says Mitler. “There was a large group of us at Stanford and we collectively had our chins on the floor.”

It turned out that in labradors and dobermans, the disorder was inherited. Dement made the decision to focus on dobermans and, by the end of the 1970s, he was the proud custodian of a large colony and had established that narcolepsy in this breed was caused by the transmission of a single recessive gene. By the 1980s, methods of genetic analysis had advanced just enough to contemplate an effort to hunt down the defective doberman gene.

Auto-Immunity

I can never reconstruct the combination of factors that led to the onset of my own narcolepsy, but the stage was set at the moment of my conception in 1972, at around the time of Monique’s birth in Saskatchewan. I inherited a particular version of a gene (known as HLA-DQB1*0602) that forms part of a set that helps the immune system distinguish friend from foe. HLA-DQB1*0602 is pretty common – around one in four people in Europe has a copy – but it plays a key role in many cases of narcolepsy, and is present in 98% of those with narcolepsy and cataplexy.

While other infections during my childhood, hormonal fluctuations and emotional stress may also have played a part, it was in late 1993 that I probably encountered a key pathogen – an influenza virus or streptococcus perhaps. It was this that took me to an autoimmune tipping point and resulted in the dismantling of my orexin system. In short, most cases of narcolepsy are probably the result of an unfortunate combination of events.

How do Cataplectic Dogs… ?

Most people with narcolepsy also have cataplexy – a state were a strong emotion from laughter to fear can cause a paralytic response so that the person might slump to the floor for instance leaving others thinking they have had an epileptic attack.  They also have hypnogogic and other hallucinations – which is where the featured image comes in.

Around this time, the doberman project in Stanford was on the verge of unravelling the genetic basis of narcolepsy. The man responsible was Emmanuel Mignot, who succeeded Dement as director of the Stanford Center for Sleep Sciences and Medicine.

Back in the 1980s, the idea of locating the gene for canine narcolepsy was off-the-scale ambitious. Breeding narcoleptic dobermans is harder than it sounds, as the afflicted tend to topple over mid-coitus, temporarily paralysed by a cataplectic thrill (a so-called “orgasmolepsy” that can occur in humans too). This impracticality aside, there was also the task of locating a gene whose sequence was not known, in a genome that was, at the time, a no-man’s land. “Most people said I was crazy,” says Mignot. It took him more than a decade, hundreds of dogs and more than $1m. And he was nearly beaten to it.

In January 1998, after more than a decade of painstaking mapping, and just as Mignot’s team was closing in on the gene, Luis de Lecea, at the Scripps Research Institute, and colleagues published a paper describing two novel brain peptides. They gave them the name “hypocretins” – an elision of hypothalamus (where they were found) and secretin (a gut hormone with a similar structure). They appeared to be chemical messengers acting exclusively inside the brain.

A team led by Masashi Yanagisawa at the University of Texas independently described the same peptides, though they called them “orexins” and added the structure of their receptors into the bargain. They speculated that the interaction of these proteins with their receptors might have something to do with regulating feeding behaviour. “We didn’t even think about sleep at all,” admits Yanagisawa, now director of the International Institute for Integrative Sleep Medicine at the University of Tsukuba in Japan.

By the spring of 1999, Mignot and his team had worked out that the recessive mutation had to lie in one of two genes. When he got wind that Yanagisawa had engineered a mouse lacking orexins that slept in a manner characteristic of narcolepsy, the race was on.

In weeks, Mignot and his team had submitted  a paper revealing a defect in the gene encoding one of the orexin receptors. “This result identifies hypocretins [orexins] as major sleep-modulating neurotransmitters and opens novel potential therapeutic approaches for narcoleptic patients,” they wrote. Yanagisawa and colleagues added their experimental evidence to the mix two weeks later in the same journal.

Under normal circumstances, a chemical messenger and its receptor work a lot like a key and lock. A key (the messenger) fits into a lock (its receptor) to open a door (cause a change within the target cell). In the case of Mignot’s Dobermans, a massive mutation had effectively jammed the lock of the orexin receptor, rendering the orexin useless.

Whether it’s the lock that doesn’t work, as in this case, or that the keys are missing, as they were in Yanagisawa’s mice, the upshot is the same. The door won’t open. The orexin system is broken. In human narcolepsy, there are many ways to break the orexin system. Occasionally, a brain tumour or head trauma is sufficient to do the damage. In most cases, however, narcolepsy is caused by the series of unfortunate events outlined above.

The orexin neurons are a very big deal, and not just for those like me who have lost them. Present in every major class of vertebrate, they have to be doing something seriously important.

When mouse neurons release orexin, all of a sudden, the mouse wakes up. When they stop, it falls asleep as rapidly as it woke.

In most other neural networks, there are parallel and multiple layers of security, so if something isn’t working properly, there are systems that can step in and pick up the slack. In the case of the orexins, however, there appears to be little or no backup at all.

What we now know about orexins also helps explain why losing just a few tens of thousands of cells should result in a disabling, multi-symptomatic disorder like narcolepsy – something that messes with wakefulness and sleep, body temperature, metabolism, feeding, motivation and mood. These proteins are giving us a privileged insight into how the human brain does what it does.

Belsomra

The pharmaceutical industry has not ignored the discovery of the orexin pathway. Within just 15 years of the publication  that linked a loss of orexin to narcolepsy, Merck had received FDA approval for suvorexant (Belsomra is the trade name), a molecule capable of getting through the blood-brain barrier and blocking orexin receptors.

A drug that promoted sleepiness was not the application that most people with narcolepsy were looking for. By preventing the orexins from binding to their receptors, Belsomra effectively creates an acute case of narcolepsy, but where the fog, ideally, will have started to lift by the morning.

The applications of Belsomra may be wider still, with clinical trials proposed to investigate its potential to help shift workers sleep during the hours of daylight, improve the sleep of Alzheimer’s patients, help those suffering from post-traumatic stress disorder, combat drug addiction and ease human panic disorder.

Pandemrix

Editorial Note: This second section comes from other sources

In an attempt to battle the 2009 swine flu pandemic, two separate pharmaceutical companies developed vaccines for the causative H1N1 strain: Pandemrix, produced by GSK, and Focetria, created by Novartis.  Following Pandemrix use there was  arise in cases of narcolepsy that didn’t happen after Focetria, which was manufactured using a different H1N1 strain. The association was too strong for even GSK to ignore.

According to a new study the vaccine can trigger the generation of antibodies that targeted both the virus and a population of brain cells critical to the regulation of sleep-wake cycles.

This finding supports ideas that narcolepsy may be the result of an autoimmune reaction, where the body accidentally attacks itself. These suspicions were aroused after scientists discovered that a significant portion of disease sufferers possess a genetic variation within a family of immune molecules that distinguish foreign invaders from the self. Additionally, narcoleptics seem to generate higher levels of antibodies to pathogens following infection.

Another important observation is that the brains of narcolepsy patients seem to have fewer neurons responsible for the generation of a signaling chemical called hypocretin that, when attached to its corresponding receptor, helps maintain wakefulness. Consequently, narcoleptics also have less hypocretin in their brains.

So what could it be that is joining all of these dots? It turns out that a chunk of one of H1N1’s proteins closely resembles a portion of the hypocretin receptor. While this protein was found in both vaccines, it was present in significantly higher concentrations in Pandemrix.

This suggests the antibodies generated as a result of the vaccine could be cross-reactive, meaning they stuck to both their viral target and the hypocretin receptor. If this turned out to be the case, it could mean that the antibodies were triggering an autoimmune reaction.

To probe this hypothesis further, the researchers examined the blood of 20 individuals who developed narcolepsy following immunization with Pandemrix and compared them to six controls vaccinated with Focetria. Piecing together the clues, they found that 17 of those in the Pandemrix group had abnormally high levels of hypocretin receptor antibodies, whereas the controls did not.

The suggestion therefore is that in those genetically predisposed to the condition, the H1N1 protein that was present in high levels in Pandemrix, but not Focetria, successfully triggered the production of antibodies to the virus, but that these also bind to the hypocretin receptor. This could ultimately drive a targeted immune response towards the hypocretin cells, triggering their destruction, disrupting the regulation of sleep-wake cycles.

Editorial Notes:  So why this detour through biology?  In cases like AM’s outlined last week, the story should convince most people in its own right – down to the benefits of Prozac.  Prozac and other SSRIs are hugely helpful for the cataplexy that is an integral feature of a lot of narcoleptic syndromes.  Facing Prozac in a narrative like this though, people will mistakenly wonder about the mental stability of the person affected.  In this case the Prozac detail helps confirm there is nothing mentally wrong with AM. 

But we doubt individuals these days and rather than work with them, we look to outside sources.  Governments and others turn to epidemiologists, who specialise in pointing out that smoking couldn’t be causing cancer because people are smoking more and living longer now (in the 1960s) than they were in the 1920s.  There will always be an annual incidence of narcolepsy in which any new cases can be hidden.   

This turn to doubt is unfortunate not only because of the harm it does to AM but also because we will ignore what she is showing us about ourselves – who knew that our dreams can go on for forty minutes or more and end in a gift shop on the second floor. 

Life and healthcare would be very different if everyone who walks in through the door was a potential researcher – or a research couple: AM and her partner – rather than a burden. 

Pandemonium and Pandemrix

Editorial Note: At the heart of RxISK is the idea that if something goes wrong for you on some medication you are the person best placed to know if there is an issue.  But again and again when people raise a problem they find they are invalidated – nonsense, rubbish, its your illness or whatever.  

If it is pointed out medicine had the same response fifty years ago to mothers whose infants were unwell – she was seen as neurotic – but we’ve learned now to run with the mother’s instinct, and a question is asked – why is an adverse event so different? – the response is usually well if this was case you’d have to believe all those people who claim they have been injured by a vaccine and we’d have pandaemonium. 

In the case below, which involves the Flu Jab Pandemrix, the question is how do we go about establishing if this is a case of vaccine induced injury or not? 

Before the Jab

I had all the normal childhood illnesses and vaccinations. I had rubella and BGC as a teen, and a few tetanus jabs, all without adverse effect.

I later had two pregnancies to term, all wisdom teeth removed, an operation to remove a bursa on my hip following a fall that hurt my back and made me walk wonky, all without problems.

Before I was given Pandemrix I was working for the Department of Work and Pensions and running a small online business. Busy life, busy mum but this was just “normal”.  I was good. I was twice call handler of the year for the whole South East, constantly getting vouchers for going above and beyond, getting all the great and the good sitting to listen in with me on visits.

Jab

After I got the jab I immediately became ill with a severe flu like illness. I had two weeks off work. The time afterwards has become a blur as to diagnoses as no one knew what was wrong.

I was so tired.  Coming in from work at two, I would fall asleep till teatime. After tea and the kids had gone to bed I’d nod off on the settee. All I seemed to do was sleep. I worked term times and I remember coming back to work after the Summer holidays and my boss asking the usual did I have a nice holiday and me replying that all I seemed to do was sleep. I used to go to the loo if I felt myself falling asleep. Endless walks to the photocopier. I reduced my hours, went home early. Work became a disaster.

Everything ached.  After much coming and going to my GP I was referred to rheumatology. They said I had fibromyalgia. Maybe I do but this didn’t help or solve anything.

I took Prozac 20 mg because for 3 or 4 days a month I turned into a very different person fuelled by PMT. It was like switch being flicked.  I would go mental for a few days and flick back to me again. I used to write letters to people and organisations if something offended me. I went to the Docs after I chased someone in my car who I felt had cut me up and sat revving outside their house like something from Duel.

As I am the type of person who never puts her head above the parapet I knew I needed to resolve this and the Prozac did help.

Deeper and Down

Then I started hallucinating sounds, specifically our buzzer.  I would get up in a panic usually around four in the morning to answer it. I would try to get the kids up thinking we had slept in.

I was becoming forgetful, not recalling conversations or events. If I fell asleep on the sofa of a night watching a programme I would wake not knowing I had fallen asleep with my brain filling in detail that didn’t exist.  I dropped things a lot. I could be seen staring off into space. I flooded the flat downstairs twice leaving the kitchen tap running. I had a small kitchen fire after turning the hob onto an electric chip pan I had left there to cool. There were multiple similar leaving the cooker on events where I just damaged things without setting fire to anything. Thank goodness for smoke alarms.

At night my dreams were becoming very vocal.  I would often talk for up to an hour. My partner still talks about my lecture on a hydro energy plant where after about 40 minutes of my guided tour I said that “and on the second floor there will be shops”.

I seemed to be going to the GP every month. Apparently, I was depressed now. I didn’t feel depressed but I had no knowledge of mental health and assumed he knew better. More Prozac and now amitriptyline on top.

What was making me depressed was that I had no control of all these things happening to me.  I thought for a time I was getting early onset dementia or something.

I recall one such GP visit where I had gone in with my usual I am tired, everything hurts, I keep falling asleep and I was given more Prozac. I was due to drive to Birmingham and I was worried about this. I told him I was falling asleep driving, hoping he would tell me not to drive or take note or do something, anything because I was panicking inside about what was happening to me. I got platitudes and was shown the door.

A few months later I was signed off work – “depression”.  All I did was sleep.

Going to my GP was largely pointless but I did it anyway because I knew there was something wrong with me. I didn’t know what, and he seemed to see a woman in her forties, Prozac, bang, out the door.

Lightbulb

My GP was off and I saw a lovely young doctor who listened and almost her first question was about my sleep. Did I snore? Sleepwalk? She referred me to a Sleep Studies unit.

It was not a quick process, the appointments were slow to come and the first two sleep studies were “inconclusive”.   I later found out this meant they had not recorded enough sleep time.  On the third one, they came in the morning and told me that I had not slept.  I said no, you are wrong, I slept great.  They were puzzled and asked – so you thought you slept?  I stayed all day and was put in a room for 15 minutes and watched still wired up etc. I fell asleep within minutes each time.

So, about a year after being referred I was diagnosed.

  • Sleep Apnea
  • Narcolepsy
  • Periodic limb movement disorder
  • Night terrors
  • Restless legs

Meanwhile, I had lost my job. My daughter told Andy, my partner, that I was hitting myself in the car and had all the windows open to stop falling asleep taking her to school and still I kept hitting curbs. So I had to stop driving.

Life?

Having the Pandermix flu jab changed everything in my life. I don’t have a life now. I have an existence which I hate. I try not to dwell on it because hey, I’m not dead but it is hard. I think what makes it worse for me is that the jab was given to me at work. I worked for the DWP. I have done various freedom of information requests but apparently the jab never happened and none of my records exist anymore.

So here I am. Hitting 50 next year, trying to work self-employed. Having the indignity of applying for support payments to the agency whose reports to the DWP saying I was unfit for work and unlikely to ever be so got me fired. But still they make me go to interviews and then write to tell me how capable I am.

I can’t be left alone. The narcolepsy is bad enough but the sleep apnea on top means that if I fall asleep, I could choke and die because I should wear a Bpap mask when I sleep. So I am babysat if my partner goes out.

I have just got the brace off my leg from when I fell down the stairs in August in my sleep when I went to answer the non-existent doorbell.

I sleep on the sofa a couple of nights a week to give Andy a break from my talking and general night mentals. I hate going to sleep knowing I am going to disturb him. Aside from the talking, and  skipping, running, and fighting, the night terrors are bad. It is as though I am in absolute mortal terror . I can’t talk. No words will come out but I get up my courage to give one massive scream or shout.  He is 11 years older than me and I am convinced I will give him a heart attack. One time, my dog wet herself and hid under the bed.

My night-times are worse if I overheat so have a fan right next to me and windows open.

I won’t go out in case I fall asleep as often my sleep talking quickly becomes sleep tourettes with very loud, very bad language.  If I get too animated my speech slurs. If I am fighting sleep my speech slurs and my neck and face muscles go into cataplexy.

One of the most painful things this condition has caused me was that it meant not going to see my once timid daughter, who got a scholarship to a really top school giving her speech as head girl on leavers day.  How could I go and risk being an embarrassment?

Treatment

I take Ropinerole/Requip for the restless legs. It has been an absolute godsend. Took a while to get used to but it has genuinely been a lifesaver.

I take Modanafil but over time this has become less good. Other stimulants haven’t been any better. Modanafil caused my BP to soar – up to 230.

I have been offered Xyrem but I don’t want it. As far as I understand, once you are on that there is no where else to go. Like a drug of last resort.

I don’t know if it is harder to treat me because I am older than people with younger onset Narcolepsy. No one really tells me that. From my own perspective it is worse, because I know what I once was and what I have become. I imagine it is like going blind after having sight. Cruel.

Vaccine Caused?

So imagine you are back in 2009 when Pandemrix was being given to prevent Swine Flu.  How do you respond to this woman if she raises a link between her Narcolepsy and her Flu Shot?

The authoritative response was – there is no link.  Does all Hell (Pandaemonium) break loose if we don’t believe the authorities?  What kind of evidence, if any, might be used to stop people from closing down a sensible debate about these questions?

A Call to H*ARMS

Editorial Note:  This is the fourth and final post in the Trick or Treat series that started with Vampire Medicines. These posts need to be read linked to the RxISK MAP posts. These are the theoretical background.  The MAP posts are the practical – what needs to be done posts.

Access to Medicines

In the 1980, we faced one of the greatest medical crises of any century – AIDs.  At its height the epidemic was claiming 50,000 deaths per year in the US.

Facing the AIDS epidemic, some called on Homosexuals to change their lifestyles.  But AIDS was caused by a human immunodeficiency virus (HIV) rather than lifestyle issues.

The answer lay in developing a science base and producing treatments. The treatments that emerged have arguably been the only decently effective treatments that have been developed in the last 40 years with the exception of Glivec.

One the extraordinary things about the response to AIDS was how the homosexual community embraced the stigma and mobilized around finding a cure.

Another extraordinary feature was a celebrated Access to Medicines campaign that took shape around 2000, when it became clear the greatest number of cases were in underdeveloped regions of Africa, and that these patients were being charged First World prices.  Campaigners led by Bill Haddad, Jamie Love and Yussuf Hamid, working to ensure access to these life-saving treatments at affordable prices, drove the price down from from $50 per day to under 50 cents.

It was one of the greatest triumphs of the human spirit and an example of what medicine and the pharmaceutical contribution to medicine could be all about.

There is a less inspiring Access to Medicines campaign under way at present, with European politicians mobilizing to control the cost of the latest drugs to hit Western markets – drugs of much less benefit that the Triple Therapy AIDS cocktails.

Access to Real Medicines (ARMs)

Starting around 1980, a new virus emerged that has led to a new and lethal and global epidemic.  One drug group alone, the opioids, now causes 50,000 deaths per year in the US.

Treatment induced drug wrecks are the leading cause of death and disability on the planet. Studies suggest treatment accounts for up to a third of deaths in hospital settings, where deaths may be caused by chemotherapy or the cardiac effects of drugs but will be put down to cardiovascular causes or cancer.  The drug induced death rate can only be greater in community settings where most deaths occur and where people are less likely to have conditions that can be blamed as the cause.

As for disability rates, roughly 1 billion people are on SSRI and related antidepressants in Western settings – that’s 1 billion people with their sexual functioning disabled.  If only 0.1% of these get PSSD or PGAD, that’s 100,000 people with their sexual functioning possibly eliminated forever.  This is the disability toll from only one drug group and one set of problems.

Faced with a Drug Wreck epidemic, the medical establishment is playing a moral card and calling on doctors and patients to change their lifestyles – diagnose less and treat less.

The answer lies in restoring a science – adverse eventology.  And in creating a climate where adverse events can be recognized and people can be got off treatments if they are maiming and killing them – something that is increasingly impossible to do at the moment.

The Drug Wreck epidemic is caused by a clinical immunodeficiency virus (CIV) whose primary mode of transmission is through major journals like BMJ, NEJM, AJP, through which it takes out the white cells of adverse event knowledge.  See Vampire Medicines and Raiders of the Lost Drug Wreck.

No doctor willingly harms patients.  If she dishes out drugs it’s because she has not been told about the harms, or has had them dissed.  No patient would take chemicals glibly – but this is what is happening increasingly as the information needed to manage the risks linked to the chemicals we take has been steadily degraded.

The reason drugs are being dished out and taken on such a massive scale is because the harms have vanished. RCTs are one reason for this. Drugs have 100 effects.  Most of them vanish in RCTs, leaving us with Vampire Medicines – actors without a shadow.

Another reason is journal funk. Our major journals are scared shitless and will not publish anything hinting at any treatment harms. Because of journals and RCTs, doctors have stopped listening to or looking at their patients – if the adverse events aren’t recognized in places like our journals it is more than a doctor’s life is worth to notice them. We might be sitting in front of our doctors but we are effectively invisible.

The hiding of harms has contributed to a growing medical nastiness, when we raise them. Faced with adverse events, some doctors get very nasty. Sensing this, and having no way to know who will and who won’t get nasty, we become increasingly nervous to mention adverse events.

Just as in 2000 the world needed an Access to Medicines campaign, we now need an Access to Real Medicines campaign. The core message of this campaign would be that a Medicine is a chemical plus information and without full access to all the information we don’t have access to the Medicine. The chemicals have always been and will always be risky.  The information component has been steadily degraded since 1980 making today’s medicines riskier than the treatments we had back then.

This campaign would be about saving lives on a global basis rather than just in parts of the underdeveloped world.  The wealthy of America and Europe are probably at greater risk than anyone.

Battle Plan

  1. Insist on access to data. No company claim to be based on science should be acceptable without access to data.
  2. Doctors should refuse to prescribed medicines where there is no access to the data.
  3. Patients should refuse to take medicines when their doctors don’t have access to the trial data.
  4. Restore a Poison sign to all new medicines, and all medicines without data access.
  5. BMJ and other journals to tell their lawyers: We are publishing harms data, among which will be case reports and articles from shady customers like Jureidini and Healy – your job is to work out how to make that happen, otherwise, although we might be a successful business, we are doing harm and may need to wind up the operation.
  6. Work out how to shrink the drugs regulator back to food regulator size and make doctors aware of their regulatory role.
  7. Before thinking about independent trials, create an independent Harms/Safety body.
  8. In the absence of data (Cisparency) to enable us to judge whether possible conflicts of interest have been realized, concerns about conflicts of interest (Transparency) create a counter-productive moral panic. Conflicting views are an important element of what drives science forward and should be resolved by data.  Claims about conflict of interest should only feature exceptionally.
  9. Prepare for the day when robots that can learn take over prescribing.

 

Raiders of the Lost Drug Wreck

Editorial Note:  This post follows from Vampire Medicines and Cisparency and Transparency and links to Relationship Based Medicine on Rxisk.  The painting is of Joshua crossing the Jordan with the Arc of the Covenant – an image that catches the essential features of climactic scene of Raiders of the Lost Arc with Joshua in the Indiana Jones position.

In every generation, there is a slayer.  In this generation, s/he will probably be female.  She need not be a doctor.  She might work for a pharmaceutical company.  She could be a patient or a family member. She will likely be a woman, if only on a probabilistic basis, as more women are injured by medicines and more women are involved in the lives of people who have been injured and now more women are in medicine than men.  And as the BMJ has recently shown even in medical specialities, such as surgery, where until very recently it was common to hear it said women were just not suited, in fact they now do a better job than men. She might be the editor of a medical journal.

In-Diana, besides, looks much more like a girl’s name than a boy’s.

The Slightest Slope

Just as water flows down the slightest slope, so drugs flow at the slightest hint of benefit – in both cases the flow is inevitable unless there are bumps in the way. It’s a bit like taking an apple off a tree. Difficult not to.

Difficult not to, short of seeing the tail of a worm sticking out of the apple and wriggling.

This is where the harms come in.  There is no such thing as a Free Apple. Its only in paradise there are worm free apples. Down here at the very least they have pesticides on them.

Since the Fall, we have lived in a world of Good and Evil – where sometimes what seems like the greatest good turns out to be more harmful than helpful. We need to be alert and make judgement calls that balance harms. In medicine, we were making progress at balancing harms to the point where we could make a reasonable stab at using poisons to do good provided everyone knew what they were doing.

But since 1990 that balance has been lost and the divide between good and evil is getting more marked.  This might sound like a good thing but its not. We are increasingly ending up with fistfuls of medicines branded as All Good Zero Harms – Vampire Medicines. The systems most people now work in or seek medical help from with would shrink in horror from the idea of bringing good out of the use of a poison. We have infantilized. The infantilization is worse by systems that are becoming increasingly brutal to those trying to work within them and those seeking care from them.

Suffer the Children

One of the best symbols is what we are doing to children. There have been roughly 30 controlled trials of antidepressants in children labelled as being depressed – all negative. The Prozac trials the most negative of the lot.

Yet prescriptions for antidepressants are soaring among teenagers, especially girls, so that they may now be the most commonly prescribed drugs in this age group.

This is because of hints of efficacy and a sustained campaign to turn the evidence that there are harms – every trial done shows an excess of suicidal events on active treatment over placebo – into a “controversy”.  The average doctor has been led to believe this is just an arcane dispute among academics.  Nothing of consequence in the real world.

In the real world children’s mental health services are close to collapse because, despite money being poured in, children are waiting so long to be seen that given antidepressants by family docs – to help tide them over – they are attempting suicide while waiting. They then get seen by services who have no sense the suicide attempts might be drug induced and they get treated for something they don’t have.  Meanwhile, the money going into children’s services goes into screening, and auditors and managers rather than clinicians in an effort to ensure adherence to guidelines. The only reason things could be going wrong is non-adherence to the guidelines – guidelines that say give Prozac.

Get that Crucifix out of Here

Another place to see the problem is with vaccines.  BMJ have just bravely run a piece by Peter Doshi on the funding of vaccine propaganda groups. Few people other than Peter could have pulled off something like this.  Others would be too scared. Still the impression left is that everything would be fine if there were transparency about the sources of funding and conflicts of interest.

The real problem is that in vaccine-land its not possible to mention harms. There can be no discussion of the fact that HPV vaccine causes problems, flu vaccines are for the birds, the Swine Flu vaccine caused narcolepsy, hundreds are suing Merck as a result of the Shingles vaccine, and earlier iterations of the MMR were withdrawn because the authorities accepted they were causing problems.

Not only is there a denial that there could be any problems but vaccine proponents have become thuggish and fascist, with alt-health diatribes turning up in the most unexpected of places – the Guardian. It’s enough to make anyone who believes in vaccination despair. The analysis of the growing vaccine resistance in healthcare professionals pays no heed to this.  It scolds us for not telling the public that the safety of vaccines is monitored thoroughly – when this is self-evidently not true.

American Women

Medical academics now discuss company creativity at gaming efficacy in clinical trials – the way scholastics once debated the number of angels that might fit on the head of a pin.  But company creativity at gaming efficacy is like nothing compared to their creativity at gaming safety.  One of their best tricks is to get doctors and patients to report harms directly and independently to regulators.  You might have thought this would help but reporting adverse events to a regulator is like pouring water into sand.

This was brought out in two posts some time ago – American Woman and American Woman2.

An entire science has been lost here – the science of adverse events/ drug wrecks.  Doctors have no training in establishing when it is possible to say that drug X is causing problem Y.  They are told that RCTs tell them what a drug causes.

The irony of this is that with most drug wrecks the causal chain is commonly so clear, so lacking in ambiguity, there is no need for an RCT – PSSD and PGAD offer great examples of this.

We Need to Medicalize

Many well intentioned people think they are contributing to a resolution of this epidemic by getting involved in campaigns against Overdiagnosis and Overmedication (ODOM).  As things stand Overmedication Campaigns are like telling people they are a little Overweight – everyone agrees they need to change but, like Augustine of Hippo, they figure they will try to put it right but maybe not just yet. While everything works – is nutritious – or everything is good – like making a diagnosis – it’s difficult to stop feeding your diagnoses.

ODOM is like AllTrials – wonderful for industry.  It gives the “good guys” the feeling they are doing something while behind the fig leaf industry get to hide ever more transformations of medical culture and practice.  Centrally important to all this is that the proponents of ODOM or AllTrials be like BMJ and Fiona Godlee, its current editor, brave and beyond reproach and better again seen as trying to rein in industry.

But this won’t work. The only way the epidemic of treatment induced death and disability can be tackled is to return pharmacotherapy (not quite the same thing as medicine) to its roots which is that everything is a poison and physicians need to act accordingly.

We are Underdiagnosing the injuries being caused by treatment and Undertreating these injuries.  We need to medicalize the problem. A campaign to recognize harms and manage them would require a lot more cojones from journal editors, scientific advisers and consultants than we are currently likely to get from any of these sources.

Relationship Based Medicine

But medicalization is not just about recognizing harms.  It’s about managing harms in a relationship. We need to get back to a Relationship Based Medicine.  The relationship used to be authoritarian. It needs to become consensual. It needs to harness the abilities of those of us who as patients take risks with medicines to contribute not only to our own wellbeing but to the wellbeing of all.  A bunch of reasons why the slayer is likely to be a ….

Of course, doctors should probably also be told they are on the way out of business unless something like this happens.  If drugs work wonderfully well and are so free of harms, nurses and pharmacists would be much cheaper prescribers.

And looming on the horizon are robots that can learn. Pretty soon putting a robot in charge of prescribing for patients, providing they were granted leave to learn by killing a few hundred patients first, would lead to fewer people being injured and fewer dying than is happening at now.  If it was let learn rather than just follow a program, the first thing the robot would learn is to junk the evidence from RCTs.

Cisparency and Transparency

Editorial Note: This post continues Vampire Medicine and links to Reformation Day on RxISK and forthcoming posts – Here We Stand.

Between 2002 and 2004, giving antidepressants to teenagers and the risks of triggering suicidality became one of the most high profile issues in medicine.  Raising a profile should be the way to put things right but things are getting much worse.  The lack of access to services is leading to adolescents self-harming to such an extent this is now accepted by the British government as the area of greatest failure in Britain’s Healthcare System.

What’s gone wrong?

Blowing up the Fishpond

It was BBC’s Panorama and a Los Angeles law firm, Baum-Hedlund who initially raised concerns. Panorama threw a hand grenade into the mostly East Coast fish pond that was American medicine. This led to a series of FDA hearings in 2004, and a derailing of company plans to get their antidepressants licensed for children.

The central event was a document obtained by Panorama which revealed that Study 329, a trial comparing paroxetine, imipramine and placebo, had been negative but was going to be portrayed as positive.  New York State took a fraud action against GlaxoSmithKline.

The document crystallized recognition that close to every article on every on patent drug in any area of medicine was ghostwritten and there was zero access to clinical trial data.

Faced with this crisis, there were two obvious courses of action.

One was go after the docs who were willing to let their names be put on ghostwritten articles whose data they had never seen and who presented these data at meetings – for a fee.

The other was go after the data. In 2004, the British Guideline maker, NICE, considered the second option but funked it.

New York State thought they had secured a commitment from GSK to make the data available which would set a precedent for other companies.  But GSK ran rings around them, making some company authored study reports available that concealed everything about everybody that had anything to do with any of their trials.

The first was the sexy option.  It offered stories the media could understand – docs on company payrolls prepared to say anything. Everyone could understand Conflict of Interest and agree it was a bad thing. Chasing this fitted a zeitgeist which said all problems could be solved with Transparency.

The second was more difficult.  Unless you are involved in clinical care it sounds esoteric and geeky. It also risked blowing up a lot the guys we think of as the good guys like BMJ, Lancet, NEJM and JAMA. And it quickly became clear there would be resistance. Let’s call this Cisparency.

Stunned Amigos

When BBC threw their hand-grenade into the healthcare pond stunned fish floated to the surface. Baum-Hedlund picked the fish up and started dumping them on Congressional and Senatorial desks. Most of the fish were ugly and had thwarted data access stamped all over them. A few others were colorful eye-catching dudes.

The key desk turned out to be Senator Grassley’s, where a formidable woman, Emilia di Santo, ran the operation and an energetic staffer, Paul Thacker, got engaged.

Some colorful flashy fish called Alan, Marty and Charlie, the type to feature in Disney movies – a great title would be Three Amigos – caught senatorial or other eyes, rather than the uglier critters. There was nothing notable about the three flashy guys in terms of contributions to medical or mental health science, but at the time details about the conflicting interests of all three were tumbling into the public domain.  Charlie had become the poster boy for conflict of interest across medicine.

If you’re a Senator what’s not to like about a guy who was willing to let himself be featured on the front of a glossy publication as The Boss of Bosses with a question Is Charlie Nemo the most powerful man in psychiatry. Marty was the first author on Study 329, the trial that had kicked everything off, then on its way to becoming the most famous trial in medicine.

Nemo was a Harvey Weinstein like character, capable it seems of charm with those who played ball with him and of being a thug to others. Close to the entire field of US psychiatrists enabled him.

He was probably a greater embarrassment to GSK and other companies than he was to academic psychiatry. GSK could not have wanted him to behave like a loose cannon in the way he did. He was probably central to losing them the Tobin case, which led to Panorama interest, and a bunch of dead fish, which they are still grappling with.

Enter Stage Left

Because of the Toronto episode Paul Thacker called wanting to know anything if I could tell him about Nemo. I told him – nothing much apart from what is in the public domain.  I tried to persuade him Nemo was not the problem. He was irrelevant.  He could even do some good if he could be turned. He and some others like Stuart Montgomery could show us where some of the bodies were buried.  Chop their heads off and others would replace them.

PT wasn’t listening. Nemo had become too juicy a morsel to give up.  But very little came out of his investigations beyond what was already in the public domain.

Let the Sun Shine In

The collapse in August 2007 on the grounds of pre-emption of a Baum Hedlund lawsuit, centered on the suicide of a 13-yr-old boy while taking Paxil, coincided with the introduction in September of a Physicians Payments Sunshine Act by Senators Charles Grassley (R-IA) and Herb Kohl (D-WI).  This act aimed to “shine a much needed ray of sunlight on a situation that contributes to the exorbitant cost of health care”, according to co-sponsor Senator Charles Schumer (D-NY). It would require manufacturers of pharmaceuticals and medical devices with annual revenues of more than $100 million to disclose gifts or payments to physicians in any form, whether cash, trips, or other.

The most bizarre aspect of this was the idea that letting the Sunshine in would bring down drug costs – See Raiders.

But the Bill fit the perceptions of many ethicists, journalists and others that the root of the healthcare problem lay in payments to opinion leaders. Transparency was crowned king despite a complete lack of evidence of opinions being changed by payments.

This model locates opinion leaders as experts – the cream of the profession.  They are only the cream in the sense of being rich and thick. No pharmaceutical company wants someone who can think. The first qualification for being picked by pharma is to be mediocre, and the second is to remain on message.

The model views other doctors and patients as airheads who will rely on a few puppets made over as smart dudes to tell them what to think.  No one would pay any heed to what some cartoon puppets were saying were it not for the iron fist inside the puppets that has all too obviously silenced BMJ, JAMA, Lancet and NEJM – see Vampire Medicines.

The Benefits of Transparency

Baum Hedlund contacted Emilia di Santo again in 2007. It put the Ugly Fish back on her desk. While Grassley wrote to the Department of Health and FDA raising cisparency issues, the die was already cast.  The transparency fish were already sitting in their bowl, scales glinting in the bright sun light. Rather than chase cisparency, Grassley continued with the low hanging fruit of transparency, scooping up a number of other prominent psychiatric academics on the way none of whom seem to have been harmed by the attention.

Just this year Karen Wagner, one of those named and supposedly shamed became the current President of the American Association of Child and Adolescent Psychiatry, despite multiple depositions conceding her articles are all ghost-written and she wouldn’t know what to do with data even if she saw it.

On July 12, 2008, the New York Times reported:

“But now the profession itself is under attack in Congress, accused of allowing this relationship to become too cozy. After a series of stinging investigations of individual doctors’ arrangements with drug makers, Senator Charles E. Grassley, Republican of Iowa, is demanding that the American Psychiatric Association, the field’s premier professional organization, give an accounting of its financing.”

The following year APA voted Alan Schatzberg in as its President.

After a brief period under a cloud, Nemo moved from Emory to Miami and was welcomed into the bosom of places like London’s Institute of Psychiatry who know a thing or two about supporting people who have been vilified by the enemies of psychiatry. A President of the World Psychiatric Association in waiting?

On March 23 2010 Grassley and Kohl’s Physician Payment Sunshine Act was enacted as part of the Patient Protection and Affordable Care Act.

Sidelining Cisparency

The resolution of New York States’ fraud action against them in 2004 involved an agreement by GSK to post details of their clinical trials on their website. This led to a set of Clinical Study Reports (CSRs) for paroxetine trials in children being posted.

GSK also posted 3-7 page summary reports of trials in other therapeutic areas, including trials of their blood sugar lowering blockbuster, rosiglitazone (Avandia). Reviewing these summaries Steven Nissen, from the Cleveland Clinic, found an increased rate of mortality on Avandia compared to placebo. Avandia was withdrawn from the European market and restricted in the US. These data laid the basis for the Department of Justice to pursue GSK for both Paxil and Avandia.

In 2009. Peter Doshi from Johns Hopkins and Tom Jefferson from Rome, working with colleagues on a review of Tamiflu, Roche’s antiviral drug for influenza, became headline news, when the data they assembled suggested Tamiflu didn’t work.

Governments around the world had stockpiled billions of dollars’ worth of Tamiflu having been told it saved lives by reducing transmission of the virus, kept people out of hospital and got them back to work faster. Fiona Godlee and BMJ helped make Tamiflu a campaign for transparency.

Then in October 2012, facing criminal charges for promoting its antidepressants for unapproved uses and failing to report safety data about Avandia, GSK accepted a $3 Billion fine, then the largest settlement in a Department of Justice lawsuit.

Far from being on the back foot, just as they had out-maneuvered New York State in 2004, GSK took the initiative. They announced plans to make their clinical trial data available to researchers on a secure website, if an independent panel of experts agreed the research proposal met a scientific need – mature transparency.

A few weeks later, AllTrials was born. The idea might have begun with Fiona Godlee. The family present at the birth included Sense about Science, the Cochrane Collaboration, the Centre for Evidence Based Medicine, Iain Chalmers, along with BMJ and PLoS, with the lot now fronted by Ben Goldacre.

The AllTrials ask was for access to the protocols for all clinical trials. The impression given was that AllTrials was seeking access to clinical trial data. It wasn’t. It was named AllTrials rather than AllData. It supported proposals that might enable some investigators, approved by companies, to access certain efficacy data. Exactly what GSK were proposing.

GSK promptly signed up to AllTrials. Within a few months of a record fine in the US, Andrew Witty, GSK’s CEO, featured on the March 9 2013 cover of the BMJ hailed as the acceptable face of the pharmaceutical industry.

Spearing Nemo?

A few years later the time came to dump fish in a Chicago jury box in the Dolin case. Trying to spear Nemo wasn’t going to get anyone anywhere with a Windy City jury – he mightn’t have been visible in a Green River anyway.

It was the ugly brutes the jury got told about. GSK’s lawyers spent their time desperately trying to block any mention of Study 329 and trying to stop jurors seeing the harms data from paroxetine trials, or hearing about the ways the company had tried to thwart access to data.

GSK’ s lawyers went apoplectic at a mention of the idea that if you owe a bank a million dollars, you have a problem but if you owe a billion, the bank has a problem.  This could be reprized as – if Senator Grassley catches GSK out in a little lie – hidden payments to Nemo – GSK has a problem but if the entire thing is a lie Senator Grassley is fucked.

Transparency, efficacy and Nemo were irrelevant in Chicago. Its the Great White Lies about Harms that count, not a few little tiddlers.

To be continued..

Vampire Medicines

Editorial Note:  This is the first of four Trick or Treat posts.  They make most sense when read in conjunction with the RxISK Prize posts especially the series of 3 posts starting tomorrow.

In 1962 RCTs were added to the regulatory requirement for marketing medicines.  This looked like a definitive stake through the heart of hucksterism. No longer would we have to carry crucifixes and garlic around to ward off blood-suckers hawking ineffective remedies.

In 1962 doctors were viewed as the key element of the regulatory apparatus. A great part of their input centred on descriptions of the harms medicines could cause. In addition to news of the latest advances, medical meetings were filled with symposia and medical journals with articles on the harms of treatment and how to manage them.

Company funded RCTs, which played a minor part in clinical practice, were all done in hospitals and universities and academics had the data.

Around 1980, as new drugs got weaker and weaker, company trials became multi-centered, coordinated by CROs, written up by ghost writers, with academic names attached afterwards.  Everyone seemed as happy to enable this increasingly Hollywood like remake of medicine as they were to enable Harvey Weinstein.  In the process access to trial data was lost.

Richard Smith

The key event that marked a transition to the modern world came in 1990, when Teicher et al published 6 cases of people becoming suicidal on Prozac in the American Journal of Psychiatry.  According to all canons of causality, this paper offered undeniable evidence SSRIs can cause suicide. Hearings were convened to discuss the need for warnings.

But coincident with these hearings, BMJ published a meta-analysis of Prozac trials which Lilly claimed showed Prozac was not linked to suicidal events.  This paper had been rejected elsewhere, The BMJ reviewer was lukewarm. But Richard Smith, BMJ’s editor, perhaps spotting an opportunity to push a new kid in town, Evidence Based Medicine, and its shiny new meta-analytic machine, published.

The published data showed an increased risk on Prozac, which Lilly and BMJ ignored, claiming nothing was statistically significant.  Beyond this, Lilly played some of the tricks other companies later played – the small print shows the only placebo event hadn’t happened on placebo, so that technically there was a statistically significant  infinitely greater risk on Prozac.

The follow-up letters told RS he had been naïve and wrong. But no one accused him of conflict of interest. What could be wrong with letting good quality evidence (even though he got that wrong) triumph over anecdote?

The way this played in public was that the stories of suicides on Prozac were tragic but anecdotal.  The scientific evidence demonstrated that patients and doctors just can’t believe the evidence of their own eyes and ears. They have to be told what’s what by experts.

This dangerous and misguided message triumphed with regulators, and later in Courts.

This message killed any interest journals like AJP and BMJ had in taking Case Reports. Besides companies didn’t buy reprints of these, whereas they handed over huge amounts of money for reprints of ghost-written fraudulent RCTs with zero access to data, and even more for the best science money could buy – meta-analyses of these trials. Evidence Based Marketing was here.

Vampire Birth

A medicine is a chemical plus information. The information about the effects of chemicals should come primarily from practice on the ground, as in the early days of antibiotic or psychotropic drug use, or street drug use now, or from use of anti-retroviral combinations for AIDS in the 1990s.

When the benefit (not the harms) of a drug is equivocal, RCTs offer a means of examining efficacy ambiguities by focusing a magnifying lens on the ambiguity. They do this at a cost – ignoring safety.  They are an act of hypnosis that gets investigators to focus on one thing while ignoring everything else going on around them.

If we ignore the ignoring of safety, as we do, we compromise rather than enhance safety. The harms vanish. The drugs that come out of an RCT have no shadow – no harms.  They are vampire medicines. Put another way, all clinical trials (RCTs) cause harm but some can also be helpful. They pose the same problem AI and viruses do – if you create one, can you control the consequences?

Co-incidentally around the time vampires began to flourish, companies had poison symbols removed from medicines and from discourse.  Any mention of the celebrated medical wisdom that all medicines are poisons in an expert report will now be met by company motions to have the word poison struck as prejudicial.

Conflict Free Blood

If there was a conflict of interest involved in linking trials to regulation, it was born from hostility to pharmaceutical companies.

But it’s now clear that even if done by angels, RCTs are the gold standard way to hide adverse events.  Their intense focus on a primary outcome rather than the overall picture means that in even the most independent of studies they necessarily neglect adverse events.  Companies overlay a lot of creative hiding on this neglect but this is an extra source of difficulties not the primary problem.

It was doctors who used to go around with stakes. Regulatory bureaucrats never did. RCTs have made life easier for the bureaucrats.  According to the head of Britain’s MHRA, Ian Hudson, formerly of GSK, if events are not statistically significant – and strictly speaking as no adverse event is ever a primary outcome measure, they can’t be – then they aren’t happening.  BMJ helped consign stakes to the twentieth century.

If there was a conflict of interest involved in the move from RCT to Evidence Based Medicine (EBM), it was born from hostility to companies.

EBM was not unreasonable in the early 1990s but it has created a bandwagon that is now out of control contributing hugely to a conversion of poisons into fertilizers to be sprinkled as extensively as possible, from as young an age as possible.

If there was a conflict of interest involved in using trials to create Guidelines in the 1980s, it was born from hostility to pharmaceutical companies.

But now, if NICE and other Guidelines, based entirely as they are in the case of on-patent medicines, on ghostwritten articles whose data is inaccessible, hadn’t been created, Pharma would have to invent them.

Drug harms that took a year or two to come to light in the 1960s take a decade or two now.  In 2003 I predicted we were on our way to having lethal and common drug harms being contested years after the drug had gone off patent. In April 2017, the Dolin case in Chicago centred on just this issue – ten years after paroxetine had gone off patent.

These problems are not being contested because it is difficult to decide if a drug is causing a harm.  They are being contested because of the power of companies to shut down debate in journals like BMJ.

BMJ’s news item about the Dolin trial missed the key issues, and it wouldn’t have occurred to them they had a role in the development of the situation.

Rosemary’s Baby

If it was just one drug harm that might be fine but drug wrecks may well now be the leading source of death and disability on the planet.

BMJ helps this happen in its educational forums by making it clear for instance that giving antidepressants to minors is just fine – no mention of harms.

BMJ helps this happen in its educational forums by making it clear for instance that giving antidepressants in pregnancy – now the most commonly used drugs in pregnancy – is just fine despite a doubling the rate of birth defects and miscarriages and behavioural abnormalities in the children of those taking them.

Buffy the Vampire?

Richard Smith was succeeded by Fiona Godlee, as free of ties to industry as RS once was.

Starting with RS and then later with FG, I and others had a series of articles on drug harms rejected with an increasingly bizarre set of reasons offered for the rejections, and increasing involvement of BMJ’s legal department.

These rejections have two elements.  One is that across all journals anyone interested in a drug’s harms appears to be deemed ipso facto not just biased but perverted. It’s like wanting to publish something about sex around the time Dracula was written.

The second is anyone who has ever been in any way linked to a lawsuit as an expert against a company is deemed irredeemably conflicted.

For those of us working on the Restoration of Study 329, the review process became beyond odd. BMJ editors kept raising queries that had been answered and talking about conflict of interest.  To which our response was everyone is biased but the way conflicts are overcome in science is to turn to the data – it’s the data that reveals whether someone’s latent bias is operative or not.

BMJ just didn’t get it. My formulation up till then was that a belief conflict of interest is of supreme importance is incompatible with recognizing the importance of accessing the data.  This is still my view in the case of most of those who champion Sunshine.

But then a predicted legal review came into the 329 frame.

BMJ’s lawyers made it clear that if the journal had anything to do with Healy and Jureidini they would be providing GSK or other companies with grounds to claim bias and to sue. This is even though BMJ and GSK are partners in AllTrials and BMJ had a short while before featured Andrew Witty on its front cover as the acceptable face of pharma, helping GSK put a $3 billion fine behind them. Partnership?

BMJ is a business that can no longer support medical practice, a key part of which is describing harms. If a doctor is not prepared to go to Court to stand up for the harms she’s put her name to, she’s writing fiction – a bit like Bram Stoker saying in real life he doesn’t believe in vampires.

That the BMJ editor handling 329 was married to a man who worked for the law firm who defended GSK against a $3 billion Department of Justice fine didn’t seem to be any kind of conflict of interest.  But then patients who have committed suicide or homicide on these drugs aren’t going to sue BMJ.

When it comes to on-patent drugs, BMJ provide news stories about medicine, medical entertainment. They are less likely than the NY Times or BBC to check the integrity of their primary sources.

BMJ and all our major journals have been turned.

Oh for the Blood of a Teenage Girl!

Water and drugs flow down even the slightest gradient unless there is something in the way.

The BMJ got involved in the Tamiflu saga in 2009 making it the basis of a “transparency” campaign – see Cisparency and Transparency next week – and later AllTrials.

Tamiflu is an efficacy story not a harms story.  As Peter Doshi and Tom Jefferson accessed more and more efficacy data the efficacy of Tamiflu shrank to almost nothing. But it only takes 1% efficacy to sell pills provided there are no bumps in the way, and nothing has happened to dislodge Tamiflu from the top of the guideline heap for use in cases of Flu.

The story of antidepressants and teenage girls is even more remarkable. There are now 30 RCTs of SSRIs and related antidepressants for adolescents and children – 29.5 negative.  Fluoxetine/Prozac is the most negative of the lot – there are 7 trials in which it has failed to beat placebo on the primary outcome measure including the two that led to its licensing by FDA and MHRA and EMA.

Surely not – you thought Prozac worked for children.  Why have you not heard of this?  Same reason you never knew Harvey Weinstein was anything other than a nice guy – with the extra reason that whatever about other enablers, bureaucrats never ever admit they’ve made a mistake, and the academic media aren’t any better.

There is an excess of suicidal events on antidepressants in every one of these 30 trials. In the only notionally non-company trial, the investigators in 7 major publications in leading journals from this trial “managed to conceal” the 34 suicidal events on Fluoxetine versus 3 on placebo – this requires an Editorial Nelson to be not just blind in one eye but very short-sighted in the other.

The BMJ has done more than conceal harms. It “enabled” a transformation of these life-ending harms into a “controversy”, when in 2014 it published close to the shonkiest, most ridiculous article any major journal has ever published on anything – the Lu et al article.

There seems no point in submitting an almost entirely data-driven, opinion-free, article on what the trials in teenagers show to BMJ, even though antidepressants are now the most commonly prescribed drugs to teenage girls.

Even though last week, the British Secretary of State for Health declared adolescent mental health services the biggest single weakness in NHS provision.  The great concern is that teenagers are self-harming while waiting for access to secondary services – now why would that be?

A few weeks before, the grisliest case report ever appeared in one of the few media still concerned about primary sources (Panorama). It covered the killing of twelve people in Aurora by a 24 year old on an SSRI, Black Boxed up to 25.  This case report is totally backed up by the RCT data. BMJ played a stellar role in dissing any possible link to the drug – abetted by a posse of Psychiatric Association Presidents and ex-Presidents.

If on a Winter’s Night a Traveller…

With the creation of Dracula, Bram Stoker, a Dubliner, globalized the Celtic feast of Halloween. Both Dracula and Stoker left their place of origin and came to England.  When last heard of, Stoker was working a few blocks down the road from the BMJ office…

To be continued

 

If on a Winter’s Night a Traveler… Trick or Treat?

Its the end of October when every Irish person going back millennia  gets taken over by Halloween – not just the Celts, those who come and stay get bitten too, as Bram Stoker could tell you.

So there will be a series of 4 posts to mark the occasion, starting next week, previewed here.  These fit closely with the RxISX Prize posts and should be read in conjunction with them.

Not every title and subtitle will remain the same – and some still need to be inked in……

Vampire Medicines

  • Richard Smith
  • Vampire Birth
  • Conflict Free Blood
  • Rosemary’s Baby
  • Buffy
  • If on a Winter’s Night a Traveller….

Cisparency and Transparency

  • Blowing up the Fish Pond
  • Stunned Amigos
  • Enter Stage Left
  • Let the Sun Shine In
  • The Benefits of Transparency
  • Cisparency
  • Spearing Nemo

Raiders of the Lost Drug Wreck

A Call to H-Arms

 

It Couldn’t Happen Here: Consent to “Treatment”

The Boy in the Striped Pajamas is a pretty harrowing movie.  In brief a new SS Kommandant and his family come to a camp.  The Kommandant seems like a reasonable man.  His family seem very normal. His son makes friends with a boy behind the wire. They ultimately create a hole in the fence between them and get to spend time together.  Finally the Boy in the Striped Pajamas is ushered along with a moving crowd toward an onsite facility.  The whole thing happens as has been described – so chillingly – naturally.  So natural, his new friend follows him in.  The movie cuts to the Kommandant trying to find his son that evening.

The Girl in the Striped Pajama

A year ago a colleague had notice that the HPV vaccine would be given to all girls in her daughters school on such and such a day the following year.  A few weeks ago the information and consent forms came around.

The consent form stated that:

“Parents must act in their children’s best interests in considering consent and need to  recognize that children who fully understand the issues are legally able to make their own decision about consent”.

After being informed about sexual activity and cancer, the leaflet tells these 12 year old children:

“Its best to involve your parent or guardian but in some cases you can give consent for yourself if you are fully able to understand what is being offered”.

In Britain it is illegal for 16 year old girls to have their ears pierced without their parent’s consent.

Peers

Theresa and Amber were chatting in the playground the week before the injection was due. Theresa mentioned she wasn’t having the injection.  Amber was surprised and said she was.  Half an hour later, my colleague had a phone call from Angela, Amber’s mother, asking why Theresa was opting out.

So Natural

On the day, one of the teachers came to the door of the class room and read out a list of names.  The girls named filed out and followed the teacher to another room, where there was a nurse with a filing box.  When Theresa sat down, the nurse flipped through her file and said to Theresa I don’t seem to have a consent form for you but we can go ahead anyway.

It was only at this point Theresa realized that this was about the vaccine.  She said she and her mother hadn’t agreed. The nurse said that must explain why they didn’t have a form and said fine – she could go.

The Day After..

Half of the girls were off sick.  Some remained off school for the rest of the week.

At the end of the leaflet on HPV, 12 year old girls are told if they have any problems they should report to MHRA (the regulator). This is about as useful as telling a Boy in Striped Pajamas c 1943 to write to the Vatican.

 

Drug Bites Man

Editorial note:  This post follows up on Leonie Fennell’s post earlier this week – Dogs and Serotonin.  The follow up comes from a celebrated event that happened over a decade ago, reported as follows in the WSJ with follow-up comments.

What to Say in the TV Ads —- By Chris Adams, The Wall Street Journal

You might call it a made-for-TV drug. Approved for human use in the U.S. but not marketed that way, an arthritis medicine called Rimadyl languished for nearly 10 years in developmental limbo, then emerged in a surprising new form: Instead of a human drug, it was now a drug for arthritic dogs. And it became a hit.

With the aid of slick commercials featuring once-lame dogs bounding happily about, Rimadyl changed the way veterinarians treated dogs. “Clients would walk in and say, `What about this Rimadyl?'” says George Siemering, who practices in Springfield, Va.

Today, those TV spots are gone. The reason has to do with dogs like Montana.

A six-year-old Siberian husky with stiff back legs, Montana hobbled out of a vet’s office in Brooklyn, N.Y., six months ago accompanied by his human, Angela Giglio, and a supply of Rimadyl pills. At first, the drug appeared to work. But then Montana lost his appetite. He went limp, wobbling instead of walking. Finally he didn’t walk at all. He ate leaves, vomited, had seizures and, eventually, was put to sleep. An autopsy showed the sort of liver damage associated with a bad drug reaction.

Pet drugs are big business — an estimated $3 billion world-wide — and Rimadyl is one of the bestsellers. It has been given to more than four million dogs in the U.S. and more abroad, brought Pfizer Inc. tens of millions of dollars in sales, and pleased many veterinarians and dog owners. But the drug has also stirred a controversy, with other pet owners complaining that nobody warned them of its risks.

Montana’s owner, Ms. Giglio, is among them. After she informed Pfizer and the Food and Drug Administration of her relatively youthful dog’s death, Pfizer offered her $440 “as a gesture of good will” and to cover part of the medical costs. Insulted by the offer and a stipulation that she agree to tell no one about the payment except her tax preparer, she refused to sign and didn’t take the money. “There’s just no way in my conscience or heart I can release them from blame,” she says.

After reports of bad reactions and deaths started streaming in to the FDA, the agency suggested that Pfizer mention “death” as a possible side effect in a warning letter to vets, on labels and in TV ads. Pfizer eventually did use the word with vets and on labels, but when given an ultimatum about the commercials — mention “death” in the audio or end the ads — Pfizer chose to drop them.

Pfizer’s director of animal-products technical services, Edward W. Kanara, says that when reports started coming in, “we acted extremely promptly based on the information we had.” Pfizer points out that reported adverse events involve less than 1% of treated dogs.

Since Rimadyl’s 1997 launch, the FDA has received reports of about 1,000 dogs that died or were put to sleep and 7,000 more that had bad reactions after taking the drug, records and official estimates indicate. The FDA says such events are significantly underreported.

While the numbers include cases “possibly” related to Rimadyl, it is hard to be sure. Many dogs given the arthritis drug are older, and few are autopsied after they die. Pfizer says it analyzed cases of Rimadyl-treated dogs that died in 1998 and found a link to Rimadyl to be “likely” in 12% of cases and “not likely” in 22%; it says there was too little information for a judgment about the others.

Despite these problems, the FDA says Rimadyl deserves to be on the market, provided vets take the proper precautions. These include advising dog owners what bad reactions to watch for and periodically doing liver-function or other lab tests.

Within a few weeks, Pfizer will begin affixing a safety sheet directly to packages of Rimadyl pills. It is the first time either FDA officials or Pfizer can recall such a step being taken in the world of animal drugs.

Rimadyl — generically carprofen — is an anti-inflammatory medicine. Developer Roche Laboratories expected to market it for people in 1988 and received FDA approval, but shelved the plan after concluding the market for such drugs was too crowded. In addition, some outside experts expressed concerns; a commentary in a pharmaceutical journal noted unusual liver-function readings in 14% to 20% of test subjects and opined that “until additional data on carprofen are available, older compounds should probably be tried initially.”

The idea of switching the product to the animal-drug track soon arose. A couple of corporate transactions later, it ended up in the hands of Pfizer’s animal-drug unit. There, it was treated to the kind of sophisticated marketing Pfizer does well. A survey of 885 dog owners was done. Besides shedding light on favorite dog names (Jake, Ginger, Lady), the poll revealed that one-fifth of dog owners would be willing to spend “whatever it took” to buy an aging dog an extra year or two of life. No fewer than 53% agreed that “my dog is a better companion than other members of my family.”

The FDA requires safety and efficacy testing for animal drugs just as for human ones, but animal-drug tests are smaller. Pfizer says about 500 dogs got Rimadyl in various trials, which is no more than a fifth of the number of subjects in comparable human-drug trials. Some dogs showed unusual liver-function readings and one young beagle on a high dose died, but for the most part, the FDA and Pfizer didn’t find side effects alarming. The drug was approved for an early-1997 launch. That same year, the FDA made it easier to market drugs directly to consumers on TV.

Soon, Pfizer was running commercials in which a once-stiff yellow Labrador retriever named Lady bounded over a fallen tree as she fetched tennis balls beside a lake. In another ad, a dog leapt through a window and slid down a banister. There were also full-page magazine ads and a public-relations campaign, whose results, the PR firm later said, included 1,785 print stories, 856 radio reports and 245 TV news reports “generating 25.5 million positive impressions on the product.” Early on, vets were floored by the drug’s effects.

“The results in some cases have been pretty darn close to miraculous,” says David Whitten of the Hilldale Veterinary Hospital in Southfield, Mich. “I’m using this drug on my own dog. It has been effective. But as with all medications, side effects are certainly a problem.” Indeed, within months of the launch, vets at Colorado State University in Fort Collins noticed troubling reactions. Labrador retrievers seemed particularly affected. Since the safety studies for Rimadyl had emphasized testing on young beagles, Pfizer went back to conduct another, small test just on Labs; it says that test showed no particular problem.

Bill Keller, an FDA veterinary-medicine official, notes that “any time you take a product from the investigation and put it into actual practice, you’re going to see things you didn’t expect.” But reports about Rimadyl came in by the hundreds. The FDA had received just over 3,000 animal-drug bad-reaction reports in 1996, the year before Rimadyl’s launch; in 1998, the drug’s first full year, Rimadyl alone produced more than that many. They swamped the FDA’s tiny Center for Veterinary Medicine in Rockville, Md. Pfizer was scrambling as well. “Basically, their response,” says Dr. Keller, ” was `Tell us what you want us to do. We love the fact that it’s selling so well, but we don’t know what to do with all these adverse reactions.'”

The FDA and Pfizer discussed a “Dear Doctor” letter to be sent to vets. FDA records show the agency found parts of an early Pfizer draft “unacceptable as they are promotional in tone. . . .” It was revised. The records also show Pfizer disagreed with the FDA’s suggestion that the letter cite “death” as a possible side effect. To get the letter out, the FDA told Pfizer it was “agreeing to your exclusion of the ‘death’ syndrome from the letter at this time. However, we will revisit the ‘death’ syndrome issue and other potential side effects for possible inclusion in labeling at a later date.” So the term didn’t appear in the first warning Pfizer sent, in mid-1997.

Meanwhile, dog owners were asking for Rimadyl. “It was their advertising that sold me on the drug,” says Michelle Walsh, a Phoenix woman who says her miniature schnauzer was given it and later died. Not that vets needed much convincing. They saw clear benefits from the drug. On top of that, they could get points from Pfizer for each Rimadyl purchase they made; points were redeemable for PalmPilots, Zip drives for PCs and other equipment.

Although Pfizer’s letter told vets to explain to owners the signs of a bad reaction to Rimadyl, such as vomiting, lethargy or diarrhea, it is evident that a great many didn’t. The FDA’s Dr. Keller says, “There are a lot of veterinarians who don’t think they need to take the time, or who forget, or for whatever reason are not providing animal owners with this information.”

Donna Allen, whose chow-mix, Maggie, started on Rimadyl last summer, says, ” All my vet did was give me this little bag of pills, with no information.” She says Maggie “didn’t want to take it, but I made her.” After four weeks, Maggie began to vomit violently, Ms. Allen says. The dog vanished from their home outside Birmingham, Ala., and later was found lying in a ditch. Ms. Allen loaded her into a truck and sped 35 miles to a veterinary clinic, but the five-year-old dog died. Her vet wouldn’t implicate Rimadyl in the death until Ms. Allen urged him to send the dog’s internal organs to the University of Illinois vet school, where an examination showed liver toxicity. Maggie was buried under a marker adorned with the figure of an angel. And Ms. Allen took to the streets, delivering a letter to all the vets in the area urging them to “understand that Rimadyl helps certain dogs, but it is poison to other dogs.”

As the complaints poured in, the FDA told Pfizer it would have to revisit the label issue. Pfizer had referred to “fatal outcomes” on the label as a possible effect of the drug class to which Rimadyl belonged, but not specifically of this drug. Now the agency asked that Pfizer cite “death” prominently as a possible side effect of the drug. Describing the back and forth with Pfizer, the FDA’s Dr. Keller says, “They did it. They weren’t enthusiastic about it, but they have always been cooperative. And that’s part of the nature of the game we play with industry.”

But the FDA also wanted the word “death” in the audio of commercials. Pfizer indicated this “would be devastating to the product,” FDA minutes of a February 1999 meeting show. A company spokesman says that “putting ‘death’ on a 30-second commercial and in proper context was something we didn’t think was possible.” Rather than do so, it eventually pulled the commercials. Pfizer says it now will do traditional marketing to vets, making sure they know the proper way to use the drug.

Another “Dear Doctor” letter will soon go out, and the company will start attaching a safety sheet to pill packages. Pfizer acknowledges it has a perception problem with some dog owners; a consumer group, for instance, has mounted a campaign dubbed BARKS, for Be Aware of Rimadyl’s Known Side-effects. The company is contacting dog owners who have told their stories on the Internet, and it is offering to pay medical and diagnostic expenses for some dogs who may have been harmed by Rimadyl.

But Pfizer stands firmly behind the value of the drug, of which it says sales have continued to grow. Most vets also remain strongly behind Rimadyl. Owners, too, generally say they think the drug is important — they just want to know the risks. Atlantan Roger Williams gave his mixed-breed terrier, William, Rimadyl for more than a year and believes it contributed to the dog’s death. “But if I had to do it all over, I would give my dog Rimadyl again,” he says. “The difference is I would have known what to expect. Without Rimadyl, William was miserable. And what’s the point of living another three years if you’re miserable?”

Comments

Physician Assists in Own Dog’s Autopsy
“I was shocked after reading The Wall Street Journal article on Rimadyl. Now I know the reason for the death of my 8-year-old female Rottweiller Athenas. She had a problem in her right hind leg and was given Rimadyl for two weeks. She died two weeks later, with exactly the same symptoms as Montana (described in the article). My husband, who is a doctor, assisted the autopsy. He saw the liver lesions, and knows exactly what people are talking about. We believed that she had died of a liver cancer. But, here in Brazil, news on the side effects has not reached the veterinary community (if it has, they’re not telling). We were told this was a new ‘miracle’ pill. It breaks my heart to remember the agony of her last moments. It happened last October, and I can’t describe how much I still miss her. Please banish this murderous pill from the market!”
Celina McCall Fortaleza, Ceará,

WasTiny Pekingese Overdosed?
“If only we had been warned about the side effects of Rimadyl…….When our 5-year-old Pekingese jumped from a one-foot high wall, she herniated a disc in her back and was paralyzed in her hind legs. We immediately took her to the vet, and she was operated on a few hours later. She was put on Rimadyl (twice a day) and did very well, considering the right hind leg was very weak. Each time we called for a refill, it was prescribed without question. Our little Mie Ling lived almost two years on the Rimadyl. I noticed blood on her fur after urinating and took her to my vet who was concerned but put her on antibiotics for a possible UTI. He said we would monitor the urine and go from there. She died 5 days later. She was vomiting the night before she died. I blame myself for not being knowledgeable enough about what was happening to this poor little dog, but I also blame the vet for not monitoring her properly. If he didn’t know about Rimadyl’s side effects, he should have been educated so he in turn could educate his clients. I wish the side effects warnings had been noted on the label of the drug bottle. Because she was so young, I think her death is especially saddening. She was such a good dog and so full of spirit. We all miss her very much. I guess I can conclude that Rimadyl did give her mobility after the surgery, but it also killed her. I believe she was on a very high doseage — too much for such a little

Schnauzer “Alex” Survives, But Vet’s Own Dog Did Not
“Our Schnauzer, Alex, at 13 years 7 months, was slipping and sliding due to arthritis. Getting up and down was very hard for him. Rimadyl was prescribed beginning in November, 1999. Initially, he seemed to be less stiff and was definitely more active than in the months previous to the medication. As the “good” effect leveled off, we wondered about continuing the drug, but reasoned that if Alex was in less pain, it would be better to give it to him. On Friday, January 28, 2000, Alex walked towards me and literally fell over. His heartbeat and breathing were all very faint. Bowel control left, and we thought he was indeed dying. Our closest emergency animal hospital revived him with fluids, but could not even read his liver enzymes diluted 4 times. Alex stayed on an IV line all weekend, and by Monday was a little more stable. His liver enzymes were almost readable when diluted. A sonogram on the following Friday showed curious “thickened” intestines and some peculiarities in the liver and kidneys, but no tumors. The ‘internal medicine’ vet said that Alex’s diet should have less than 5% protein and under 4% fat. Alex refused to eat commercial preparations until I adapted a Hill’s homemade diet for restricted protein. Alex miraculously survived and actually loves his diet of mostly rice ad bread with a little meat and vegetable supplemented with vitamins and calcium. Somehow, I never trusted the Rimadyl and never gave it to him again. The Wall Street article on Rimadyl was indeed an awakening. One week of hospitalization and testing cost well over $1,000.00, but Alex is well worth the cost. We are upset that our vet didn’t know about the very bad effects of Rimadyl. His own dog, a well-loved Lab, died suddenly about two weeks before Alex got ill, and he was also on Rimadyl.”

Had WSJ Article Been Published Sooner, It Might Have Saved Casey
“We took our Labrador Retriever, Casey to the vet in the beginning of March because she had been limping when she rose from sleep. She is 5 years old and approximately 80 lbs. Our Vet prescribed Rimadyl. I’m not sure of the dosage. Her limp improved, but after being on the drug for two weeks and completing the prescription, we noticed that she seemed depressed or lethargic, and had a loss of appetite. She was even refusing treats. She was drinking a lot and asking to go out in the middle of the night. Then, we had two accidents in the house. I called the vet, and a urine sample showed an abnormally high glucose. They thought she might be diabetic, but a CBC showed she had extremely high liver enzymes and a subsequent sonargram showed that she had a small liver and they felt that is why she had a adverse reaction to the drug. Since being off the drug, she has shown steady improvement in her appetite and energy level. We are just praying that her next blood test for enzymes in another week will show that the levels are better. The thought that we almost lost our beautiful Lab is so frightening. I really wish the article in the Wall Street Journal had been published earlier than 3/13 (ironically, our dog’s birthday). I never would have put her on the drug. I think her injured front leg would have run its course and healed fine without it.”

Boarding Kennel Owner Feels Responsibility to Inform Clients about Rimadyl
As the owner of a boarding kennel, I have tried to keep myself informed and open-minded regarding the use of Rimadyl because we see a number of dogs taking the drug, which we administer in accordance with the veterinarians instructions. Your site and the Wall Street Journal article have been very informative. What has been surprising is that not one of our clients with a dog on Rimadyl was informed by their veterinarian about the severity of side effects! While I am not a veterinarian and don’t pretend to be one, I do feel a responsibility to my clients and have been informing them of your site and what I know and advising them to contact their veterinarian. I also was the owner of an 11-year-old Sheltie that died not long after being put on Rimadyl. At the time, I attributed his death two years ago to old age. Now, I have my doubts. Bill Roessler, Legacy Boarding Kennel, Winston-Salem, NC

Rimadyl Never Mentioned as Possible Cause of Symptoms
Our Boxer ‘Lady’ passed away in December of 1999. In September 1999, we noticed that she was having some difficulty breathing and took her to an emergency vet. They did x-rays and noticed something in her lungs; they thought it was possibly pneumonia. We then took her to our regular vet, who gave us Rimadly because Lady was having problems moving around; she was about to be 12. An ultrasound of her complete body was also performed and found no growths in her; they even performed a fungal blood exam. Shortly after she began taking Rimadyl, she started having problems. First, she had what our vet called a ‘stroke.’ Then she started walking in circles and had blood in her vomit, urine and stools. She had at least three more ‘strokes,’ as they called them, even though we thought they were more like seizures. One vet guessed she might have brain cancer, though it was never officially diagnosed. Nonethelss, they would still always sell Rimadyl to us; believe me, we spent hundreds of dollars on these pills. We noticed that our vet started to avoid us when we would bring Lady in. We’d hear comments like, “Quality of life is an important issue,” hinting towards putting her down. On Sunday, March 26, I was catching up on reading some past issues of the Wall Street Journal and saw the article on Rimadyl. How can a company like Pfizer put this drug out and not warn the vets about the possible side effects? We trusted our vet with Lady’s life for 12 years; it seems to us that, in the end, she was sold out to Pfizer. Lady was our daughter. She was loved by everybody who ever met her; she had a magnetic personality. We never for a moment thought it possible that she was suffering from a drug reaction — especially when we were taking her to the vet two to three times a week. To many, a dog is just a lower life form; but, to us, our dog was an individual with a personality, humor, love and a thrist for life that was taken away because somebody wasn’t advised of the problems or chose to ignore them.

Dog Died Before Her Time
Quisha was an Akita; she was my every breath. She was 13 years old, with several years left to live. I wished she could live forever. She was very healthy and strong and proud. I loved her more then anyone in this world. She had a slight favoring of her back legs. I hated the thought of arthritis being the reason ever to have to put her down. I saw a commercial on TV one day. I thought, my god, I don’t beleive it! This would be wonderful! All it could mean is more time with my most treasured friend! Off to the vet we go. One tablet of 75mg twice a day is prescribed; there’s a pamplet that says nothing, and the vet’s words, which I’ll never forget, ”You’ll notice the difference tomorrow.” Well, he was right about that. I noticed a lot of differences in the next ten months. In fact, my dog would still be here if I had been told about the side effects. He’s the vet; don’t I pay him enough to know those things and to tell them to me? I guess I don’t pay as much as Pfizer can. My best friend died on February 25, 2000. It’s hard to find a reason to get out of bed, and when I do, I don’t go back for as long as possible, because I’m affraid I won’t get back up.To die of old age is one thing; but to die when it wasn’t time is hard for those of us that are left here to live with.”

Family Suffers Several Deaths, Including That of a Beloved Dog from Suspected Rimadyl Side Effects
“I’m sure you’re being flooded with mail following today’s front page piece in the Wall Street Journal about Rimadyl. This is the first I am hearing of it. We did not know the dangers of the medication and lost a dog a month ago, exactly as outlined in the article.

“My mom’s dog, a 12-year-old Shepherd, had a slow, progressively degenerating neurological disorder in the hind quarters. Organ functions and general health were normal to excellent for her age, but Lovee was having increasing difficulty walking, especially up steps. Rimadyl was prescribed and her ‘recovery’ (four hours!) was indeed the miracle we had seen advertised on television.

“A short few weeks later, she began to urinate less frequently and lost her appetite. She ate grass on occasion. On night, she seized, vomited, could no longer stand and shook. We took her to the vet just after dawn. He examined her, and we made the extremely painful decision to put her to sleep. It seemed like something resembling a stroke had caused her seizure, and it was clear that to let her live on in that condition would have been cruel. We believed it was ‘her time,’ and let her go. Our vet was very caring and sensitive to my family, and he did not, nor did we, request an autopsy due to Lovee’s age.

“We lost my brother to heart failure in 1997and my father to cancer in 1998. To lose my mother’s only at-home companion to a pharmaceutical company is about as much as we can stand. A drug isn’t good enough for humans, so slip it through on helpless animals?? It is beyond my comprehension that Pfizer continues to market this product at all; safety sheets are not enough. Pfizer has caused animal deaths and untold suffering and grief for pet owners, while taking in millions — and even offering perks to the veterinarians who prescribe the drug. Frequent testing ‘just in case’ is an unsatisfactory and costly alternative to the consumer, and invasive to our animals. The product should be removed from the market. Pfizer should be ashamed.”

Rusty’s Guardian Rues the Day “Rimadyl” Was Mentioned
“I read the Wall Street Journal article yesterday and realized that we had unintentionally contributed to the death of our beloved Chesapeake Retriever, Rusty. He was a large Chessie, nearly 120 lbs, with severe arthritis. When we first learned of Rimdadyl, it seemed like a wonder drug. At my request, our vet special ordered the drug, which we administered daily to Rusty for several months. At first, it seemed like a miracle; he was 11 years old and like a puppy. After probably 6 months on the drug, he developed all the symptoms described in the article — the worst occurred shortly before we made the painful decision to have him put to sleep. He had severe diarrhea, wobbled, had difficulty rising and walking and vomited 1-2 times daily. He appeared to be in discomfort and clearly suffered from a loss of dignity, as well. At the too young age of 12, Rusty was put to sleep in November 1997. As nice as our vet is, he did not give us any literature about any known side effects and did not equate Rusty’s decline with this drug. I wish that we had merely continued the regimen of baby aspirin in peanut butter and had extended his life. He was truly the best dog ever. As a side note, one of the people in my office had given her dog Rimadyl for a very brief period and, as her dog was much younger, recognized and had her vet test for liver problems. Withdrawal of the Rimadyl and providing proper treatment enabled her dog to recover. I now rue the day I heard of Rimadyl.”

Could a Stroke Be Coincidental Following One Dose of Rimadyl?
“After reading an article in the Wall Street Journal, I immediately knew what had caused our dog’s untimely death. He was 14 years old and had one dose of Rimadly The morning I gave him that initial dose, I returned from work to find him collaped on the floor, unable to stand or move his head without vomiting The vet advised to watch him until the next day, when we carried him to the office. I asked the vet at that time if it could possibly have been an adverse reaction to the drug and was assured that it could not and that he’d probably had a stroke. After three days without improvement and with great anguish, we decided to have him put to sleep. It was very traumatic and preventable according to this information. I had always suspected it was not coincidental.”

Veterinarian’s Dog Cannot Walk Without Rimadyl
“Shady is my dog. I do not know how old she is. I was called to an emergency involving a stray dog, and there she was, under a parked car, bleeding. I coaxed her out and carried her to my veterinary hospital two blocks away. We gave her IV fluids and treatments for shock, and hospitalized her. The next day, her owner called the animal shelter and described her. He was told where she was, but he did not leave his name or phone number. He never came for Shady.

“Shady was not hurt that badly. She had an ugly tumor over her eyelid, and her face was totally grey. She was very, very stiff and hurt all over. She had a moderate heart murmur, but she was so friendly and quiet, she was no trouble at all. We waited for her owner to claim her, but, after a week, we decided he would not show up, so I took her home.

“I think Shady is probably about 14 years old. She is a retriever mix, apparently spayed, with severe hip dysplasia and aches and pains in most of her joints. She cannot walk without Rimadyl. I have checked her bloodwork periodically, as a pre-anesthetic check before removing tumors, and her health is good. When Shady missed just one dose of this drug, she started limping again.

“I prescribe Rimadyl for my patients who need it. I always offer bloodwork before starting the medication, and recommend rechecking it periodically. Some of my clients choose to have the bloodwork, others don’t. In most cases, the Rimadyl is prolonging the life of the dog with good quality and comfort. In my opinion, that’s all that matters to a dog. Longer life means nothing if it just means longer pain.”

Rimadyl Not Withdrawn, Despite Classic Symptoms; Dog Dies
“I took my 12-year-old Lab to the vet after noticing her urine was dark orange. Five days later, an ultrasound showed an enlarged liver, and she was put on a course of antibiotics. She showed improvement in eating and energy. My vet did not mention that Rimadyl should be withdrawn, and I continued to give it to her. Three weeks later, she stopped eating and developed diarrhea and vomiting. I saw the article about Rimadyl in the New London Day and immediately took her to the vet. She was put on an IV and given antibiotics but died in her sleep that night. I feel that if I had not given her the Rimadyl when she was ill, she might have lived. Her name was Mabel and she was the sweetest dog of about 20 I have owned.”

What If the Wall Street Journal Hadn’t Been Read? …..Would This Dog Have Been a Victim?
“On Monday, March 13, 2000, we took our 15.5-year-old Brittany Spaniel, Rusty, to our vet. We were concerned about his limp. He was already taking Cosequin for his joints. We thought maybe his time was done. Our vet suggested Rimadyl. I asked if there were any side effects or interactions with the Cosequin. …None that he knew of…The very next day our Rusty began to vomit. I thought nothing of this, as Rusty has a nervous stomach. When I arrived at work Tuesday morning, I mentioned the new medicine the vet prescribed. Someone told me to read the Wall Street Journal article on Rimadyl, and I became very concerned. I immediately stopped the medication and phoned the vet. ….Yes, possibly this was a side effect. ….Why was I not told beforehand? What if I had never seen the article? Would my beloved Rusty be a victim to this miscommunication? Thank God for the article and stories posted on this network.”

Rimadyl Article Leads Dog’s Guardian to Discover That EtoGesic Has Side Effects, Too
I read the Wall Street Journal article through Animal Talk:Digest and was led to your wonderful Senior Dogs website. I am writing about the drug Etogesic — which recently almost killed my senior dog. I wish I had known what I just read about this drug on your site. My vet, knowing my aversion to Rimadyl and its side effects, had suggested this drug as an alternative for my Dalmatian who has suffered from arthritis and spondilitis for some time. I was not warned of the possible side effects. (He was taking Dexamethsone but didn’t seem to be getting better.) Within a week (and at first I didn’t associate it with the drug), he had the most severe case of diarrhea I have ever witnessed (thick, bloody, including parts of the bowel lining). It was literally shooting out of him. (sorry to be so graphic). I thought he was dying. After one night at the vet, I kept him at home, giving subcutanious fluids as he couldn’t eat for days. Already weak from age and arthritis, this practically killed him, but he rallied — though he is much weaker from the ordeal. NOW I also realize, after visiting your web site, that the runny stuff from his eyes was probably caused by this drug as well, something never mentioned to me either. It is obviously very painful to him as he has tries to bite me when I clean it. It seems to be better but is still present. Needless to say, he is back on the Dex and I give him glucosamine supplements, as well. He turned 14 today. Again, we must get this information out to people. Our beloved and trusting companions should not be, forgive the term, ‘guinea pigs’ for these supposed miracle drugs.”

“Logan, Our Beautiful Sheltie”
“I didn’t know about the article in the Wall Street Journal until my husband brought the paper home and pointed it out to me. My dog Logan had been put on Rimadyl for his arthritis when he was 12. He was our beautiful Shetland Sheepdog that loved to do anything as long as it was with us. He was our ‘miniature Lassie’ — only a lot more beautiful. He was never well again after the Rimadyl. The vet kept saying it was his old age; I had never had an older dog before, so I believed it. He started having loose stools and occasional vomiting for no apparent reason. One year later, he went to the vet for diarrhea and vomiting, was given an antibiotic. Four months after that, we took him to the emergency vet for uncontrolled vomiting and diarrhea along with what appeared to be seizures. He could not even move — we thought we had lost him then. He was given IV fluids, put on Tagamet and force feedings, as he no longer would eat. We followed-up with his regular vet and liver enzymes were done that were elevated. I asked the vet if this could be the Rimadyl; her reply was possibly, but it’s probably his age. I stopped giving him the drug at this point, but he remained very sick. Two months later, he could not get up again and had more seizures and vomiting, diarrhea — he was given injections for apparant infection and IV fluids but became even worse on the medication at home. He had another severe illness 4 months later and was euthanized on July 27, 1999. He had been started on Rimadyl on 3-24-97; he took it for 16 months (until 7-12-98). There was no necropsy done. I have spoken with the vet at the FDA and called Logan’s vet to request a copy of his vet record. When this arrives, I’ll know exactly what the liver tests results were. As suggested by the FDA vet, I’ll call Pfizer to inform them. I may never know clinically for sure, but I do know personally Logan didn’t get sick until he was on Rimadyl. I’m sure it killed him.”

Two Dogs in the Same Family Appear to Suffer Adverse Reactions to Rimadyl
“My sister’s 10-year-old Standard Schnauzer dropped dead on 3-17-00 after exhibiting the typical toxic symptoms from Rimadyl — vomiting, diarrhea, loss of appetite and bloody stools. Rimadyl was the only different thing in his diet, and he had taken it for several weeks. My mini-Schnauzer took Rimadyl for about a week or less, shortly after it came on the market. The vet had prescribed a dosage of 25mg twice daily. He was 9 years old at the time. He exhibited similar toxic symptoms. The Rimadyl was the only thing different in his life, also. I am just thankful that I was observant enough to see the symptoms, look up the drug on the internet, and immediately discontinue use. My dog recovered soon after I discontinued the drug and is apparently fine, over two years later. Although the evidence is ‘anecdotal,’ neither my sister nor I was warned of the possible dangers. I was given the pills in a plastic bag with no manufacturers sheet or anything but a sticker on the bag stating that the pills were 25mg Rimadyl and should be administered twice daily. It’s just too suspicious that dogs who were otherwise fine would become so ill or die when nothing had changed in their lives other than the Rimadyl Rx.”

“Death Of Our Dog Due To Rimadyl Use”
“Last Wednesday, March 22, 2000, we were forced to put our Labrador/German Shepard mix to sleep. Our dog, Sheba, was 11 years old and had been using Rimadyl for approximately 7 months. An ultrasound was performed Wednesday morning, which showed a large tumor in her liver. In addition, her liver and kidney’s were perforated from the bacteria of the tumor. Our veterinarian had been treating her with antibiotics for two weeks, and several blood tests were performed, but she would not eat, had severe gastric pains, lost over ten pounds, became very lathargic and weak, and could not recover. In addition to her taking Rimdayl, she had been taking Predinisone on an every other day basis for the past several years. Our vet did no blood or liver testing (screening) during her use of Rimadyl. We were never informed of any serious risks or possible problems. We believe that our vet did what he thought was best but was probably not well informed of the precautions in using Rimadyl. This has been a very upsetting experience; we wish we had done research or had known of this Rimadyl information seven months ago. Had we been informed, we’re confident our precious pet would still be alive today.

 

 

 

Dogs and Serotonin

Editorial Note: This post by Leonie Fennell is the first of two on related themes. We would love to hear any observations you or your veterinarian have on drugs in animals in general.

Depression, once a disease deemed too rare to merit study, has become so common that it is now a booming business. More and more people are asking: “When we stop at the pharmacy to pick up our Prozac, are we simply buying a drug? Or are we buying into a disease as well?” In the last 20 years  depression numbers have rocketed and according to the World Health Organisation, more than 300 million people of all ages are suffering globally.

And it seems to be spreading to pets.

An article last week caught my attention – ‘Serotonin Syndrome in Dogs: Symptoms, Causes, & Treatment’. The article warns of the dangers of antidepressant-induced Serotonin Syndrome (SS), a condition that if left untreated, can result in ‘illness, altered mental states, and even death’. Considering I’ve seen first-hand the effects that antidepressants can have on humans, particularly depersonalization, aggression and suicidality, I have always wondered whether similar effects can be seen in canines. What might the growing practice of drugging our pets lead to?

An increased risk of antidepressant-induced ‘suicidality’ may be impossible to detect in animals, but it seems the deleterious effects of the drugs on us are similar in our canine companions. Symptoms of SS include confusion, depression, hyperactivity, lethargy, agitation, aggression and behavioral abnormalities. Bizarrely, it seems that vets are far more clued-in to the pharmacological effects on man’s best friend, than doctors are.

Given the unashamed push to medicate the masses, whether sick or healthy (as illustrated by the widespread use of statins), the progression to animals is hardly surprising. With the human market arguably close to saturation, dogs are increasingly being diagnosed with many psychiatric disorders, such as anxiety, depression and ‘separation anxiety’. While some of this is down to neurotic owners, the pharmaceutical industry also have clear motives in targeting the pet market – the market is an extremely lucrative one, with a recent report by the Federal Trade Commission estimating that U.S. retail sales of pet medications are expected to grow to $10.2 billion by 2018.

Reconcile

Undoubtedly, dog-owners do not set out to harm their beloved pets, yet when giving them psychotropic drugs, it is a distinct possibility. For instance, while benzodiazepines and tricyclic antidepressants are often prescribed to an ‘anxious’ canine, it seems far more likely that a vet will recommend an SSRI antidepressant (Selective Serotonin Reuptake Inhibitor).

Lilly’s SSRI fluoxetine (more widely known as Prozac) was approved for canine use by the FDA and repackaged for your doggie or moggy as ‘Reconcile’ for separation anxiety. Two other SSRIs, Paroxetine and Sertraline, although not approved for use in animals, are also prescribed by veterinarians for your dog’s woes. In the case of Reconcile, separation anxiety (dogs being left alone for lengthy periods) was the most common reason for prescribing in dogs, and in cats, inappropriate elimination (of urine).

Lilly’s own literature(1) report the following adverse reactions with dogs taking Reconcile/Prozac:

  • Calm/Lethargy/Depression – 32.9%
  • Shaking/Shivering/Tremor – 11.1%
  • Restlessness –  7.4%
  • Aggression –    4.2%

So, almost one in three dogs became depressed on Reconcile and an estimated 4 in 100 became aggressive. Furthermore, the reaction coded as ‘restlessness’ (at 7.4%) might sound innocuous but seems likely to be an indication of akathisia, a severe emotional state that often precipitates suicide in humans (see Dolin v GSK).

Considering little Fido cannot verbalise a drug-induced effect, it seems bizarre that the American and European drug regulators (FDA & EMA) felt that the benefits outweighed the risks for dogs taking an SSRI. If we consider that so many humans have died or indeed, been maimed by SSRIs, is drugging your dog really the best option?

Would leaving a child at home alone for many hours justify prescribing them an antidepressant?

There are many mothers, fathers, siblings and spouses who are left bereaved because of an SSRI prescription – who now know what psychotropic drugs can do to the human psyche. It gives a whole new meaning to ‘I wouldn’t give this to my dog’.

Being Irish though one more thought occurs to me. The IRA would probably have had the English out of Ireland long ago if they bombed Crufts Dog Fair, perhaps Pharma are making a bigger mistake agitating our pets than they are agitating us.

  1. Lilly. Reconcile PIL. In: FDA, editor. Online2007.