The witches’ prophecy of Macbeth’s promotion to Thane of Cawdor (Baron, or Earl), as reward for his fight saving King Duncan, has only just been fulfilled. Yet he can’t enjoy the moment, as his thoughts run away with what is yet to be – their other prediction that he’ll be King. This rumination troubles him, as he contemplates murder, and all else is as nothing. Plans and possibilities take over completely.

Two decades ago fMRI studies showed the brain’s resting-state connectivity to be just as active as when deeply focused. Raichle then showed neural energy consumed, in what he termed the ‘default network’, to be just 5% below levels in tasking (considering that this organ burns one fifth of our energy, and double that in adolescence, it is a very inefficient rest). The circuits which light up are very specific, unlike noisy & chaotic concentration networks, and match those when a subject is asked to imagine their future.

“The structural-functional connectome and the default mode network of the human brain”. NeuroImage, 2013.

Humans are perhaps uniquely prospective, running simulations on future possibility whenever possible. This can lead to unfortunate consequence in failing to be mindful of the present, or leading into dangerous speculation. We had been warned: Shakespeare wrote Banquo’s lines in the scene prior warning Macbeth of temptation that ‘instruments of Darkness win us to our harm‘ over four centuries ago; and the Buddha two millennia prior. Fearful futures are often suppressed through anxiolytics such as Valium or Lyrica, to name two of the most dangerous drugs. Such abuse is on the increase, by persons feeling isolated and suffering troubling thoughts.

Society grows ever less connected, and the social media that we’ve become reliant upon has increased our Darkness. Two hour documentary ‘The FaceBook Dilemma‘ reveals our networking to be manipulated for commercial and political gain. It’s horrifying to consider Putin’s strategy of seeding hyper-patriotic groups (each either virulently pro-Clinton or Trump) to have also been used by Duterte in the Philippines, and Myanmar’s inciting genocide against the Rohingya. We connect to  groups based on agenda and issue, oblivious to their construct of a polarised and fragmented society. A deceit, but all the while we’re supposedly exercising free will in chat with these unseen ‘Friends’. Einstein was of the same mind as Donne (No man is an island…) in writing: “A human being is a part of the whole, called by us ‘Universe’, a part limited in time and space. He experiences himself, his thoughts and feelings as something separated from the rest — a kind of optical delusion of his consciousness.”

I’m following just a few on Twitter, instead. @Gergyl is a brilliant mind, and one whose climate science skills informs my winter planning too. Onetime BMJ editor Richard Smith also cleverly articulates our place in time through his blog drawing heavily on literature for inspiration. For we aren’t spatial islands, within some fixed time period. We’re inherently seeking connected-ness with others and, if the Buddhists are right, we’re spirits incarnate in endless cycles. I’m of the opinion that the past was lived (by others) so as to inform the present. Thus we evolve.

The Hon George W. Cole, cousin to my great great great grandfather.

Perhaps genealogy speaks to us. Wikipedia offers several motives for tracing ancestry, including placing one’s family in a historical picture. Unable to find a picture of my forebear Thomas Cornelius Cole, I’m nonetheless feeling kinship to G.W. Cole. Both cousins * came to Melbourne in 1840 – one a market gardener, t’other an ex-Naval Officer (from humble entry as a Midshipman).

They were bold pioneers, experiencing success and great wealth. Today’s structured society holds little respect for maverick entrepreneurs – despite business paradigms embracing ‘disruptive thought’ platitudes, I can assure you that playing the game pays out better in the end. I nonetheless take inspiration from their endeavours, and find solace for impossible morning hair as being in my genes. And this connection to past greatness helps me see into a future ripe with possibility.

 

* Presumed cousins. All from northern England, similar ages, area settled, passions eg horticulture, etc.

 

 

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Bad Medicine (part 5)

Martin Seligman’s 2018 ‘The Hope Circuit’ is his autobiographical account of the field of Positive Psychology’s (PP) evolution. As a popularly elected President of the American Psychology Ass’n (APA), despite being unpopular with legacy professorial clinicians, his object was usurp of the American Psychiatric Assn’s cornerstone: mental disorders. This other APA manages the Diagnostic & Statistical Manual (DSM), which establishes thresholds of ‘what’s normal’ in behavior and perception. The DSM pigeon-holes us, much like the museum pins taxonomy labels on insects, but PP refutes the idea of correcting faults. Better that we play to strengths, and let the defects be.

Nailed to a diagnosis

The last chapter is his epiphany – in his seventies, he realizes that he’s been wrong all along. His theory of learned helplessness had been proven in the labs – beat an animal down with inescapable suffering, and they’ll lose the will to fight their way out of the predicament. But his colleague Steve Maier turned that upside down. Our vulnerable infants are nurtured through their helplessness, but based upon success against adversity they build a neural circuit, simple neuroplasticity, that gives resilience. I repeat: we learn to thrive from achieving, else feebly succumb and remain dependent for life.

To be fair to Marty, the neuroscience had only recently matured so as to enable Maier & Watkins’ breakthrough. Though the seminal work is a dozen years old, it’ll be awhile yet before its significance drives psychotherapy dinosaurs into extinction. My personal enthusiasm is kindled by Linda Watkins’ other, amazing insight into fibromyalgia, where along with Prof Younger and Adelaide Uni’s Prof Mark Hutchinson this autoimmune disorder was attributed to the brain’s innate defence mechanism – glial response to perceived viral attack* . Sufferers can’t yet take comfort from that breakthrough, there’s more Randomised Control Trials of an anti-viral combo (IMC-1) to be done over many years.

Back to the ‘hope circuit’. By default the brainstem’s DRN produces serotonin, which calms down the ‘fight or flight’ sympathetic nervous system – but also amplifies anxiety driven by the amygdala in the limbic system. I’ll re-word that for emphasis: serotonin treats panic attacks, but worsens fear. One could ponder the backlash of research, through the likes of David Healy’s Rxisk.org, asking why antidepressants that elevate serotonin have side-effects such as increased suicidality. The simple ‘chemical imbalance’ theory has been thrown out awhile ago (don’t get me started as to whether bloods to review serotonin levels in patients should be analysed, before being handed the happy pills on a presumption of necessitating boost via an SSRI), because we’re not machines but rather systems. Tinker with one process and another will compensate. All this isn’t in the pharmaceutical company brochures, though it’s been well-known for two decades. And the growth market is for teenagers, despite halting the formation of circuits required for later resilience.

DRN hijack of emotions is dampened by previous cognitive rewards from the Pre-Frontal Cortex (PFC, the learning brain) using successful control over situations to increase kinase proteins – described as an ‘immunization’. In animal models the dissected brains are tested for a change to successfully build resilience, and in the last few years studies have been designed for humans using fMRI. Do-it-yourself at home is a no-brainer. PP gives all the tools you need to focus on success, and protect your brain: simply do the survey to ascertain strengths, then determine how best to use them. If that fails, then seek professional help… being prescribed an anti-depressant isn’t the worst possible outcome from a trip to the doctor – script for Lyrica holds that ignominy.

The 2009 Stanford study damning Lyrica as blocking formation of new synapses, connections between neurons, has been cited a further 245 times. The most recent further investigation ‘The α2δ-1–NMDA receptor coupling is essential for corticostriatal long-term potentiation and is involved in learning and memory’ describes how gabapentinoids break the hope circuit (nasty biochem, but Lyrica and Neurontin are designed to block α2δ-1 Calcium subchannels, and the PFC pathway to moderate the DRN is via ERK->NMDA Calcium channels. Please don’t ask for an explanation).

This fresh knowledge has no commercial application, PP will never be packaged in a pill (picrotoxin is used in research as an ‘anti-gabapentinoid’ to artificially create PFC->DRN control, but is deadly!). Worse, the accreditation Master of Applied PP is only taught in Australia at Melbourne Uni – where it’s sequestered away in the School of Education, not Health. An inceptual program is underway centred on Heathmont College, which follows Geelong Grammar’s wonderful work. It’s unlikely that the medical industry’s stranglehold on wellbeing will loosen without generational change through these schoolkids achieving professorship. TheMindfulGap was a partnership with my then wife, doing all we could to prepare the way for chronic illness sufferers to escape helplessness. Hopefully someday someone’s children will value those efforts.

Good luck in the meantime, Geoff

 

* So what? Well to measure societal suffering through subscribers to forum PatientsLikeMe.com, where the medically disenfranchised seek answers to their condition, 106 thousand fibromites vastly outnumber Major Depressive Disorders 2:1, or backpain 100:1, or arthritics 4:1. Great research tackles great problems.

Bad Medicine (Pt4)

cont’d

A few years back I was volunteer non-emergency driver for Red Cross ambulant patients going to clinical appointments. The car was fully booked, and the third for the backseat was my last pickup. They had an an older Left Ventricle Assist Device, with huge powerpack. “Would you all squeeze up on the backseat to make room for the artificial heart?”

Talking to the new client en route to the Alfred’s Heart Failure clinic, ‘Chris’ went to the same Uni as me. Did the same course! I tell my anecdote of mathematician Tom Peachey, how I’d been restoring an old BSA and was tardy in attendance at lectures by this angry little man. “You’ll fail and make nothing of your life, Kirwood“, but I shrugged – I was on my way to 98% … Chris agreed, Tom annoyed him too, “so I slept with his girlfriend“.

Karma. Tom may’ve been ultimately right about me, but Chris sure was heartless!

In the most privileged portion of my career, working at the HyperMed clinic with high level of autonomy in dealing with seriously ill patients, there was a fatality. The deceased, Craig, was stage9 MS, and there is no stage10. He’d been rushed to ICU repeatedly, including an airlift from the Latrobe Valley. At the committal for trial pathologist Dr Sarah Parsons claimed cause of death was “Too much oxygen“. The planet certainly would benefit if we evolved to breathe CO2 instead, and I hope her team at Monash are working on this. Sure O2 is a vasoconstrictor, which is why hyperbaric is under pressure of around 30ft underwater – every moist tissue then carries oxygen. And this isn’t quackery – Monash’s physicians at the Alfred hospital also have novel uses for hyperbaric eg adjunct therapy in cancer. Perhaps The Age journo misunderstood Sarah’s evidence (after all, she claimed I had ‘no medical background’ despite the court transcript showing I’ve two decades as a skifield paramedic and a postgrad Dip in Clinical Research)?

Craig also suffered epilepsy. Dr Parson seemingly hasn’t heard that Sudden Unexplained Death in EPilepsy (SUDEP) is actually a thing, despite Prof Chris Semsarian hailing from Sydney and his ‘Post-Mortem Review and Genetic Analysis of SUDEP Cases’ begins: “Sudden unexpected death in epilepsy (SUDEP) is the most frequent epilepsy-related cause of death and is characterized by an absence of any identifiable cause of death…” (Brain Pathology, 2010). And he goes on to point the finger at familial long QT syndrome genes.

QT-interval-long

The QT interval is the time for the heart’s ventricle to get the signal to pump, and then recharge. Long QT can cause otherwise healthy people to suddenly die, and is the #1 monitoring of concern in ‘first-in-humans’ drug trials. The anti-epileptic drug Lyrica/pregabalin is known to lengthen QT in rabbits, but there’s no data in humans. When Pfizer’s Phillip Berry was asked where’s this key safety info, the reply was Dunno. Yet he received Medicine Australia’s Code of Conduct Award in 2013! Pfizer’s chief pharmacist Manal Nessim also couldn’t help.

The US FDA’s approval letter of Lyrica for neuropathic pain section Safety Q19 “Has the applicant submitted adequate information to assess the arythmogenic potential of the product e.g., QT interval studies?” is answered NA. And Q25 “Have narrative summaries been submitted for all deaths and adverse dropouts?” is answered No (will request from sponsor).

Craig was on many drugs, including Lyrica. But the chiropractor killed him, right everyone?

Cochrane and Gotzsche

Marcellus: Something is rotten in the state of Denmark (Hamlet 1.4.5)

These words, spoken to Horatio and Hamlet as they look upon wanton and drunken behavior, which has destroyed the nation’s reputation, are apt to the sacking of Danish Prof Gotzsche by the Cochrane Collaboration – the gold standard in medical evidence. Archie Cochrane founded an independent scrutineering of medical trials in 1993, so as to impartially evaluate claims of drug efficacy. Rules and tools for trainsmashing data from systematically gathered results are intended to provide an overview of pros and cons. Peter Gotzsche was an early appointee, directing the Nordic Centre of six neighbouring countries. The last half a dozen years has seen increasingly vocal criticism of commercial influence, and doubters of the Cochrane ideal often focused on mental health solutions. Gotzsche was stubbornly strident in criticism of psychiatry, disregarding my advisory sent 5th Nov ’14 that his condemnation of the profession as being the most lucrative for industry kickbacks was wrong – per his reference it was actually 4th most (in Australia 2009), with rheumatology #1. The download of a chapter ‘Pushing children into suicide with happy pills’ , linked in the flyer for his 2015 Mentalaz tour, concludes thus: Our citizens would be far better off if we removed all the psychotropic drugs from the market, as doctors are unable to handle them.

Followon book to ‘Deadly Medicines and Organised Crime’

Not that the rheumies were off the hook. Peter’s 1989 ‘Methodology and overt and hidden bias in reports of 196 double-blind trials of nonsteroidal anti-inflammatory drugs in rheumatoid arthritis’ warned that “the quality of RCT trials in rheumatology may be so weak that it may be impossible to place any confidence in the … conclusion“. And on pg84 of Deadly Medicines “A rare admission that doctors’ opinions are for sale to the highest bidder was provided by Canadian rheumatologist Peter Tugwell, who wrote a letter to several major companies soliciting funds for CME conferences on behalf of an organisation called OMERACT: We think that support for such a meeting would be very profitable for a company with a worldwide interest in drugs targeted in these field.” Gotzsche aint a team player. Tugwell co-authored with Gotzsche, as well as 19 times with revered Cochrane founder Dave Sackett, whose HARLOTplc article at least gave humour to the reality that their business is for profit.

This month Cochrane’s Governing Board sacked Gotzsche, sparking outcry and protest resignations by 4 other of its 13 members. Six weeks earlier he’d written a critique of a Cochrane review for the HPV vaccine’s efficacy against cervical cancer. Peter’s team had worked on this since Jan 2017, when their analysis protocol was published. Points of disagreement raised were uncontroversial and moot, other than that the outcome of concern only developed after such a long time that surrogate indicators of lesions were instead analysed as being predictive of protection. Rather than dismissal being an exasperated or last straw reaction, the timing was merely coincidental. The Board’s statement informs us that lawyers had been on Gotzsche’s case since March, with a QC conducted independent review underway a month before publishing of the HPV challenge caused contention.

I suggest coincidence, rather than ruse, since the February trigger was possibly a letter attacking a Cochrane chief editor – Andrea Cipriani of the Common Mental Disorders group, over their recent review of 21 anti-depressants as being flawed and untrustworthy. However that team declare no conflicted-interest, and perusal reveals no alarming endorsements. Yet there’s no reference to the unwarranted attack or its target in the Board’s attempt at damage control – is this to protect the privacy of an innocent party, from their shaming by a woefully ill-informed press? Another, diplomatically worded re-analysis of Cipriani’s earlier 2009 anti-depressant report did highlight shortcomings of trial quality assessments, cautioning against the endorsement given for Pfizer’s Zoloft.

The muddy waters turn darkly Stygian.  Cipriani is Prof of Psychiatry at Oxford, which also homes Cochrane’s Pain & Palliative group under Prof Robert Andrew Moore (aka RAM, aka Andrew Moore), whose authoring name varies with context – independent and impartial, or sponsored spokesperson. There’s much overlap between pharmacotherapies with these groups, notably duloxetine/Cymbalta. Cochrane Editor-in-Chief David Tovey would be aware of the industry influence, since he acknowledged an email in March 2015 titled: ‘A 2nd Cochrane group is recruited’ – complaining about the rheumatology group and also including this: [Dr Nnoaham’s] 2008 Cochrane review on TENS for chronic pain and fibromyalgia was censored by your organisation’s Pain, Palliative and Supportive care (PaPaS) editors. Who are excellent examples of transparency, by not hiding their allegiances. Phil Wiffen and Andrew Moore et al chose to include a Pfizer employee in 2010 when conducting their own review into anti-convulsants for pain – surprisingly finding that “For gabapentin and pregabalin only we found reasonably good second tier evidence for efficacy..” (quoting the 2013 update). They reckon duloxetine’s pretty good too – http://www.bmj.com/content/348/bmj.g139/rapid-responses (well you would if you were paid as a consultant by Eli-Lilly, wouldn’t you?)

Grounds for disallowing Nnoaham’s complementary therapy review were that it shall be split into two reviews of TENS – one for fibromyalgia, and one for neuropathy. Except that Wiffen and Moore’s 2013 ‘Lamotrigine (an antiepileptic drug) for chronic neuropathic pain or fibromyalgia’ is an allowable combo! PaPaS also censored an unfavourable review of Pfizer’s gabapentin & pregabalin for pain relief in fibromyalgia on the grounds that lead author Nurcan Üçeyler had been paid speaker’s fees by Pfizer at neurology conferences. However Cochrane’s rule that neither the majority of authors nor the lead can be on the manufacturer’s payroll was also broken by their 2014 review into Neurontin/gabapentin, although Moore then complied in their 2017 update – by re-arranging the order of names to put Phil Wiffen first.

This is a coverup of misconduct. A façade. Gotzsche was certainly going beyond boundaries of expertise, and using his senior position within Cochrane to add weight to his personal opinions, which is contrary to the spokesperson policy allowing only statements on behalf of the collaboration. Years of emotive rants took a toll on his reputation – a tragic folly, when misconduct was there for all to see.

Disclaimer: I consider that the psychiatric profession takes prescribing of psychotropic meds VERY seriously, but worry about GPs playing at amateur shrink on the basis of dubious research evidence. I do not endorse Prof Gotzsche’s attitude, best expressed in his memo to Dr Dawson “Incidentally, I found out that some one has written about you and the way you treated my paper about the 10 myths in psychiatry. See attached [‘Asshole of the day – George Dawson MD’]”. George seems rather professional, actually: http://www.youtube.com/watch?v=ZyINjdCXkAQ

 

 

 

 

 

Excluding opium, (which the Creator himself seems to prescribe… as if it were foreseen that wherever there is hunger to be fed there must also be a pain to be soothed) … I firmly believe that if the whole materia medica [medical drugs], as now used, could be sunk to the bottom of the sea, it would be all the better for mankind,—and all the worse for the fishes. Harvard Medical School dean, 1860

This is a man who hadn’t experienced the wonder of penicillin, or appreciated commercialization of aspirin for quick and easy pain relief, so the quote from Oliver Wendell Holmes Sr is merely quirky. The opioids have become contentious today, as though dictated by fashion, but dissent on the merit of miraculous pills is a constant. Psychiatrist and pharmacovigilante David Healy wrote with exasperation on the irresponsible prescription of meds for mental health, using images of hanging victims to drive home their accompanied risk of suicidality. After an outcry his next post ‘Spectre of Dissent’ used pictures of self-immolation, such as a Buddhist monk protesting the Vietnam war, in order to emphasise the seriousness of medication harm, legally, by doctor’s orders.

Movie ‘The Constant Gardener’, based on actual events.

In 1996 Pfizer rushed researchers to trial their experimental antibiotic Trovan at a meningitis outbreak in Nigeria. Ethical approvals were forged, and the drug trial comparator was only administered at 1/3rd the standard dose. Similar numbers of recipients of Trovan died as those in the (undertreated) control group, and the FDA approved the drug for adults although not for children. Within one year, over 100 cases of acute liver failure led to withdrawal of any approval. The Nigerian govt was given $75m to settle the case. The horror/thriller plot of the film, described by its author thus: “by comparison with the reality, my story [is] as tame as a holiday postcard“, stemmed from Pfizer’s damage control by discrediting the Nigerian prosecutor – done in collusion with the US ambassador. Considering that the corpse shown hanging had their genitals cut off and stuffed in its mouth as an inducement to keep quiet, wow.

This was a human rights abuse. “Happens all the time” was the response of Monash’s School of Public Health biostatistics Professor to my concern at another atrocity. Billion dollar fines have been about as worthless as a tax on criminality. A cost of doing business. Trump’s appointee to head up the FDA, Scott Gottlieb, was universally acclaimed as a good choice. But his ‘user-pays’ concept of charging pharma for their time, $905m for reviews  in 2017, has been accompanied by a threefold drop in rejections since 2010.

Does fast-tracking approvals carry a greater risk?

Undoubtedly, yes. But that must be weighed against the harm of delay. A dozen years are easily lost between the translational research breakthrough, through safety and then comparative benefit studies, before availability to the public. The question of risk vs benefit becomes a moot point though, when regulators are not sufficiently independent from industry influence. The Drug Utilisation SubCommittee reports to PBS on the subsidies for the market, the consumer patients testing ground. It’s chaired by a Professor who’s taken Pfizer sponsorship for a study, and writes on the benefit of branded over generic, but omits mentioning the commercial conflict of interest. Double standards are rife.

State AMA President doesn’t advertise, eh?

Under AHPRA rules, testimonials are banned: no reviews, or views on a service provider. Head of Victorian AMA, Dr Julian Rait knows it’s OK for a review on a third party website that he does not control – Google reviews clearly aren’t promotional. They can be brutal. Sharing experience is very much in the public interest, and Rait’s recent reply to my memo on open disclosure (‘Duty of Candour’) was appropriately candid. Telstra’s HealthEngine is an alternative service however it is indeed an advertising & booking service, since negative reviews are edited out.
The non-response on this matter from AHPRA chair Dr Joanna Flynn (an aide stating that “All registered medical practitioners are expected to abide by the [Good practice] code)” is merely wishful. And they endorse HealthEngine’s censorship, ostensibly to remove clinical performance ratings, but in effect encouraging a smokescreen for shoddy conduct.

In the UK there’s a statutory Duty of Candour – when a medical error is made, a conciliatory conference is enforceable. It affords a learning opportunity for the contrite doctor, although apologies are non-prejudicial i.e. not an admission of guilt. Our regulatory body in Oz maintains exclusivity on registered practitioners – no public ratings, and all complaints dealt with behind the scenes. An incredible dismissal of an AHPRA complaint and then an expert physician making contentious, unsubstantiated on-air comments led to my testing procedural rigour through such a complaint. Again, dismissed as it was “reasonable for the Prof to proffer an opinion“.  Except that this wasn’t a personal, but a professional, opinion that was disparaging to complementary medicine.

Perhaps medicine will one day be called before a Royal Commission, so as to expose the kickbacks paid to advisors, much as financial services has been. I’m overwhelmed by the ‘smoke and mirrors’, and am off to do a ‘snow job’ myself. A real one, as an honorary ski patroller, at the mountain retreat of Mt Stirling. I’ll return after contemplation of humanity’s evils. Geoff

Bad Medicine (Pt3)

What does (S)-3-(aminomethyl)-5-methylhexanoic acid do for you? That depends on whether you’re a doctor prescribing Lyrica, a pharmaceutical company making pregabalin, or a patient:

Stop the drug, swelling goes.  © Canadian Medical Ass’n

 

It’s four years since my last incredulous post on the alliance between researchers and Pfizer, a collusion formalized in business collaboration at Monash University in Jun ’17. This revisit begins with the TGA (equiv to US FDA) Product Info for health professionals on Lyrica/pregabalin as of Sept ’16. The first condition of painful Diabetic Neuropathy (PDN) lists 5 completed studies in Table 1, showing pain was halved for ~26% of those administered 150mg, and ~45% if on 600mg. This would encourage doctors to increase dosage up to the maximal 600mg daily (double that allowed in the US). The most frequently reported side-effects are weight gain, dizziness and sleepiness. The manufacturer has checked on driver safety, but research simply doesn’t encompass a thought that harms should be measured systematically: Prof Nadine Attal replied to my concern with “I agree… because the methods used to assess side effects are seldom standardized, particularly as regards cognitive effects of drugs“. This is an obvious pharmacovigilance problem, but another risk lurks. Pg13 of the TGA brochure informs doctors that less than 4% of trial participants suffered peripheral oedema (pictured). None of their advice is referenced, so let’s fact-check.

Peripheral Oedema/swelling

Pfizer reported in ‘A Comprehensive Drug Safety Evaluation of Pregabalin in Peripheral Neuropathic Pain’ that they’d run 13 Randomised Controlled Trials of Lyrica for PDN up to May ’12. Somewhat surprising that the TGA only found 6, which also included independent investigations. Oedema was reported in 9% of neuropathy patients. The manufacturer paints a harms picture that’s doubly worse  than the govt regulator does! One Pfizer trial continued for another year with volunteers, of whom 16% reported oedema (10% resolved inside 2 months). Oedema is associated with congestive heart failure, so it matters. And the worsened circulation is associated with non-healing ulcers in diabetics, and that can lead to amputation. Wondering what have you got to lose by starting with this drug – a foot, perhaps? Regardless of adverse events/side-effects, stopping the drug resolves that issue – but at the end of any study there’s limited data captured on withdrawal effects.

Addictiveness

Enriched Enrollment Randomised Withdrawal is a legitimate study design, whereby everyone is dosed and only responders continue into the trial. If it didn’t work for you, goodbye. This means that the group randomized to placebo go through withdrawals, and Pfizer ran this protocol thrice (twice including DPN). After an avg of 400mg daily for a month, then 150mg for one week tapering, pain was marginally worse in the placebo group after a month. 2.5% of the Lyrica group withdrew due to adverse events compared with 6.5% of the placebo arm, hinting at withdrawals suffering. The same protocol with backpain participants finished with both groups reporting the same level of pain, although the withdrawal arm experienced worsening sooner. The endpoint is in accord with the PRECISE study’s finding that Lyrica doesn’t work for backpain.

A lengthier and larger study was run, but this time concomitant meds other than paracetamol were disallowed. Previously patients had continued their own opioids or gabapentin (a Lyrica predecessor), but now the effect of withdrawal was pronounced – some 2 months of worsened pain. Interestingly this study team included Dr Cory Toth *, who’s had 9 papers retracted due to fabricated results. The team then ran a study without Toth, which showed no benefit whatsoever for Lyrica in PDN.

 

Placebo group suffering withdrawals from run-in period

Another protocol requiring drug withdrawal is the crossover design. This study on pre-diabetic neuropathy , again funded by Pfizer, shows a pain spike lasting just 1 week upon switching from drug to placebo.

© 2016 Wolters Kluwer

Another PDN crossover study is intriguing – worse withdrawals were suffered going from placebo onto pregabalin in the first week, altho’ actual withdrawals from the drug lasted 3 weeks. Again, the outcome was of a nearly worthless drug, but it’d seem that the fear of losing relief from pain (even if just an imaginary benefit) caused hurtful anguish.

© 2015 Wolters Kluwer

An independent review aggregated 15 trials up until Mar ’16 and concluded …”an overall small effect size with significant heterogeneity in the findings. Reporting bias was a particular concern, due to the high number of unpublished studies.” The 5 TGA examples chosen in their approval decision were an obvious cherrypick of the best results from the picture, being Refs: 17, 18, 19, 21, and 22. It seems that the benefit is arguably small, and data on withdrawals is limited. A recent review on Lyrica’s abuse potential coincides with transfer to Class C schedule in the UK underway, informed by little more than frequent discovery in prisons. Public forums are informative: this group, including recreational users, has a couple of hundred user comments… http://www.bluelight.org/vb/threads/531159-Lyrica-Withdrawal/page8 ** Surprisingly, a ‘comprehensive’ report in Oct ’17 came up with only 4 reported cases of withdrawal symptoms ever, where usage had been within therapeutic guidelines. The gulf of understanding between medicine and its recipients widens. Impressive commentary from the Trump-appointed FDA head on their concern with Lyrica notes that monitoring Bluelight is a gauge of potential for abuse.

Although not the decision makers, patients were treated to $USD344m of Lyrica TV advertising in 2016 (per Nielsen). Half of which was promoting use in diabetic pain. Small comfort can be found in Pfizer’s report that glycaemic control is only fractionally worsened. I do not feel the need to examine every condition for which Lyrica is approved – one instance of systemic failure suffices. For more on the politics of pain, you’d have to ask Chronic Pain Australia’s President or Executive Director as to why they refuse to share this article with their membership: read on…. Geoff Kirwood GDip Clin Research

* Cory apologized, but whether he was ‘sincerely’ sorry is questionable (Confidence Interval bounds not given): “I am significantly apologetic”. His resignation isn’t mentioned on the faculty page, and vice-dean MacQueen accepted his declared failure to oversee his 9 instances of data manipulation. She consults to Pfizer. Scott Reuben went to jail for fraud in 21 papers, which must exceed the threshold of acceptable levels of mistakes. Colleagues Buvanendran and Kroin on Reuben’s retracted pregabalin study went on to publish a favourable study on pregabalin. Paid for by Pfizer.  However it doesn’t taint the evidence base, oh no, no, no.

** Bluelight  is dedicated to drug harm reduction, and is named after the flame of crystal meth.

 

2015 blog cont’d…. Another massive campaign to discredit the authors of the PACE study into three ME/CFS interventions is underway. Over 12,000 signed the first petition to request retraction of supposed claims that some one quarter ‘recovered’ – even though the Lancet paper clearly states potential to just ‘moderately improve outcomes’, specified per the Mayo Clinical Significance Consensus. Another lobbying is underway, so far 6,300 have signed a demand to the GMC regulators that the study doctors be disciplined – suggesting 10 years custodial penalty for the crime of Fraud. The gist of concerns is than consequent to PACE report practitioners have distressed sufferers from ME/CFS with callous disregard. Claim is even made of “… harm done to children being forced to go to school and being subject to child protection plans“. This irrational outburst references the Tymes Trust’s Jane Colby regarding the potential for healthcare authorities to intervene so as to enforce adherence to clinical guidelines after PACE recommendations.

First in GP Sarah Myhill’s complaints beginning on pg 7 of 25 are that PACE “has effectively determined CFS/ME as a psychological condition“. Recall that the interventions detailed in the Lancet article were: Cognitive Based Therapy (CBT) with a psychologist; Graded Exercise Therapy (GET) with a physio; Adaptive Pacing (APT) with an Occupational Therapist (OT); and against a control group receiving standard care from a CFS specialist. CBT and GET were significantly better for fatigue and functioning, while APT was no better than the control/placebo. The authors state clearly: “The effectiveness of behavioural treatments does not imply that the condition is psychological in nature.” Dr Myhill’s 2012 reprimand by GMC and recently concluded cautionary period must be considered in grading her opinions, when the disciplinary ruling declared: “statements in relation to contraception and breast cancer screening that were factually incorrect; clinically unsubstantiated; and contrary to national guidelines. In so doing she used her position as a registered practitioner to exploit patients’ lack of medical knowledge by arousing ill found fears for their health.” Myhill’s website promotes powerlifting as High Intensity Training – but not for ME/CFS, where diet and detox are advised. And vaccinating is discouraged.

Another line of advocacy comes from Tuller, Geraghty, Wilshire et al. The link has a number of articles, including the PACE authors’ refuting of complaints re research quality. More telling is the activist’s collated manuscript ‘Rethinking the treatment of chronic fatigue syndrome’, which begins with an allegation that the Randomised Controlled Trial did not control nuisance variables, such as contact hours. This is alarming. ‘Control’ in this situation means that the intervention was compared with a control group, not their idea that control be applied so as to enforce participant compliance. The scientific complaints differ over time, but this paper zeroes in on statistical analysis in that the published protocol considers every possible comparison between therapies, and the Bonferroni principle requires stronger levels of proof ie the more permutations (ie 6 pairwise comparisons), the greater likelihood of a random fluke (odds of 1 in 125 actually) supporting the hypothesis of a therapy being better than the control ie standard care. The pairwise tests were a change to the stats plan, by dropping consideration of combo-therapy eg is APT and GET better than GET alone etc….explained as being overly convoluted.

Access to raw data was achieved by activist’s FoI request. Looking at their re-analysis of supplied data in Table1, people improved most under two therapies. No argument. The control group also did over time, where a placebo or Hawthorne effect can result from the satisfaction of working with supportive professionals towards a solution.

To the impartial eye, CBT and GET worked ‘better’

 

 

Expert opinions and agendas at play

Independent commentators are worth noting: OT Bronnie Thompson admires the study, but is concerned that their APT protocol failed to set goals to work towards. Their envelope of maximal activity was fixed within a ‘disabled identity’ focused on what COULDN’T be achieved, a problem noticed by Prof Leonard Jason. His Energy Envelope Theory relies upon success in avoiding crashes being inducement to better achievements in future. This is similar to Feldenkrais practice, progressing away from fear of movement through progressive challenges. Medical journalist Dr Norman Swan discusses the unprecedented outrage in the patient community with a study author and journal editor, but only considers the absence of harm during the trial (1% of all treatment arms reported worsening conditions). They suggest that activists hijacking the CFS community does them harm, without stopping to think about why there is even an outcry and whether their GPs are at fault.

It is obvious that distress results from unsympathetic doctors who’ve simplified the study conclusion as “get active, get counseling, and get out of my practice“. Indeed, practitioners proudly state conviction in their ability to discern CFS patient agendas. “I often use it as a diagnostic tool for MUPS (Medically Unexplained Physical Symptoms), that I get irritated by patients.” A vulnerable population then becomes prey to peddlers of solutions that are accompanied by rather more sympathetic caring. At a patient forum Dr Daniel Lewis agreed with Tuller’s complaint that the participant inclusion criteria of ‘Oxford Research’, rather than ‘Canadian Consensus’, was the problem. They weren’t suffering real ME/CFS, whatever that is. He sells meditation courses targeting chronic fatigue or pain in general however, without quibbling about specific diagnoses in attendees. Likewise a clinician’s summit unanimously supported their client’s grievances against PACE conclusions being given as guidance to doctors.

Personal injury specialist legal firm Maurice Blackburn sponsors Australia’s Emerge ME/CFS foundation, and seeks litigants who’ve been refused disability payment. They also advertise on SBS TV, who have requested patient’s stories for a program. CFS guru Dr Jacob Teitelbaum initially took a rational stance that PACE results were being misinterpreted in the media, but five years later joined the herd by stating in his blog: “… the PACE trial that wrongly concluded that CFS patients should be treated with psychotherapy.” Other experts such as Jose Montoya just focus on their research.

The study team took the controversy onboard, replying with rational argument to editorial letters. It then seemed that the time was ripe to shoot themselves in the foot. Perhaps the declared conflicted interest of team member’s consulting to insurance companies, presumably over disability payouts, made the Lancet article just a testing of the waters. Another writeup appeared, declaring ‘Recovery is possible!’ much as Chamberlain did in saying “Peace in our time”. And war broke out.

This wasn’t the only investigation into exercise as therapy for CFS. Last year’s update to the meta-analysis of 7 trials affirmed the results, every one of them showing benefit for reported Fatigue. But once again, researchers do themselves no favours with clinicians or patients: the publishing/editorial group is Cochrane’s ‘Common Mental Disorders’ .

My thoughts

CFS is an unmet challenge to medicine. There’s no fix, only symptom relief. LowDose Naltrexone relieves the brain fog (presumed to result from glial inflammatory response), beta-blockers may be used against POTS in orthostatic intolerance (light-headedness upon arising), and supplements such as CoQ10 or D-Ribose aid mitochondrial energy production. Post-exertional malaise is a constant however, which reinforces the lost sense of identity that was once based upon our function. Patient experience is of an invariant, and lifelong struggle. For anyone else we experience affliction as mostly transitory, even chronic illness can go into remission upon treatment. They who experience anxiety attacks, also know there’s moments of achievement. Joy counters sadness, emotions rise and fall again. It is possible to mentally step back and observe thoughts and sensations that may come and go, without attaching identity or sense of self to such temporary states. This is infinitely harder when the disease is so poorly understood.

CBT and GET offer slight improvement, a readiness for future solutions rather than idling whilst deconditioning – where practitioner’s pushing of anti-depressant meds worsens weight gain. Meanwhile however, you’re powerless prey to commercialism.

Right of Reply & Disclosure

Dr Lewis’ office has never replied to my correspondence. SBS passed a message on to their producer. David Tuller wrote back that the trial authors assumption of the CFS sufferer’s [de]reconditioning biased their choice of interventions offered, which is fair comment. If only there were better answers to this perplexing problem.

I’m married to a MUPS, and like others I know well, am struck by their hitherto overachieving.