RxISK Stories – Azathioprine withdrawal

This post was written by Ken Spriggs and comes from his DIYEHR (do it yourself electronic health record) site, and is the third in a series of ‘RxISK Stories’ taken from the RxISK.org website. 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. Ken writes:

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?

20 COMMENTS

  1. This is a very good article, because it points to that *natural* phenomena that psychiatry does NOT want to talk about? PLECEBO! What is it, and how does it work?

    Perhaps we shy away from discussing this well known phenomena because it cannot be analyzed with our deductive, cause & effect logic? Is this because its more of a whole organism response, largely mediated by the autonomic nervous system?

    “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.”

    In my own search for an understanding of this curious phenomena, and its role in my experience of bipolar disorder type 1. A *label* that perhaps I should not mention because it will have a depressing, placebo *affect* on me? Reading that I expected to improve my understanding of brain function and its role in my so-called mental illness, led me into understanding my auto nervous system, and its role in organismic functioning. Please consider;

    “A CHEMICAL IMBALANCE THEORY OF PLACEBO? – ANYONE!

    The placebo affect and the phenomena of hypnotic suggestion beg interesting questions as to what is going on inside the body/brain to produce these unusual effects/affects. Psychiatry doesn’t try to explain how placebo works because its an unusual affect which generally does not disturb its owner much, or anyone else. Yet considering the brain works through electrochemical processes, we might ask if there is a “chemical imbalance” theory to explain placebo.

    Even more intriguing is our capacity to use self hypnosis to avoid pain sensations during major surgery, such as I witnessed during hypnotherapy training in Sydney Australia. I sat in stunned silence watching video footage of a 65 year lady with a history of bad reactions to anesthesia, lie calm and relaxed through a major operation, using only self hypnosis for pain control. It had taken over a year to find a surgeon willing to perform this operation, and he was certain he would have an emergency on his hands as soon as he made the first incision. Yet with the help of her hypnotist trainer she provided her own analgesia through an hour long process, and surprised nurses with the speed of her post op recover.

    Does psychiatry have a chemical imbalance theory for any of these amazing abilities?

    So how can we affect such amazing altered states of being, and what could my examples possibly have too do with the meaning of mania? Well my quest to find science insights into my own mania, led me into neurobiology and the unconscious power of my autonomic nervous system, and its role in so-called mental illness. Eastern awareness has recognized such unconscious powers for centuries, where a less agressive acceptance of life advocates letting nature in rather than shutting her out and concreting her over.

    At Dreamhut Hypnotherapy the link between the unconscious powers of our autonomic nervous system and its ability to affect altered states is explained from a more spiritual view point, which accepts all phenomena and does not seek pathology in behaviors:

    “The subconscious has been likened to a super-intelligence, vastly exceeding the powers of the conscious mind. The subconscious, the other 90% of the mind, is responsible for a variety of functions, such as the physiology of the autonomic nervous system, our dynamism or energy, and our habitual patterns. The subconscious is the seat of instinct and intuition, the dreaming mind, and our higher human potentials.”

    The brain works in a complex process of electrochemical activity intimately connected with feedback signals to and from the nervous system. This two way feedback between body and brain cannot be ignored when seeking an awareness of affective states, normal or disordered. The lopsided search for mental illness in the brain alone is foolish, and stimulated by lazy cause and effect thinking and the accidental discovery of an introduced chemical affect. Only our dependent nature and the hierarchy of a status and rank social structure, keeps us stuck in the false belief that somehow the medical profession is sainted and beyond reproach.

    Science has its false prophet’s too, when a shining intellect is emotionally blind.

    Robert Whitaker’s exposure of the lies behind the success of drug therapy, and the way it has increased mental ill health, rather than revolutionize mental health care, paints a depressing picture of our so-called sanity. When asked to explain these shocking outcomes from 50 years of psycho-pharmacology, psychiatry replies by blaming the patients and telling us that introduced drugs simply unmask a latent illness. In the East they call this “saving face.”

    http://bipolarbatesy.blogspot.com/2011/05/meaning-and-mania.html

    • “This two way feedback between body and brain cannot be ignored when seeking an awareness of affective states, normal or disordered. The lopsided search for mental illness in the brain alone is foolish, and stimulated by lazy cause and effect thinking and the accidental discovery of an introduced chemical affect. Only our dependent nature and the hierarchy of a status and rank social structure, keeps us stuck in the false belief that somehow the medical profession is sainted and beyond reproach.”

      http://youtu.be/-yKCbnI0IjQ
      Former Paralympian Defies Labels

  2. Another thing Ken’s story teaches us is that when doctors say you must take a drug long-term or worse yet “for the rest of your life” this advice was probably not generated in a hospital clinic, but a MARKETING DEPT. This has become an economic strategy for the drug companies and a potential disaster for our health. Psychiatric patients are the canaries in the coal mine for this disaster but the majority of the population will be at risk pretty soon.

    Just recently I read the official “patient information” for the soon-to-be-released diet drugs Belviq and Qsymia. These are potentially dangerous drugs — Qsymia is half Topamax and half speed; Belviq can be habit forming and cause hallucinations — nice stuff! Each has only been shown to help you peel off about 5% of your body weight — and that’s with proper diet and exercise! For a 200-pound person, just ten pounds … if everything goes right.

    And how are we to take these pills? You guessed it: “People are supposed to keep taking Qsymia or Belviq for the rest of their lives, unless they develop side effects or have other reasons to stop,” according to WebMD.

    If penicillin were discovered today, they would declare strep throat to be a lifelong illness. Take penicillin for the rest of your life to avoid relapse.

    • Any credibility, shame and caution has been thrown out long ago by our ruling class and institutions that we are now seeing its logical conclusion. Every minute a line is being drawn in America where you are either siding with the government/corporations, or against it. Are you going to keep your head down and keep filing your papers, or are you going to engage in some form of protest or opposition? This line is becoming clearer and clearer.

      • Hi Scott,

        I think the *line* is highlighted by *stress*, as the future becomes more, and more uncertain? Stress reactions of either for or against arguing, good or bad thinking, us vs them reactions, which are hopefully pushing us towards a *realization* that physiological reactions underpin our so-called intelligent reasoning, far more of than we care to admit?

        Perhaps we are falling into Murray Bowen’s prediction that the failure of our emotionally charged reasoning, would come to head in the middle of this century? Like government reactions of buying private sector debt, for fear of the emotional backlash of letting banks & lending institutions fail?

        These actions of cover-up, of hiding structural flaws, which are a desperate effort to avoid pain, are all proposed with a posture of intelligent reasoning? Bowen suggests we suffer from *fusion* in our emotional-intelligence? That we don’t really think with clear eyes? That we all suffer from this fusion, not just *them,* and we all avoid looking within, perhaps because we’ve lost the art of *embodied* awareness? Have we fallen into a trap, of believing that we are, what we think?

        Warm regards,

        David Bates.

        • I’m not really sure what you are saying but i can elaborate on what i was trying to say. What i was trying to say is that institutions like psychiatry, our banking system and our military-industrial-complex to name a few, are not heeding any calls for reform but are entrenching itself. This entrenchment if not doubling down on their criminal activities will continue until we collectively put an end to it (if we can). The reason why I wrote this under Johanna’s thread is because big pharma and the rest of the corporate structure has no boundaries in the ways they can exploit us, like the new bogus diet pill. Their are no more impediments to big-time corporate plundering in America.

          • Hi Scott,

            What I’m saying, is about our common tendency to look at the world, and think that we really do perceive what is going on out there, and why society functions the way it does?

            Yet consider the role of *unconscious* motivations, and ask yourself if perhaps there is a system within, which creates the so-called *system* we observe, without sensing how each of us functions, on an unconscious level? Consider;

            “The subconscious, the other 90% of the mind, is responsible for a variety of functions, such as the physiology of the autonomic nervous system, our dynamism or energy, and our *habitual patterns*.

            I think these unconscious habitual patterns create the system, we call society, and we are all far less self-aware than we admit to? Keeping a focus on *them* serves the useful purpose of avoiding our own internal motivation?

            Its the *realization* of our common humanity, in the way we all function, that I think is required to change *the system.*

            Why do we take an “us & them,” perception completely for granted, without questioning the internal stimulation, to our thoughts? How many of us take language for granted, with no idea about the internal functioning of our body/brain?

            This webzine is concerned with mental health, and yet the word unconscious is hardly ever mentioned, as if we are all fully conscious and understand exactly what makes us tick?

            Perhaps its a common lack of self-awareness, which allows any person to *exploit* another? Perhaps we need to examine how we all function more with unconscious reactions, beneath our so-called reason, to explain this tendency of entrenched, self-preservation behaviors?

            My point is, that we can’t change the world *out there* without first understanding the world within?

            Regards,

            David.

          • Hi Cledwyn,

            Thanks for your comment, I do think we are in a time when unconscious motivation is starting to bite us all, and assumptions about an insightful intelligence need to be questioned.

            There’s an interesting letter in an Australian newspaper, which has sparked a debate about our preference for self soothing lies, over seeing the truth, and it relates to this issue of placebo, which nobody seems to want to address on either side of the mental health debate;

            “If only …
            IN LIGHT of the apology regarding thalidomide (”Mother’s angry tears at thalidomide apology”, The Sunday Age, 2/9), there is another article we would love to read. Datelined September 1, 2032, the article would be headlined: ”Drug companies apologise for diabetes, brain damage and deaths caused by anti-psychotic drugs”.

            The article would say that: ”A joint statement, issued yesterday by seven international drug companies, acknowledged that ‘anti-psychotic’ medications used for decades to treat ‘schizophrenia’ (a term abandoned in the early 2020s due to lack of a scientific basis) had caused neurodegeneration, diabetes, sexual dysfunction and serious heart conditions in millions of people. The companies also apologised to the families of the tens of thousands for whom the drugs had contributed to premature deaths.”

            The statement would acknowledge that ”for the last 20 years that the drugs were used – before being removed from the market in 2019 – it had been known that the drugs were only slightly better than placebo for about 25 per cent of recipients and no better than placebo for the remaining 75 per cent. The Royal Australian and New Zealand College of Psychiatrists declined to comment.”

            We just hope we don’t have to wait two decades for such a statement to be published.

            Professor John Read, University of Auckland, and Professor Philip Thomas, University of Bradford, England.”

            It seems, we take placebo completely for granted without ant inquiry into it, just as we assume that our thoughts are sound perceptions, not influenced by an unconscious emotional need? IMO The higher up the intellectual tree of academia, the more blind to unconscious motivation, most people become.

            Best wishes,

            David.

  3. I am not 100% sure I’m comfortable with this blog series. All of us discussion what the person should do without their participation feels like grand rounds to me.

    I did look at the Rxisk site and it seems to have great potential. I’d like to put together an infographic and the site might have good data to put it together. I’d like to graph all the prescribed and non-prescribed drugs our societies use and show harm vs. dependence. I have a Chocolate Fairy project where my character says, “We all use drugs, so we might as well pick the ones that harm us (personally) the least and that we can control the most.” But where do people get this info?

    Does anyone want to work with me to make a chart of drug harm vs. dependence for all drugs? Including sugar and caffeine and chocolate and psych meds.

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