The influx of Chinese to the Californian goldfields brought with them homegrown remedies for the pain and inflammation of their labour. So impressive was the effectiveness of their snake-oil, that an entrepreneur also made extracts from the local rattlesnakes. It was ineffectual, and sales events were followed by the salesman’s hasty exit. But Chinese water-snake’s oil is 20% EPA – more than that from our preferred source of omega-3, salmon. It’s vital for the species in the cold conditions, whereas the rattlesnake’s blood has no issue with glugging up in the desert.

Why the history lesson?

It’s because Harvard Med School has just blogged that fish-oil supplements are worthless as preventatives. This surprised me, since my BP reduces markedly on the minimal dosage of 2000mg fish oil, twice that obtained from an ACE inhibitor. Sure, that’s just a surrogate outcome and not reflective of survival into senility. So is the American Heart Association to be trusted? Our Heart Foundation’s never untangled themselves from industry ties, so….

The detailed article needs to be read from bottom to top, starting with declarations of conflicted-interest. Dariush Mozaffarian has received no grants or support from industry? That’s not what Mozza’s CV says on pg8&10: $83k from Pfizer to trial Lipitor in ’02, and $5.1m from GSK & SigmaTau pharmaceutical companies to trial fish oil on cardiac patients. His collaborator on that one, Jason Wu also forgot to disclose same in the article. He’s done a lot of work with the George Institute, a partner in the Australian public’s generously sponsoring of a $5m NHMRC trial of Lipitor. Pfizer and SigmaTau also ran a 5 year trial of omega-3 supplements on twelve and a half thousand elderly patients having cardiovascular risk factors, finding no advantage conferred to survival rates. That’s a big study, and pretty generous of Pfarma.

You have to wonder: why do we pay to study Pfarma’s meds, and they pay to study the competition?

The Harvard expert Eric Rimm’s quoted in their blog: “Taking fish oil… may not only have no benefit, it may even have some risks that we don’t realize because we haven’t studied them.” And they’re the ones dismissing complementary medicine’s lack of evidence base! Dr Rimm’s Pfizer-sponsored study on erectile dysfunction is a rerun of the  Heart Foundation’s apologists Grenfell and Banks advisories to take Pfizer’s infamous blue pills OR DIE. Despite this geek’s degree being Computer Sc, he’s pulled $400k to study floppys, and is now a Professor of Medicine.

In the movie ‘Dope’, drug-hustling Malcolm is fixated on Harvard. For the easy money?

It’s ironic to think that better treatments were available in the Wild West, and those cowboys had no problems with shooting their gun.

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‘The Strange Case of Dr Jekyll and Mr Hyde’ was an 1886 novel written to contrast public and private lives of a reputable gentleman. Duplicity is a constant failing, but often what’s revealed is just an iceberg’s tip above massive issues. Thanks to the only mandatory Pfarma reporting in Oz, Medicine Australia’s Education Events, we know that Pfizer spent an average of $12k on each of the 23 rheumatologists they recently sent to European and American conferences EULAR and ACR. The full reports give an insight into specialist’s lives outside the surgery, as $43.3m was spent on them in the 6 months to Sept 2015. Worse still in 2010 pharmaceutical companies reported $637m expenditure on research, but nobody knows who received the money *. There is monumental potential for conflict-of-interest as the scope of new-gen bio-agents increases (monoclonal antibody drugs, hereafter referred to as the  _mab drugs).

Tony Abbott recovers after finishing Pfarma-sponsored 'Pollie Pedal' in 2013

Tony Abbott recovers after finishing Pfarma-sponsored ‘Pollie Pedal’ in 2013

Amgen sponsored 799 events in the last 6 months. Focusing in more closely, we really can’t be sure just how safe is their anti-inflammatory _mab for arthritis, Enbrel. Regulatory authority TGA advises physicians under Adverse Effects: “In placebo-controlled trials, no increase in the incidence of serious infections (fatal, life-threatening, or requiring hospitalisation or intravenous antibiotics) was observed“. Uhuhh.

Allegations it caused Eagles frontman Glenn Frey’s death due to pneumonia can’t be verified. In the latest EULAR journal ‘Annals of Rheumatic Diseases’ Winthrop & Smolen et al suggest it’s a good idea to track outcomes of _mabs. ‘Opportunistic infections and biologic therapies in immune-mediated inflammatory diseases’ reveals the shortcoming that “no consistent OI [Opportunistic Infection] definition was identified across [368] studies“. Hence a list of OIs was drawn up, topped by the pathogen responsible for pneumonia. The best evidence for their recommendations was the publicly accessible meta-analysis by Kourbeti, Ziakas, & Mylonakis which put the odds of infections 1.8 times higher for _mab recipients than controls (usually patients on frontline med, methotrexate)  in Rheumatoid Arthritis (RA) trials – a small but significant risk. But note that RA doubles that risk over healthy comparators already.

That’s short term though, a trial median of around 6 months for the drug to prove its worth. Aust Rheumatology Association’s Rachelle Buchbinder established the ARAD tracking database a decade ago to determine _mab safety. It’s paid for by Pfizer, BMS and AbbVie. The few reports published in journals thus far inform us of customer satisfaction such as subjective Quality of Life surveys, and that no increased risk of cancer occurs, and that herpes/shingles virus infection rates are 1.7 times higher. Specifically for Enbrel, this result came after a median of 3 years followup. So the longterm prognosis is much like the brief studies would indicate. A worsening, but hardly deadly. Glenn’s manager wisely declares he has taken legal advice to limit his accusation.

This drug inhibits TNF, a cytokine messenger that augments our innate immunity system. As understanding of the molecular basis of many diseases improves, an inflammatory aspect is a recurring theme. The prospects for treatment with anti-TNF therapy look promising, but for the fact that the body needs to be regulated by internal controls. And not shareholders, salesfolk, or Jekyll. Interestingly, a trial for Enbrel in Alzheimers found that TNF levels rose. Feedback systems are adaptive.

Future studies could well heed the EULAR belief that their “… list of infections should be considered potential indicators of alterations in host immunity, and that this list and the associated case definitions should be used to standardise reporting of OIs in future biologic and other disease modifying antirheumatic drug clinical trials“. It’d also be helpful if an outcome tracking registry reported on all OIs, instead of the trickle of data from ARAD. But unease over industry manipulation of research is fuelled by the doctors themselves. When a weakened version of the US Sunshine Act for disclosing contents of the unmarked envelope was being considered by the Aust Competition and Consumer Commission, the AMA submission sought a deferral: “A twelve month delay in implementing the ACCC’s condition would allow health practitioners to think about and plan for their ongoing relationships with pharmaceutical companies.”

Gap payments cover the weekender, the kid's schooling ....

Gap payments

EULAR 2016 is in London. The UK has an Office of Research Integrity, let’s hope some fresher ideas than creative accounting are brought home.

* Source: College of Psychiatry submission to the ACCC. They’re concerned: “Clinical research should be included in the transparency model. All payments above the threshold that are made to individual researchers, or research institutions, including hospitals, should be publicly reported. This would better enable doctors and other health professionals to interpret the research outcomes while taking into account their funding sources.”

The butterfly emblem is frequently chosen by carefree souls, which suits my care-less persona also! My attention has flitted to continued controversy over two chronic pain studies – PACE for chronic fatigue, and Auckland University’s Stroke and Applied Neurosciences report: ‘Daytime napping associated with increased symptom severity in fibromyalgia syndrome’. Blogs and commentaries frequently generate traffic by highlighting controversy (but not mine, of course). Digging out the truth is easier by discarding any opinionated article which doesn’t link the original study for scrutiny, since both were published in open publicly accessible forums. If it matters, it’s usually in PublicLibraryofScience or the like. If hidden behind the commercial barrier of a medical journal, then it was probably just an extension of Pfarma’s marketing (if the statement by past editor of the unimpeachable British Medical Journal is to be believed). The late, great Dr Dave Sackett tickled my humours with his Clinical Trial Organisation HARLOT (How to Achieve positive Results without actually Lying to Overcome the Truth).

Linked study PACE was of very high quality. UK govt sponsored and large enough to be powerfully conclusive, it randomised sufferers from chronic fatigue into four arms:- standard medical care alone, or in combination with either of Cognitive-Based Therapy (CBT), Graded Exercise Therapy (GET), or Adaptive Pacing Therapy (APT). The outcome published in The Lancet in 2011 showed improvements in fatigue and physical functioning scores for CBT and GET, but not APT. An outraged patient community expressed alarm that doctors would prescribe exercise to reverse lack of physical condition resulting from illness. A planned followup investigation this year re-ignited the furore, explaining that CBT and GET mediate changed belief and citing a Belgian study “…the role of beliefs in chronic fatigue syndrome and fibromyalgia, which suggested that fear and avoidance of movement were associated with poorer outcomes.” Criticisms include the PACE protocol’s broad inclusion criteria, that their participant’s syndrome wasn’t real CFS are quite ironic given the difficulties experienced by anyone seeking validation for their own sero-negative invisible illness. Emotive catastrophisation reflects the shame felt at being stricken to bed – when the reality uncovered by another Belgian team is that CFS suffferers were hitherto over-achievers. This study isn’t published for the public, but I’m grateful for someone breaching Elsevier© copyright. It also seems free from bias.

cat

All the evidence is clearly presented in the links, so I won’t insult by advising what you ought to think of it all. Complaints will have to be made to the 640 who presented their results. However, the failure of ABT bears editorialising. It was a program delivered by experienced Occupational Therapists per PaceTrial.org published manuals . ABT wisely directs diarising of activity and subsequent post-exertional malaise to establish baselines of safe achievement, thus the salient lesson of ‘you play, you pay’ is documented in order to inform self-management. Advice is given on the need to inform work, family or friends on limited capacity to give of oneself. Diaphragm breathing exercises are explained with the importance of control over fight/flight responses. How could this not improve wellbeing? The answer awaits further analysis, but clearly deficient is any strategy for activity which may increase the envelope of energy. The therapist manual requires joint devising with the client of goals and aims  in CBT and GET only, and instructs not to motivate for an improvement in function in ABT. Emphasis on self-compassion  without guidance for rehabilitation will leave patients stuck where they are. Mindfulness of the condition without movement to actively re-engage with the world, is analogous to theory without the practical.

Onto psychologist Alice Theadom and her survey. The implication is of causality between resting up and worsening symptoms, under the heading of Results: “Daytime napping was significantly associated with increased pain, depression, anxiety, fatigue, memory difficulties and sleep problems.” Worsened relationship with one’s boss too, I’d reckon. If the order of words was changed, one would presume that fibromites suffering worsened symptoms take more naps. But in each presentation of facts uncovered, the order is naps -> bad outcome. Briefly consider the impact to sleep, and the difference reported by nappers being an average of 17 minutes less each night. Mmm ‘kay. When strong pain hits, hit the couch and make up for that lost quarter hour. Incidentally, table 4 shows that the use of opioids is as strong a predictor of likelihood to nap as is gender. That one’s overlooked in the text, and close behind come gabapentin and pregabalin for sending you to sleep.

mackey

The Oz equivalent to the US FDA is the TGA, and their advisories provide both patient and doctor with assurances of drug safety. Ours can be searched at http://www.ebs.tga.gov.au to find that they consider the evidence for cardiovascular risk in Celebrex/celecoxib as being wholly provided by the report ‘Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study’. This is a trial conducted by the manufacturer Pharmacia – five doctors were employees and Fred Silverstein MD was a consultant, hence another employee, but a contracted one. CLASS ran for 27 months, but only the first 6 were written up. Any heart attacks or strokes 48 hours after stopping the drug were excluded, so if chestpain led to dropping out of the trial then any subsequent event was deemed to be irrelevant. Even if fatal. Flimsy, verging on dodgy grounds – so some detail is provided here for your discerning evaluation.

Steroids such as Prednisone are awesome, but awful in longterm usage. Celecoxib is a non-steroidal anti-inflammatory drug (NSAID) for pain relief, a second generation inhibitor of COX-2 (_coxib)  inflammatory prostaglandins with less stomach risk than COX-1 inhibitors of prostaglandins (so far, seemingly so good). COX-2 is a driver of the PEG2 level controlling your hypothalamus’ setting of core temp – last flu bout, you noted fever came with pain? And the hypothalamus initiates inflammatory cascades via the HPA axis: churning out cortisol, adrenalin… oh dear. Some prostaglandins encourage herpes virus – to which everyone will have had exposure by the age of three. It’s everywhere. The likeness between fibromyalgia and viral-induced chronic fatigue hasn’t been overlooked by surgeon Skip Pridgen, who’s patented combo of celecoxib and an anti-viral is claimed to have commercial prospects for treating FM. But it’s also associated with a 37% increase in heart attacks and strokes – as Wikipedia would tell you. Their citation is the 2013 Lancet article by the CNT collaboration (including Cochrane group’s usual suspects Bombardier * and Tugwell), systematically reviewing trials for adverse events associated with NSAIDs, which are fortunately rare during the monitored period. Especially since the inclusion criteria for arthritic participants precludes existing cardiovascular disease – hardly representative of real patient’s co-morbidities! The breakdown in a supplementary report shows that in fact 200mg has an indeterminate risk, but volunteers testing 400 should be nervous, or those on 800mg must be wondering about misplaced trust and whether insurance is paid up. A similar result during a trial of pain relief for colorectal cancer on 2,000 patients caused the safety committee to terminate, even though the elevated risk for those on only 200mg was non-significant. The Forest plot shown is named for its ability to show with confidence the wood amongst the trees, aggregating many trial results and weighting according to their reliability.
celebrexOK
Vioxx, or rofecoxib COX-2 inhibitor scandal of FDA corruption and pharma coverup of heart attacks during trials was summarized by the court trial statement of “malicious, oppressive, and outrageous” conduct. Every suspicion of misconduct was confirmed. Complicit medical journals, doctors recruiting patients for ‘seeding’ of the market, and off-label promotion accompanied by false claims resulted in a settlement of $4.85bn. It’s equally easy to be fearful of Celebrex, even though Pfizer’s fight against patent expiry has conviction. Of its merit and benefit, not just the criminal convictions 😉 Along with CNT, the Safety of NSAID group meta-analysis of 25 studies found that higher dosages doubled the lower dose’s slightly increased risk of a heart attack. But declines to define where the dose cutoff lies.  The International NSAID Consensus Group think it’s good for those without elevated cardiovascular risk or with hypotension (likely to be evident in fibromyalgia and CFS). The cheque-red (sic) history of disdain for truth and ethical behavior exposed by court evidence demonstrates the need for systemic overhaul, because the truth is suppressed by industry.

Pfizer bought celecoxib via Monsanto’s drug subsidiary Pharmacia&Upjohn along with patent rights and their falsified trial data – since internal memos described their “cherry-picking” of only the favourable results (mentioned in the opening paragraph). The new owner’s marketing efforts have been formidable, but accounts department was tardy in paying bills – the drug’s original discoverer Brigham Young University only recovered royalties from Pfizer through a half $bn court settlement. Anaesthetics Professor Scott Reuben was jailed for fabricating celecoxib trial results, coincidental with his promotion of combo therapy with Lyrica or Neurontin (No! Really?) Pfizer’s sponsorship of the studies doesn’t appear in hospital financial records however, raising the possibility that funding was paid directly to the fraudster. A 2002 BMJ article addressed fear of ulcers, independently reviewing studies on 15,000 participants. It was co-authored by Pfizer associate director of R&D. And omitted to collate adverse events of a cardiovascular nature ie those likely to kill you, since ”… While it is important to evaluate this concern, this was not possible here as the celecoxib trials we included did not report outcomes comparable with those assessed in Vioxx Gastrointestinal Outcomes Research.”

Meantime, the jury’s out. If pain relief affords you better Quality of Life, then individual decision making would be far easier if evidence wasn’t provided by dishonest researchers. Longterm study registered as NCT00447759 includes cardiovascular risk in the ‘Standard Care versus Celecoxib Outcome Trial’, without mentioning that Pfizer invested $43m (it’s a note within a press release, but no sponsors logo appears alongside nine of those for collaborating universities) – rather it’s claimed to be “an academic, investigator-initiated study, requested by the European Medicines Agency (EMEA) and sponsored by the University of Dundee.” The website states that “The study commenced in January 2008 and is expected to run until at least 2012”. Also concluding soon is NCT00346216, tracking some 20,000 patients over 7 years by Pfizer sponsored researchers, who’re reticent to declare conflicts of interest in their article on ‘Rationale, design, and governance of Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen Or Naproxen’ (PRECISION) – other than having signed an undertaking to avoid commercial relationships during the conduct of the trial. Coincidental report: ‘Celecoxib, but not rofecoxib or naproxen, attenuates cardiac hypertrophy and fibrosis‘, co-authored with Pfizer staff and published in 2010  must come under the category of unavoidable (certainly it’s promising, since this re-modelling is a leading cause of heart failure in fibromites). These two studies could be win-win for Pfarma’s master puppeteer, and shareholders seem likely to be Celebr-ating. Pfizer’s statin Lipitor, being the highest grossing drug of all time, means that commercial interests are inexorably intertwined with every conference-attending cardiovascular expert’s research funding, but the secrecy is disturbing … (to be continued).

2017 update: PRECISION reported to ACR a couple of months ago. It’s safe enough.

* Claire Bombardier reported consultancies for Abbott, Amgen, AstraZeneca, Bayer Inc., Biogen Idec, Bristol-MyersSquibb, Hoffmann-La Roche, Merck(Schering Plough Canada), Pfizer and UCB Canada Inc., and is a member of an advisory board for Janssen (Merck & Company Inc.), Combinatorx Incorporated, Schering Plough, Pfizer, and Takeda Canada and holds research grants from Abbott Laboratories, Bristol-Myers Squibb Canada, Janssen, Hoffman La-Roche, Pfizer, Schering Canada and UCB as listed  at doi:10.1093/rheumatology/kes032. The disclosure of conflicts-of-interest in the Lancet  the year following has only three consultancies listed. Near enough’s, good enough.

2014© Medscape staff surveyed physicians on ethical issues, finding less than half confessed to a weakness for a freebie. That’s encouraging to drug reps, since influencing just a few Key Opinion Leaders pays dividends. So long as the flock all think alike, this being exemplified by a disclosure. The practitioner failing to practice what he preaches!drugreps
Dr Justin Coleman boldly challenged pharma thru his official position with Royal Aust College of GPs, fronting a well-publicised ‘no reps’ in the surgery campaign which raised ire among his fellows. Seriously, who’d ever believe wealthy physicians could be bought with a Bic? A humour-laden registrar tutoring session blogged recently under ‘Uncertain Dealings’ raises doubts. “Thus, when a patient complains of a painful lower back, my eventual diagnosis, after a thorough history and examination, is ‘low back pain’…. And, as for assuming my intervention of massage or gabapentin directly causes the pain’s eventual resolution, well…call me Dr Doubt!” Bon mots over a patient suffering pain aside, this is revealing. Gabapentin is an anti-convulsant for epilepsy, which happens to also fix everything – if Pfizer’s offlabel marketing is to be believed. Fines for such of $430m in 2004, $142m in 2010, and $615m (including $325m class settlement) in 2014 were just incidental costs alongside their promotional budget. The best evidence from Cochrane states that less than half of those with postherpetic neuralgia or diabetic neuropathy will obtain pain relief. So uncertainty over cause leads to a stab (glad he didn’t become a surgeon) that the pain originates from damaged nerves, and an indirect consequence of a hundred Pfizer Aust pain presentations to doctors in the previous 6 months just happens to be a prescription for Neurontin. And a little rub down there, in case of a herniated disc perhaps.

There’s been 6 studies into gabapentin for nociceptive pain, ie hurting without malfunctioning nerves, and all the results were suppressed by the company. They weren’t published, because they were negative. This disturbed Kaye Dickerson sufficiently to inspire a 57 page dissertation on the subject, with a few hundred pages of supporting appendices.
The white knight * can offer no other assistance, and how did this come to pass? A letter from Pfizer Aust in 2003 prefaces the corporate strategy – avoid offlabel fines by investing in more approval trials. Dawn Carroll was recruited by Pfizer in ’07 and co-authored an updated Cochrane review in ’10, which was surprisingly favourable to their products gabapentin and pregabalin for chronic pain. All up, she’s published 50 articles with the Pain & Palliative Support group of Cochrane’s Editorial boardmember Prof Andrew Moore. Moore’s 2014 article for Jnl of the American Medical Association, ‘Antiepileptic Drugs for Neuropathic Pain and Fibromyalgia’ confirms that marketing-based medicine penetrates everywhere: “The Neuropathic Pain Special Interest Group of the International Association for the Study of Pain and the National Institute for Health and Care Excellence recommend gabapentin and pregabalin as first-line treatments for neuropathic pain. These results support the recommendations.”

The future holds little promise, since a check of registered ANZ Clinical Trials of gabapentin for bad backs tells us Pfizer is comparing gabapentin against pregabalin for sciatica – which won’t offer us much of a choice (they’re related drugs having identical mechanisms). The obvious difference is that pregabalin is more expensive – the fine for offlabel promotional bribery was double that of its stablemate, at $USD2.3bn

I’d ridiculed medicine’s adoption of the caduceus previously. Perpetually going in circles makes the ouroboros – the snake eating itself, a more appropriate motif.

*Justin claimed in a memo that his example was an ironic motif, because he campaigns against industry influence on prescribers such as for gabapentin.  I value his opinion on popular culture as an illustrative means, and intend to  incorporate same next month. But perhaps the somewhat more socially critical Southpark, than the sagely Gandalf.

Regulation of research results in painfully slow progress, as each proposed intervention is tried singly against a control group. Those participants being duped by allocation to the placebo arm may well wonder if the feel-good/self-resolving* factor hasn’t already been examined sufficiently to be quantified. However conformity within academic rules is the only safe option for the investigator, rather than gamble a decade’s investment in higher education by following any heretical notions. It’s been suggested in ‘Bad Pharma’ by Dr Ben Goldacre that drugs should be compared against each other, in trials conducted  by GPs within the real-world of practitioner ℞ (pending removal of the roadblock placed by Ethics Committee approvals etc, that all research be conducted by institutions).

Where the disorder is conveniently profiled to the satisfaction of the institutions, patient registries give an advantageous shortcut of study recruitment effort. Fibro is inconveniently enigmatic in this regard, and a disenfranchised community lacks trust in the specialists who’ve pushed antidepressants in lieu of solutions. Enlightened mavericks have extended the notion of online support forums into Patient Reported Outcomes for inductive study. Unashamedly intrusive gathering of data is openly shared – meds, QoL ratings, pathology results etc, in the hope of expedited understanding (of both the syndrome itself, and the qualitative, subjective experience of the person’s suffering). 20,000 diagnosed fibromites report their medications and psychometric Pain & Fatigue Rating Score (PFRS) at PatientsLikeMe. Without adjustment for any factors such as an individuals’s symptom duration or other confounders, anti-convulsants Lyrica and Neurontin (discussed previously under ‘Bad Medicine’) showed imperceptible nett improvement, although cold comfort can be drawn from opioids being associated with even worse scores. Endep and Cymbalta are reported more favourably, and surpassed again by anti-inflammatory interventions such as NSAIDs or corticoids. Far better were supplements D-Ribose, Omega-3 and CoQ10, along with massage therapy, exercise and yoga. Raw rankings have no better merit than a wet finger in the air as a meteorological report, but is a pointer to investigations conducted in an approved manner. Psychiatrists Carta & Cacace et al extended the drug trial’s usual brief therapy monitoring of wellbeing on takers of antidepressants out to a year, observing psychometric Fibromyalgia Impact Questionnaire FIQ worsened by 26% compared to unmedicated fibromites.relax Not so good.

Prof Rob  Bennett set aside his Eli-Lilly commitments for a study on the effect of a yoga course of 8 by 2 hour classes. The FIQ-Revised dropped an impressive 27% average, more regular adherents to the program having better results. Strength (rising from chair) also showed significant improvement, compared to controls. But on what basis are claims for yoga’s strengthening of the immune system made, and why have practitioners been given unconventional names, and is fibro an auto-immune disorder anyway?

The wet-finger ranking of therapies, as voted by the patients’ PFRS points to lowdose naltrexone or LDN as winner. At one tenth the approved dosage for withdrawing from alcohol or drug dependence, Adelaide’s Prof Hutchinson achieved inhibition of Toll-Like Receptors (TLR) response to antigens. Antibody mediated immunity is actually a little over-the-top within the central nervous system and brain, where overmuch is at stake. The alarm is sounded by a cytokine (inter-cell signaling) InterLeukin-8 (IL-8), mediated by TLRs and the ominously named Tumour Necrosis Factor. The idea of shooting the messenger in this situation gave rise to the concept of specific Monoclonal AntiBodies or the _mab biological DMARDs, indeed fibros on these report nearly as good a PFRS as the natural supplements can achieve!

Overall there’s more systems functioning as they should than those which aren’t, even if somewhat dysregulated and anyway anti-inflammatory cytokine  IL-10 being elevated in fibro is an example of the body’s fighting back. Suffice to say, it is how homeostasis is maintained. Pro-inflammatory IL-6 was given the alternative description by Pederson & Febbraio as a muscle function myokine in 2012, since its message is integral to the response to exercise.  IL-8 links to fibro pain and IL-6 links to CFS fatigue. Wang & Schiltenwolf et al multidisciplinary program dropped fibromite IL-8 levels (that were initially double those of healthy controls) by half, in 6 months of self-directed application of techniques from a 15 day physical and psycho therapy course. Bote & Ortega et al took physically inactive fibromites and healthy controls for a 45minute moderate intensity cycle ride. Baseline IL-8 levels were fourfold in patients, but one day later the tables had turned. Controls were elevated, and FM levels were now healthy. At the beginning of their extended 8-month water aerobics regime for non-exercisers, IL-6 levels were one eighth higher in FM patients than controls, and mid-course they’d risen another eighth. But dropped by study’s conclusion, to less than healthy control levels. Kiecolt-Glaser compared yoga experts and novice IL-6 levels, finding them 41% higher in the beginners. Pullen & Khan et al dropped IL-6 levels in heart failure patients by 20% in 8 weeks of 1 hour yoga sessions twice weekly. Randomised trials of yogic breathing techniques found improved cardiac autonomic balance in diabetes, asthma, hypertension, IBS and epilepsy.

Baker Heart and Diabetes institute poached Febbraio’s skeletal muscle team after his discovery that concentric contraction is non-damaging, in that it doesn’t exacerbate IL-6 and IL-8 levels. Fair enough too, there’s no money in fibro research. Anyway, play it safe by cycling, or rowing. A good Spanish Open Source study points to many examples through its references, such as ‘Effects of physical exercise on serum levels of serotonin and its metabolite in fibromyalgia: a randomized pilot study’.

* Voltaire: “The art of medicine consists of amusing the patient while nature cures the disease.” or Ben Franklin: “God heals, and the doctor takes the fee.”

Fibromyalgia appears destined to remain the elephant in the room if this month’s Rheumatology edition of Australian Family Physician is anything to go by – not a mention of it. So what do healthcare specialists offer? In 2006 Drs Littlejohn and Guymer published, through their work as Monash Director of Rheumatology and trainee respectively “Fibromyalgia Syndrome: Which Antidepressant Drug Should We Choose”. Linking their Medical Centre with the University seems a worthy approach so as to redress physician misconceptions  – indeed, shortly thereafter the Journal of Clinical Rheumatology published a survey of Southeast Asian rheumatologists. 87% of them believed fibromyalgia incorporated aspects of psychological illness and only 40% of those associated with an institution reported inclusion of FM in their undergraduate training.

Dr Littlejohn then contributed to the 2009 yearlong study on effectiveness of duloxetine/Cymbalta led by Eli-Lilly employee Amy Chappell, which was discredited by exclusion on quality grounds from the independent Cochrane musculoskeletal group’s systematic review of studies on SNRIs . Their supposedly * impartial conclusion drawing upon another five, unbiased assessments was that 10% more people reported significantly reduced pain with duloxetine than those duped by a placebo, however another 9% discontinued treatment due to side-effects. Withdrawal in itself is harmful, the US FDA has published a safety advisory for Cymbalta Discontinuance Syndrome. Agreements posted in 32,000 blogs are somewhat alarming! Any benefits obtained are ‘figure-atively’ outweighed by weightgain reducing propensity to exercise, consensus being that moderate exercise is beneficial for fibro.

2009 was a bad year for pharma. Eli-Lilly pleaded guilty to illegal marketing of anti-psychotic drug Zalprexa for off-label use, and was fined $1.4bn. A recent out-of-court settlement was made with the family of a boy who suicided whilst on Cymbalta, whose claim being that another suicide during drug trials should have prompted warnings.  And Pfizer paid a record $2.3bn for fraudulent marketing of painkillers, including Lyrica. Nonetheless these two medications remain highly profitable with an estimated $18bn in sales in 2012…. which trivialises the settlement for $43m with US attorneys generals that year for once again marketing Lyrica other than for an approved purpose. With such monetary power, when federal NHMRC funding was approved for only 17% of applications for 2014 is it any wonder that Littlejohn and Guymer are reliant on consultancy fees paid by  Eli-Lilly and Pfizer declared (inconsistently*) under their conflicts of interest? “The medical profession—in the US, Europe, and beyond—remains heavily reliant on industry funded continual medical education, and many doctors have accepted substantial hospitality and consultancy fees. Very few have been prosecuted. Disclosure remains patchy and inconsistent. Yet it is their decisions that ultimately determine if medicines are reaching patients for whom they are not suitable. If drug companies need to change their attitude, so do prescribers“. Andrew Jack, Financial Times correspondent writing in the BMJ July 2012.

Evidence update: Two books elaborate these concerns from a practitioner’s perspective. Dr Ben Goldacre’s ‘Bad Pharma’ and leader of the Nordic Cochrane Centre, Prof Peter Gøtzsche’s ‘Deadly Medicines and Organised Crime: How Big Pharma Has Corrupted Healthcare’. Peter’s alarmist chapter title: ‘Very few patients benefit from the drugs they take’  explains that “… apart from such scientific misconduct, insufficient blinding can also make us believe that ineffective drugs are effective.” In damning the exalted gold-standard comparison – the randomised control trial, he warns of assessor bias if they’re aware to whom they gave placebo. To give weight to this claim that doctors lie, his colleague Asbjørn Hróbjartsson is cited … the effect was exaggerated by 36% when evaluated by nonblinded observers. Wow, this Cochrane review ‘Observer bias in randomised clinical trials with binary outcomes: systematic review of trials with both blinded and non-blinded outcome assessors.’ needs a read. Ooops, the title omits the keyword ‘subjective’, and 71% of the studies were surgery or the like. cochraneFigure 1 meta-analysis shows that two weighty transmyocardial laser revascularisation outcome reports by Oesterle et al and Burkhoff et al dragged the conclusion from one of no significant difference to a non-blinded bias Odds Ratio of 0.64! So, if you ask F.I.G.J.A.M. whether they THINK the patient’s angina has improved recently, there’s a leaning towards affirmation if they’re aware that surgery has been done? Cardiologists genuinely believing that their interventions are beneficial can hardly be extrapolated to mandating that all trials must be blinded in order to avoid falsification of data, but that’s what’s happened. Peter’s Mentalaz speaking tour claimed that all anti-depressants were ineffective – arguing that severe side-effects results in unblinding. And the effect size was typically <36%, whereby he proves all benefit of the med resulted from bias! And these are the watchdogs? When Cochrane’s doctors stretch the truth about the 36% shift in truth by other research doctors, they’re all damned.
 infinityCochrane pioneers Gotzsche and Chalmers are much alike in their evidence fudging. The Handbook warns  that sneaky research doctors will try to break the blind and fudge the facts. The last para of ‘Rationale for concern about bias’ cites a study by Schultz, Altman, and Sir Iain Chalmers et al in Feb 1995 JAMA. Just one review, covering studies particular to pregnancy & childbirth actually contradicts their own argument: “Trials with inadequate sequence generation yielded estimates of treatment effects that were similar to those derived from trials with adequate sequence generation, after adjusting for the other three methodological dimensions”. But on pg410 a subgroup analysis limited to those trials reporting adequate allocate concealment only managed to find a statistically insignificant p=0.07 (ie close, but no cigar) exaggeration in effect size as a result of poor sequence generation.

This cracks me up. That’s a negative outcome elsewhere than the Cochrane Collaboration, and it relied upon data dredging to obtain a semi-significant conclusion. But it underpins one of their criteria for downgrade of all studies – sanctimonious dogma used thereafter in box-ticking exercises, which actually detracts from quality analysis of evidence trustworthiness. This recalls the classical Ouroboros, the snake eating itself – as a symbol of perpetuation.
*Aust Family Physician Oct 2013: “Competing interests: None”

<Jan 2016 update: an Austrian survey found 89% of GPs would refer fibromyalgia to a rheumatologist, but only 12% of those wanted to treat the patient. With great neuro research nearby by Uçeyler, Sommer & Hauser you’d hope for more than just a handpass: http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0146149 >