Analgesics

FDA Guidance

Opioid Epidemic

Q2 2022

Regulatory

<h3>Pain is nearly ubiquitous in the United States. According to a 2016 National Health Interview Survey featured by the CDC, one in five Americans — 50 million people — suffer from chronic pain. For 8% (19.6 million Americans) of chronic pain sufferers, this pain is so debilitating that it interferes with their daily lives.1 Groups particularly at risk of severe pain include women, people living in poverty, the elderly, adults with lower education levels (less than a high school diploma), and people on public health insurance. Aside from causing obvious discomfort, chronic pain is correlated with additional health issues.1 </h3>

This chronic pain is not a condition to be dismissed — for some patients, the pain can be so severe that it can drive them to end their lives. A study published in the Annals of International Medicine tracking the relationship between pain and suicide from 2003 to 2014 found that, of the 123,181 suicide decedents, 10,789 (8.8%) experienced chronic pain. That percentage increased steadily from 7.4% in 2003 to 10.2% in 2014.2
The National Health Interview Survey also attributes restrictions in mobility and daily activities, anxiety and depression, poorly perceived health, and/or a reduced quality of life, as well as a dependence on opioids, as comorbid with chronic pain conditions.1
<h3 style="font-weight: normal;">Lack of Options</h3>
Unfortunately, for many dealing with pain who no longer want to be limited by it, the only available choice is to turn to opioids. While these drugs remediate pain and, for many, make life livable again, they must be taken constantly and are terribly addictive. If patients on intermediate- to long-term opioid treatment want to stop their medication, extreme withdrawal symptoms occur immediately, typically including an exacerbation of the underlying chronic pain. For short-term injuries especially, this can create an entirely new set of problems for patients who often struggle to detox. 
This situation has created a much-publicized opioid epidemic in the United States and beyond, belatedly leading to fewer opioids being prescribed. From 2011 to 2022, opioid prescriptions fell by 44.4% and markedly dropped 6.9% from 2019 to 2020.3 Not only are physicians prescribing opioids less, but they are also using state prescription drug monitoring programs (PDMPs) more to confirm that patients aren’t seeking multiple prescriptions from different doctors. According to an American Medical Association (AMA) report, healthcare providers used state PDMPs more than 910 million times in 2020, up from 750 million in 2019. However, despite fewer opioids being prescribed and patients being highly monitored by doctors for opioid use, overdoses have spiked. 
<h3>Overdoses on the Rise</h3>
The Centers for Disease Control and Prevention (CDC) report that deaths caused by overdose totaled approximately 48,000 in 2015, with that number climbing to more than 103,000 in 2021.4 Though counterintuitive, this is largely due to a lack of access to opioids. As doctors are now more fearful of prescribing, many patients have resorted to purchasing counterfeit, mostly lethal drugs, which are easily available on deceptive e-commerce sites or through social media. 
In a September 2021 public safety alert issued by the U.S. Drug Enforcement Agency (DEA), the agency warned of a sharp increase in oxycodone (Oxycontin®, Percocet®) and hydrocodone (Vicodin®), counterfeits containing deadly doses of fentanyl and/or methamphetamine.5 According to the report, the number of DEA-seized counterfeit pills made with fentanyl has jumped nearly 430% since 2019, which is a staggering increase. This indicates that illegal drugs have filled the gap created by a reduction in doctor-prescribed opioids, with negative outcomes for all. &nbsp;
Most at risk of an overdose are black Americans, further highlighting inequities in health. The rate of opioid-related deaths increased by 38% for blacks from 2018 to 2019 — while plateauing for whites over that period.6 Likewise, black teens are more likely to be impacted by fentanyl-related overdoses. Overdoses attributed to fentanyl have tripled among teens overall and increased five times among black teens in the past two years, according to the CDC.7 
<h3 style="font-weight: normal;">The Cost of the Opioid Crisis</h3>
Aside from being tragic, the opioid crisis is expensive, with Pew Research calculating that it has cost the country over $100 billion. Of that total, $35 billion is attributed to healthcare costs, and approximately $14.8 billion is linked to criminal justice spend, including drug-related crimes such as theft. However, the greatest percentage of the overall total is due to lost productivity. Losses in human capital related to premature death due to overdose, opioid-related incarceration, or other productive hours lost to opioid use disorder (OUD) adds up to $92 billion.8 Pew concludes that, in 2020, there were almost 70,000 deaths related to opioids. However, improving access to evidence-based treatments for OUD has been associated with savings of $25,000–105,000 in lifetime costs per person.8
<h3 style="font-weight: normal;">Encouraging an Alternative</h3>
It’s clear that many patients will do almost anything (whether buying illegal drugs or taking their own lives) to be pain-free. Recognizing the incredible need for non-addictive pain medication (which would theoretically solve much of this), the FDA released a draft guidance in February 2022 on the “Development of Non-Opioid Analgesics for Acute Pain.”9 The industry recommendation document encourages an alternative to opioids, clarifies future labeling claims, and incentivizes companies with an expedited program to advance a non-opioid painkiller. 
The FDA defines acute pain as lasting 30 days or more, especially due to injury or trauma, such as surgery, that will lessen with healing. Although one pain medicine isn’t expected to treat each patient, the document states that “products with well-established analgesic mechanisms of action may be able to obtain a general acute pain indication when supported by at least two clinical trials, each in a different pain population.” The guidance continues to detail what that might look like. “For example, a novel nonsteroidal anti-inflammatory drug with two successful clinical trials in postoperative pain, one following bunionectomy and one following herniorrhaphy, may be suitable for a general acute pain indication.” Labeling would have to reflect any shortcomings of the drug, so patients are prepared. “As it is generally not feasible to study all possible populations that fall within a general acute pain indication, it may be necessary to include language in labeling describing the limitations of the indication,” the guidance advises. 
The document continues that the non-opioid analgesic would have to be as effective as current painkillers, though without the potential for misuse or abuse. If a drug were to meet these standards, the FDA recommends clear labeling to specifically explain the benefits provided by eliminating or reducing the need for opioids. As the FDA “encourages the development of non-opioid analgesic products and novel study designs,” programs designed to safely replace or reduce the use of opioids are likely eligible for one or more of the agency’s expedited reviews. 
By incentivizing the industry to create a non-opioid analgesic by offering faster approval, the FDA is acknowledging that the nation is in crisis. It’s clear that simply removing opioids has not solved the problem, and, despite best efforts to the contrary, has actually made the situation worse, as counterfeits flood the market. While much of this drug use is no doubt recreational, we must assume that legitimate patients are included in all groups, given that at least 50 million citizens are pain sufferers. With this guidance, the FDA is hoping to encourage a treatment that gives patients a light at the end of the tunnel, without having to turn to addictive and/or illegal medication to simply live their lives.
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References:
<ol>
<li>Dahlhamer J., et al. “<a href="http://dx.doi.org/10.15585/mmwr.mm6736a2external%20icon">Prevalence of Chronic Pain and High-Impact Chronic Pain Among Adults — United States, 2016</a>.” Morb. Mortal. Wkly. Rep. 67:1001–1006 (2019). DOI: </li>
<li>Petrosky, Emiko et. al. “<a href="https://www.acpjournals.org/doi/10.7326/M18-0830">Chronic Pain Among Suicide Decedents, 2003 to 2014: Findings From the National Violent Death Reporting System</a>.” Ann. Int. Med. 2 Oct. 2018.</li>
<li><a href="https://www.ama-assn.org/press-center/press-releases/report-shows-decreases-opioid-prescribing-increase-overdoses#:~:text=Opioid%20prescriptions%20have%20decreased%20">Report shows decreases in opioid prescribing, increase in overdoses</a>. American Medical Association. 21 Sep. 2021.</li>
<li>“Provisional Drug Overdose Death Counts.” National Center for Health Statistics. 11 May 2022. </li>
<li><a href="https://www.dea.gov/alert/sharp-increase-fake-prescription-pills-containing-fentanyl-and-meth">Public Safety Alert: Sharp Increase in Fake Prescription Pills Containing Fentanyl and Meth</a>. Drug Enforcement Agency. 27 Sep. 2021.</li>
<li>Penaloza, Marisa. “Black Opioid Deaths Increase Faster Than Whites, Spurring Calls for Treatment Equity.” npr. 10 Sep. 2021.</li>
<li>Muller, Madison and Ella Ceron. “Teenage Fentanyl Deaths Are Soaring, and Black Teens Are Hit Hardest.” Bloomberg. 11 Feb. 2022.</li>
<li>“The High Price of the Opioid Crisis, 2021.” Pew. 27 Aug. 2021.</li>
<li><a href="https://www.fda.gov/media/156063/download">Development of Non-Opioid Analgesics for Acute Pain: Guidance for Industry</a>. U.S. Food and Drug Administration. Feb. 2022.</li>
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The Price of Pain: Acknowledging a Crisis and Encouraging an Alternative