Friday 4 November 2016

Lyrical on pain

Let's hear it for drugs?  Young chap I know is a champion mountain-biker and trail-rider.  He's a champ because he can drive that mother down the side of a mountain and not come off . . . often. The problem is that, when he does leave the saddle, he's travelling fast and there are no fall-mats or safety-nets. I'm not sure how fair it is but his pals, many of whom don't have the bottle to get off the sofa, let alone zzzing downhill on wheels, call him biscuit-bones.  It may be just that he puts his body to the limits so often that he sustains broken bones OR there might be something in his make-up to suggest that he'd be better off playing Grand Theft Auto like his tubby and unhealthy pals. Whatever and, like, who knows?  ANNyway a few weeks ago, he was hurtling down a Welsh mountain and mis-judged a turn. He came off and so did the skin of his arm from wrist to shoulder and he broke his leg . . . again.  He's been in and out of hospital since then getting pins put in, pins took out and having his horrible arm-wound debrided.

If it was 200 years ago, he would have been given a leather quid to chew on as the surgeon worked away down there - no point in cracking a tooth as you gritted them in pain. Nowadays they do all the invasive stuff under full anesthetic but you still have to deal with the ragged nerve endings when you wake up and aspirin doesn't seem to work. One of his doctors wrote a script for Lyrica aka Pregabalin which is a bit of a cure-all when it comes to tricking the nervous system into behaving differently.
Pregabalin is an analog for gamma-amino-butyric acid GABA and it was discovered  in 1990 at Chicago's Northwestern U by Richard Silverman and Ryszard Andruszkiewicz. They were looking for molecules that resembled GABA which is known as an inhibitory neurotransmitter. Inhibitory NTs are one way in which you can maintain homeostasis in the nervous system. If you have excitatory NTs as well, and we do [glutamate, serotonin, adrenalin] you can imagine, and we apparently have, a system that pulses out teeny amounts of each so that everything is held in check.  It's like having accelerator and brakes on your car. Pregabalin works in a round-about way: because it looks like GABA it stimulates a protein called glutamate decarboxylase which converts glutamate to GABA by removing a CO2. Glutamate? Isn't that one of the excitatory NTs? Yup: we convert one NT to another of wholly opposite effect by a simple chemical modification. I tell ya, you couldn't design this better if you were god almighty.

So much, so normal. What happens when this delicately balanced system goes wonk? One case of this is epilepsy where neurotransmitters go on a drunken spree and cannot be stopped because they've thrown the brake-pedal out the window. The result is a positive feedback loop that culminates in seizures which are distressing and dangerous. That's what Silverman was working towards: a drug which would gee up the GABA to damp down this run-away process. After the requisite decade+ developing and characterising the drug, testing it on mice, checking for adverse side-effects, administering it to people under carefully controlled conditions and checking back always to ensure that it was safe and efficacious, it was brought to market after approval from the FDA in 2005.  It will have cost something North of 1 billion US$ to carry out all this research and testing, and Pfizer, the multinational MegaPharma which owns the marketing rights, wants to claw those costs back for its shareholders. The current stock price is $30.

Did someone say side-effects: they are many and various: blurred vision, diplopia, increased appetite and subsequent weight gain, euphoria, confusion, vivid dreams, changes in libido (increase or decrease), irritability, ataxia, attention changes, feeling high, abnormal coordination, memory impairment, tremors, dysarthria, parasthesia, vertigo, dry mouth and constipation, vomiting and flatulence, erectile dysfunction, fatigue, peripheral edema, drunkenness, abnormal walking, asthenia, nasopharyngitis, increased creatine kinase level; less common: depression, lethargy, agitation, anorgasmia, hallucinations, myoclonus, hypoaesthesia, hyperaesthesia, tachycardia, excessive salivation, hypoglycaemia, sweating, flushing, rash, muscle cramp, myalgia, arthralgia, urinary incontinence, dysuria, thrombocytopenia, kidney stones. Jakers, I can't spell some of those conditions but I'm sure I have them all . . . and I'm not even taking the drug.  It gives a clue about how systemic neurotransmitters are: there are only a few handfuls of them and they manage the 100 trillion cells, 50 organs and 12 systems [circulatory, endocrine, digestive etc.] that is the miracle of a walking, talking, thinking and urinating human being.

In contrast to Morquio Syndrome's drug of choice Vimizim [prev], there are thousands of epileptics across the Western World, so the doses can be sold cheap -  about $4 / 150mg capsule - because they are sold in bulk. Not cheap like aspirin but cheaper than Vimizim which comes in at €400,000/yr. 9 million people in the US have been prescribed Lyrica over the last 10 years. That might have been enough for an olde style druggist turning an honest penny by pedalling cures. But that's not how capitalism works: the drug company sends out reps to pharmacies, hospitals and doctors and these chaps (mostly chaps, still, I think) get paid by results. And the VP of the marketing division of MegaCorp also gets his Xmas bonus depending on how much stock they have shifted that year.

In 2009, Pfizer and its subsidiaries agreed to pay a $2.3 billion fine for promoting Lyrica and 3 other top-performing Pfizer drugs as if they were suitable for conditions other than those approved by the FDA. As I say above, the FDA weighs the benefits of a new drug against the potential side-effects and comes to a balance-of-probabilities utilitarian assessment about the use of This drug for That condition. The punter is assumed to be willing to suffer pain and feeling crap and even risk death if the drug will avert a death sentence from cancer or infection.  It is  neither appropriate nor ethical to prescribe /market that same drug for an ear-ache. That is all quite apart from the fact that someone is paying for the drugs. Part of the fine went to the administrators of Medicare/Medicaid which had, the case claimed, been fraudulently persuaded to pay for these drugs when they were not FDA approved or appropriate. $2.3billion is a lot of sugar but to put it in context, Pfizer acquired 1) Warner-Lambert for $90bn in 2000 2) Pharmacia for $60bn in 2003 3) Wyeth for $68bn earlier in 2009.  Three years later, Pfizer was fined a further $43 million [chicken feed these mere millions] for persisting in pushing Lyrica for chronic pain, post-operative ditto and migraines. Tellingly, the Pfizer sales-force was instructed to trash-talk Pfizer's own earlier pain-killer Neurontin to promote Lyrica. Ahem: Neurontin was then off-patent and so Pfizer was also bad-mouthing the yellow-pack generic equivalents such as gabapentin because the profit margin was much higher for Lyrica which is still patent-protected until 2018.

Well, is Lyrica appropriate = safe-and-effective for a teenager who has come off his bike . . . again??  That's what his Mum asked me a tuthree days ago. She had seen a lot of adverse comment: kills brain synapses dead etc. and wanted some guidance a) about Lyrica for her boy b) generally about authoritative /objective sources for truth-in-medicine. I suggested the Cochrane Index which has on The Blob dissed Tamiflu and paracetamol but given cautious appro to Feverfew. Cochrane says that 90% of people with fibromyalgia show no benefit from Lyrica. Cochrane is in the business of reviewing all the evidence on a particular topic, doing the stats and coming up with an executive summary. I also suggested that a scan of the original scientific literature at Pubmed might be helpful. But scientists write for each other not for mothers and lots of the papers in Pubmed are hidden behind a pay-wall.  I also caution you to check out the affiliations of the authors of scientific studies: this paper, which is positive about Lyrica, is written by people on the Pfizer payroll.

Down in the small print of the Pfizer fraud story is the information that the investigation was triggered by a whistleblower called John Kopchinski, a Pfizer drug rep who baulked at off-label selling of some of the drugs in his portfolio. He grassed his employer up to The Feds and spent several years testifying but was awarded a $50 million share of the pay-out. That is way more than he'd earn in a working lifetime as a sales rep.  You can see how that might act to help recruitment in the industry: work for a few years hawking drugs and then !Payola! and retirement. Not much different from the Northwick Park story.  That was when 6 young men blew up [cytokine storm] in a drug trial and hundreds of other young men signed up for future drug trials . . . because it transpired that trialees got paid a few hundred £££s for participating.  There is a certain class of 20 y.o. chaps who will risk their health, happiness and immortal soul for £800 and all the food you can eat. There are others who prefer mountain biking.

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