- Speech by
Scott Gottlieb, M.D.
Commissioner of Food and Drugs - Food and Drug Administration ( May 2017 - April 2019 )
Remarks by Scott Gottlieb, M.D.
Commissioner of Food and Drugs
National Academies of Sciences, Engineering, and Medicine
Public Session of the Committee on Evidence-based Clinical Practice Guidelines for Prescribing Opioids for Acute Pain
(Remarks as prepared for delivery)
I want to thank you for the opportunity to join this meeting today.
We’re here to continue an important effort and open a new phase in our work to combat America’s epidemic of addiction to opioids.
To advance our public health goals, confront the addiction crisis, and help support appropriate clinical practice; it’s critical that we develop objective, evidence-based prescribing guidelines to help assure the proper use of opioid analgesics for the cautious treatment of acute pain in appropriate patients.
Consensus guidelines have an important purpose in promoting these efforts. But consensus guidelines are often purposefully different from evidence-based guidelines in a critical way. Consensus guidelines are an accretion of our current, expert opinions. They reflect a common view. They’re developed in settings where we lack rigorous evidence to guide clinical practice.
We’re here today to embark on an effort to develop that rigorous clinical evidence. We want to develop new science where more rigorous evidence is needed on the proper dose and duration of opioid analgesic use for the treatment of pain in some common, acute pain indications. Development of this evidence is needed in many areas when it comes to the treatment of pain.
We’ll develop this evidence by studying how patients respond to treatment. In doing this, we’ll inform the development of new evidence-based guidelines that can form the basis of safe prescribing. We hope that in many cases, these new guidelines can meet the standard for being incorporated into drug labeling, where they can be used to help rationalize prescribing and dispensing.
The development of these evidence-based guidelines is just one of a number of new efforts we’re taking to expand our work to forcefully confront the opioid crisis. We’re going to open some new fronts, and set some new goals, to address this crisis as part of a 2019 Policy Roadmap that we plan to release in the coming months.
At FDA we’re also taking other new steps to more forcefully confront this crisis. We plan to put more focus not only on the duration of use, but also on the doses of opioids that are being prescribed. And we plan to take new steps to require some immediate release formulations of the opioids to be made available in unit of dose packaging like blister packs. This can be an effective way to make shorter duration prescriptions the more common decisions doctors make.
For too long, it’s been too easy for doctors to prescribe lots of pills. We want to make the easy and sensible decision the one to dispense just a day or two of medicine, where that makes sense for the medical condition or procedure.
It’s still the case that there are too many prescriptions being written for opioid analgesics, and when prescriptions are written, they’re for durations of use that are often too long for the clinical situation. There are still too many 30-tablet prescriptions being written for acute pain indications where the evidence shows that leftover tablets are all too common.
Reducing unnecessary exposure is key to reducing the risk of new addiction. At the same time, we must ensure that our efforts to address the crisis don’t in any way jeopardize patients with serious pain conditions, for whom an opioid analgesic is sometimes the only drug that’ll work. Having clear, evidence-based guidelines can help make sure that patients are appropriately treated.
That’s what we’re here today to discuss. Having clear, rigorous, evidence-based guidelines that guide the optimal dosing and duration of opioid analgesic use for the most common indications is the key to achieving these twin obligations.
We know that some patients will require long-term treatment with opioid analgesics. But we also know that opioid analgesic use has generally been too liberal over the last few decades. This is true across all medical specialties. But it’s especially true in general surgery and other settings where doctors confront a lot of acute pain; and where prescribing 30 tablets of an Immediate Release (IR) opioid analgesic was too often a reflex decision. That must change.
Much of the addiction that we now confront was formed in the medical setting. It was formed among patients who were prescribed opioid analgesics, and who were sometimes poorly managed. Where prescribers were too cavalier about -- and in some cases were indifferent to -- the risks that these drugs harbored.
We now know that a number of patients who are exposed to opioid analgesics go on to form addiction to these powerful medicines.
And so, we need to work together to make sure that when opioids are dispensed, it’s for a medical purpose that couldn’t be treated with other means. And it’s for a dose and duration that matches the clinical purpose for the prescription.
To advance these public health goals, the FDA has taken many steps over the last 18 months to rationalize prescribing. Among other actions, we’ve expanded our Opioid Analgesic risk evaluation and mitigation strategy to include immediate release formulations of these drugs. And we’ve updated our education to prescribers to inform them about alternatives to opioid analgesics. We’ve also expanded this training to non-physician providers who help care for patients with pain. Today, we’re advancing another effort – to develop evidence-based guidelines on the proper dosages and durations of use for common post-surgical indications for which opioids are often prescribed.
Working together with providers, we’ll develop evidence that guides how many pills should be dispensed for some of the most common post-acute indications. We must address the duration of use – how many days of opioid analgesics people are prescribed. But I also want to raise another, critical consideration today. We also need to focus more attention on the strength of the dose of the opioid analgesics that are being used, and the total exposure a patient receives -- measured by the total daily dose of opioid analgesics that patients get.
Three things matter when it comes to helping manage the risk of new addiction formed in the medical setting. And we need to consider each of them.
First and foremost is the reason why the prescription is being written in the first place. We need to make sure that an opioid analgesic isn’t being used when, for example, an NSAID is appropriate and can suffice.
Second is the duration of the prescription. We need to make sure that a five-day prescription isn’t being filled when one or two days of drugs is adequate.
And third, we need to consider the total dose of the opioid analgesic that’s being used. We need to make sure that the lowest possible daily dose is being prescribed in every case. We need to reduce total exposure.
Each of these considerations impacts the risk of developing dependency and addiction. We need to advance policies that address each of these parameters.
At the FDA, we’ve spent a lot of time talking about the number of prescriptions that are being written, and the duration of those prescriptions. We’ve advanced new policies to try and rationalize how many days of opioid analgesics are being prescribed and the instances where a thirty-tablet prescription is written for a condition that merits less for adequate treatment for pain. But we’re going to also be focusing attention on the strength of those opioid analgesics that are being prescribed, and the total daily dose that a patient is receiving.
We know that dose matters. This is seen when we look at some of the common ways that people are led to addiction through exposure in the medical setting.
Different people have different routes to developing opioid use disorder. But as a general matter, there are some common paths to addiction.
One path is a younger person who might have been prescribed a short course of opioid analgesics for a wisdom tooth extraction or another minor procedure.
What happens is that this young person who’s exposed medically is then more likely to use opioids non-medically later in their life. We know from the medical literature that high school students exposed medically are more likely to use opioids in young adulthood in a non-medical setting.
Giving someone that first exposure increases the likelihood they’ll use opioids in a recreational fashion. They tolerated that first exposure, and maybe even liked the reaction. In this situation, higher doses at the time of that first prescription increase the likelihood of a euphoric effect. And that, in turn, can increase the likelihood that someone will want to use these drugs again.
Another common route to developing an opioid use disorder is at the other end of the age continuum. It’s an older individual who might have received a medical prescription for a lower back injury or some other acute problem. This person might become physiologically dependent to the opioid analgesic with prolonged use. They require escalating doses to address their growing tolerance to the drugs, and to mitigate the underlying pain.
In this case, the initial prescription might have begun as treatment for acute pain. But as little as five days of continuous use of an opioid drug can cause some individuals to develop a physiological dependence. For some, the neuro-adaptations that arise during long-term opioid therapy can reduce analgesic efficacy while also making it hard to discontinue the treatment. This can happen despite declining efficacy of the drugs and increasing risks.
Some proportion of those who develop physiological dependence and require higher doses and chronic administration to address these symptoms, meet the criteria of an opioid use disorder. Here again, higher doses at the outset may increase the likelihood of developing a physical dependence to these drugs.
I posit these two hypothetical scenarios to describe some possible routes to addiction. But they’re broad generalities. No two patients are the same. No route to an opioid use disorder is identical. I know these scenarios are painted with a very broad brush. But I use these circumstances to illustrate some of the ways that the total daily dose at first script can matter. Addressing the dose of opioid that’s dispensed is an important matter in addressing addiction.
Our research shows that for many post-surgical indications like laparoscopic appendectomies and cholecystectomies, or other minor surgeries, a one or two-day prescription for an IR opioid analgesic appears to be all that’s typically needed to provide appropriate pain relief. The duration of use can matter, when it comes to how many patients will become addicted to these drugs as a result of a medical application. And we know that excess supply leads to more opportunities for diversion, misuse, and abuse. But the strength of the opioid prescription is also an important factor. The dose. What’s sometimes referred to as the morphine milligram equivalents that are dispensed, or the MME.
If one pink Percocet will be sufficient every six hours, two tabs shouldn’t be prescribed. And if two pink Percocet will adequately control an acute episode of pain, then a higher dose of oxycodone IR shouldn’t be used.
In multiple studies, patients prescribed multi-week courses of treatment at higher doses were shown to have a sharply greater risk for developing an opioid use disorder than if those longer-duration scripts were written for lower daily doses. In one such study, higher volume prescriptions were associated with a markedly increased risk of continued use. There seems to be a cumulative effect, where dose and duration each play a role in expanding exposure that in turn raises the risk of dependency. In another study examining these relationships, researchers evaluated patients with ankle injuries who received a total daily dose of greater than 225 morphine milligram equivalents – which is equivalent to more than 30, 5mg tabs of oxycodone. This study was also suggestive of a link between dose and long-term use. Still other studies similarly show a correlation between the proportion of patients who became long-term opioid users and increasing dose dispensed on an initial fill, with the proportion of long-term users rising consistently with increasing dose.
Dose matters when it comes to the risk of forming addiction. Period. Higher potency opioids generally have a greater rewarding effect. And it’s this rewarding effect that, with repeated use, can contribute to development of addiction in vulnerable persons. We need to pay careful attention to the dose that we’re prescribing – and to whom we’re prescribing that dose.
As physicians, we sometimes don’t think carefully enough about how much drug we’ll be delivering to the patient when we choose between different formulations of opioid analgesics. The total daily dose, in addition to duration of therapy, can be a more precise measure for standardizing opioid prescribing levels and helping guide prescribing behaviors that reduce overall exposure.
It’s generally hard to study dose or duration and the risk of addiction. The easier thing to study is dose and how it relates to the long-term use of opioids.
We know that higher doses at initiation leads to a greater risk of long-term use; although in insurance claims data, where most of these studies are done, it’s hard to adjust for the reason the prescription was written and whether the medical indication justified a higher starting dose. But we also know that some proportion of those people who develop a long-term use of opioids meet the criteria for Opioid Use Disorder (OUD). The dose matters. It can be a predictor for long-term use along with duration. Initial dose matters. But the literature on these relationships is incomplete. Most of the studies that look at dose look at the relationship to the risk of overdose, not to the risk of developing addiction.
To address these issues, we’re going to be taking a number of new actions in the coming months. It starts with gathering more data relating the total daily dose of opioid analgesics with the risk of developing an OUD.
To begin, we’ll be holding an advisory committee meeting at the FDA where we’ll solicit perspectives and data on the relationship between total daily dose and the risk of developing addiction. Among the questions we’ll ask is what rigorous data exists to correlate total daily dose and the risk of developing addiction. What information gaps should we address. And how our policy should be informed by the existing data that correlates the total daily dose with risk of addiction. We also plan to ask about the clinical niche and patient needs for high daily dose, and dosage forms with high levels of opioid analgesic – so to better understand the circumstances where higher doses may be appropriate. We’ll be trying to understand and better define the benefits and risks of high daily dose and dosage forms with high levels of opioid analgesics.
If we can better understand this link between dose and the risk of addiction it can influence a range of important decisions, from how we develop evidence-based guidelines, to how we approach the regulation of higher dose opioid analgesics. We’ll also address this relationship between total daily dose and the risk of addiction with new regulatory actions that we’re considering.
Using this information, we’re going to look hard at requiring some of the common IR opioid drugs like Percocet and Vicodin to be made available in unit of dose packaging such as blister packs that would dispense limited amounts of drug. For example, based on work we have done, we know that for many common acute, post-surgical indications, as little as one or two days of an IR opioid analgesic may be the most appropriate duration to meet most patients’ needs. If these drugs are available in short duration packs, we believe more doctors may default to these convenient packs.
Such a framework could cut the total amount of pills that are dispensed, and total dose that patients are exposed to. In turn, this approach could reduce the risk of someone developing an addiction. It could also reduce the number of unused pills that are left over, sitting in peoples’ medicine cabinets and available for the risk of misuse, abuse, diversion, and accidental poisonings.
Many of us, as providers, helped fuel this crisis. For too many years, we as doctors were too cavalier about the prescribing of these powerful and addictive drugs. An entire generation of physicians was trained – inappropriately we now know – on opioid prescribing practices that were far too loose.
My generation of physicians fell squarely in the cohort that were trained that pain was the fifth vital sign and that the risk of addiction from opioids was very low. In the hospital, a standing order for PRN Percocet was the norm.
We now know that these beliefs, and these practices, were dead wrong.
The FDA is also not immune from responsibility. We were too slow to act at some key moments. We were too slow to change labelling on certain drugs to discourage chronic prescribing in situations where it is inappropriate. We were too slow to recommend changing the scheduling of hydrocodone to restrict its access when there were signs of mounting abuse. And we were too slow to advance efforts to make proper physician education more routine.
We could have done better. We should have done better. And right now, we have to do better. We don’t want to look back in the future again and say we didn’t act quickly enough or forcefully enough to address this crisis.
We need to learn from these mistakes. Some had tragic consequences, but collective blame shouldn’t be the conversation now. We know where the mistakes were made. Going forward, we need to embrace a shared commitment to correct the burdens of our past mistakes. At the FDA, we need to make sure that our actions today are forceful enough to reverse this while in no way harming patients in need. Having allowed a crisis of historic proportions to get firmly planted, our actions today are going to have to be more forceful than the steps that might have been sufficient to address these same challenges two or five or ten years ago – if we had the foresight to intervene earlier and more aggressively as this tragedy continued to grow in depth and proportion.
We also shouldn’t lose sight of the importance of a comprehensive approach to the pain that doesn’t just rely on drugs, but other interventions, including careful counseling that addresses the fidelity between psychological and physical aspects of pain. Sometimes the perceived source of pain and its meaning can influence what’s required to help control its influence. This is where good medical practice can counter the need to use powerful medicines.
But even as we take more aggressive measures to curtail new addiction and help those currently addicted transition to lives of sobriety, we must still ensure proper care for those who suffer lives of chronic pain, and for whom opioid analgesics are sometimes the only effective alternative.
The relief of suffering and the cure of disease are our twin obligations as physicians. There’s an urgency to take immediate and robust action to stem the opioid crisis – but we must continue to be thoughtful and science based. There remains a risk that our actions today aren’t going to be robust enough to get ahead of this burgeoning crisis; just as our actions in the past failed to prevent a lot of human tragedy. But there’s also another risk.
That our efforts to address the epidemic don’t properly target the root causes of addiction, and don’t properly discriminate enough between patients who need effective analgesia for significant medical conditions, and those for whom the risk and benefit ratio doesn’t merit prolonged or high dose use of opioid analgesics, if it merits an opioid analgesic prescription at all.
One of the principal ways that we’ll establish the clear lines that distinguish between these two settings is with evidence-based guidelines that can inform proper prescribing and rationalize how these drugs are being used. The mission that we’re on, to develop these guidelines, is a key part of these goals. My FDA colleagues and I are grateful for your contribution to these efforts.