Making medicines safer for all of us

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

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

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

Archive for RxISK Stories

We are the Ninety Nine Percent

99 percent

Editorial Note: This is a Coda to the four posts about Sense about Science and AllTrials – Follow the Rhetoric, First Admit no Harm, Follow the Lawsuit & Follow the Patient.

The last post ended on this note:

Over 18 months ago, RxISK attempted to open up a debate on the ambiguities and conflicts at its heart. Doing what it does, could it operate as a business in the marketplace or should it be a Foundation or an Occupy your Doctors’ Office movement?

It seems clear that although legally obliged to access any adverse event data they are aware of, pharmaceutical companies seem unlikely to endorse RxISK in the way they have endorsed AllTrials. They seem to be pushing us toward finding something more co-operative – perhaps something that is not out there yet – perhaps something that David Graeber or Thomas Piketty might have views on.

Over the next few weeks on RxISK, we will be featuring a series of just published articles based on RxISK data – one on what is now a Ninety-Nine + case series of SSRI induced Alcoholism. A second on what is an over one hundred and twenty case series of persisting sexual dysfunction following SSRIs, isotretinoin or finasteride. The third will be on a novel ethical dilemma linked to reports of QT-interval changes.

There are several hundred cases embodied in these articles covering most antidepressants and a number of other drugs. Companies who are interested in the safety of their drugs, or companies simply keeping to the letter of the pharmacovigilance law should be contacting us to enquire further whether their drug was involved, as might also the companies gearing up to market S-3 antagonists for alcoholism. How do we deal with this? Who pays for the work involved in establishing which version of paroxetine was involved?

Could RxISK be captured?

Quite possibly. Industry can capture almost anything – they may have captured AllTrials. They are making great efforts to capture, defang or otherwise manage patient adverse event reporting systems. GSK’s ability to hide clinical trial data pales compared to the subtlety of their approach to and lengths to which they appear to go to block or otherwise hide adverse event reporting – See American Woman, American Woman 2.

Some pre-capture RxISK principles

  • Doctors and patients make medicines. Industry make chemicals. A medicine is a combination of a chemical and information about how to use that poison to bring good out of a bad situation. Doctors, nurses, pharmacists and patients make the information that transforms a chemical into a medicine.
  • Doctors and patients are the only bulwark against the degradation of medicines caused by branding and marketing. Regulators and academics or other experts aren’t.
  • Medicine involves following the patient. It’s the inconvenient patient, with the inconvenient problem that points the way forward.
  • The marriage of patient and doctor is often cast as a marriage of scientific and personal expertise with lip-service paid to the equality of both forms of expertise. But in fact faced with an inconvenient fact, a doctor’s expertise almost by definition risks getting in the way – this is the time for doctors to work with patients as genuine equals. This is where doctors find out that a motivated patient, even one with no academic credentials, is far more likely to turn up an answer than a bored researcher. This is where each finds out if the marriage is enduring. As part of a dowry, the patient who finds the answer to a problem will often happily let the doctor take the credit.
  • Embracing adverse events can restore the fun to medicine. It calls on doctors, pharmacists, nurses or others to be generalists rather than partialists. None of our drugs act on one system – there is more serotonin in the gut than the brain and more cholesterol in the brain than in the blood. To work out what is going wrong and put it right you have to draw on everything you have ever learned rather than just stick to the tramtrack of standard practice.
  • This is about making the market work properly. We ultimately are where the value lies.

The RxISK report

The main tool to move things forward is the RxISK report. When some anomalous event happens on the street, its axiomatic that the police get as many eye-witnesses as they can. In clinical practice this means you don’t want to leave reporting to hurried and disengaged doctors and you definitely don’t want to leave it to pharmaceutical companies for whom collecting details on a case is all about collecting excuses to rule out an effect of their drug.

It makes much more sense if a doctor or pharmacist or nurse comes to an agreed account with the person affected who has usually spent time with the problem and is motivated to nail down what is going on.

  1. It’s about good quality rather than degraded quality adverse event reports in the belief that good words come before good numbers.
  2. It’s about us being willing to make a judgement call that this event is likely to be linked to a drug in a way regulators will never do.
  3. It’s about intervening early in adverse events to reduce harms.
  4. It’s about adding local knowledge to the mix – getting people in Swindon and London (or Hamilton and Toronto; or Lyon and Bordeaux, or Verona and Milan, or Chicago and Milwaukee) to account for why something is happening in one place and not another rather than thinking someone with no local knowledge is going to sort it out
  5. It’s about taking on the power imbalance between doctors and patients.
  6. It’s about changing doctors into listeners – this can be done by getting patients to quality mark doctors based on those who agree to engage in the process versus those who don’t. We can force the deaf to hear us. We are the Ninety-Nine Percent.
  7. The RxISK report has led to the idea of a RxISK clinic and report as an even more potent way to equalize the power imbalance.

It’s about medicine as it needs to be if its going to survive. Leaving reporting to doctors alone has not worked – at present only 1% of adverse events are reported. The question is whether doctors have what it takes to save themselves by insisting on the evidence of their own eyes and reporting adverse events. Saving themselves will do more to save their patients than anything else could.

RxISK Stories: Go Ask Alice

Editorial Note: RxISK is all about people discovering things for themselves and alerting others to something that can make a real difference.

There have been some wonderful examples outlined in posts here on RxISK from Anne-Marie Kelly’s discovery of a cure for Alcoholism – stop your SSRI and perhaps try a serotonin-3 antagonist like mianserin or ondansetron – to Samantha Dearnaley’s discovery that Champix (Chantix) had caused her epileptic convulsions. These were things that none of the experts knew.

Johanna Ryan gives another example below. As the resident psychiatric and psychopharmacologic expert, it’s worth noting that I had never heard of ‘Alice in Wonderland Syndrome’. It just shows that putting people with interest and/or motivation together can do far more to solve problems than going to see an expert – there are far too many things out there for one expert to know. Even if you think your expertise doesn’t amount to much, we have reached a point where pooling our expertise is a much better bet than relying on experts. (DH)

Go ask Alice

One pill makes you larger, and one pill makes you small
And the ones that Mother gives you don’t do anything at all
Go ask Alice, when she’s ten feet tall.

“White Rabbit,” by the Jefferson Airplane

Alice-in-Wonderland

I first heard of “Alice in Wonderland Syndrome” last year while reading Oliver Sacks’ book, Hallucinations. Sacks is a neurologist who is fascinated with the range of experiences, good, bad and strange, that the human nervous system can give rise to.

In Alice in Wonderland Syndrome (AIWS), objects in the environment and even parts of your own body are strangely distorted. Just like Alice, you may perceive your own head or arms as huge, while the people around you seem tiny – or you may feel suddenly shrunk, while the furniture in the room towers over you. It’s best known as a rare effect of migraine headaches and Sacks speculates that Lewis Carroll may have gotten some of the trippy inspirations for his classic story from his own chronic migraines. It’s also been known to occur in epilepsy and in viral infections, especially in children. Anticonvulsant drugs used to control epilepsy and migraines are a standard treatment. Which was why it startled me to stumble across a case on RxISK.org – as a side effect of an anticonvulsant drug!

RxISK patient narratives link Topamax & hallucinations

On the Patient Narrative page for Topamax, someone reported the following:

“Intense visual hallucinations. Objects in the visual field (e.g., computer monitor, hands, arms, desk, etc.) would move far, far away in regular time then come back and be grossly enlarged. It is almost like making an MS Word document change font sizes, from 12 pt to 2 pt to 350 pt, but it was everything I saw.”

Using RxISK.org’s features gave me some clues about this person’s experience, and how common it might be. Using the “A-Z Search” function under Reported Side Effects I found the FDA had eight reports of Alice in Wonderland Syndrome on Topamax, with a “PRR” of 438.8. That means the odds were overwhelming that the drug and the AIWS were connected.

The “Location” tab in Reported Side Effects told me that six of these were from Germany! One was from the UK, but absolutely none from the USA, even though Topamax is widely used here. Checking the Location tab for All Side Effects, well over half have come from America, with no other country even coming close.

Checking “Gender” and “Age” told me that all eight were female, and seven were teenagers.

Our friend on RxISK sounded more like an American adult than a teenage girl from Germany. Was she (or he) the first? Well, she’d probably never heard of Alice, so she reported this as a “visual hallucination.” Maybe others had too.

Back to the Reported A-Z side effects, where I found 69 reports (PRR 4.9) for Visual Hallucination, 103 (PRR 1.6) for plain old Hallucination, and 73 (PRR 3.2) for Visual Disturbance. “Disorientation” might be relevant too, and there were 106 reports of that (PRR 2.4).

Fifteen of the 69 Visual Hallucination reports came from the USA, 18 from the UK, and only two from Germany. Two-thirds were female. There were nine children and 21 teenagers, but there were also twenty adults, and nineteen cases were “age unknown.”

Going to the “Outcomes” tab, I found that 39 of these 69 people had been hospitalized! That told me that probably only the more extreme cases were being reported – those where the person was terrified by their experience or it happened alongside more serious side effects.

Treatment of migraines

By now I was hooked, so I went to Google. I found one professional paper on Alice in Wonderland Syndrome as a side effect of Topamax – a case report on a teenage girl in Germany who was taking the drug to prevent migraines. The authors had probably made that initial report to the FDA and may have alerted other German headache specialists to a symptom that certainly breaks up a dull workday.

There were a couple of American papers as well, though, including one about two patients with “palinopsia” and one with AIWS. All were taking Topamax for migraines. Fellow medical wonks can Google palinopsia – it’s even stranger than AIWS but I could not find a single report to the FDA.

Another paper described “Steroid-induced Psychosis Presenting as Alice in Wonderland Syndrome” and implied that the patient, who was on heavy steroids for severe asthma attacks, had been misdiagnosed with “schizophrenia.”

I also found several reports on patient discussion boards of AIWS on Topamax, including both Epilepsy.com  (“Feeling a Bit Like Alice in Wonderland on Topamax”) and the psych board CrazyMeds. They were mixed in with reports of other strange symptoms – hallucinations, delusions, feelings of unreality or of standing outside one’s own body.

I was struck by something the moderator of CrazyMeds (who by the way is resolutely pro-med and will not tolerate any psychiatry-bashing on his board) said: “As with all anticonvulsants, anything Topamax can fix is also a potential side effect.” In other words, a range of symptoms of epilepsy, migraine and even bipolar disorder could also be side effects of an anticonvulsant drug taken to treat these conditions.

‘RxISK allows us to describe what’s going on and how it affects us’

If this is true then RxISK and similar efforts could make a huge contribution. As Kalman Applbaum noted, many FDA reports filed by doctors consist only of ticking a box on a list, say for “hallucination” or “anxiety.” RxISK allows us to describe what’s going on and how it affects us, as the Alice in Wonderland sufferer did. If we know people taking anticonvulsants for one condition (say, depression) experience symptoms typical of other conditions (weird visual effects associated with migraine auras), the link to the drug becomes clearer.

In the case of Cymbalta, another drug highlighted on RxISK, people taking the drug for back pain have experienced the same side effects (nightmares, moodswings, etc.) as those taking it as an antidepressant. Observations like this could teach us more about the drug and help prevent patients from being misdiagnosed with new “diseases”, like that asthma patient with AIWS.

Reporting to RxISK

I looked at a few of the other anticonvulsants (Neurontin, Lyrica, Lamictal). No reports of AIWS. However, all have a fair amount of Visual Hallucination and Visual Disturbance reports and all include far more Americans and adults as opposed to German teenagers. So who knows! The FDA has a category called “Feeling Abnormal” which is very large and could be hiding almost anything including Alice. We need people to report to RxISK to find out what’s going on – FDA is like Humpty Dumpty for whom words where what he chose them to mean.

RxISK reporting could help bring together communities of doctors and patients who seldom talk to each other, even though we are increasingly prescribing or taking the exact same drugs. Reading the discussion boards, I noticed psychiatry patients complained that their doctors denied these problems could be happening or connected to the drugs. Neurology patients found that their doctors were much quicker to concede that these effects were drug related, although they complained of being told to just ‘hand in there’ by doctors who didnt take the side effects seriously enough. We can also share reports from various countries where the drug-use practices can be very different, even for the same illnesses.

Reports to RxISK could also reveal a lot about the brain and the mind. Oliver Sacks first made me aware how much neurologists owe to accidents, breakdowns and “side effects”, and the reports of non-scientists who had lived through them. Who could forget poor Phineas Gage, the railroad worker who survived a sharpened crowbar being driven through his left frontal lobe? Doctors and experts flocked to examine and quiz him, trying to learn more about the brain works. Fortunately, most people logging on to RxISK don’t have anything nearly as awful as Phineas Gage had but because we know more now about the brain than we did then, reports of much less dramatic things can teach us a huge amount.

Editorial Note: The only thing a psychiatry expert can add to this is that it’s not a surprise that the recognition that this is ‘Alice in Wonderland Syndrome’ came from Germany. For well over a century, the Germans have been much interested in paying close attention to superficially similar things and distinguishing between them than anyone else has.

RxISK Stories: If You’re Going To Look After Patients, Man Up

Man up!

This post also appears on RxISK.org and can be viewed here.

Pharmalot has just posted a piece – ‘Controversial FDA official, Tom Laughren, retires.’

This is a must read for anyone with anything to do with mental health – both the post and the comments afterwards where some have posted that they still believe the Black Box warnings on antidepressants arose because of pressure from the Church of Scientology rather than in response to the data.

Despite my billing as a must-read, the Pharmalot post will likely seem boring to many. But the comments won’t – they seethe with anger. This is one of those cases in which if you weren’t there its hard to appreciate the depth of feeling this man generated in many as he – and a few others including Paul Leber and Bob Temple – appeared to stand in the way of natural justice and patient safety. The most comprehensive cover is on the AHRP website where Vera Sharav dubs Laughren a double-agent.

He seemed a quiet man. He was grey. He behaved like a functionary. But he was the focus of one of  the most dramatic moments I have ever witnessed. This was at the FDA hearings about antidepressants and suicide in children, some 8 years ago now. Because of FDA procedures, the public get a chance to offer views. There were 73 three-minute slots. At this hearing a range of doctors and other men usually with affiliations to pharma spoke against the Black Box warnings and it was down to a series of mothers to plead for warnings.

Many of the pleas were aimed straight at the bureaucrats – Laughren and Temple. The moment is at the center of Pharmageddon, where I compared what happened then and happens over and over to the Greek Myth in which Demeter implores Zeus to restore her child to life. It is appropriate perhaps in that unlike the other Gods, who were dashing and colorful, Zeus often seems to have the character of the bureaucrat who ran Olympus rather an all-powerful Jehovah.

Demeter’s stories

Demeter was the Greek goddess of the Earth and of fertility whose daughter, Cora, was forcibly abducted and carried off to the underworld by Hades. Demeter protested to Zeus, who professed himself helpless, until Demeter threatened Earth with permanent Winter. Zeus intervened and restored Cora to her mother as Persephone. Because Persephone had eaten some pomegranate seeds while in the underworld, however, she must return to Hades each year, the several months of Winter each year.

Winter’s tale

Mary Ellen Winter confronted Laughren and the FDA about her 23-year-old daughter, Beth:

“Beth was looking forward to a career in communication and was experiencing some anxiety and having trouble sleeping when she consulted our family physician. He prescribed Paxil and said she would start feeling better in two weeks. Seven days later Beth took her own life.

We, like most of you in this room, grew up with confidence in the strides made in medicine and accepted with faith antibiotics and vaccinations prescribed. We believed the FDA would always act to protect our family’s well being. When my daughter went to our family GP last year, we trusted that our doctor was well educated and informed. We were wrong. We now know that pharmaceutical sales are a high stake business, driven to increase shareholder wealth. The consolidation of pharmaceutical companies like GlaxoSmithKline has resulted in increased sophistication in the quest to market and distribute pharmaceutical products. Priority has moved from health to profit. Not all doctors are equipped to understand the marketing targets they have become. The FDA has allowed our daughter to be the victim of a highly commercial enterprise that selectively releases clinical data to maximize sales efforts and seeks only to gain corporate profits…

As residents of the State of New York, we thank our Attorney General, Elliot Spitzer, for addressing issues that the FDA has been unwilling to address…”

[This action on the part of Ruth Firestein within Spitzer’s department in many ways triggered the Access to Data issues that have since engulfed GSK and gave rise to the recent EMA hearings and a debate within RxISK and its supporters about what to do with the data that arises from people reporting to RxISK].

Thy neighbour’s child

But Demeter came right into the room in the last but one slot when Mathy Downing singled out Tom Laughren:

“On January 10, 2004 our beautiful little girl, Candace, died by hanging four days after ingesting 100 mg of Zoloft. She was 12 years old. The autopsy report indicated that Zoloft was present in her system. We had no warning that this would happen. This was not a child who had ever been depressed or had suicidal ideation. She was a happy little girl and a friend to everyone. She had been prescribed Zoloft for generalized anxiety disorder, by a qualified child psychiatrist, which manifested in school anxiety… . She had the full support of a loving, caring, functional family and a nurturing school environment.

Her death not only affected us but rocked our community… When Candace died her school was closed for the day of her memorial service, a service that had to be held in the school gym in order to seat the thousand or so people who attended. How ironic, Dr. Laughren, that your family attended Candace’s memorial service. Our daughters had been in class together since kindergarten. How devastating to us that your daughter will graduate from the school that they both attended for the past eight years and that Candace will never have the opportunity to do so.

Candace’s death was entirely avoidable, had we been given appropriate warnings and implications of the possible effects of Zoloft. It should have been our choice to make and not yours. We are not comforted by the insensitive comments of a corrupt and uncaring FDA or pharmaceutical benefactors such as Pfizer who sit in their ivory towers, passing judgments on the lives and deaths of so many innocent children. The blood of these children is on your hands. To continue to blame the victim rather than the drug is wrong. To make such blatant statements that depressed children run the risk of becoming suicidal does not fit the profile of our little girl.” [1]

Laughren’s defence

I cannot remember seeing anything ever about or by Tom Laughren where I have thought you know the man’s right on that – except the bits where he has been dragged screaming to a table and been forced to agree. But in the Pharmalot obituary on his career there for the first time was something where I jumped and said “Yes, he’s right on that”.

In another setting, faced with a barrage of criticism of FDA, “Tom Laughren, director of the FDA’s division of psychiatry products, told the panel that the agency could do little to fix the problem and, instead, pointed the finger at medical specialty societies, which he insisted must do a better job educating doctors about side effects”.

He’s right. Doctors are failing patients far more than FDA. (See Professional SuicideModel DoctorsWe need to talk about DoctorsScaremongers of the world uniteSo Long and Thanks for all the Fish). Doctors have become infantilized for whatever reason and turn to a parental figure, a Zeus, to rescue them. If you take on the responsibility of looking after people the very least you can do is Man up – or better again Mother up.

Crusoe

The next two Crusoe posts will deal with these issues. It seems right to mark the end of one year and the start of the next by stepping back from the realm of real human drama and place these in their mythic context. Taking the issues out of the domain of data, science and real clinical histories into the realm of myth seems to confuse some readers – the hope is rather to engage with a wider readership and get artists or story-tellers or poets to engage with RxISK and its issues – as Bill James has done with his cartoons and images. We are dealing here with lives and in particular the fact that we each have one life only. The two Crusoe posts will attempt to capture the spirit of RxISK.

[1] Joint Meeting of the CDER Psychopharmacologic Drugs Advisory committee and the FDA Pediatric Advisory Committee, Bethesda, Monday Sept 13th 2004, p 435.

[2] Joint Meeting of the CDER Psychopharmacologic Drugs Advisory committee and the FDA Pediatric Advisory Committee, Bethesda, Monday Sept 13th 2004, p 332.

RxISK Stories: Listening to Parents

parents

Anonymous

When you lose a child or a partner from a rare illness, everyone is supportive, no-one denies you. They listen. But if a child dies from suicide or a complication of treatment with a drug especially a psychotropic drug no-one listens. Our culture has no place for this kind of death. They say maybe it’s for the best. He’d never have been able to face the life he’d have had – something they would never say this about a child with cancer.

The system tells you that your child had a serious mental illness, when in fact he might have started on drugs for ADHD or anxiety. It tells you his diabetes was a complication of his schizophrenia when it was caused by Zyprexa or Quetiapine. If you are like me, you assume no doctor would give your child a drug that wouldn’t benefit him. You see the deterioration but unless you keep a record and can show that each time things got worse the change coincided with treatment, you do not think it could be the drugs. It’s easier to live with the idea that the problems come from an illness rather than from the treatment. I told my son he had to take the treatment when he begged me to let him stop.

If he fails to get better the dose will go up – in other areas of medicine a failure to respond leads to a change of strategy. But in this case drugs are added to drugs. If he becomes edgy or paranoid or can’t sleep these are all excuses to add more drugs rather than stop the treatment. Cold turkey from one drug might be thrown into the mix of other drugs.

If you later figure out somehow that what happened was drug related – you get angry. You phone the doctor – you want to talk to them. They tell you no it’s not the drug – your son was mentally ill. They’re in denial. Their vested interest lies in not believing the treatment they gave might have caused the problem.

You meet other people who introduce you to all that was known about the problem before you ended up locked in it – because they have been there before you. You may get in contact with the few experts who seem to accept there is a problem. You cannot believe that others new about this but still nothing was done.

You want to correct things and you try to use the system. You’ve discovered this problem and you think if people hear the issues they will be as horrified as you and will say we mustn’t let this happen again. You might look for an inquest, get in touch with the Department of Health, the body responsible for licensing the doctor, the regulator, local politicians.

The regulator will refer you to the Department of Health, who will refer you to the licensing body for doctors, who will refer you to the professional body, who will refer you back to the regulator. We have all written to the regulator and the minister for health and we all get the stock letters back (Ed: See Margaret’s Story).

I went through the thing of doing suicide statistics to show there is a problem but got nowhere. The data are in fact corrupt and useless but not even the media want to know about this newsworthy story. The government is going broke because of its spending on drugs and you think it could use this as an opportunity to cut back on drug spending – but no. The professional body will decide that at least some fraction of other doctors would have done the same.

If an inquest implicates the drugs, you think that the next set of practice guidelines which you have heard are in development will reflect this but they never do.

You lose your faith and become a zombie. On TV there is always a good guy to put things right but here there isn’t. You will never be the same person again.

You’re alone with each other – husband and wife. First you blame yourself – then the other. It’s very hard to not blame each other. Husbands and wives break up. You need to be able to give to keep any relationship going, but you’ve got nothing left to give. You can’t make love anymore because love was all about children. You’re doing things because you know you have to, not out of any sense of fun. You can’t stand the memories even though you don’t want to lose them. You may be told you are depressed and your doctor is highly likely to suggest you need a pill.

You meet others who have lost children who have become advocates for more treatment. Other members of your family think you are deluded and family meetings become difficult. After time you find that the parents who see things the same way as you stop getting in touch, not because they have changed their mind but in an effort to get on with their lives. It just isn’t possible to grieve to a conclusion.

I was once you. I was middle class too. I believed in the system. I totally believed in the medical system. I used to pass the wastelands and see the disenfranchised, smoking dope or taking drugs, who rejected the system and were rejected by it – and thought can they not see if you just approach the world trustingly you bump into people whom you can in fact trust. Now I know no certainty. I have no choices. I have a wonderful GP but even there I have to be suspicious. I have become one of the disenfranchised.

Unforgiven

You want to forgive but you can’t forgive people who don’t ask for forgiveness. The doctor thinks he is doing a good job – all doctors think they are doing well. Maybe they couldn’t function if they thought otherwise.

I have – many of us have – fantasies about getting a hired gun – Clint Eastwood in Unforgiven. He might set up as a sniper near a pharmaceutical company, bomb its premises or lock up the doctor and force feed him the pills he put our loved one on.

The system needs to stop Listening to Prozac and start Listening to Parents and Partners. We need to be acknowledged. This will not be through an adversarial forum which has to rule one way or the other. It should have the power to acknowledge that drugs come with unavoidable risks and perhaps offer a 60-40 judgment that your husband or son was caught in a spiral that is easier to see in hindsight than at the time.

Doctors need a forum like this because if the drugs are not poisons that need expert input, they may end up being administered by nurses and pharmacists. At present treatment would often be safer if it were dispensed by a machine – the machine could be programmed not to keep you on treatments that don’t suit.

Doctors might have a more interesting and rewarding job if they recognized the problems treatment can cause. This is the moment when they could engage in genuine team work with patients or with parents or partners. Instead their default is – come back when you have had 10 years of medical training. They are fundamentally not team players.

We are the second hand sufferers of adverse events – the ones who get driven to suicide or premature death from heart attacks by the effects of prescription drugs on our children or partners. A grisly inversion of the DES story, where the daughters of mothers who had taken diethylstilbestrol developed cancer of the vagina in their teenage years. Rather than DES Daughters we are DSE Parents. Where are the doctors who want to recognize this side effect of treatment and bring healing?

RxISK prize

I would like to establish an annual prize for a piece of work covering the adverse effects of treatment – the wider impacts these can have and the ways people or families may have found to overcome them. I cannot afford to fund this on my own. I would like to call for donations through RxISK.org to help fund this. RxISK has foundations in the US, Canada and the UK.

Report drug side effects

Help us make medicines safer for all of us by reporting drug side effects at RxISK.org. Less than 5% of serious drug side effects are reported. Our mission is to capture this missing data directly from patients through RxISK.org’s free drug side effect reporting tool and use this data to help make medicines safer for all of us.

When you report your drug side effect on RxISK.org, you also receive a free RxISK Report to take to your doctor or pharmacist. This report serves as a means to initiate a more detailed discussion of your treatment and the option to send a report to your country’s health authority — beginning with the FDA in the United States and Health Canada in Canada (more countries will be added soon).

Adverse events are known to be the 4th leading cause of death. Our goal is to knock these off the top 10 list. We can only accomplish this with your help.

Tell us your story today at RxISK.org.

RxISK Stories: Cora’s Story – A Benzodiazepine Story

This blog post has first been published on the RxISK.org website and can be viewed here.

In RxISK Stories, we regularly take you to dark places where few would wish to go. We have perhaps become too used to the horrific consequences of medicines going wrong that we fail to appreciate how off-putting this sequence of posts can be. It is like a doctor taking a friend into an operating theater just when the surgeon is sawing through the breastbone failing to appreciate that the friend is likely to faint away.

We want you to give us some good news stories – about new uses for drugs, or discoveries about how to manage side effects. The supporters of drugs classically say that critics fail to take into account all the lives that would be lost if the drug were not used – nowhere more so than in the case of the antidepressants where warnings they argue will deter people from seeking and getting the benefits of treatment. But the efforts to persuade doctors to prescribe and the rest of us to take antidepressants went hand in hand with efforts to persuade doctors to stop prescribing and the rest of us to stop taking benzodiazepines. And this gives rise to deaths also.

Cora’s story

Cora was 18 and beautiful. Slim, with long blond hair, about average height. She had just finished high school, where she had been the homecoming queen. She was set to attend college, though she wasn’t certain what direction to take there. She had a boyfriend but was worried he might want to leave her, while at the same time knowing her parents didn’t approve of him.

At a rock festival with her boyfriend, she got lost and, trying to find him, had taken a fall and injured her arm. She was admitted to a local hospital for treatment and sent home from there. Several days later, in a state of perplexity she was brought to the psychiatric unit where I have inpatient beds.

Had she been traumatized or abused in some way? Had she been taking drugs and had a trip gone awry? Had her boyfriend left her? Her mental state was quite unstable, but despite having input from the many people involved in looking after someone in hospital I couldn’t make a diagnosis. Cora was not hearing voices, did not have delusional beliefs, and was not consistently depressed, elated or anxious. But she was volatile. At times in the ensuing weeks, apparently improved, I gave her leave to go out with her parents, but she was typically brought back severely confused again – sometimes only minutes after having walked out through the hospital doors. At other times she was almost completely unresponsive and inaccessible. I could see no reason to give her an antidepressant or an antipsychotic. On occasion when she seemed particularly agitated I wrote her up for a minor tranquilizer – a benzodiazepine.

Finally after about 6 weeks she went on weekend leave with her parents, held her own, and did not come back. I was happy to file her case as diagnosis unknown. I heard she was doing well at college and was still dating the same boyfriend.

I saw her again a year later – 8½ months pregnant. She was clearly too unwell to be managed at home. But where she had been mute and inaccessible previously, now she was over-active, manipulative, and attention-seeking while still seeming confused; her actions did not seem fully under her own control. She looked as though she might go into labor at any moment, so I held off medication.

After the birth, I sent her to a hospital that had a mother and baby facility. The psychiatric team that took over her care there, I learned, thought she had schizophrenia. She was put on regular antipsychotics, but apparently was not making much progress and the baby was taken from her. Some months later, I heard she had been given weekend leave; one evening of that weekend, having told her parents she was going out for a walk, she laid her neck on the track in the face of an oncoming express train.

Looking back at Cora’s confusion, emotional lability, and switches between immobility and overactivity, I came to see that she had a textbook case of uncomplicated catatonia. Few readers of this blog will know what catatonia is, as it has supposedly vanished, even though 50 years ago up to 15% of patients in asylums were estimated to suffer from it, and it was one of the most horrifying mental illnesses, with a much greater fatality rate than any other disorder except General Paralysis of the Insane (tertiary syphilis). While mental health professionals are aware catatonia is listed in the DSM, few would spot a case if faced with it.

If Cora had a rare condition that doctors do not now need to recognize, if she was the exception that proves the rule of medical progress, she would have been unfortunate. But in fact up to 10% of patients going through mental health units in America and worldwide still have the features of catatonia – if they are looked for (Chalasani et al). Sometimes the only condition they have is catatonia; other times catatonic features complicate another disorder and resolving the catatonia may make it easier to clear whatever other problem is present. But almost no-one thinks of catatonia and so, like me, they miss the diagnosis. Cora was given antipsychotics, which are liable to make a catatonia worse. She died when a few days’ consistent treatment with a benzodiazepine would almost certainly have restored her to normal, making her death scandalous rather than accidental.

But the benzodiazepines are a group of drugs that are no longer on patent, and no company has thus any incentive to help doctors see what might be in front of their eyes when it comes to a disease like catatonia. Instead, all of the pharmaceutical exhortations are to attend to diseases for which on-patent drugs are designed, even if this means conjuring diseases out of thin air—disease mongering—such as  fibromyalgia, to market  on-patent medications such as Pfizer’s Lyrica, or restless legs syndrome, a disorder conjured up as a target for GlaxoSmithKline’s Requip (ropinirole).

Catatonia and other vanishing diseases are part of the “opportunity cost” of disease mongering, lost in the chatter about disorders that match up with on-patent drugs.

No one has any idea how many versions of Cora’s story play out in daily clinical practice — versions in which the diagnosis of a treatable disease goes unnoticed by doctors pleased with themselves for making a fashionable diagnosis like fibromyalgia and who, even in the face of treatment failure, will add ever more on-patent drugs to a patient’s treatment regimen rather than go back to the drawing board and look more closely at the patient in front of them. Once upon a time the height of medical art lay in being able to go back and look at cases afresh and match the profile of symptoms against less fashionable or apparently uncommon disorders – no longer.

The dark side

Studies this week in BMJ and BMJ Open linked benzodiazepines to an increased risk of developing dementia and early death. For many the benzodiazepines like Valium remain much darker drugs than Prozac, Cymbalta, Pristiq and other drugs. The risks of getting diagnosed with dementia are quite likely to turn out to be much higher in those given an antidepressant than in those given benzodiazepines and the risks of suicide and premature death are certainly greater on antidepressants. The antidepressants are in many ways much darker drugs than the benzodiazepines. We need to find a way to bear this in mind while still holding on to the idea that for the right person either of these drug groups could be life-saving.

Cora’s story can be found in Pharmageddon which was written as a tribute to many who have died like her and especially to the people, mostly women, who have campaigned to make treatment safer for all of us.

RxISK Stories: Gambling on the Side Effects of Antidepressants – Does Pfizer Play Dice?

Editorial note: This post also appears on RxISK.org and can be viewed here.

This piece by Daniel O’Sullivan was first posted on Crikey.com. Our interest was stimulated by a query to RxISK from Daniel who had been told by the Australian regulator (the TGA) that they only had one report of this. Looking for gambling in RxISK, gives 1 case in Australia, but 4 cases of pathological gambling – more than from all the rest of the world combined, and 8 cases of impulsive behavior. In the FDA database, there are many more reports from the US and Europe with a Proportional Reporting Ratio for impulse control disorder of 11.2 and for impulsive behavior is 10.0. These are very strong signals.

This illustrates how RxISK can be useful for anyone interested in the effects of drugs including journalists – once RxISK reporting takes off we will be able to tie reports not just to Australia or the US but to Charlotte and Tampa, and Brisbane. It also illustrates that you cannot depend on the word of regulators – you need to research for yourself. It is not a lie that there is only one report of gambling on Efexor in Australia. It also clearly is a lie that there is only one report of gambling on Efexor in Australia or at least deeply misleading.

Betting your brains on antidepressants

(Click on the image to read the text)

In June last year, three months into a prescription for anti-depressant drug Efexor, former financial analyst Tim Hillier left his hotel to wander the empty streets of Alice Springs in an attempt to clear his head. An hour earlier, he had wagered $80,000 — almost the entirety of his life-savings — on a first-round Wimbledon tennis match featuring Aussie hope Sam Stosur.

With Stosur faltering in the opening set, Tim knew he should be sick with panic. Instead, the fear just gnawed away at the fringes, relegated to the background by a thick, medicated haze from the Efexor intended to dull his severe obsessive compulsive disorder. “I was walking the streets just thinking ‘f-ck, have I actually placed this bet?’,” Tim said. “Have I actually wagered all this money on a single tennis match?”

“Paul”, a father of two from Adelaide, took Efexor for almost three years after being diagnosed with depression on his first visit to a psychologist. Initially hesitant at jumping head-first into the world of anti-depressants, Paul was reassured by his doctor about Efexor’s high success rate. But Paul too began to suffer crippling gambling addiction.

“It’s not a targeted drug, it doesn’t target depression specifically, it targets everything. It takes away all of your feelings, so you become a shell of a person. You’re still able to function, but you just don’t feel anything, you don’t feel any fear of consequences at all,” he said.

Paul and Tim, both in a search to understand their unexplained gambling binges, came across an online discussion thread entitled “Efexor and Gambling”. The thread, first started in 2007, reads like the rawest form of group therapy as strangers congregate to offer up accounts of reckless and compulsive behaviours acted out while being prescribed Efexor. There are tales of thousands of dollars frittered away on pokies machines, on casino floors and at the track, stories of ruined relationships and shattered careers. The common theme is an unexplained and seemingly unnatural disregard for consequences.

Jolted by the possibility of a link between his destructive behaviour and his long-term medication, Paul decided to seek more information from Efexor manufacturer, Pfizer. When he contacted the pharmaceutical giant directly, he was met with a surprising admission.

“I contacted Pfizer and I asked if they knew that Efexor could possibly cause gambling and sexual misconduct and they responded with, ‘oh yes we knew that, 0.8% of people will get that’,” he said. Pfizer informed Paul these dangers were presented as a possible side effect in the medication packaging under the umbrella term “uninhibited behaviours”.

“How am I supposed to know what an ‘uninhibited behaviour’ was?” he said. “What a cloaking of an evil thing is that? That could be me parachuting or hang gliding or running down the beach with Speedos on! How was I to know it was going to be the type of addictive behaviours that would ruin my life?”

Efexor, first introduced to the American market in 1993, is now well established as one of Australia’s most commonly prescribed anti-depressant medications with more than 1.2 million prescriptions serviced in Australia in the past 12 months. At low and moderate doses, it acts only on the brain’s mood control neurotransmitters, serotonin and norephinephrine. But at high doses of over 300mg a day it also effects a third neurotransmitter called dopamine, which is responsible for reward-driven behaviours and has been associated with risk-taking behaviour and addiction.

It’s this dopamine effect that can cause problems, according to world-renowned psychiatrist, psychopharmacologist and author Dr David Healy. “When Efexor is taken at high dosages it triggers a flood of dopamine and becomes what we call a ‘dopamine agonist’. This can be responsible for the types of dangerous impulsive behaviours.”

While dopamine agonist drugs, such as Pfizer’s Cabaser, have been successful in the treatment of neurological disorders such as Parkinson’s disease, they made headlines in 2010 when hundreds of Parkinson’s sufferers filed a class action against pharmaceutical manufacturers after allegedly becoming addicted to gambling and pornography due to their medication.

A data-based research paper published on www.davidhealy.org by Dr Sarah Richards called “Dopamine Agonists for Takers” identifies the major risks associated with dopamine agonists as “uncontrollable gambling, hypersexuality, shopping, binge eating and other behaviours collectively referred to as Impulse Control Disorders (ICD)”.

In the same paper, Dr Richards describes the attempts by pharmaceutical manufacturers to disclose the risks related to dopamine agonists to patients as “shameful”. It’s a valid assessment, says Dr Healy.

“Pharmaceutical companies have absolutely not done enough,” he said. “They have seemingly gone out of their way to deny that such effects could be happening.

“There is a management of adverse effects that at times seems aimed at closing off all loopholes from reporting. Companies are better placed than anyone to bring hazards to light but they seem to go into denial mode instead.”

While declining to comment on a possible link between Efexor and ICDs, Pfizer’s Amy O’Hara maintains all product information provided to doctors and patients is correct. “Pfizer rigorously monitors the safety of its medicines and works with the Therapeutic Goods Administration to ensure that the product information for doctors is up to date … based upon clinical trials and post-marketing surveillance,” she said.

Dr Jon Jureidini, spokesman for the global collective of health professionals Healthy Skepticism, believes it’s this “post-marketing surveillance” that is being neglected. While figures supplied by the TGA show that only one out of 1451 registered adverse reactions relating to Efexor actually link the drug to pathological gambling, Dr Jureidini believes patients aren’t getting the full picture.

“The TGA spends a lot of its money on assessing and improving new drugs which they need to do, but they don’t spend enough proportionately on monitoring what’s in existence,” he said. “The amount of people that test the drug in the research phase is minuscule compared to the amount of people that take the drug when it has gone to market and the reality is, about half of the serious side effects don’t emerge until after the drugs have been on the market for a couple of years.

“It is frustrating that the burden is then put on individuals to monitor adverse affects of drugs instead of regulatory bodies.”

Paul is certainly frustrated. “I can almost understand it from my doctor’s point of view, they get sold all these drugs by these salesmen who give them pens and pads and showbags and probably take them off to Paris once year when they’ve reached certain targets. They get told it’s a great drug by these reps, they don’t actually get emphasised the dangers that can happen — the type of things that happened to me,” he said.

According to Dr Jureidini, the cosy relationship between pharmaceutical companies and doctors is not fuelled by money but is more subtle. “Most doctors are honest about that and wouldn’t accept bribes,” he said, “it actually involves helping their careers along and mutually beneficial research education opportunities.

“It is [these types of relationships] that are going to lead to doctors choosing certain drugs just because they’ve got a free hand to hand [sample] when that might not be the best choice for the patient.”

Dr Michael Baigent, national clinical adviser for depression initiative beyond blue, disputes the notion of undue influence wielded by pharmaceutical manufacturers such as Pfizer.

“There are safeguards in place via the TGA and the Pharmaceutical Benefits Scheme, so there is a lot of pressure on them to be very, very open and forthcoming about any side effects,” he said. “Also, most doctors and most clinicians when they have time with the patient will go through and mention side effects that are commonly experienced, but they may not talk about side effects that affect one in 50,000 because the list is long and it can be very hard to actually go through them all.

“The expectation is that the people will actually have a look at the sheets of the information that go out with the boxes of medication.”

While Dr Baigent is supportive of the current regulatory system, he believes there is still a long way to go in the research and development of anti-depressants in Australia.

“There are two big concerns in this area in my view,” he explained. “One is that people will be prescribed the medication that might not need it. And the second one, which is just as a big a concern, is that people who will really benefit from it — and it would be lifesaving — will not receive it.”

Dr Baigent’s dual concerns are perhaps best reflected in the fortunes of two men inextricably linked by an Efexor prescription and the same fateful Google search.

Almost a year since he gradually weened himself off Efexor, Tim has yet to lay a single bet. But despite conquering his gambling demons, he remains enslaved to the OCD that has dictated most of his adult life. The ongoing search for medicinal help and a shot at normality continues.

“For me, the loss of the money is really a secondary issue. If someone said to me they could take away my OCD for $80,000, I’d do it in a heartbeat,” he said. “I often think it would be nice for once to pursue something that’s going to bring me a little bit of joy rather than just moping around and feeling shit all the time … there needs to be a point to it all at the end of the day. You need a bit of hope and something at the end of the rainbow, otherwise you can lose heart.”

The flipside of the same coin is family man Paul, who remains entrenched in his own, very different, battle for normality.

“I would never ever take an anti-depressant ever again,” he said. “To be honest I don’t think I even needed it to begin with. I was just expecting to be laid down on the couch like they do in the movies, but I came out with a prescription for one of the most powerful anti-depressant drugs there is.”

Four months since extricating himself from Efexor, Paul is still attempting pick up the pieces of a life decimated by ICDs. “You don’t fix three years of that type of behaviour in three months,” he said.

“It’s really the family side of things, its healing the wounds there that is going to be the big thing, I might not be able to keep the family together. I’ve got a wonderful wife and I’ve got to fight for that.”

Now firmly in recovery mode, all that is left to ponder is the endless parade of “what-if” scenarios.

“I honestly believe I just needed a pep talk, I needed to be told to “do a bit of exercise, change your diet, drop the beer, get on with life”. That would have been so much cheaper and easier in the long run.

“And I think that if Pfizer’s aim wasn’t just to get Efexor to the marketplace as quick as possible and they had of invested another half a billion dollars,” he considered ruefully, “they could have come out with a perfect drug.”

[Details of this article also appeared on ABC News]

Illustration: Betting your brains on antidepressants, © 2012 Billiam James

RxISK Stories: The Myth of the Magic Bullet – Flox Tox

This blog post has first been published on the RxISK.org website and can be viewed here.

In July this year, Antimicrobrial Agents & Chemotherapy had an article – Fluoxetine is a Potent Inhibitor of Coxsackievirus Replication by Zuo J, Quinn KK and colleagues. “No antiviral drugs currently exist for the treatment of enterovirus infections, which are often severe and potentially life-threatening. Molecular screening of small molecule libraries identified fluoxetine, a selective serotonin reuptake inhibitor, as a potent inhibitor of coxsackievirus replication. Fluoxetine and its metabolite norfluoxetine markedly reduced the synthesis of viral RNA and protein”.

Another blog on the latest developments recently billed both Prozac and Zoloft as anti-microbials.

These come over as good news stories. That wonderful little Prozac, see what else it can do, isn’t it smart? Except the definition of a smart drug – a Magic Bullet – is that it should only do what it is told to do. Evidence that Prozac or Zoloft do more indicates they may be poisonous rather than medicinal. If we turn the story on its head, the problem may be a little clearer. If an antidepressant can be an antibiotic, what might an antibiotic do, and would we like it? If smart drugs do just what they are supposed to do, the fluoroquinolone antibiotics are in the running to be the dumbest drugs ever.

Myth of Floxing

Joanne’s story

In April 2011, I was prescribed Cipro for an uncomplicated, routine Urinary Tract Infection. After only 6 days of 250mg twice daily, I was suddenly hit with a host of symptoms. Within two hours I went from being a healthy, 49 year-old to someone mutilated from head to toe, fighting for my life. My life has changed irreversibly. I have medical documentation of partial paralysis, head to toe tendon damage, hearing loss, heart murmur, kidney and liver damage, erythema multiforme, extreme food allergies.

I was initially told that these symptoms, especially appearing collectively, was “rare”. While this did little to help me, at least I thought I was just unlucky. Imagine my horror when I found that, even using conservative numbers, hundreds of people are poisoned from fluoroquinolones each year with the same devastating result I endure. Not only are there countless scores of FaceBook, YouTube, and blogs on the internet from people with crippling stories almost exactly like mine, there are many people I have met within just my local area that are suffering in this same way.

There is ample documentation to show that the FDA knows that these effects appear syndromically. The FDA knows the devastation caused by fluoroquinolones. Yet, the FDA allows these “medications” to be used in a flippantly casual manner by unknowing doctors with only a black box warning of possible tendon damage. Possible tendon damage implies a bad case of tennis elbow or, at worst, a rupture of the Achilles tendon. Nothing can explain my terror at suddenly having every tendon in my body as fragile as wet tissue paper. Nothing can explain the heartache of having to be fed like a baby by my eight year-old child or being unable to use the bathroom without the assistance of others. Although I have made improvements in the last seven months my chance of complete recovery, based upon expert information, is almost non-existent.

MedWatch, as it currently stands, does not work as an accurate reporting system. It requires doctors to report on their own errors. If physicians recognized the error, it is doubtful they would have made it in the first place. My PCP is a conscientious physician but just did not have enough information on the effects of fluoroquinolones. He reported to MedWatch that I was “recovered” only about 10 weeks out from the onset of my initial symptoms because I was no longer using a wheelchair full-time. He simply could not believe that the plethora of symptoms I suddenly had could be caused by a drug. I have to agree that it is completely unbelievable that anything so dangerous would be out on the market.

The subsequent specialists I now see: cardiologist, nephrologist, endocrinologist, immunologist, orthopedist, GI specialist, neurologist, physical therapist, etc., feel they cannot report my symptoms to MedWatch because I was not under their care at the time of the poisoning and, so, cannot confirm the cause and effect.

There is no established first-aid protocol for those poisoned by fluoroquinolones. We called the Poison Control Center. They confirmed that the effects I was experiencing were caused by Cipro but when we asked what to do they said, “Well, if you rupture, go to the emergency room.” This was not helpful. My doctor also prescribed NSAIDS. Not only should physicians be informed that NSAIDS and steroids are contraindicated, there should be an intervention that includes the immediate administration of antacids or something to bind the remaining fluoroquinolone in an attempt to reduce damage.

Truth of Floxing

Erin’s story

May 5, 2004. I was having dinner at Le Cirque at the Belaggio Hotel in Las Vegas. I paid the price for 6 years. Eight hours later I was rushed by the hotel security to a cab because they didn’t think an ambulance would get there in time to save me. The description of what Ecoli is like is too gruesome to share. I was taken to the ER and shot up with Levaquin. The E-coli nightmare stopped. I was to take 500 mg twice a day for 7 days.

OK, I can do that, not a problem. I slept for 4 days straight in a hotel room and boarded a plane and went home where I was kept on Levaquin for a total of 14 days. I could not get out of bed for 2 months. No one recognized me because I looked so deathly. I was sure it was the E-Coli. I struggled with the diarrhea and cramping, the rashes, the memory loss, sore body and broken mind. Then the eight month came. It began with itching and my lips and eyes swelling shut. Well, I do have allergies so maybe that’s it. I began to have severe reactions to every food I ate so I became very selective. As my food choices narrowed my diet adjusted and I eliminated almost everything.

Doctors had no idea what this was and kept giving me cortisone shots and telling me to take Advil for pain. They knew as much about Levaquin as I did. I had developed full blown angioedema, a life threatening condition that makes everything from the neck up swell so badly that the windpipe can swell shut. I couldn’t go anywhere. I needed to be within 15 minutes of a hospital at all times. I was down to being able to eat rice, milk products, apples and green vegatables. I did this for 6 years. No meat, a very hard task for a carnivore like me. I was lucky enough to have a good marriage. My husband watched me go through all of this in disbelief but gave me complete support.

Then after 6 years without any sign it was going to happen, it did pass. The constant burning of my neck and face and the looming threat of the angioedema quietly came to an end.

Three months later I ended up in the ER with a nasty case of cellulitis. I have run out of standard antibiotics due to severe allergic reactions and so Levaquin, once again was the drug of last resort. After my very verbal protest as to how horrible my last round of Levaquin was the ER doctor actually told me that it was this or nothing at all. It was actually the only drug that could get me out of there with a pill rather than an IV administered drug that had to be done once a day for 4 days as an out patient. Cost is everything here. With the thought of losing my leg, I said OK, maybe this time it will be better.

I could not have been more wrong. I took one pill and immediately checked out mentally. I have very few recollections of the 7 days of 500 mg once a day. All I knew was that I was determined to finish this pill and go on with my life. My symptoms on the medication ranged from extreme nightmares, depersonalization, inability to sleep, anxiety attacks, missing time, delirium, fever for 2 hours after I took the pill, then dropped to 96.2 degrees and I was unable to get my body temp up, frozen to the core, inability to empty my bladder, itching, tinnitus, hair falling out, burning skin, broken teeth both times, irregular heartbeats, shaking so bad that I could barely feed myself, semi-hysteria, depression, suicidal thoughts, my skin literally hung from my bones due to collagen degeneration. I lost 15 pounds

I now have to wear glasses because my vision was damaged. My bones hurt. My tendons snapped. My body ached. My joints swelled. A week after I stopped the meds, I suffered a severe tendon pull from opening a bottle of water. The same arm had tendonnitis of the shoulder and felt like it would fall out of the socket. I could not extend my arm for 3 months. It burned like fire from the pull and my elbow filled with blood. My thyroid seemed to stop working as all of my hypothyroid symptoms returned on top of the Levaquin induced symptoms. The first two month after the discontinuation of the drug was hell, really hell. My blood pressure was so high it terrified my doctor. I was a stroke just waiting to happen.

It took me four months to regain my memory. I still remember very little of the floxing week. I do remember freaking out over the periods of missing time. I did tell everyone around me that I was having dark thoughts and voices telling me to kill myself. Fortunately, no matter how out of my mind I am, I know in my soul that God determines my check out time, not me. I now know that I probably had a small stroke as I could barely talk for almost a month.

It has been almost 2 years. Here’s the good news. The first time I was poisoned I knew nothing. I did everything wrong and allowed doctors to do everything wrong to me. The first time I was given 3 cortisone shots for the rashes and told to take Advil for the pain. A more appropriate recommendation would have been to dowse myself in gasoline and have a cigarette.

References

1. Fluoroquinolone-induced suicidal ideation
https://www.deepdyve.com/lp/elsevier/fluoroquinolone-induced-suicidal-ideation-LfMBv3r2mB
A case study about man who became suicidal after being given fluoroquinolone. The introduction notes that adverse CNS reactions to FQs affect up to 1in 25 patients, with severe problems affecting 1 in 200.

2. Fluoroquinolone therapy and idiosyncratic acute liver injury: a population-based study
http://www.cmaj.ca/content/early/2012/08/13/cmaj.111823, published Aug 13, 2012: “Fluoroquinolones are among the most widely prescribed antibiotic agents in North America, and the use of broad spectrum fluoroquinolones such as levofloxacin and moxifloxacin is increasing. Despite their popularity, safety concerns have led to the restriction and, in some cases, withdrawal of several members of this class of drugs… The varied and unpredictable nature of these adverse reactions has led to the ongoing scrutiny of the entire class of drugs.”

3. Based on number direct reports to FDA in 2011, Levaquin is FDA’s 3rd most dangerous drug.
QuarterWatch: http://www.ismp.org/quarterwatch/pdfs/2011Q4.pdf

Illustrations: The Myth of Floxing and The Truth of Floxing, © 2012 Billiam James

RxISK Stories: Facts About FACS

epilepsy

This blog post has first been published on the RxISK.org website and can be viewed here.

Janet’s story

I was diagnosed with epilepsy at the age of 14. After trying different drugs my seizures were controlled by a combination of Phenytoin (Epanutin) and Sodium Valproate (Epilim). What they didn’t tell me was that Sodium Valproate carried the highest incidence of birth defects to the unborn baby. In my ignorance I continued to take the drugs in all of my pregnancies thinking I was doing the best thing for my child.

Fetal AntiConvulsant Syndrome (FACS) has been known about since about 1968 and Fetal Valproate Syndrome specifically was first talked about in a 1980 journal paper. Latest figures conclude that up to 40% of babies exposed to sodium valproate will develop neurological defects.

I had the first of my four children in 1988. I was told about risks like hare lip and cleft palate and spina bifida, but I was also told that it would be safer for me to remain on my medication. I was scanned more often than normal throughout the pregnancy to check for these risks. All of my children seemed normal. I had my last child in 1999, and not once in all that time was I told of the potential risks to my children. I believed them to have been unaffected by my drugs because they didn’t show any of the classic problems – like spina bifida.

My younger two had health and behavioural problems from birth. It was as they grew that their problems with social interaction and communication brought their many other problems to light and showed me that my older children had in fact also been affected but not so obviously. My two youngest have been diagnosed with Autism as part of FACS and are both statemented into specialist schools in different areas. The problems with social interaction left them isolated and depressed in main stream primary education. They lead lonely lives with few friends. They also have asthma, bowel problems, joint pain, problems with memory, attention and concentration, sleep problems, sensory issues and more.

One of the hardest things for them has been the fact that they can communicate verbally and look like any other child but their cognitive ability and comprehension is poor and this leads them to get stressed and confused. They don’t show their emotions facially and don’t say when things are too much for them – instead they have a melt down or get very upset. This has led them, and us as a family, to become socially ostracised in the neighbourhood. There is a lack of knowledge and understanding that makes other people judge you poorly as parents. It leads to bullying also. I remember one time when our son came home saying his friend couldn’t come to tea as her mum thought our family were ‘weird’!

I heard about the condition from an Article by Janet Williams from OACs (the Organisation for AntiConvulsant Syndrome – http://www.oacs-uk.co.uk/) and from FACT (http://www.fact-uk.co.uk/) about the litigation. I heard nothing from the medical profession. It was through OACS that we were seen by top geneticist Peter Turnpenny who diagnosed my youngest two with FVS (Fetal Valproate Syndrome).

As a mother you feel guilty beyond belief, but also so angry and you don’t know how to deal with those emotions which can be so destructive. I decided to join OACs  to meet and help others in the same situation. Last year we founded FACT in the hopes that we can raise awareness and get the government and drug companies to accept responsibility for the fact that the warnings were not given and 1000’s of children will need lifelong support as a result. The numbers continue to grow as the drug is still being prescribed not just for epilepsy but many other conditions also like bipolar disorder, depression, blood pressure, headaches etc. Latest figures estimate that the numbers of children affected are potentially growing by 1354 each year (these are calculated by our medical researchers based on latest available data).

Because of the lack of awareness and knowledge many children are being wrongly diagnosed with Autistic Spectrum conditions or they are classed as naughty children caused by bad parenting. There are incidences of Social services accusing families of child abuse because of their lack of awareness of the condition which then adds to the pressure already felt by the parent. Many families exist on benefits as the mother already has a disability of her own and because of the lack of warnings many families have more than one child affected and the parents become full time carers. We as a family have been criticised and questioned by the authorities so much and had such little support that it has resulted in my husband also becoming ill due to the stress. Many couples don’t survive.

We are working to increase awareness within the government, health and social care, and education. By doing so we hope that the children affected can then receive the lifelong support that so many will need. We have parents and parent groups across the globe and have several MP’s supporting us as we set up an All Party Parliamentary Group to lobby about the Syndrome within Parliament. We have already attended and are due to attend meetings in Whitehall to bring the Syndrome to the attention of the relevant people and we are being guided by the Thalidomide Trust on our journey.

Janet Stockley-Pollard

RxISK response

Just this week Chemie-Gruenenthal, the makers of Thalidomide have been in the news.  They have asked for forgiveness. All the indications are that Thalidomiders would be prepared to forgive but believe that the asking is hollow if the company are not prepared to say what happened in the first instance. And they aren’t. There is still a veil of secrecy over the origins of the drug, and the extent to which the company both hid problems they became aware of and marketed the drug despite growing evidence of a problem.

Just this week, the Lancet has run a self-congratulatory editorial whose primary author appears to be A Breckenridge, now head of the MHRA (Britain’s FDA), who previously had links to many of the major pharmaceutical companies including GlaxoSmithKline and who has been a vocal defender of drugs like Seroxat-Paxil in the public domain right up to the moment when it became illegal for the company to defend certain issues further. The editorial gives the impression that nothing like Thalidomide could happen again. Janet’s story gives the lie to this.

Just a few weeks ago, Martha Rosenberg posted an interview with Ronald Kavanagh, a former scientist at FDA, who makes a strong case that if Thalidomide were ever to happen again, the FDA would not act. And many drug company personnel are on record stating that if disasters like Opren-Oraflex were to happen again that companies have gotten so good at “managing” problems, they could keep the drug on the market for ever.

Meanwhile, in the United States GlaxoSmithKline have resolved a series of birth defect cases linked to Paxil-Seroxat apparently to the tune of over $1 billion. Other SSRI companies face the same. There is clear evidence that these drugs also lead to substantially increased miscarriage and voluntary termination rates and growing evidence that they lead to behavioral delay and other abnormalties just as anticonvulsants do, but FDA and MHRA do nothing.

RxISK Stories – Azathioprine Withdrawal

Crohn's Disease

This post was written by Ken Spriggs and comes from his DIYEHR (do it yourself electronic health record) site, and has first been published on the RxISK.org website. If you would like to comment on this post, please do so using this link. It brings out nicely how some people are only aware of the problems their drug causes when they stop. This is particularly true for people taking statins, but can be found taking anything from aspirin to azathioprine. Poison is an emotive word but all drugs are poisons which taken chronically will poison. Think arsenic; when taken in the short-term it clears skin and eyes but long-term not so good.

I found myself browsing the second or third page of azathioprine related google results and an abstract about withdrawing from azathioprine when Crohn’s is in remission. It’s personal because I’m someone who stopped taking azathioprine against the advice of my physician. I ended the drug about 15 months ago and I’ve not only remained in remission but I no longer have to deal with the side effects. There’s a lot I’d like to discuss about the article because I disagree with the conclusion and would like to question their process as well.

Title: A Randomized, Double-Blind, Controlled Withdrawal Trial in Crohn’s Disease Patients in Long-term Remission on Azathioprine Source: Gastroenterology – June 2005 (Vol. 128, Issue 7, Pages 1812-1818, DOI: 10.1053/j.gastro.2005.03.031)

Here’s a link to the full article and below is the abstract in its entirety. See what you think:

Background & Aims: An open study reported that patients with Crohn’s disease in remission who have taken azathioprine for longer than 3.5 years are at low risk of relapse when azathioprine is discontinued. To confirm this observation, we performed a multicenter, double-blind, non-inferiority withdrawal study.

Methods: Patients who were in clinical remission on azathioprine for ≥42 months were randomized to continue azathioprine or to receive an equivalent placebo for 18 months. The primary end point was clinical relapse at 18 months.

Results: Forty patients were randomly assigned to receive azathioprine and 43 to receive placebo. Characteristics of patients at entry were similar in the 2 study groups. At 18 months, 3 patients had a relapse in the azathioprine group, and 9 had a relapse in the placebo group. Kaplan-Meier estimates of the relapse rate at 18 months were 8% ± 4% and 21% ± 6%, respectively. The hypothesis that placebo was inferior to azathioprine was not rejected (P = .195). Among the baseline variables, C-reactive protein level >20 mg/L, time without steroids <50 months, and hemoglobin level <12 g/dL were found to be predictive of relapse in the multivariate analysis.

Conclusions: This study shows that azathioprine withdrawal is not equivalent to continued therapy with azathioprine for maintenance of remission in patients with Crohn’s disease who have been in remission on azathioprine for ≥3.5 years. Thus, azathioprine maintenance therapy should be continued beyond 3.5 years.

Ok so I had to read that last sentence twice because it doesn’t seem to go with the rest of the abstract. To me it looks like in the placebo group there were 34 out of 43 which didn’t relapse. That’s phenomenal! That means 79% don’t need azathioprine! Yeah! No more achy joints, nausea, fatigue, diarrhea, trips to the pharmacy, money spent, blood tests, not to mention azathioprine is listed as a carcinogen.

Let’s look at the azathioprine group, they experienced 3 relapses out of 40. If you apply that knowledge to the placebo group it implies that not 9 people relapsed because of azathioprine withdrawal but only 6 relapsed. Three, we expect, would have relapsed anyway. This means we should expect 37 out of 43 to remain in remission. That changes the 79% to 86%! Even better!

Based on the evidence here’s the conclusion I would think is more responsible to give a Crohn’s patient: There was as trial done which included a fairly small number of patients and it showed that if you’ve been in remission (a Crohn’s Disease Activity Index  score of less than 150) for at least 42 months and are still taking azathioprine then you can consider stopping. You stand an absolute chance of 9 out of 43 (21%) of coming out of remission but only a 6 out of 43 chance (14%) of coming out of remission because you stopped azathioprine.

Contrast this with their conclusion: “Thus, azathioprine maintenance therapy should be continued beyond 3.5 years.”

If you didn’t get my point think about it this way. Suppose you had a treatment which worked for 79% of patients and it had no side effects to speak of. Would this not be a wonder drug? Of course it would! Call the marketing department, this one’s gonna be an easy sell! In this case the “wonder drug” is NOT taking the azathioprine and, unfortunately, there is no marketing department to call for that.

Further consider you’re one of the 34 patients in the placebo group who remained in remission for 18 months and then your doctor tells you that you were in the placebo group but to start taking your azathioprine again. What? Would this seem like reasonable advice? There’s no possible way I’d start the medication again. Why would anyone in remission want the side effects? It’s a senseless conclusion for the vast majority of the placebo group.

To turn their conclusion on its head again, we can say that staying on azathioprine only helps about 14% of patients stay in remission.

This brings me to questions about methodology and resourcefulness. The paper acknowledges that azathioprine has side effects but it makes no attempt to quantify them. What they could have done is to ask the study participants at the end of the trial if they thought they were in the placebo group or not. It’s crazy to me the researchers overlook this. Participants could also be asked if their quality of life improved during the trial. That’s actually the most important thing of all! Suppose 79% of participants in the placebo group said their quality of life improved while no one in the azathioprine group did. (It’s also possible, though unlikely, for someone who did relapse to report that their quality of life improved. This would happen if the side effects were worse than the relapse.) But alas, this information is MIA. But why? Quantifying side effects should mean a lot to a study about a drug. It could always turn out that side effects are worse than treatment. These researchers completely ignore this possibility. Bad science.

To shore up this massive design flaw in the study participants should be asked questions about the side effects of azathioprine before the study begins, during the study, and also after.

I’m reminded of a quote by David Healy from Pharmageddon:  There is no evidence based approach to determining whether treatments have injured a patient or what to do when it happens. Why ever not?

(RxISK.org is a patient oriented organization dedicated to researching and reporting side effects.)

There’s another important issue I’d like to touch on. When I went through my simple analysis I didn’t once mention statistical significance. In order to disagree with the conclusion there was no need to think about statistical significance, we just had to count.

Now I’d like to question that perhaps the entire design of the experiment was amiss. Bare with me cause this is gonna get simple. The first sentence of the abstract says: “…patients with Crohn’s disease in remission who have taken azathioprine for longer than 3.5 years are at low risk of relapse when azathioprine is discontinued.” Why do you need statistical significance to answer this? You don’t. Instead what you do is gather a bunch of people who meet the criteria and tell them to stop taking their azathioprine. Then count the number of relapses over the next 18 months. That’s it. Really. You can then report that X% of patients relapse when they withdrew from azathioprine. If you wanted to say how many relapsed because of azathioprine withdrawal then you’d have to have one group stay on the medication and count the number of relapses. My take on the second step is to say it might be interesting to try and predict who will relapse based on bloodwork results or genetics or something related to lifestyle and diet. I’d guess the sample size of participants needed probably renders the idea prohibitive. And if a study like that isn’t plausible then the added knowledge is academic since it’s not possible to have any idea who will relapse. I think the study wasted half the participants, the entire control group isn’t necessary.

Ok so now you’re wondering why these authors with their PhD’s and MD’s did what they did. Well, they followed “This method universally used in non-inferiority trials…”. When I read something like that I’m reminded of the Sokal affair and Fashionable Nonsense. As these ideas apply to medicine Healy sums it up with this quote from Pharmageddon:

Explaining why Fisher’s ideas have such traction within medicine is not easy. Regulators have followed this line because the definition of statistical significance offers them a rule of thumb, an almost mechanical procedure that takes the place of a judgment call. For pharmaceutical companies, the issue is simple; Fisher’s ideas mean that positive effects in a minority of clinical trials can transform a weak and inessential drug into one apparently certified by science, while at the same time airbrushing its hazards out of existence.

But why do doctors follow this line? A number of medical academics have attempted to grapple with this, pointing out that current dependence on statistical significance testing has created a “junk epidemiology” in the domain of therapeutics. So Louis Lasagna, the first professor of clinical pharmacology in the United States, and later dean of medicine at Tufts University, who introduced randomized controlled trials into drug development, described the approach outlined above as “p-value madness”. For Sandor Greenland, professor of epidemiology and statistics at UCLA, “statical thinking [of this type] has produced a chronic psychosis” – by which he means that researchers relying on Fisher’s idea have lost touch with reality. Ezra Hauer, a professor of civil engineering from the University of Toronto and authority on analyzing road traffic accidents, explains that “in this manner good data are drained of real content. The direction of the empirical conclusions is reversed and ordinary human and scientific reasoning is turned on its head.” For Charlie Poole, professor of statistics and epidemiology at the University of North Carolina, “Statistical significance should be abandoned immediately and universally.” Ironically when faced with this issue in 2011, with investors’ dollars at stake, the US Supreme Court argued that statistical significance cannot be the arbiter of what an investor might deem as significant risk. But patients it seems do not have the same rights as investors.

The differences between much of clinical practice and other branches of science were starkly framed by Kenneth Rothman, professor of epidemiology at Harvard and editor of the journal Epidemiology, in a note about submissions to the journal:

“When writing for Epidemiology, you can . . . enhance your prospects if you omit tests of statistical significance… We would like to see the interpretation of a study based not on statistical significance, or lack of it, for one or more study variables, but rather a careful quantitative consideration of the data in the light of competing explanations… Misleading signals occur when a trivial effect is found to be ‘significant,’ as often happens in large studies, or when a strong relation is found ‘non-significant,’ as often happens in small studies.”

At the beginning of this post I mentioned I stopped taking azathioprine. It was about 3 and a half years after surgery and I’d been in remission the entire time. It’s been about 15 months since I stopped talking it and I haven’t felt this good since I was 17 and Crohn’s was years away from wrecking me. So here’s what makes me upset: Azathioprine has serious side effects. When I was on it I suffered diarrhea, chronic fatigue and my knees often ached as if I had arthritis. After I stopped taking the drug these symptoms cleared up in about 3 weeks with the exception of the diarrhea. I was like a new person. I went and took tennis lessons, joined a league, and started getting out of bed much easier and an hour earlier. The researchers never even tried to quantitate the effects of the drug. It was passively acknowledged at most. Side effects weren’t even considered in the conclusion. There’s probably physicians who have read this paper and they go on prescribing azathioprine even though someone’s been in remission for years. It’s sad and it’s irresponsible. Patients should demand an exit strategy from their physicians but that’s a different issue.

Lastly a few more questions to ask: What was the financial role of GlaxoSmithKline? The company was mentioned as providing the azathioprine in the form of their brand name Imuran but that’s it. Was the paper ghostwritten? Do the researchers have financial ties to GSK?

RxISK Stories: Withdrawal from Antidepressants – V’s Story

withdrawal symptoms

For the next few weeks, this blog will take a feed from RxISK.org. If you would like to comment on this post please do so on the RxISK website using this link. RxISK is open to stories from anyone on drugs who have adverse events and are in need of answers or from doctors managing adverse events on any medical drugs.

Question from V

This is what V wrote on filing a RxISK report.

I quit taking Prozac using a step-down method. Started in Sept. 2011 and finally off in January 2012. I experienced severe loss of balance early on, which progressed into full-blown ataxia & parasthesia. Have had extensive blood-testing & MRIs of brain & cervical spine, all negative! I have to believe this is a result of coming off Prozac, although most sites say the withdrawal side effects don’t last this long.

Quite frankly, I am terrified that I may never get well. I am very ADHD now, tired always, and uninterested in performing normal daily activities (I guess because everything too hard!). My family doctor is a good guy, but he (like many other docs) is clueless re SSRIs and the dangers of taking them. I am pretty much on my own with this. Any help, recommendations, or hope would be so welcome!

Response to V

The single commonest question to RxISK.org has been about dependence on and withdrawal from treatments, such as anticonvulsants, statins, diuretics, and others. (See Medicine Induced Stress Syndromes, Dependence and Withdrawal, Stopping Antidepressants, Clopidogrel Withdrawal and Azathioprine Withdrawal).

On completing the RxISK report, V scored 10 on the Terminator Algorithm. A score of 9 makes it highly likely this is a withdrawal syndrome. Our hope is that printing out a RxISK report will give people something to take to their doctor that will engage the doctor. There are an astonishing number of doctors still who do not recognize that antidepressants cause dependence and withdrawal, even though many people give convincing stories of how these drugs can be more difficult to stop than heroin, speed or other illegal drugs.

The companies knew dependence and withdrawal were a risk even before these drugs were marketed. Studies in healthy volunteers had shown convincing evidence of dependence and withdrawal in normal people after they had been exposed to the drugs for a little as two weeks. The main symptoms these healthy volunteers had on stopping were anxiety, and depression, along with dizziness and fatigue. The data from these studies is buried.

So the first thing to say to V is this is not in your mind – you need to hold on to this point during what may be a trying time. Second, not getting help for your doctor even if he is a good doctor is par for the course.

There are three key questions for each person having the problems V outlines. First what is it? Second how long can this go on for. Third what can be done to help.

On the what is it question, there are a few things that can happen other than simple withdrawal. The obvious condition in most cases will be enduring withdrawal. This almost by definition should stop at some point. But another option is a stress syndrome and no-one really knows how long these might go on for. Finally there are legacy effects.

As regards how long this can last for, I hear from many people for whom this problem has continued for some years. It may be that these people are the exception – I don’t hear from people when things clear up. What we all need is some estimate of how long these problems last on average. A complicating factor is that some of those with enduring problems slip seamlessly from withdrawal to a stress syndrome.

Based on my experience there appear to be a number of things that might help. These ideally need to be targeted at the condition they are most likely to help – withdrawal or stress syndrome. A graded program of physical and mental activity is helpful for withdrawal, stress syndromes and legacy effects. It’s almost impossible to know how helpful the various supplements sold as part of withdrawal management strategies are. They all sound like they should be doing the right thing but it is by no means sure they are.

As regards drugs treatments, it is important to get the taper right in the first instance – using liquids and taking it gradually. Tapering slowly does not guarantee success. Many people who taper extraordinarily slowly still have problems.

One option aside from taping is to switch to a low potency serotonin reuptake inhibitor, such as the anti-histamine chlorpheniramine, a serotonin reuptake inhibiting antihistamine that comes in liquid form.

Second, a triptan such as sumatriptan appears in some cases to relieve features such as dizziness and anxiety almost instantly but the relief is only temporary – while the drug lasts in the body. Restarting Prozac (fluoxetine) or another SSRI rarely does this, which is why the triptan effect is interesting. Getting a few hours benefit like this however may make it easier to carry on.

Another treatment is donepezil. This acts on the cholinergic system. Varenicline, the smoking cessation agent, also acts on the cholinergic system and may be helpful. It may be a mistake to think that these treatments help by acting on the brain. In the case of the triptans, they likely help by acting on blood vessels and on the middle ear rather than in the brain.

In the case of drugs like these, your doctor may object that this use is off-label. He may ask where’s the evidence? If this happens, you may need to find a doctor who is prepared to explore some of these issues with you.

Another source of help out there are all the people who have been on antidepressants who may have coincidentally been put on donepezil, varenicline, sumatriptan or other drugs and found that when they take these treatments their problem clears up. We need to hear from such people. The example of Anne-Marie in Out of My Mind shows what can be done.

This post with a question from V and response shows how little is actually known. RxISK would love to hear from people out there who may be able to explain just what is happening in these withdrawal and stress-states and what can be done to help. There are many programs out there offering to detoxify people. At present we have no reliable knowledge of anything that would detoxify in the sense of remove drugs that may have accumulated in bodily systems, in particular in nerve endings.

As regards supportive therapy, we are working on putting together a cognitive-behavioral approach that may be of some help. If one can be developed, this will be made available.

Finally we are interested to get other accounts of dependence on and withdrawal from antidepressants or other drugs.

In the next few weeks there will be an update covering issues such as detoxification, how your doctor is likely to react to being presented with withdrawal problems and what you can do about it.