In response to the opioid crisis, the Food and Drug Administration (FDA) has taken action on multiple fronts. We have approved better measures for treating opioid use disorder and preventing deaths from overdose, have launched efforts to inform more appropriate prescribing as a way to limit clinical exposure to opioids, have taken actions to reduce the excess opioids available for abuse, and are working to facilitate development of new therapeutics that can effectively and safely help patients suffering from pain. Going forward, the FDA needs to remain vigilant to recognize shifting trends in the addiction landscape. Taking a systematic approach to monitoring such trends should allow us to intervene promptly and appropriately and protect the public from associated risks.

Meanwhile, we must be aware that any decisive actions taken to reduce prescription opioid abuse and stem the tide of overdose and death can have unintended consequences, including prompting people to turn to alternative, potentially dangerous substances. In addition, as clinicians seek to help patients with pain, new prescribing patterns will emerge. Deciding on a course of action that will sustain appropriate use of prescription drugs while curtailing drug abuse is essential. Our assessment of changing patterns in drug use and abuse must be informed by an understanding of the complex social environment in which changing patterns of drug consumption occur. The FDA is committed to using a multicomponent system of pharmacovigilance so that we can intervene proactively and effectively, in anticipation of changes in drug abuse. Three recent examples illustrate the necessary elements of this system, which draws on clinical, epidemiologic, basic science, and social science expertise.

To begin with, an effective system of pharmacovigilance for drugs such as opioids must include the capacity to determine the reasons behind changing patterns of prescription-drug use and to elucidate the dynamics of misuse, abuse, and appropriate changes in prescribing. For example, the gabapentinoids (gabapentin and pregabalin) are approved for the treatment of seizures and certain forms of neuropathic pain. But U.S. rates of gabapentinoid use tripled between 2002 and 2015,1 and pregabalin ranked as one of the 10 best-selling drugs in 2017.2 Increased prescription rates have raised concerns about possible abuse of gabapentinoids,3 although their appropriate use for pain, alone or in combination with opioids and other medicines, complicates the matter.

To understand why usage patterns are shifting, the FDA used a social media “listening platform” to set up a dashboard to track traditional social media sites (such as Twitter, Facebook, Instagram, blogs, and forums) that we monitor for conversations about opioids. When we find mention of additional substances on social media or elsewhere, we conduct more specific searches for relevant, publicly available conversations through our listening platform, as well as through Reddit, Google, and various online forums that don’t require registration or subscription. These may include forums associated with drug misuse or abuse, such as Bluelight.org and talk.drugabuse.com. A preliminary appraisal of social media topics revealed a shift between 2013 and 2017 from a discussion of legitimate gabapentinoid use for pain and seizures to a focus on misuse and abuse of these drugs.

We are also exploring health care databases to assess the consequences of using gabapentinoids in combination with opioids. For example, the FDA Adverse Event Reporting System allows us to explore reports of respiratory depression (sometimes fatal) that may occur in association with use of these products in combination with other central nervous system depressants, including opioids. Additional epidemiologic data will help us understand the potential risks associated with the use of gabapentinoids concomitantly with opioids, benzodiazepines, and other drug products. Our preliminary epidemiologic assessments suggest that the number of patients to whom gabapentinoids are dispensed concurrently with opioid analgesics or benzodiazepines has increased in recent years, with more than half of patients, according to some analyses, concurrently receiving an opioid analgesic. Our continued investigations may underpin future regulatory action to address any harmful trends, and our experience with the opioid crisis has instructed us to act with speed and vigilance when potential new addiction trends emerge.

A second example of changes in drug use occurring in response to mitigation efforts for the opioid crisis is the use of kratom, a botanical substance available through online commerce and retail outlets specializing in tobacco and cannabis paraphernalia. Although kratom has no approved use in the United States, it has been widely discussed in the media as an alleged treatment for opioid use disorder and pain, and many lay coalitions advocate for its continued availability. Kratom has also become widely used as a recreational drug, and the Centers for Disease Control and Prevention reports that calls to poison-control centers citing kratom exposure rose approximately 10-fold between 2010 and 2015.4 The FDA has expressed important concerns about its use.

To understand these trends and to determine how to respond, the FDA recently investigated kratom constituent compounds and found that they have essential opioid pharmacologic properties and are being used in place of approved opioids. In addition to reviewing the published scientific studies of the compounds, FDA researchers found that more than 20 specific compounds within kratom are predicted to bind to the mu-opioid receptor. Separate analyses of data from social networks reflect the lay use of kratom to treat pain, to lessen opioid withdrawal symptoms, and for recreational purposes, often without regard for its safety or addiction potential and despite the lack of clinical studies involving this substance. In addition, injuries, including scores of deaths, associated with kratom use have been reported, reinforcing fears about the dangers of its use.

A third illustration of the need for a multimodal, proactive approach to emerging drug trends is the dramatic increase in misuse and abuse of loperamide, a common over-the-counter (OTC) opioid product. When used at approved doses, loperamide is a safe, effective treatment for diarrhea, and its OTC availability is beneficial. However, analysis of social network data reveals that some people have begun using loperamide at very high doses in an attempt to self-manage opioid withdrawal or achieve euphoric effects.5 Analyses of spontaneous adverse event reports and other epidemiologic data indicate that this increasingly frequent behavior is having serious health consequences, and in 2016, the FDA announced that serious heart problems (including torsades de pointes) and death can occur in persons taking high doses of loperamide. To counter potentially deadly abuse, the FDA recently began working with loperamide manufacturers and distributors on ways to limit the amount of drug packaged (per sales unit) for OTC sale and other voluntary approaches to encouraging safe use.

The FDA thus faces challenges as we confront the opioid crisis and monitor changing patterns of use, abuse, and misuse of other products. Some changes could be appropriate, such as the use of gabapentinoids instead of opioid analgesics for selected pain conditions in appropriate patients. But we are also seeing a shift away from the use of prescription opioids toward plant materials containing unrecognized opioids or to OTC products with potentially lethal opioid effects. In other cases, nonopioid drugs such as gabapentinoids are being prescribed, alone and in combination with opioids, and the consequences of those uses are under close investigation.

Finally, new drugs of abuse can emerge (e.g., tianeptine) and patterns of use and abuse can change (e.g., gabapentinoids). Going forward, we will need to understand and be ready to respond to such challenges. The right approach to regulating these substances is best determined through a multifaceted system of pharmacovigilance, using various tools to mine traditional and new sources of epidemiologic data, assess products’ pharmacologic properties, and evaluate the social contexts in which substances are being used. The FDA has invested new resources in developing these capabilities, including convening a group of professionals to evaluate epidemiologic signals that may presage new usage trends. Our goal is to identify emerging trends earlier and intervene more quickly. The agency will continue to use all tools available to assess shifts in patterns of substance use and protect the public from risks that may emerge as we combat our nation’s opioid problem.