Controlled Substances


Healthcare providers prescribe medications for various diseases. These medications can be divided into two sub-categories: non-controlled and controlled substances. Most prescriptions for infections or chronic conditions are non-controlled, including over-the-counter medications. For example, blood pressure and cholesterol medications, cold and cough medications, diabetes mellitus medications including insulin, asthma inhalers, and antimicrobials are all non-controlled medications.

Controlled substances are medications or illicit drugs primarily active in the central nervous system and can potentially cause a relative physical and mental dependence leading to addiction.[1] Further, these substances can have significant deleterious health consequences at high doses.

Controlled substances are prescribed for the treatment of insomnia, anxiety, severe pain, and even attention-deficient/hyperactivity disorder (ADHD), among other conditions as well. For example, benzodiazepines and opioids with high abuse potential are used to treat anxiety and seizures.[2] Over the years, an increased overuse of opioids has occurred, which has caused numerous cases of opioid use disorders and even overdose cases. As a result, federal and state regulations have been enforced to prevent further drug abuse cases due to their high potential to cause physical and mental dependence.

Controlled medications require prescriptions from a healthcare provider, as do many non-controlled medications. However, controlled substances require special prescription paper or specific protocols if prescribed through other means such as telephone, fax, or digital, and refills are not available under certain circumstances.[3] Certain controlled medications have explicit restrictions on how they can be filled and refilled. These restrictions were established through the Controlled Substances Act of 1970. The Controlled Substances Act of 1970 established five separate 'Schedules' delineating abuse potential, with Schedule I having the highest potential for abuse and each Schedule having progressively less abuse potential after that.[4][5]

Schedule I medications have the highest potential to be abused. These medications currently have no medical use due to the lack of accepted safety data from the U.S. Food and Drug Administration (FDA). Some examples of Schedule I medications include LSD, marijuana, heroin, mescaline, and methylenedioxymethamphetamine (MDMA).[3]

Schedule II medications are also considered to have a high potential for abuse but less than Schedule I medications.[3][6] The abuse of Schedule II medications can lead to serious consequences such as severe physical or physiological dependence such as vomiting, nausea, seizures, and hallucinations, but not always limited to these. Some examples of Schedule II medications are amphetamines, codeine, fentanyl, methadone, morphine, and oxycodone.

Schedule III medications have less abuse potential than Schedule I and II drugs. These medications are currently accepted for medical use where abuse may lead to moderate to low physical dependence or high psychological dependence.[2][6] Some examples of Schedule III medications include Fiorinal, Subutex, Marinol, and anabolic steroids.

Schedule IV medications have less potential to be abused than Schedule I, II, or III drugs.[2] These medications are typically used for treating anxiety and seizures. Some examples of Schedule IV medications include benzodiazepines, phenobarbital, Ambien, Zaleplon, Lunesta, and Provigil.

Schedule V drugs are considered the least potential for abuse among the other scheduled drug classes. Any level of Schedule V drug abuse may potentially lead to limited physical or psychological dependence.[3][6] Some examples of these drugs include diphenoxylate, guaifenesin with codeine, Lyrica, Vimpat, and Epidiolex.

Although these schedules occur on a federal level, differences also occur on a state level. Significant state regulatory variations occur; differences may occur between state and federal regulations.[5][6] For example, benzodiazepines are controlled substances used for anxiety and seizures, which are Schedule II drugs in New York but are Schedule IV drugs federally. Such variations can differ between states while having the same effect as federal regulations. These regulations are in place to control regulation and distribution and prevent controlled substance abuse.[5]

Any individual or entity involved in disseminating controlled substances, from manufacturer to pharmacy, requires registration with the Drug Enforcement Agency (DEA), the primary organization responsible for regulating these substances at the federal level.[4][5][6]

Issues of Concern

Controlled substances are an important asset in the toolkit of a healthcare provider in any practice setting, primarily because these medications act quickly and potently. Schedule II opioids (oxycodone, hydrocodone, morphine, hydromorphone, fentanyl, etc.) are among the top drugs administered in the clinical setting as well as misused outside of the medical purview. Because of this, opioids contribute a significant portion to drug overdose, the top cause of unintentional death in the United States.[7][8]

Common misused controlled substance practices include obtaining medications from multiple sources. To obtain multiple prescriptions for controlled medications, patients visit different healthcare providers.[3] These controlled medications are often used for self-medication or diversion.

Diversion refers to the illegal distribution of regulated medications to other sources which have not prescribed these drugs. Diversion, or the redirection of legally prescribed controlled medications for unlawful use, is an ongoing regulatory battle undertaken by the United States Food and Drug Administration (FDA), Drug Enforcement Agency (DEA), and other federal organizations.[9]

However, a lack of guidelines can lead to serious adverse events, including patient harm and exposure to bacteria and infections, while also causing risks to the provider.[2]

Due to the uptick in drug overdoses and addiction, many states have also implemented drug monitoring programs. These programs enable a more effective and efficient way to track prescription drugs and prevent drug abuse. In 2012, New York State created a monitoring system known as the Internet System for Tracking Over-Prescribing (I-STOP), which requires physicians and pharmacists to consult a prescription monitoring program before prescribing scheduled controlled substances.[10] The I-STOP program resulted in a significant decrease in the number of prescribed opioids in New York, creating a sense of a reduction in opioid overprescribing and drug abuse. Such monitoring systems can prevent widespread prescriptions of controlled substances from healthcare workers to constant consumers.

With the help of the DEA, numerous registries are available to help prescribers properly monitor patterns among their patients before dispensing the scheduled substance.[11]

The increase in controlled substance abuse can correlate to a lack of proper education, socioeconomic disparities, provider education, and varying laws that have created significant challenges in regulating controlled medications. However, adequate training and education can tremendously help resolve this issue.[3]

Clinical Significance

The propensity of an individual to misuse a controlled substance is multifactorial, taking into account life experiences (notably stressors), especially in childhood, in conjunction with the specific neurobiology of the individual. It is well known that the dopamine reward system is implicated in addiction. However, specific gene sequences and transcription factors are also involved in addiction phenotypes.[1] These factors can combine to create a compelling and perpetual motivation, which can only be sated with progressively increasing quantities of the implicated substance.

This concept brings up the principle of supply and demand, and demand is high for controlled substances, whether legal or otherwise. The two ways supply is available are straightforward; unregulated (i.e., drug cartels) vs. regulated (pharmaceutical companies). Both create significant burdens for federal organizations such as the FDA and DEA in limiting ease of access to the general public.[9] Besides conditions such as acute traumatic injuries or cancer-related pain, indications for the short or long-term use of opioid medications are not explicitly defined. They are somewhat subjective from provider to provider. Moreover, a patient's pain tolerance and personal opinion of appropriate opioid usage can turn a short-term course into a longer and possibly chronic course of treatment.

To prescribe a scheduled medication, certain rules must be followed at the clinician level. These rules are most strict with Schedule II drugs and are monitored at the state and federal levels through various means, such as prescription drug monitoring programs.[8] Schedule I drugs are agents deemed to have no approved medical application and are considered illicit drugs; the only exception (as of the publication of this article) is marijuana, which has approval for limited medical use (i.e., palliative, pain, psychiatric, seizure, etc.) in several states, but not at the federal level.[3][5][12][13][14] Substance III drugs are agents deemed approved for medical application and are usually allowed up to five refills within six months of the written prescription, obtaining a maximum supply of medication for 30 days. Despite these regulations, the 30-day supply may vary based on state regulations and the patient's condition.[5][12]

There are a few scheduled drugs with an exception to the 30-day rule. The 30-day exception applies to Schedule III, IV, and V drugs. A healthcare provider may prescribe a patient up to a three-month supply of Schedule II to V medications for certain approved medical conditions and a six-month supply of Schedule III medications.[9] However, approval of such prescriptions requires specific codes:

  • Code A is related to patients with panic disorders
  • Code B is for patients with minimal brain dysfunction
  • Code C is for chronic debilitating neurologic conditions
  • Code D is for the relief of pain in chronic and incurable patients
  • Code E is related to patients with narcolepsy
  • Code F is related to patients with a hormone or gonadotropin deficiency and those with metastatic breast cancer

Healthcare providers authorized to prescribe controlled substances must have a DEA number and include it with prescriptions for scheduled medications. The DEA registration number is a computer-generated sequence that allows other healthcare providers, such as pharmacists, to verify the validity of the prescription to prevent fraudulent dispensing of controlled medications.[15] Healthcare providers must be familiar with the different codes and regulations on a federal and state level to avoid drug overprescribing and diversion.

Although triplicate prescriptions were previously the only means to prescribe schedule II drugs, the 2010 Controlled Substances Act introduced a revised rule called the "Electronic Prescriptions for Controlled Substances" (EPCS) which provides the prescriber with the option to send any scheduled medication (except Schedule I) prescription digitally.[16] Before electronic prescriptions can be sent by a prescriber or institution, specific infrastructure, audits, and approvals are required according to the Interim Final Rule of the DEA. Schedule II, III, and IV drug prescriptions cannot be refilled.[1][9] However, these regulations may vary based on different states. For example, New York and South Carolina have state regulations requiring Schedule II, III, and IV drug prescriptions to be issued in a 30-day supply without any refills. 

Due to these different state regulations, if a scheduled drug prescription from an out-of-state healthcare provider were dispensed by law, the prescription would fall under the rules and regulations of the dispensing state.[6]

Nursing, Allied Health, and Interprofessional Team Interventions

With the introduction and integration of EPCS and PDMP, prescribing and monitoring controlled substances has become much more efficient. While overprescribing controlled substances may have decreased, it is still prevalent among healthcare providers, and working as an interprofessional team can help further reduce overprescription.[17] It is also necessary for physicians, advanced practitioners, and pharmacists to properly utilize these tools to deter abuse and diversion while simultaneously delivering quality patient-centered care.[11]



Azhar Hussain


4/8/2023 1:40:15 AM



Fluyau D, Charlton TE. Drug Addiction. StatPearls. 2023 Jan:():     [PubMed PMID: 31747190]


Clark HW. Policy and medical-legal issues in the prescribing of controlled substances. Journal of psychoactive drugs. 1991 Oct-Dec:23(4):321-8     [PubMed PMID: 1813603]


Preuss CV, Kalava A, King KC. Prescription of Controlled Substances: Benefits and Risks. StatPearls. 2023 Jan:():     [PubMed PMID: 30726003]


Gabay M, The federal controlled substances act: schedules and pharmacy registration. Hospital pharmacy. 2013 Jun;     [PubMed PMID: 24421507]


Kenny BJ, Preuss CV, Zito PM. Controlled Substance Schedules. StatPearls. 2023 Jan:():     [PubMed PMID: 30860707]


Institute of Medicine (US) Committee to Study Medication Development and Research at the National Institute on Drug Abuse, Fulco CE, Liverman CT, Earley LE. Development of Medications for the Treatment of Opiate and Cocaine Addictions: Issues for the Government and Private Sector. 1995:():     [PubMed PMID: 25121209]


National Academies of Sciences, Engineering, and Medicine, Health and Medicine Division, Board on Health Sciences Policy, Committee on Pain Management and Regulatory Strategies to Address Prescription Opioid Abuse, Phillips JK, Ford MA, Bonnie RJ. Pain Management and the Opioid Epidemic: Balancing Societal and Individual Benefits and Risks of Prescription Opioid Use. 2017 Jul 13:():     [PubMed PMID: 29023083]


Paulozzi LJ, Strickler GK, Kreiner PW, Koris CM, Centers for Disease Control and Prevention (CDC). Controlled Substance Prescribing Patterns--Prescription Behavior Surveillance System, Eight States, 2013. Morbidity and mortality weekly report. Surveillance summaries (Washington, D.C. : 2002). 2015 Oct 16:64(9):1-14. doi: 10.15585/mmwr.ss6409a1. Epub 2015 Oct 16     [PubMed PMID: 26469747]


Drug Enforcement Administration, Department of Justice. Controlled Substances Quotas. Final rule. Federal register. 2018 Jul 16:83(136):32784-90     [PubMed PMID: 30020581]


Pylypchuk Y, Parasrampuria S, Smiley C, Searcy T. Impact of Electronic Prescribing of Controlled Substances on Opioid Prescribing: Evidence From I-STOP Program in New York. Medical care research and review : MCRR. 2022 Feb:79(1):114-124. doi: 10.1177/1077558721994994. Epub 2021 Mar 11     [PubMed PMID: 33703961]


Schiller EY, Goyal A, Mechanic OJ. Opioid Overdose. StatPearls. 2024 Jan:():     [PubMed PMID: 29262202]


Sarris J, Sinclair J, Karamacoska D, Davidson M, Firth J. Medicinal cannabis for psychiatric disorders: a clinically-focused systematic review. BMC psychiatry. 2020 Jan 16:20(1):24. doi: 10.1186/s12888-019-2409-8. Epub 2020 Jan 16     [PubMed PMID: 31948424]

Level 1 (high-level) evidence


Hill KP. Medical Marijuana for Treatment of Chronic Pain and Other Medical and Psychiatric Problems: A Clinical Review. JAMA. 2015 Jun 23-30:313(24):2474-83. doi: 10.1001/jama.2015.6199. Epub     [PubMed PMID: 26103031]


Basinski H, Jensen HB, Stenager E. [There is evidence for the use of cannabinoids for symptomatic treatment of multiple sclerosis]. Ugeskrift for laeger. 2014 Mar 17:176(12A):. pii: V09130552. Epub     [PubMed PMID: 25350886]


Gabay M. Federal controlled substances act: controlled substances prescriptions. Hospital pharmacy. 2013 Sep:48(8):644-5. doi: 10.1310/hpj4808-644. Epub     [PubMed PMID: 24421533]


Kaldy J. Controlled Substances Add New Layer to E-Prescribing. The Consultant pharmacist : the journal of the American Society of Consultant Pharmacists. 2016 Apr:31(4):200-6. doi: 10.4140/TCP.n.2016.200. Epub     [PubMed PMID: 27056356]


Rundio A Jr. Peer assistance for nurses with substance-use disorders. The Nursing clinics of North America. 2013 Sep:48(3):459-63, vi. doi: 10.1016/j.cnur.2013.05.002. Epub 2013 Jul 22     [PubMed PMID: 23998771]