I have a significant interest in opioids, specifically opioid use disorders or addiction to opioids. We have seen an opioid epidemic in this country largely due to a naïve approach to chronic pain and exposing people unnecessarily to the risk of addiction. At one level this is a failure of regulators who adopted the idea that chronic noncancer pain is best treated on a mass basis with opioids. At another level it is a failure of American culture. Americans are focused on abusable medications and they always have been. This is not a recent phenomenon. The reason that addictive drugs are regulated in the first place is that they were widely abused when they could be purchased over the counter from any pharmacy. Advocates of legalizing drugs almost universally ignore that fact. It is common to find people hoarding opioid prescriptions, giving them to their neighbors, and taking them for indications other than pain like insomnia, depression, or anxiety. At the cultural level, opioids are generally regarded as magical pills that will cure whatever ails you. But there is no such pill.
Physicians are not blameless in this process. Around the turn of the 19th century, some physicians were maintaining large numbers of people in addiction as part of their medical practice. At the turn of the 20th century, some physicians advocated “pain as the fifth vital sign” and the widespread practice of recording a patient’s pain rating in routine clinic visits with their vital signs. In some cases this rating was mischaracterized as an “objective” measure like the other vital signs. Any physician who is told that the pain rating is a “14” on a scale of 1-10, knows that little objectivity is involved. The opioid epidemic is often viewed as a problem in physician education or a cognitive deficiency. I doubt that is the problem. Every physician knows the basics about prescribing opioids by the time they leave medical school. I can recall working in a clinic of chronic pain patients while I was a medical student in the 1980s. In that clinic we prescribed hundreds of opioid prescriptions per month. I also recall that none of those patients was ever asked about addiction or why they still wanted to take the medications even though their pain never seemed to improve.
This problem has also led to significant insights into the real function of the US Food and Drug Administration (FDA). The FDA web site has three paragraphs on “What we do.” The first paragraph highlights what I always thought was the main function of the agency:
“FDA is responsible for protecting the public health by assuring the safety, efficacy and security of human and veterinary drugs, biological products, medical devices, our nation’s food supply, cosmetics, and products that emit radiation.”
That seems like a straightforward definition. In practice it is more complicated. The best example I can think of to illustrate that is the FDA approval of the sustained release, high-dose hydrocodone product Norco. The FDA’s own scientific committee overwhelmingly recommended against approving this product in the midst of an opioid epidemic. They were overruled and the product was approved based solely on the manufacturer meeting regulatory requirements. Despite concern about getting medications to market fast enough it seems like there are few obstacle to opioid preparations that are basically old medications repacked in a new form.
The financial considerations in this field are significant. Several years ago speculation was that any successful abuse-deterrent opioid formulation would be a billion dollar a year drug for that manufacturer. That is highlighted by the number of recent approvals for these drugs noted in the table below.
The current market for abuse-deterrent opioids is estimated to be about $7 billion. The global pain market is estimated to be worth about $50 billion growing at a rate of 10% annually. From the table above it is apparent that this is basically a patent extension market. All of the main ingredients in these medications are generic opioids that are very inexpensive on their own. By putting them in a special formulation or combining them with opioid antagonists (naltrexone or naloxone) the manufacturers claim they are producing a medication that is less likely to be abused. Whether or not that ultimately happens is anybody’s guess. I tried to pull up one of the more notable prodrug use web sites and have not seen those compounds and so far no suggestion on how to defeat the abuse deterrence. There are historical precedents. Abusable drugs generally follow a predictable course of oral use to smoking or insufflation (snorting) to intravenous use. Breaking up that chain of events is one strategy that may lead to less severe drug use, but the fact remains that the original oral formulation is still a potent medication that can lead to addiction. The original case in point was the reformulation of Oxycontin in 2013. The original capsule could be breached and the contents snorted, smoked, or injected. The reformulation put the oxycodone in a hydrogel making it less available for snorting, smoking or injecting. The detailed package insert still says that this formulation and the original formulation place the user at risk for addiction.
What can be learned about the proliferation of abuse deterrent formulations? There is a strong incentive both in terms of market size and low production costs. All of the medications in the table are very inexpensive generics that are reformulated with an inexpensive antagonist or a different pill matrix. The main safeguard is the FDA in terms of the total number of these medications on the market. The FDA has the potential to decrease the incidence of opioid use disorders. There is no evidence that is their strategy because they are approving medications over the objections of their own Scientific Committee. In some cases they discuss post marketing surveillance as being a measure of whether the abuse deterrent medication is working. Neither of those strategies would seem to be very likely to me. It is well known that reports of signifiant medication related events are probably very low relative to the actual incidence of these events. I have previously advocated for a pharmacosurveillance/data-mining solution that would produce results before the expected complications of opioid dependence and unintentional overdoses. The FDA’s current approach seems to be that further education of physicians will solve the problem. This is not a problem of physician education.
As the formulations of opioids continue to propagate, there needs to be an awareness that the FDA is not attempting to contain the number of new opioid products released and that a preventive approach is necessary and is more likely to save lives than waiting for people to report complications or waiting for the Drug Enforcement Agency to make arrests. It is also time to consider what can be done at the level of American culture and focusing on some basic misperceptions that result in the overvaluation of opioids. The idea that opioids can alleviate chronic pain, that they are the best treatment for chronic pain and that everyone can take them safely are primary among them.
There also needs to be a better understanding of opioid use disorders. Recent stories in the popular press make it seem like addictions are easy problems to get over. Just make a decision to stop and most people are able to. Tell the old story about returning Vietnam vets and how easy it was for most of them to stop using heroin. These are not the people who are seen in acute care settings or who are treated for drug overdoses. Many of those people will say that they knew they were using a lot of the drug, that they were not thinking about suicide but they did not care if they lived or died because: "All I wanted to do was get high."
That is a powerful incentive for defeating abuse deterrent pills.
George Dawson, MD, DFAPA
Supplementary 1: What is an New Drug Application (NDA)? This is the formal application to the FDA where the sponsor (usually a pharmaceutical company) proposes that a new drug be approved for sale and marketing in the United States. For detailed information from the FDA web site follow this link.
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