Pain Management: The Final Frontier
Everyone reading this article will have had a pain at one time or another that required you to pop a pill. Probably it was aspirin, paracetamol or ibuprofen or some branded version of them. A few of you perhaps with arthritis or post surgical pain may have taken codeine or even a morphine derivative. Whatever you took you were probably glad to have taken it.
What is unavoidable is that your consumption of pain medications is likely to increase as you age due to wear and tear, illness and the side effect of "active retirement". Given demographics Pain Management is big business, a $35bn annual market with very few new drugs. But Merck's withdrawal of Vioxx from the market in 2004 highlighted the difficulty in providing a safe drug to such a vast customer base and killed significant innovation in this therapeutic area. The result has been a recycling and repackaging of older drugs into creams, patches and pills - primarily as this combination of mechanism and molecule provides the manufacturer with a shot at new patent life.
Pain is a very elusive symptom to treat. This is partly because of the multiple types of pain that you can experience and partly because each of us has a different pain threshold. Famously women can withstand greater pain than men, who suffer noisily with such genuine ailments as "man flu".
The Placebo effect is powerful in pain management. This is the effect that the mind has on our appreciation of pain when given something we believe is medicine but in reality contains no therapeutic substance whatsoever. In these circumstances our mind fools ourselves that we have taken a real drug and the pain reduces. The more elaborate the placebo the more pronounced the effect. Intravenous dosing of saline labelled as "pain relief" is far more effective for example than a dummy pill. This effect is so powerful that most therapeutic drugs are only marginally more effective than placebo in trials. It's a low hurdle to leap.
Pain management is part of modern culture. For a certain generation "plink plink fizz" means something powerful to deal with a hangover. Movies are full of hard boiled heroes popping pills. In US cult TV series Ballers, Dwayne "The Rock" Johnson crunches codeine like candy. But these seemingly anodyne drugs can have serious and long lasting side effects.
The Medicines Control Agency in the UK is the repository of all adverse drug reactions reported by General Practitioners. Sitting in a nondescript building in London the staff at MCA process dozens of records a day of patients who responded badly to approved medicines. You know those side effects that are catalogued on the huge folded piece of paper inside the box that you throw away? That's what the MCA sees daily. Internal bleeding, heart tissue damage, liver damage, kidney damage and addiction are some of the more severe symptoms. These side effects are all dose dependent. This means that the more drug you take and the longer you take it for, the worse it is for you.
The US CDC reports that 46,471 Americans died of a drug overdose in 2013 – the last year for which information regarding overdose deaths is available – compared with 35,369 deaths due to car crashes and 33,636 as a result of firearms. Chuck Rosenberg, at the DEA describes it thus:
“Drug overdose deaths have become the leading cause of injury death in the United States, surpassing the number of deaths by motor vehicles and by firearms every year since 2008,”
“Overdose deaths, particularly from prescription drugs and heroin, have reached epidemic levels.”
In the analgesic space the most talked about culprit is Oxycontin - which has been reported by the Wall Street Journal as being at the epicentre of use and abuse http://www.wsj.com/articles/the-great-opiate-boom-1433531938 There were 29,000 deaths in 2014 from opiate abuse. This is over 300 times as many deaths as Islamic terrorists have caused since 9/11.
What is not so well known is that you can also experience severe side effects from very common drugs. Ibuprofen, sold as Nurofen in the UK and Motrin and Advil in the US is a good example. In 2015 the US FDA ramped up its warnings about the risks of these types of drugs for their role in causing heart attacks and strokes.
It has been known for some time that these drugs — called nonsteroidal anti-inflammatory drugs, or NSAIDs — have serious side effects and are a major cause of drug-induced injury. They are estimated to cause at least 16,000 deaths per year. The most common problems they cause are digestive ulcers and associated bleeding but studies also have shown increased risk of other conditions, including rapid and weakened heartbeat, kidney damage and delayed healing of fractures and soft tissue injuries. The British Medical Journal is the most recent voice to highlight the risks in this drug class, reporting on 28th September 2016 a study on 10 million european patients that showed a clear relationship between use of NSAID's and heart failure.
These side effects can be generated from a single dose of drug. I know this as I once worked at the MCA and processed the reports. It is a form of lottery. Like all lotteries the more tickets you buy the more likely you are to win. For those with a chronic illness like arthritis who take grams of drug a day the side effects are guaranteed. As a result - aside from the human toll the cost to the health service and health insurers runs into billions.
Given all of this you would think that when I presented a new FDA-approved class of drug that dramatically reduces the load necessary to achieve the same level of pain relief to venture capitalists, that they would be climbing over each other to invest.
In reality you could have heard a pin drop.
Pain it turns out is not very sexy and VC's like sexy. Selling new pain drugs that have significant long term benefits for patients but no significant short term payoff is hard. Unsurprisingly the health insurers immediately grasped the value proposition - approving the drug in record time for their patients for reimbursement - as it is the insurers that bear the brunt of long term care expenses. (or the taxpayer in the UK). But the "J" curve much beloved of VC's everywhere is simply not steep enough outside of Big Pharma to get attention. Selling long term benefits into a huge (multimillion patient population) is a long term undertaking for which classical funding paradigms are ill-suited.
However the tide may be turning:
Generic strategies such as Valeant Pharmaceuticals debt-fuelled acquisition spree or Turing Pharmaceuticals price gouging approach to generating profitability are over. The continued poor productivity of mainstream fundamental chemistry and the early stage progress of genomic medicine offers very little in terms of scalable benefits for patients in the near to medium term.
Against this backdrop, optimising proven molecules for faster onset of action, lower dose and less variability in terms of eating between doses isn't sexy, but according to the meta-data it should pay huge dividends in terms of health outcomes. That is a major public health benefit and big win for patients also.
As a result is may be that that this type of therapeutic optimisation strategy may soon come in vogue.
We've taken the pain, now it's time for the gain.