Bad medicine (Part 2)

Lyrica/pregabalin continued…… Integrity of research is maintained under an accord struck with journal publishers, whereby trial results will only ever be reported if the goal is declared upfront when the study is registered with a govt agency. This ensures inconclusive or negative results aren’t hidden in secrecy, and thus trial NCT00333866 in 2009 is open to scrutiny – a sponsor’s restrictive agreement on investigators publishing or discussing trial results notwithstanding. Under the leadership of Lynne Pauer (a Pfizer Director) 73 facilities worldwide randomly allocated fibro patients to either placebo control or else one of three dosages of pregabalin. 30% dropped out over the 14 weeks, and only the 450mg dosage yielded a statistically significant result in efficacy for pain. Paracetamol was allowed as a rescue therapy, surprisingly the amount needed for pain relief increased with higher dosages of pregabalin. Data from this and other trials was analysed by Oxford University who determined the Number Needed to Treat at 450mg to obtain one person benefiting by a moderate 30% reduction in pain intensity was eleven. On the other hand, worsening side-effects with increased dosage led a rheumy with a sense of humour to plot the Schwindel.

Pfizer has a patent thru’ to Dec 2018 on Lyrica however, and if all you have is a hammer then everything looks like a nail. American audiences are aware of their ad campaign which follows the “Here’s your answer, regardless of your problem” school of thought. Diabetic neuropathy? The ads announce “No worries”, although others are concerned about suicidality. And NonSignificant result study at 300mg dosing shows it’s every bit as good as placebo in reducing pain. whack-a-mole

Writing in the Medical Journal of Aust this year, rheumatologist Prof Rachelle Buchbinder complains that NationalHealth&MedicalResearchCouncil “funding is disproportionally low compared with the burden of these (musculoskeletal) conditions”. Her co-author Prof Chris Maher should impress then, in obtaining a $618,590 NHMRC grant for the PRECISE study trialing pregabalin as a treatment for sciatica. Coincidentally, The Age newspaper published on 24th July their promotional article against standard care claiming that: “This month the prestigious NEJM published a paper reporting that steroid injections are no more effective than a sham …”, but if you read Friedly and Jarvik et al’s report the placebo was lidocaine.  Yeah right, an anaesthetic is a sham control! Experts condemned the trial, writing: “This critical assessment shows that this study suffers from a challenging design, was premised on the exclusion of available high-quality literature, and had inadequate duration of follow-up for an interventional technique with poor assessment criteria and reporting.” Discouraging guided lumbar injections is pleasing to a Govt cutting health funding in 2015, since imaging is expensive. Pills can keep the pain at bay. 

PRECISE trial protocol cites Pfizer’s  Dr Zahava Gabriel on the cost-effectiveness for pregabalin, who previously participated in a team providing supposedly independent evidence with ‘A Systematic Review and Mixed Treatment Comparison of the Efficacy of Pharmacological Treatments for Fibromyalgia’ – whose conclusion “confirms the therapeutic efficacy of pregabalin”. The NHMRC’s funding submission includes the justification: “Currently there is limited, direct, high quality research to inform the use of pregabalin in the treatment of people with sciatica. A small prospective randomised trial of patients with chronic low back pain (n = 36), which included some patients with sciatica, suggested that pregabalin may produce a statistically significant reduction in back pain in the short term”. The cited pilot study by Romano & Mineo et al wasn’t placebo controlled – patients being allocated to consecutive periods on either pregabalin, an NSAID celecoxib, or both. The least improvement was shown by the pregabalin only group, so surely Maher’s colleague Prof Ric O’Day would endorse additional celecoxib therapy (especially after having served on Pfizer’s advisory committee)? Unless coming off-patent next year resulted in a commercial decision to dump Celebrex? A supposed risk of cox-2 inhibitors cardiovascular disease hasn’t been investigated, which makes Pfizer’s March 2014 contest against generic manufacturers in Court appear financially risky (tho’ rash judgements are rather clouded by memories of Vioxx corruption! 2015 update here suggests that 200mg is a safe dosage).

Money appears to be not a factor in NHMRC deliberations, otherwise $4.6bn in sales of Lyrica last year would have deemed that Pfizer themselves can reinvest to break a new market with backpain. Hopefully they’ll read other New England Jnl of Medicine articles before gifting in future. 

Regulatory compliance appears to have been taken to an all-time low within health research ….. obedience to industry! It also shows how hit and miss medicine is based on commerce rather than science – pregabalin having been developed as an anticonvulsant for epilepsy echoes Pfizer’s subsidiary Searle re-purposing of misoprostol (declared protective against ulcers by Dr Fred Silverstein & co) for inducing labour. A $70m birth injury litigation set a record, and spawned an industry for lawyers suing hospitals for off-label use of mistoprostol.

Fibromyalgia breakthrough!!!

A reason for the perplexing nature of FM syndrome has been found. It’s an ophthalmic disorder afflicting the ability of the sufferer’s specialist to discern the blindingly bloody obvious. This monochrome blindness results in denial of discernable difference between pathology results for patients and healthy controls. It’s 20 years since Wolfgang Muller determined such a difference in serotonin levels between fibromyalgics (‘GTM’ on the right) and healthy controls, with less than 1 in 10,000 possibility that it arose due to chance.Muller1993

Jascko, Hepp and Sprott et al decided that “Serum serotonin levels are not useful in diagnosing fibromyalgia”, although their immunoassay showed a range of 10-115ng/ml in patients – compared to 131-322ng/ml measured in the control group. Why there’s as many fibromites prescribed serotonin boosters as are treated with anti-convulsants*, without pathology evidence confounds me. Eduardo Ortega has led many discoveries of markers such as the inflammatory Interleukin-8. Hollenberg and Blanco et al found ten times the number of mast cells in FM skin, releasing inflammatory histamines when triggered. Cordero, deMiguel and Sánchez Alcázar et al studies also show no overlap in the FM or healthy ranges of the cell fuel ‘ATP’, oxidative stressor MDA, or its peroxidation counterpart catalase between their samples of three dozen women. Although a bonus that they publish in the open-access Public Library of Science, it’s disappointing that peer-reviewed journals showing interest are the likes of the obscure ‘Mitochondrion’. Contrast this with the publicity afforded sponsorship by Eli-Lilly of Dr Frank Rice’s findings of peripheral blood vessel pathology – announced in the American Academy of Pain Medicine and lauded widely in mainstream press articles for months as a breakthrough, along with commentary which “….explains why some selective serotonin reuptake inhibitors such as Cymbalta seem to help.

Although no one test has specificity to exclude Rheumatoid Arthritis or depression, in totality there is overwhelming evidence for an exact diagnostic determination by the lab. Assuming impartiality, of course. When Dr Bruce Gillis declared “..no competing interests” in ‘Unique Immunological Patterns in Fibromyalgia’, he clearly wasn’t speaking as CEO of his company which markets the fmtest ®. Medical evidence basis demands a decision which disproves any element of chance or individual perspective. The humanities are somewhat more subjective, and in being so are also sensitive to the person. Hamlet avoids an argument by not passing judgement on a seemingly black and white issue by proclaiming “There is nothing either good or bad, but thinking makes it so… “.

*Endep & Cymbalta vs Lyrica & Neurontin

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 >

Painting the wrong picture

“ And I think my head is burning, & in a way I’m yearning, to be done with all this measuring of proof…“ Dr Nick Cave sums it up well. For want of a diagnostic test for fibromyalgia, the malaise is investigated by a process of elimination. This takes years, and an average of 3.7 doctors shopped (since the majority consider their training inadequate for the purposes of diagnosis : Perrot & Choy, 2012). Sponsored studies paint the illusion of progress towards a solution. Announcements of conclusions are promoted in the media with ‘Breakthrough’ in the headline, yet FM remains a syndrome of unknown causality. The diagnostic criteria of the 1990 American College of Rheumatologists for specified points of pain was loosened somewhat in 2010, and cynics point to the opportunity thus afforded for a greater market. With no prospects for a cure, palliative medications represent a secure financial investment for pharma with each and every case.

13-Things-Mentally-Strong-People-Dont-DoBuffington and Hackshaw et al described in the august journal (Aug 2013) of the Royal Society of Chemistry a promising analysis for catabolites in blood, explaining “Because accurate FM diagnosis is so crucial for improved patient outcomes, reliable disease markers are urgently needed.” Unfortunately, in excluding fibromyalgia from the Flinders University immunological bloods bank that opportunity for investigations is closed. Prof Roberts-Thomson justifies the selectivity on the grounds of funding. So let’s look at the business case. If Australian prevalence is assumed typical at 3% (let’s ignore the advice by the Mayo clinic that diagnosed patients are only the ¼ tip of an iceberg) there’s 0.6 million sufferers here. Dr Guymer surveyed Monash outpatients to find 41% were on disability due to FM, and if we take the income protection lower limit of $3000/month as a minimum loss in productivity then $20m per day is an extremely conservative estimate of the cost to this nation. That’s a lot of research dollars.

Looking in the wrong places is condemned as unethical waste of resource by Sir Iain Chalmers, knighted for services to medical ethics : “The pharmaceutical industry, for example, does research for its primary need – to fulfill its overriding responsibility to shareholders to make a profit…… Yet only rarely in recent decades has this commercially targeted approach led to important new treatments, even for ‘mass market’ disorders. Rather, within groups of drugs, industry has usually produced many very similar compounds – so-called ‘me-too’ drugs.” His book Testing Treatments is readily accessible, in its entirety.

Quite a clever illusion being created by the healthcare industry, which really doesn’t seem to be up to the challenge.