The opioid crisis in the United States is an ongoing problem with historical significance. Regulatory insight has evolved in response to abuse of and addiction to opioids, sedatives, and stimulants, with federal and state governments implementing and enforcing regulations for oversight of drugs defined as controlled substances.1 Following is a review of basic regulatory structure and the impact on gabapentin and xylazine.
Federal & State Regulations
The federal Controlled Substances Act lists all scheduled drugs and drug precursors (see Suggested Reading). Inclusion on the list indicates a controlled substance that is under federal control in all states. States also have controlled substance acts that may include additional substances. In cases in which there is a difference between federal and state laws or regulations regarding which drugs are classified as controlled substances, which schedule a drug is designated, and/or any additional legal requirements, the more stringent requirements must be followed.
Controlled substances are divided into 5 schedules based on potential for dependence and abuse, with schedule I being most restrictive and schedule V least restrictive (see Federal Drug Schedules).2 In veterinary medicine, schedule II is more restrictive than schedules III, IV, and V, which can be grouped together, as they have a similarly low restriction from a clinically applicable, regulatory standpoint.
Federal Drug Schedules
Schedule I: Drugs, substances, and chemicals with no established medical use and high potential for abuse. Examples include heroin and lysergic acid diethylamide (ie, LSD).
Schedule II: Drugs, substances, and chemicals with established medical use and high potential for abuse. Use may result in severe psychological or physical dependence. Examples include hydrocodone, hydromorphone, methadone, fentanyl, and codeine (as a single agent).
Schedule III: Drugs, substances, and chemicals with moderate to low potential for physical and psychological dependence. Examples include buprenorphine, ketamine, and acetaminophen with codeine.
Schedule IV: Drugs, substances, and chemicals with low potential for abuse and low risk for dependence. Examples include butorphanol, diazepam, and midazolam.
Schedule V: Drugs, substances, and chemicals with lower potential for abuse compared with schedule IV. Examples include pregabalin and cough preparations with <200 mg of codeine/100 mL.
Federal Drug Scheduling
Federal drug scheduling is a long process in which the Attorney General, Drug Enforcement Administration, Department of Health and Human Services, and FDA use an 8-factor analysis (see Factors for Analysis) to place substances in the controlled substance schedule.3
Factors for Analysis
Actual or relative potential for abuse
Known scientific evidence of pharmacologic effects
Current scientific knowledge of the substance
History and current pattern of abuse
Scope, duration, and significance of abuse
Risk to public health
Psychological or physiologic dependence liability
Whether the substance is an immediate precursor to an existing scheduled substance
Alternative pathways to becoming a federally scheduled controlled substance include emergency scheduling into schedule I (substances with no established medical use) and passing legislation through Congress that is then signed by the president, which is costly and time-consuming. Some states therefore apply their own drug schedules to substances not federally scheduled.
Gabapentin and xylazine have received attention due to increasing public health concerns. Because federal scheduling can be a long process, some states have scheduled these drugs through modifications of their own state controlled substance acts. Processes for scheduling differ among states but may be more time efficient than federal scheduling.
Gabapentin
Gabapentin can potentiate the effects of opioids, making it a highly diverted drug, but it is still noncontrolled at the federal level. Some states are implementing requirements for increased oversight for gabapentin compared with other noncontrolled medications; however, because this is a fragmented geographic approach compared with federal scheduling, benefits (eg, fewer reports of abuse) have been modest.4,5 Requirements vary by state, ranging from increased pharmacovigilance (ie, science of and activities related to detection, assessment, understanding, and prevention of adverse drug effects or other drug-related problems) to controlled substance scheduling. Several states also use prescription drug monitoring programs to increase monitoring of gabapentin use, but impact varies.
Pregabalin, a newer drug comparable to gabapentin, has been designated schedule V at the federal level, indicating improved understanding of the addictive potential compared with when gabapentin was approved.
Xylazine
Xylazine is added to fentanyl primarily to boost the effects of fentanyl and extend the associated high in humans; however, xylazine is not safe in humans. In a study to evaluate potential use in humans, xylazine caused severe CNS depression.6 Xylazine can potentiate the effects (eg, sedation, respiratory depression) of opioids through CNS depression, which blunts the response to hypoxia associated with an opioid overdose, making naloxone reversal of opioid overdose less effective compared with treatment for fentanyl overdose alone. There are no xylazine reversal agents approved for use in humans. In addition to the systemic effects of xylazine, eschars (dead tissue shedding/falling from the skin) commonly occur and can lead to amputation.3 Increased use of xylazine in humans has resulted in increased opioid addiction and mortality rates.6 More research is needed to fully understand the addictive potential of xylazine, but early research has indicated withdrawal symptoms are more intense with xylazine and fentanyl in combination compared with fentanyl alone.7
In early 2023, it was announced that the 8-factor analysis for xylazine had been performed and federal scheduling had been in process since 2021, with supplemental information provided in 2022 to help accelerate the process.8 The FDA has been working to restrict unlawful entry of xylazine (in finished dosage form and as a bulk chemical) into the United States, including reviewing all xylazine shipments to ensure they are sent to the appropriate recipient (eg, clinicians).9 Although this will not resolve the problem, it is the first step in giving the FDA authority to seize shipments not directed to an appropriate recipient.
Congressional legislation is also being pursued. The AVMA has endorsed the Combating Illicit Xylazine Act, which would make xylazine a schedule III controlled substance for illicit use (including all use in humans) but unscheduled for use in veterinary medicine.10 At the time of writing, no official determination has been made on federal scheduling of xylazine.
Some states have scheduled xylazine for veterinary use, meaning xylazine has been added to the controlled substances list and is treated like a controlled substance. Other states have scheduled xylazine but exempted veterinary use, meaning human use of xylazine can be punished similar to other controlled substance violations but xylazine does not need to be treated as a controlled substance in veterinary medicine.11,12
Conclusion
Controlled substance scheduling provides a classification framework for sorting drugs into groups based on their potential for dependence and diversion that is then used to develop regulatory requirements. Federal scheduling is slow, often resulting in states enacting scheduling decisions when diversion is a public health concern. The regulatory landscape thus changes with time and varies by state.